@article {3190298,
	title = {Metamaterial-based injection molding for the cost-effective production of whole cuts},
	journal = {Nature Communications},
	year = {2024},
	abstract = {The escalating global demand for meat products has intensified ecological concerns, underscoring the need for sustainable meat alternatives. Although current methods effectively imitate ground meat, mimicking whole cuts, which constitute 54\% of the global market, remains challenging due to the lack of scalable technology. Injection molding is a massively scalable manufacturing technology developed for the polymer industry. Here, we introduce two injectable metamaterials: a thermally irreversible fat composite we named proteoleogel, and a multi-scaled meat analog produced by low-temperature extrusion. Viscoelastic screening of plant proteins identifies mung bean for its ability to stabilize complex oleogel structures, mimicking the mechanics of adipose tissue. Mechanical analysis reveals that low-temperature extrusion produces microscale isotropic fibers and mesoscale anisotropic structures mimicking muscle and fascia. These metamaterials can be injection-molded into various whole cuts, from chops to T-bones. Blinded taste tests indicate a 43\% preference for our plant-based steak analog. Moreover, technical economic analysis shows injection molding is more cost-effective than 3D printing, costing $9/kg compared to $38/kg. This research represents a step in sustainable food production, offering cost-effective and scalable solutions for the entire meat market.},
	url = {https://www.nature.com/articles/s41467-024-54939-y},
	author = {Ghosheh, M. and Ehrlich, A. and Fischer A. and Pasitka, L. and Cohen, M. and Nahmias, Y.}
}
@article {Pasitka2024693,
	title = {Empirical economic analysis shows cost-effective continuous manufacturing of cultivated chicken using animal-free medium},
	journal = {Nature Food},
	volume = {5},
	number = {8},
	year = {2024},
	note = {cited By 0},
	pages = {693-702},
	abstract = {Cellular agriculture aims to meet the growing demand for animal products. However, current production technologies result in low yields, leading to economic projections that prohibit cultivated meat scalability. Here we use tangential flow filtration for continuous manufacturing of cultivated meat to produce biomass of up to 130 {\texttimes} 106 cells per ml, corresponding to yields of 43\% w/v and multiple harvests for over 20 days. Continuous manufacturing was carried out in an animal-component-free culture medium for US$0.63 l-1 that supports the long-term, high density culture of chicken cells. Using this empirical data, we conducted a techno-economic analysis for a theoretical production facility of 50,000 l, showing that the cost of cultivated chicken can drop to within the range of organic chicken at US$6.2 lb-1 by using perfusion technology. Whereas other variables would also affect actual market prices, continuous manufacturing can offer cost reductions for scaling up cultivated meat production. {\textcopyright} The Author(s), under exclusive licence to Springer Nature Limited 2024.},
	doi = {10.1038/s43016-024-01022-w},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85201948444\&doi=10.1038\%2fs43016-024-01022-w\&partnerID=40\&md5=6dcdf48b472122a01cdc68c26440a4cc},
	author = {Pasitka, L. and Wissotsky, G. and Ayyash, M. and Yarza, N. and Rosoff, G. and Kaminker, R. and Nahmias, Y.}
}
@article {Ehrlich2023,
	title = {Efficacy and safety of metabolic interventions for the treatment of severe COVID-19: in vitro, observational, and non-randomized open-label interventional study},
	journal = {eLife},
	volume = {12},
	year = {2023},
	note = {cited By 7},
	abstract = {Background: Viral infection is associated with a significant rewire of the host metabolic pathways, presenting attractive metabolic targets for intervention. Methods: We chart the metabolic response of lung epithelial cells to SARS-CoV-2 infection in primary cultures and COVID-19 patient samples and perform in vitro metabolism-focused drug screen on primary lung epithelial cells infected with different strains of the virus. We perform observational analysis of Israeli patients hospitalized due to COVID-19 and comparative epidemiological analysis from cohorts in Italy and the Veteran{\textquoteright}s Health Administration in the United States. In addition, we perform a prospective non-randomized interventional open-label study in which 15 patients hospitalized with severe COVID-19 were given 145 mg/day of nanocrystallized fenofibrate added to the standard of care. Results: SARS-CoV-2 infection produced transcriptional changes associated with increased glycolysis and lipid accumulation. Metabolism-focused drug screen showed that fenofibrate reversed lipid accumulation and blocked SARS-CoV-2 replication through a PPARα-dependent mechanism in both alpha and delta variants. Analysis of 3233 Israeli patients hospitalized due to COVID-19 supported in vitro findings. Patients taking fibrates showed significantly lower markers of immunoinflammation and faster recovery. Additional corroboration was received by comparative epidemiological analysis from cohorts in Europe and the United States. A subsequent prospective non-randomized interventional open-label study was carried out on 15 patients hospitalized with severe COVID-19. The patients were treated with 145 mg/day of nanocrystallized fenofibrate in addition to standard-of-care. Patients receiving fenofibrate demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to patients admitted during the same period. Conclusions: Taken together, our data suggest that pharmacological modulation of PPARα should be strongly considered as a potential therapeutic approach for SARS-CoV-2 infection and emphasizes the need to complete the study of fenofibrate in large randomized controlled clinical trials. Funding: Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). The interventional study was supported by Abbott (project FENOC0003). Clinical trial number: NCT04661930. {\textcopyright} 2023, Ehrlich et al.},
	doi = {10.7554/eLife.79946},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85148210123\&doi=10.7554\%2feLife.79946\&partnerID=40\&md5=246c6d56865d9a86540fdbfef1333344},
	author = {Ehrlich, A. and Ioannidis, K. and Nasar, M. and Abu Alkian, I. and Daskal, Y. and Atari, N. and Kliker, L. and Rainy, N. and Hofree, M. and Shafran Tikva, S. and Houri, I. and Cicero, A. and Pavanello, C. and Sirtori, C.R. and Cohen, J.B. and Chirinos, J.A. and Deutsch, L. and Cohen, M. and Gottlieb, A. and Bar-Chaim, A. and Shibolet, O. and Mandelboim, M. and Maayan, S.L. and Nahmias, Y.}
}
@article {Ghosheh20231493,
	title = {Electro-metabolic coupling in multi-chambered vascularized human cardiac organoids},
	journal = {Nature Biomedical Engineering},
	volume = {7},
	number = {11},
	year = {2023},
	note = {cited By 8},
	pages = {1493-1513},
	abstract = {The study of cardiac physiology is hindered by physiological differences between humans and small-animal models. Here we report the generation of multi-chambered self-paced vascularized human cardiac organoids formed under anisotropic stress and their applicability to the study of cardiac arrhythmia. Sensors embedded in the cardiac organoids enabled the simultaneous measurement of oxygen uptake, extracellular field potentials and cardiac contraction at resolutions higher than 10 Hz. This microphysiological system revealed 1 Hz cardiac respiratory cycles that are coupled to the electrical rather than the mechanical activity of cardiomyocytes. This electro-mitochondrial coupling was driven by mitochondrial calcium oscillations driving respiration cycles. Pharmaceutical or genetic inhibition of this coupling results in arrhythmogenic behaviour. We show that the chemotherapeutic mitoxantrone induces arrhythmia through disruption of this pathway, a process that can be partially reversed by the co-administration of metformin. Our microphysiological cardiac systems may further facilitate the study of the mitochondrial dynamics of cardiac rhythms and advance our understanding of human cardiac physiology. {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.},
	doi = {10.1038/s41551-023-01071-9},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85166947990\&doi=10.1038\%2fs41551-023-01071-9\&partnerID=40\&md5=39c5f93ee52f4bb0196f6685889a9b30},
	author = {Ghosheh, M. and Ehrlich, A. and Ioannidis, K. and Ayyash, M. and Goldfracht, I. and Cohen, M. and Fischer, A. and Mintz, Y. and Gepstein, L. and Nahmias, Y.}
}
@article {Pasitka202335,
	title = {Spontaneous immortalization of chicken fibroblasts generates stable, high-yield cell lines for serum-free production of cultured meat},
	journal = {Nature Food},
	volume = {4},
	number = {1},
	year = {2023},
	note = {cited By 61},
	pages = {35-50},
	abstract = {Cellular agriculture could meet growing demand for animal products, but yields are typically low and regulatory bodies restrict genetic modification for cultured meat production. Here we demonstrate the spontaneous immortalization and genetic stability of fibroblasts derived from several chicken breeds. Cell lines were adapted to grow as single-cell suspensions using serum-free culture medium, reaching densities of 108 {\texttimes} 106 cells per ml in continuous culture, corresponding to yields of 36\% w/v. We show that lecithin activates peroxisome proliferator-activated receptor gamma (PPARγ), inducing adipogenesis in immortalized fibroblasts. Blending cultured adipocyte-like cells with extruded soy protein, formed chicken strips in which texture was supported by animal and plant proteins while aroma and flavour were driven by cultured animal fat. Visual and sensory analysis graded the product 4.5/5.0, with 85\% of participants extremely likely to replace their food choice with this cultured meat product. Immortalization without genetic modification and high-yield manufacturing are critical for the market realization of cultured meat. {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.},
	doi = {10.1038/s43016-022-00658-w},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85144734313\&doi=10.1038\%2fs43016-022-00658-w\&partnerID=40\&md5=8a6fc1b9f5520fa86d7d7421ecd1a2b7},
	author = {Pasitka, L. and Cohen, M. and Ehrlich, A. and Gildor, B. and Reuveni, E. and Ayyash, M. and Wissotsky, G. and Herscovici, A. and Kaminker, R. and Niv, A. and Bitcover, R. and Dadia, O. and Rudik, A. and Voloschin, A. and Shimoni, M. and Cinnamon, Y. and Nahmias, Y.}
}
@article {Fischer2023,
	title = {Stimuli-Responsive Hydrogel Microcapsules Harnessing the COVID-19 Immune Response for Cancer Therapeutics},
	journal = {Angewandte Chemie - International Edition},
	volume = {62},
	number = {43},
	year = {2023},
	note = {cited By 9},
	abstract = {The combination of gene therapy and immunotherapy concepts, along recent advances in DNA nanotechnology, have the potential to provide important tools for cancer therapies. We present the development of stimuli-responsive microcapsules, loaded with a viral immunogenetic agent, harnessing the immune response against the Coronavirus Disease 2019, COVID-19, to selectively attack liver cancer cells (hepatoma) or recognize breast cancer or hepatoma, by expression of green fluorescence protein, GFP. The pH-responsive microcapsules, modified with DNA-tetrahedra nanostructures, increased hepatoma permeation by 50 \%. Incorporation of a GFP-encoding lentivirus vector inside the tumor-targeting pH-stimulated miRNA-triggered and Alpha-fetoprotein-dictated microcapsules enables the demonstration of neoplasm selectivity, with approximately 5,000-, 8,000- and 50,000-fold more expression in the cancerous cells, respectively. The incorporation of the SARS-CoV-2 spike protein in the gene vector promotes specific recognition of the immune-evading hepatoma by the COVID-19-analogous immune response, which leads to cytotoxic and inflammatory activity, mediated by serum components taken from vaccinated or recovered COVID-19 patients, resulting in effective elimination of the hepatoma (>85 \% yield). {\textcopyright} 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.},
	doi = {10.1002/anie.202311590},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85171435791\&doi=10.1002\%2fanie.202311590\&partnerID=40\&md5=7664a4e7c23b2a15db1adbdf3b3a441e},
	author = {Fischer, A. and Ehrlich, A. and Plotkin, Y. and Ouyang, Y. and Asulin, K. and Konstantinos, I. and Fan, C. and Nahmias, Y. and Willner, I.}
}
@article {Ioannidis2022,
	title = {Aminoglycoside-induced lipotoxicity and its reversal in kidney on chip},
	journal = {Lab on a Chip},
	volume = {6},
	number = {6},
	year = {2022},
	note = {cited By 3},
	abstract = {Aminoglycosides are an important class of antibiotics that play a critical role in the treatment of life-threatening infections, but their use is limited by their toxicity. In fact, gentamicin causes severe nephrotoxicity in 17\% of hospitalized patients. The kidney proximal tubule is particularly vulnerable to drug-induced nephrotoxicity due to its role in drug transport. In this work, we developed a perfused vascularized model of human kidney tubuloids integrated with tissue-embedded microsensors that track the metabolic dynamics of aminoglycoside-induced renal toxicity in real time. Our model shows that gentamicin disrupts proximal tubule polarity at concentrations 20-fold below its TC50, leading to a 3.2-fold increase in glucose uptake, and reverse TCA cycle flux culminating in a 40-fold increase in lipid accumulation. Blocking glucose reabsorption using the SGLT2 inhibitor empagliflozin significantly reduced gentamicin toxicity by 10-fold. These results demonstrate the utility of sensor-integrated kidney-on-chip platforms to rapidly identify new metabolic mechanisms that may underly adverse drug reactions. The results should improve our ability to modulate the toxicity of novel aminoglycosides. {\textcopyright} 2022 The Royal Society of Chemistry.},
	doi = {10.1039/d2lc00825d},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85141544098\&doi=10.1039\%2fd2lc00825d\&partnerID=40\&md5=5fd1500d95c42611af06a1bc9811c2a8},
	author = {Ioannidis, K. and Cohen, A. and Ghosheh, M. and Ehrlich, A. and Fischer, A. and Cohen, M. and Nahmias, Y.}
}
@article {Karmi2022,
	title = {A VDAC1-mediated NEET protein chain transfers [2Fe-2S] clusters between the mitochondria and the cytosol and impacts mitochondrial dynamics},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {119},
	number = {7},
	year = {2022},
	note = {cited By 27},
	abstract = {Mitochondrial inner NEET (MiNT) and the outer mitochondrial membrane (OMM) mitoNEET (mNT) proteins belong to the NEET protein family. This family plays a key role in mitochondrial labile iron and reactive oxygen species (ROS) homeostasis. NEET proteins contain labile [2Fe-2S] clusters which can be transferred to apo-acceptor proteins. In eukaryotes, the biogenesis of [2Fe-2S] clusters occurs within the mitochondria by the iron-sulfur cluster (ISC) system; the clusters are then transferred to [2Fe-2S] proteins within the mitochondria or exported to cytosolic proteins and the cytosolic iron-sulfur cluster assembly (CIA) system. The last step of export of the [2Fe-2S] is not yet fully characterized. Here we show that MiNT interacts with voltage-dependent anion channel 1 (VDAC1), a major OMM protein that connects the intermembrane space with the cytosol and participates in regulating the levels of different ions including mitochondrial labile iron (mLI). We further show that VDAC1 is mediating the interaction between MiNT and mNT, in which MiNT transfers its [2Fe-2S] clusters from inside the mitochondria to mNT that is facing the cytosol. This MiNT-VDAC1-mNT interaction is shown both experimentally and by computational calculations. Additionally, we show that modifying MiNT expression in breast cancer cells affects the dynamics of mitochondrial structure and morphology, mitochondrial function, and breast cancer tumor growth. Our findings reveal a pathway for the transfer of [2Fe-2S] clusters, which are assembled inside the mitochondria, to the cytosol. {\textcopyright} 2022 National Academy of Sciences. All rights reserved.},
	doi = {10.1073/pnas.2121491119},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85124289196\&doi=10.1073\%2fpnas.2121491119\&partnerID=40\&md5=5f30321a2cb4394afe41bf112d84e5f1},
	author = {Karmi, O. and Marjault, H.-B. and Bai, F. and Roy, S. and Sohn, Y.-S. and Yahana, M.D. and Morcos, F. and Ioannidis, K. and Nahmias, Y. and Jennings, P.A. and Mittler, R. and Onuchic, J.N. and Nechushtai, R.}
}
@article {Nahmias2021203,
	title = {Circadian Effects of Drug Responses},
	journal = {Annual Review of Biomedical Engineering},
	volume = {23},
	year = {2021},
	note = {cited By 23},
	pages = {203-224},
	abstract = {Circadian rhythms describe physiological systems that repeat themselves with a cycle of approximately 24 h. Our understanding of the cellular and molecular origins of these oscillations has improved dramatically, allowing us to appreciate the significant role these oscillations play in maintaining physiological homeostasis. Circadian rhythms allow living organisms to predict and efficiently respond to a dynamically changing environment, set by repetitive day/night cycles. Since circadian rhythms underlie almost every aspect of human physiology, it is unsurprising that they also influence the response of a living organism to disease, stress, and therapeutics. Therefore, not only do the mechanisms that maintain health and disrupt homeostasis depend on our internal circadian clock, but also the way drugs are perceived and function depends on these physiological rhythms. We present a holistic view of the therapeutic process, discussing components such as disease state, pharmacokinetics, and pharmacodynamics, as well as adverse reactions that are critically affected by circadian rhythms. We outline challenges and opportunities in moving toward personalized medicine approaches that explore and capitalize on circadian rhythms for the benefit of the patient. {\textcopyright} Copyright 2021 by Annual Reviews.},
	doi = {10.1146/annurev-bioeng-082120-034725},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85110548098\&doi=10.1146\%2fannurev-bioeng-082120-034725\&partnerID=40\&md5=0957643f9d178ebcf7583aa5d4219999},
	author = {Nahmias, Y. and Androulakis, I.P.}
}
@article {Karmi2021,
	title = {A combined drug treatment that reduces mitochondrial iron and reactive oxygen levels recovers insulin secretion in NAF-1-deficient pancreatic cells},
	journal = {Antioxidants},
	volume = {10},
	number = {8},
	year = {2021},
	note = {cited By 9},
	abstract = {Decreased insulin secretion, associated with pancreatic β-cell failure, plays a critical role in many human diseases including diabetes, obesity, and cancer. While numerous studies linked β-cell failure with enhanced levels of reactive oxygen species (ROS), the development of diabetes associated with hereditary conditions that result in iron overload, e.g., hemochromatosis, Friedreich{\textquoteright}s ataxia, and Wolfram syndrome type 2 (WFS-T2; a mutation in CISD2, encoding the [2Fe-2S] protein NAF-1), underscores an additional link between iron metabolism and β-cell failure. Here, using NAF-1-repressed INS-1E pancreatic cells, we observed that NAF-1 repression inhibited insulin se-cretion, as well as impaired mitochondrial and ER structure and function. Importantly, we found that a combined treatment with the cell permeant iron chelator deferiprone and the glutathione precursor N-acetyl cysteine promoted the structural repair of mitochondria and ER, decreased mi-tochondrial labile iron and ROS levels, and restored glucose-stimulated insulin secretion. Addition-ally, treatment with the ferroptosis inhibitor ferrostatin-1 decreased cellular ROS formation and improved cellular growth of NAF-1 repressed pancreatic cells. Our findings reveal that suppressed expression of NAF-1 is associated with the development of ferroptosis-like features in pancreatic cells, and that reducing the levels of mitochondrial iron and ROS levels could be used as a therapeutic avenue for WFS-T2 patients. {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.},
	doi = {10.3390/antiox10081160},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85110732792\&doi=10.3390\%2fantiox10081160\&partnerID=40\&md5=aa6b73bbcc14e9de504f030bc28b1949},
	author = {Karmi, O. and Sohn, Y.-S. and Marjault, H.-B. and Israeli, T. and Leibowitz, G. and Ioannidis, K. and Nahmias, Y. and Mittler, R. and Cabantchik, I.Z. and Nechushtai, R.}
}
@article {Rauti2021,
	title = {Effect of sars-cov-2 proteins on vascular permeability},
	journal = {eLife},
	volume = {10},
	year = {2021},
	note = {cited By 47},
	abstract = {Severe acute respiratory syndrome (SARS)-CoV-2 infection leads to severe disease associated with cytokine storm, vascular dysfunction, coagulation, and progressive lung damage. It affects several vital organs, seemingly through a pathological effect on endothelial cells. The SARS-CoV-2 genome encodes 29 proteins, whose contribution to the disease manifestations, and especially endothelial complications, is unknown. We cloned and expressed 26 of these proteins in human cells and characterized the endothelial response to overexpression of each, individually. Whereas most proteins induced significant changes in endothelial permeability, nsp2, nsp5_c145a (catalytic dead mutant of nsp5), and nsp7 also reduced CD31, and increased von Willebrand factor expression and IL-6, suggesting endothelial dysfunction. Using propagation-based analysis of a protein{\textendash}protein interaction (PPI) network, we predicted the endothelial proteins affected by the viral proteins that potentially mediate these effects. We further applied our PPI model to identify the role of each SARS-CoV-2 protein in other tissues affected by coronavirus disease (COVID-19). While vali-dating the PPI network model, we found that the tight junction (TJ) proteins cadherin-5, ZO-1, and β-catenin are affected by nsp2, nsp5_c145a, and nsp7 consistent with the model prediction. Overall, this work identifies the SARS-CoV-2 proteins that might be most detrimental in terms of endothelial dysfunction, thereby shedding light on vascular aspects of COVID-19. {\textcopyright} Rauti et al.},
	doi = {10.7554/eLife.69314},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85118218997\&doi=10.7554\%2feLife.69314\&partnerID=40\&md5=c60cbc61f1a3dd9ebf31f82e6e3ed651},
	author = {Rauti, R. and Shahoha, M. and Leichtmann-Bardoogo, Y. and Nasser, R. and Paz, E. and Tamir, R. and Miller, V. and Babich, T. and Shaked, K. and Ehrlich, A. and Ioannidis, K. and Nahmias, Y. and Sharan, R. and Ashery, U. and Maoz, B.M.}
}
@article {Cohen2021,
	title = {Mechanism and reversal of drug-induced nephrotoxicity on a chip},
	journal = {Science Translational Medicine},
	volume = {13},
	number = {582},
	year = {2021},
	note = {cited By 53},
	abstract = {The kidney plays a critical role in fluid homeostasis, glucose control, and drug excretion. Loss of kidney function due to drug-induced nephrotoxicity affects over 20\% of the adult population. The kidney proximal tubule is a complex vascularized structure that is particularly vulnerable to drug-induced nephrotoxicity. Here, we introduce a model of vascularized human kidney spheroids with integrated tissue-embedded microsensors for oxygen, glucose, lactate, and glutamine, providing real-time assessment of cellular metabolism. Our model shows that both the immunosuppressive drug cyclosporine and the anticancer drug cisplatin disrupt proximal tubule polarity at subtoxic concentrations, leading to glucose accumulation and lipotoxicity. Impeding glucose reabsorption using glucose transport inhibitors blocked cyclosporine and cisplatin toxicity by 1000- to 3-fold, respectively. Retrospective study of 247 patients who were diagnosed with kidney damage receiving cyclosporine or cisplatin in combination with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin showed significant (P < 0.001) improvement of kidney function, as well as reduction in creatinine and uric acid, markers of kidney damage. These results demonstrate the potential of sensor-integrated kidney-on-chip platforms to elucidate mechanisms of action and rapidly reformulate effective therapeutic solutions, increasing drug safety and reducing the cost of clinical and commercial failures. Copyright {\textcopyright} 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works},
	doi = {10.1126/scitranslmed.abd6299},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85101784927\&doi=10.1126\%2fscitranslmed.abd6299\&partnerID=40\&md5=35a963a0a92b15c6295ec79834c04384},
	author = {Cohen, A. and Ioannidis, K. and Ehrlich, A. and Regenbaum, S. and Cohen, M. and Ayyash, M. and Tikva, S.S. and Nahmias, Y.}
}
@article {Wang20204516,
	title = {Biocatalytic reversible control of the stiffness of DNA-modified responsive hydrogels: applications in shape-memory, self-healing and autonomous controlled release of insulin},
	journal = {Chemical Science},
	volume = {11},
	number = {17},
	year = {2020},
	note = {cited By 38},
	pages = {4516-4524},
	abstract = {The enzymes glucose oxidase (GOx), acetylcholine esterase (AchE) and urease that drive biocatalytic transformations to alter pH, are integrated into pH-responsive DNA-based hydrogels. A two-enzyme-loaded hydrogel composed of GOx/urease or AchE/urease and a three-enzyme-loaded hydrogel composed of GOx/AchE/urease are presented. The biocatalytic transformations within the hydrogels lead to the dictated reconfiguration of nucleic acid bridges and the switchable control over the stiffness of the respective hydrogels. The switchable stiffness features are used to develop biocatalytically guided shape-memory and self-healing matrices. In addition, loading of GOx/insulin in a pH-responsive DNA-based hydrogel yields a glucose-triggered matrix for the controlled release of insulin, acting as an artificial pancreas. The release of insulin is controlled by the concentrations of glucose, hence, the biocatalytic insulin-loaded hydrogel provides an interesting sense-and-treat carrier for controlling diabetes. {\textcopyright} The Royal Society of Chemistry 2020.},
	doi = {10.1039/d0sc01319f},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85084501957\&doi=10.1039\%2fd0sc01319f\&partnerID=40\&md5=ca72af9920a26366bdb89145bf20e4da},
	author = {Wang, C. and Fischer, A. and Ehrlich, A. and Nahmias, Y. and Willner, I.}
}
@article {Lilienthal2020,
	title = {Constitutional Dynamic Networks-Guided Synthesis of Programmed "Genes", Transcription of mRNAs, and Translation of Proteins},
	journal = {Journal of the American Chemical Society},
	volume = {142},
	number = {51},
	year = {2020},
	note = {cited By 14},
	abstract = {Inspired by nature, where dynamic networks control the levels of gene expression and the activities of transcribed/translated proteins, we introduce nucleic acid-based constitutional dynamic networks (CDNs) as functional modules mimicking native circuits by demonstrating CDNs-guided programmed synthesis of genes, controlled transcription of RNAs, and dictated transcription/translation synthesis of proteins. An auxiliary CDN consisting of four dynamically equilibrated constituents AA', AB', BA', and BB' is orthogonally triggered by two different inputs yielding two different compositionally reconfigured CDNs. Subjecting the parent auxiliary CDN to two hairpins, HA and HB, and two templates TA and TB and a nicking/replication machinery leads to the cleavage of the hairpins and to the activation of the nicking/replication machineries that synthesize two "genes", e.g., the histidine-dependent DNAzyme g1 and the Zn2+-ion-dependent DNAzyme g2. The triggered orthogonal reconfiguration of the parent CDN to the respective CDNs leads to the programmed preferred CDN-guided synthesis of g1 or g2. Similarly, the triggered reconfigured CDNs are subjected to two hairpins HC and HD, the templates I'/I and J'/J, and the RNA polymerase (RNAp)/NTPs machinery. While the cleavage of the hairpins by the constituents associated with the parent CDN leads to the transcription of the broccoli aptamer recognizing the DFHBI ligand and of the aptamer recognizing the malachite green (MG) ligand, the orthogonally triggered CDNs lead to the CDNs-guided enhanced transcription of either the DFHBI aptamer or the MG aptamer. In addition, subjecting the triggered reconfigured CDNs to predesigned hairpins HE and HF, the templates M'/M and N'/N, the RNAp/NTPs machinery, and the cell-free ribosome t-RNA machinery leads to the CDNs-guided transcription/translation of the green fluorescence protein (GFP) or red fluorescence protein (RFP). {\textcopyright}},
	doi = {10.1021/jacs.0c10565},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85097747343\&doi=10.1021\%2fjacs.0c10565\&partnerID=40\&md5=fbba6d7b29712c41b91840dbe164371f},
	author = {Lilienthal, S. and Luo, G.-F. and Wang, S. and Yue, L. and Fischer, A. and Ehrlich, A. and Nahmias, Y. and Willner, I.}
}
@article {Ehrlich2019219,
	title = {Challenges and Opportunities in the Design of Liver-on-Chip Microdevices},
	journal = {Annual Review of Biomedical Engineering},
	volume = {21},
	year = {2019},
	note = {cited By 84},
	pages = {219-239},
	abstract = {The liver is the central hub of xenobiotic metabolism and consequently the organ most prone to cosmetic-and drug-induced toxicity. Failure to detect liver toxicity or to assess compound clearance during product development is a major cause of postmarketing product withdrawal, with disastrous clinical and financial consequences. While small animals are still the preferred model in drug development, the recent ban on animal use in the European Union created a pressing need to develop precise and efficient tools to detect human liver toxicity during cosmetic development. This article includes a brief review of liver development, organization, and function and focuses on the state of the art of long-term cell culture, including hepatocyte cell sources, heterotypic cell-cell interactions, oxygen demands, and culture medium formulation. Finally, the article reviews emerging liver-on-chip devices and discusses the advantages and pitfalls of individual designs. The goal of this review is to provide a framework to design liver-on-chip devices and criteria with which to evaluate this emerging technology. {\textcopyright} 2019 by Annual Reviews All rights reserved.},
	doi = {10.1146/annurev-bioeng-060418-052305},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85067046533\&doi=10.1146\%2fannurev-bioeng-060418-052305\&partnerID=40\&md5=d7f95f2bd97c8d4a46b3e86030eaff5d},
	author = {Ehrlich, A. and Duche, D. and Ouedraogo, G. and Nahmias, Y.}
}
@article {Ordov{\'a}s2018673,
	title = {Erratum: Efficient Recombinase-Mediated Cassette Exchange in hPSCs to Study the Hepatocyte Lineage Reveals AAVS1 Locus-Mediated Transgene Inhibition (Stem Cell Reports (2015) 5(5) (918{\textendash}931)(S2213671115002660)(10.1016/j.stemcr.2015.09.004))},
	journal = {Stem Cell Reports},
	volume = {10},
	number = {2},
	year = {2018},
	note = {cited By 3},
	pages = {673},
	abstract = {Main Text: (Stem Cell Reports 5, 918{\textendash}931; November 10, 2015) The karyotype pictures of iPSC clones iMCL$\#$3 and iMCL$\#$11 shown in Figure S1D in the original Supplemental Material were incorrect and have been replaced online. This graphical error does not affect the results and conclusions of the article. The authors apologize for this error. {\textcopyright} 2018},
	doi = {10.1016/j.stemcr.2018.01.034},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85041928226\&doi=10.1016\%2fj.stemcr.2018.01.034\&partnerID=40\&md5=402aa41d3d278f1f4b9adbf07ae7f8c8},
	author = {Ordov{\'a}s, L. and Boon, R. and Pistoni, M. and Chen, Y. and Wolfs, E. and Guo, W. and Sambathkumar, R. and Bobis-Wozowicz, S. and Helsen, N. and Vanhove, J. and Berckmans, P. and Cai, Q. and Vanuytsel, K. and Eggermont, K. and Vanslembrouck, V. and Schmidt, B.Z. and Raitano, S. and Van Den Bosch, L. and Nahmias, Y. and Cathomen, T. and Struys, T. and Verfaillie, C.M.}
}
@article {Keinan2018,
	title = {High-Reynolds Microfluidic Sorting of Large Yeast Populations},
	journal = {Scientific Reports},
	volume = {8},
	number = {1},
	year = {2018},
	note = {cited By 9},
	abstract = {Microfluidic sorting offers a unique ability to isolate large numbers of cells for bulk proteomic or metabolomics studies but is currently limited by low throughput and persistent clogging at low flow rates. Recently we uncovered the physical principles governing the inertial focusing of particles in high-Reynolds numbers. Here, we superimpose high Reynolds inertial focusing on Dean vortices, to rapidly isolate large quantities of young and adult yeast from mixed populations at a rate of 107 cells/min/channel. Using a new algorithm to rapidly quantify budding scars in isolated yeast populations and system-wide proteomic analysis, we demonstrate that protein quality control and expression of established yeast aging markers such as CalM, RPL5, and SAM1 may change after the very first replication events, rather than later in the aging process as previously thought. Our technique enables the large-scale isolation of microorganisms based on minute differences in size ({\textpm}1.5 μm), a feat unmatched by other technologies. {\textcopyright} 2018, The Author(s).},
	doi = {10.1038/s41598-018-31726-6},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85053344757\&doi=10.1038\%2fs41598-018-31726-6\&partnerID=40\&md5=f071c53a9eb9a1fe5071797af1a2976a},
	author = {Keinan, E. and Abraham, A.C. and Cohen, A. and Alexandrov, A.I. and Mintz, R. and Cohen, M. and Reichmann, D. and Kaganovich, D. and Nahmias, Y.}
}
@article {Ehrlich20182510,
	title = {Microphysiological flux balance platform unravels the dynamics of drug induced steatosis},
	journal = {Lab on a Chip},
	volume = {18},
	number = {17},
	year = {2018},
	note = {cited By 31},
	pages = {2510-2522},
	abstract = {Drug development is currently hampered by the inability of animal experiments to accurately predict human response. While emerging organ on chip technology offers to reduce risk using microfluidic models of human tissues, the technology still mostly relies on end-point assays and biomarker measurements to assess tissue damage resulting in limited mechanistic information and difficulties to detect adverse effects occurring below the threshold of cellular damage. Here we present a sensor-integrated liver on chip array in which oxygen is monitored using two-frequency phase modulation of tissue-embedded microprobes, while glucose, lactate and temperature are measured in real time using microfluidic electrochemical sensors. Our microphysiological platform permits the calculation of dynamic changes in metabolic fluxes around central carbon metabolism, producing a unique metabolic fingerprint of the liver{\textquoteright}s response to stimuli. Using our platform, we studied the dynamics of human liver response to the epilepsy drug Valproate (Depakine{\texttrademark}) and the antiretroviral medication Stavudine (Zerit{\texttrademark}). Using E6/E7LOW hepatocytes, we show TC50 of 2.5 and 0.8 mM, respectively, coupled with a significant induction of steatosis in 2D and 3D cultures. Time to onset analysis showed slow progressive damage starting only 15-20 hours post-exposure. However, flux analysis showed a rapid disruption of metabolic homeostasis occurring below the threshold of cellular damage. While Valproate exposure led to a sustained 15\% increase in lipogenesis followed by mitochondrial stress, Stavudine exposure showed only a transient increase in lipogenesis suggesting disruption of β-oxidation. Our data demonstrates the importance of tracking metabolic stress as a predictor of clinical outcome. {\textcopyright} 2018 The Royal Society of Chemistry.},
	doi = {10.1039/c8lc00357b},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85051920173\&doi=10.1039\%2fc8lc00357b\&partnerID=40\&md5=947dca03d27465ee05ee4bf90538f6fd},
	author = {Ehrlich, A. and Tsytkin-Kirschenzweig, S. and Ioannidis, K. and Ayyash, M. and Riu, A. and Note, R. and Ouedraogo, G. and Vanfleteren, J. and Cohen, M. and Nahmias, Y.}
}
@article {Hinden2018434,
	title = {Modulation of Renal GLUT2 by the Cannabinoid-1 Receptor: Implications for the Treatment of Diabetic Nephropathy},
	journal = {Journal of the American Society of Nephrology},
	volume = {29},
	number = {2},
	year = {2018},
	note = {cited By 63},
	pages = {434-448},
	abstract = {Altered glucose reabsorption via the facilitative glucose transporter 2 (GLUT2) during diabetes may lead to renal proximal tubule cell (RPTC) injury, inflammation, and interstitial fibrosis. These pathologies are also triggered by activating the cannabinoid-1 receptor (CB1R), which contributes to the development of diabetic nephropathy (DN). However, the link between CB1R and GLUT2 remains to be determined. Here, we show that chronic peripheral CB1R blockade or genetically inactivating CB1Rs in the RPTCs ameliorated diabetes-induced renal structural and functional changes, kidney inflammation, and tubulointerstitial fibrosis in mice. Inhibition of CB1R also downregulated GLUT2 expression, affected the dynamic translocation of GLUT2 to the brush border membrane of RPTCs, and reduced glucose reabsorption. Thus, targeting peripheral CB1R or inhibiting GLUT2 dynamics in RPTCs has the potential to treat and ameliorate DN. These findings may support the rationale for the clinical testing of peripherally restricted CB1R antagonists or the development of novel renal-specific GLUT2 inhibitors against DN. Copyright {\textcopyright} 2018 by the American Society of Nephrology},
	doi = {10.1681/ASN.2017040371},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85041457312\&doi=10.1681\%2fASN.2017040371\&partnerID=40\&md5=b3a71350d50095800a41ed88a7ad0db7},
	author = {Hinden, L. and Udi, S. and Drori, A. and Gammal, A. and Nemirovski, A. and Hadar, R. and Baraghithy, S. and Permyakova, A. and Geron, M. and Cohen, M. and Tsytkin-Kirschenzweig, S. and Riahi, Y. and Leibowitz, G. and Nahmias, Y. and Priel, A. and Tam, J.}
}
@article {Schwartz2018113,
	title = {Neuregulin 1 discovered as a cleavage target for the HCV NS3/4A protease by a microfluidic membrane protein array},
	journal = {New Biotechnology},
	volume = {45},
	year = {2018},
	note = {cited By 2},
	pages = {113-122},
	abstract = {The hepatitis C virus (HCV) non-structural protein 3 (NS3) is essential for HCV maturation. The NS3/4A protease is a target for several HCV treatments and is a well-known target for HCV drug discovery. The protein is membrane associated and thus probably interacts with other membrane proteins. However, the vast majority of known NS3 host partners are soluble proteins rather than membrane proteins, most likely due to lack of appropriate platforms for their discovery. Utilization of an integrated microfluidics platform enables analysis of membrane proteins in their native form. We screened over 2800 membrane proteins for interaction with NS3 and 90 previously unknown interactions were identified. Of these, several proteins were selected for validation by co-immunoprecipitation and for NS3 proteolytic activity. Bearing in mind the considerable number of interactions formed, together with the popularity of NS3/4A protease as a drug target, it was striking to note its lack of proteolytic activity. Only a single protein, Neuregulin1, was observed to be cleaved, adding to the 3 known NS3/4A cleavage targets. Neuregulin1 participates in neural proliferation. Recent studies have shown its involvement in HCV infection and hepatocellular carcinoma. We showed that NS3/4A triggers an increase in neuregulin1 mRNA levels in HCV infected cells. Despite this increase, its protein concentration is decreased due to proteolytic cleavage. Additionally, its EGF-like domain levels were increased, possibly explaining the ErbB2 and EGFR upregulation in HCV infected cells. The newly discovered protein interactions may provide insights into HCV infection mechanisms and potentially provide new therapeutic targets against HCV. {\textcopyright} 2018 Elsevier B.V.},
	doi = {10.1016/j.nbt.2018.02.004},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85042145306\&doi=10.1016\%2fj.nbt.2018.02.004\&partnerID=40\&md5=4c92ef13cd4bda813a5981b1194d1ab7},
	author = {Schwartz, N. and Pellach, M. and Glick, Y. and Gil, R. and Levy, G. and Avrahami, D. and Barbiro-Michaely, E. and Nahmias, Y. and Gerber, D.}
}
@article {Radzinski2018,
	title = {Temporal profiling of redox-dependent heterogeneity in single cells},
	journal = {eLife},
	volume = {7},
	year = {2018},
	note = {cited By 21},
	abstract = {Cellular redox status affects diverse cellular functions, including proliferation, protein homeostasis, and aging. Thus, individual differences in redox status can give rise to distinct subpopulations even among cells with identical genetic backgrounds. Here, we have created a novel methodology to track redox status at single cell resolution using the redox-sensitive probe Grx1-roGFP2. Our method allows identification and sorting of sub-populations with different oxidation levels in either the cytosol, mitochondria or peroxisomes. Using this approach, we defined a redox-dependent heterogeneity of yeast cells and characterized growth, as well as proteomic and transcriptomic profiles of distinctive redox subpopulations. We report that, starting in late logarithmic growth, cells of the same age have a bi-modal distribution of oxidation status. A comparative proteomic analysis between these populations identified three key proteins, Hsp30, Dhh1, and Pnc1, which affect basal oxidation levels and may serve as first line of defense proteins in redox homeostasis. {\textcopyright} Radzinski et al.},
	doi = {10.7554/eLife.37623},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85051931605\&doi=10.7554\%2feLife.37623\&partnerID=40\&md5=64905fb7eaecf482661ac978d8a9762c},
	author = {Radzinski, M. and Fassler, R. and Yogev, O. and Breuer, W. and Shai, N. and Gutin, J. and Ilyas, S. and Geffen, Y. and Tsytkin-Kirschenzweig, S. and Nahmias, Y. and Ravid, T. and Friedman, N. and Schuldiner, M. and Reichmann, D.}
}
@article {Tsytkin-Kirschenzweig2018241,
	title = {Tracking GLUT2 translocation by live-cell imaging},
	journal = {Methods in Molecular Biology},
	volume = {1713},
	year = {2018},
	note = {cited By 4},
	pages = {241-254},
	abstract = {The facilitative glucose transporter (GLUT) family plays a key role in metabolic homeostasis, controlling the absorption rates and rapid response to changing carbohydrate levels. The facilitative GLUT2 transporter is uniquely expressed in metabolic epithelial cells of the intestine, pancreas, liver, and kidney. GLUT2 dysfunction is associated with several pathologies, including Fanconi-Bickel syndrome, a glycogen storage disease, characterized by growth retardation and renal dysfunction. Interestingly, GLUT2 activity is modulated by its cellular localization. Membrane translocation specifically regulates GLUT2 activity in enterocytes, pancreatic β-cells, hepatocytes, and proximal tubule cells. We have established a system to visualize and quantify GLUT2 translocation, and its dynamics, by live imaging of a mCherry-hGLUT2 fusion protein in polarized epithelial cells. This system enables testing of putative modulators of GLUT2 translocation, which are potential drugs for conditions of impaired glucose homeostasis and associated nephropathy. {\textcopyright} Springer Science+Business Media LLC 2018.},
	doi = {10.1007/978-1-4939-7507-5_18},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85037585536\&doi=10.1007\%2f978-1-4939-7507-5_18\&partnerID=40\&md5=2f25790653856d4cd9bb400e4d17f7e3},
	author = {Tsytkin-Kirschenzweig, S. and Cohen, M. and Nahmias, Y.}
}
@article {Drori2017261,
	title = {Erratum to: When Every Second Counts: Novel Device to Shorten Chest Tube Insertion Time in a Pre-hospital Setting (Pulmonary Therapy, (2016), 2, 2, (215-219), 10.1007/s41030-016-0020-4)},
	journal = {Pulmonary Therapy},
	volume = {3},
	number = {1},
	year = {2017},
	note = {cited By 0},
	pages = {261},
	doi = {10.1007/s41030-017-0031-9},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85103043619\&doi=10.1007\%2fs41030-017-0031-9\&partnerID=40\&md5=03d64c056fe592a5ef370da360055b29},
	author = {Drori, A. and Kan-tor, Y. and Nadorp, B. and Goldstein, C. and Buxboim, A. and Nahmias, Y. and Levy, L.}
}
@article {Nevo-Yassaf201730,
	title = {Live cell imaging and analysis of lipid droplets biogenesis in hepatatis C virus infected cells},
	journal = {Methods},
	volume = {127},
	year = {2017},
	note = {cited By 9},
	pages = {30-36},
	abstract = {Lipid droplets (LDs) are regulated neutral lipid storage organelles having a central role in numerous cellular processes as well as in various pathologies such as metabolic disorders, immune responses and during pathogen infection. Due to the growing significance of LDs, extensive efforts are made to study the mechanism and the dynamics of their formation and life history and how are these diverted or modified by pathogens. Real-time visualization of lipid droplet biogenesis can assist in clarifying these and other important issues and may have implications towards understanding the pathogenesis of the associated diseases. Typically, LDs are post-experimentally stained using lipophilic dyes and are visualized under a microscope. Alternatively, overexpression of LD-associated proteins or immunofluorescence analyses are used to identify and follow LDs. These experimental approaches only examine a single end point of the experiment and cannot answer questions regarding LD dynamics. Here, we describe a simple and novel experimental setting that allows real-time fluorescence staining and detection of LDs in cultured living as well as infected cells. This method is quick and simple and is not restricted to a specific dye or cell line. Using this system, the biogenesis of LDs and their growth is demonstrated in cells infected with hepatitis C virus (HCV), confirming the strength of this method and the wide range of its applications. {\textcopyright} 2017 Elsevier Inc.},
	doi = {10.1016/j.ymeth.2017.05.010},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85019613226\&doi=10.1016\%2fj.ymeth.2017.05.010\&partnerID=40\&md5=4c7c035fafeaa706d1ba0b473c661c11},
	author = {Nevo-Yassaf, I. and Lovelle, M. and Nahmias, Y. and Hirschberg, K. and Sklan, E.H.}
}
@article {Tsur2017,
	title = {Microfluidic concentric gradient generator design for high-Throughput cell-Based studies},
	journal = {Frontiers in Bioengineering and Biotechnology},
	volume = {5},
	number = {APR},
	year = {2017},
	note = {cited By 16},
	abstract = {Gradients of diffusible signaling molecules play important role in various processes, ranging from cell differentiation to toxicological evaluation. Microfluidic technology provides an accurate control of tempospatial conditions. However, current microfluidic platforms are not designed to handle multiple gradients and cell populations simultaneously. Here, we demonstrate a rapidly adaptable microfluidic design able to expose multiple cell populations to an array of chemical gradients. Our design is based on pressure-equilibrated concentric channels and a pressure-dissipating control layer, facilitating the seeding of multiple cell populations in a single device. The design was numerically evaluated and experimentally validated. The device consists of 8 radiating stimuli channels and 12 circular cell culture channels, creating an array of 96 different continuous gradients that can be simultaneously monitored over time. {\textcopyright} 2017 Ezra Tsur, Zimerman, Maor, Elrich and Nahmias.},
	doi = {10.3389/fbioe.2017.00021},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85040224349\&doi=10.3389\%2ffbioe.2017.00021\&partnerID=40\&md5=f9fac76b608df08bc3d05dcae3d921e1},
	author = {Tsur, E.E. and Zimerman, M. and Maor, I. and Elrich, A. and Nahmias, Y.}
}
@article {Ezra2016,
	title = {Development of Three-Dimensional Streamline Image Velocimetry Using Superimposed Delaunay Triangulation and Geometrical Fitting},
	journal = {Journal of Fluids Engineering, Transactions of the ASME},
	volume = {138},
	number = {1},
	year = {2016},
	note = {cited By 5},
	abstract = {Flow behavior in complex three-dimensional (3D) microscale domains is the key in the development of microcirculatory pathologies and the design of 3D microfluidics. While numerical simulations are common practice for the derivation of velocity fields in such domains, they are limited to known geometries. Current experimental methods such as micron-scale particle tracing comprise of intricate algorithmic approaches for the accurate tracing of numerous particles in a dense moving liquid suspension and are fundamentally limited in resolution to the finite size of the interrogated steps. Here, we introduce 3D streamlines image velocimetry (3D-SIV), a method to derive fluid velocity fields in arbitrary resolution for fully developed laminar flow in 3D geometries. Our approach utilizes 3D geometrical fitting and superimposed Delaunay triangulation to reconstruct streamtubes and to trace their volumetric changes. Our algorithm has applications in out-of-plane velocimetries, which we demonstrate in a 3D dilated curved geometry and in an ascending aorta. The 3D-SIV can be applied for high-resolution derivation of velocity fields in microcirculatory pathologies and to 3D microfluidic circuits, extending the potential of out-of-plane velocimetries to complex geometries and arbitrary resolution. Copyright {\textcopyright} 2016 by ASME.},
	doi = {10.1115/1.4031611},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84945920946\&doi=10.1115\%2f1.4031611\&partnerID=40\&md5=ca6791ec22870a12041aadc473651782},
	author = {Ezra, E. and Keinan, E. and Liberzon, A. and Nahmias, Y.}
}
@article {Levy20161037,
	title = {Nuclear receptors control pro-viral and antiviral metabolic responses to hepatitis C virus infection},
	journal = {Nature Chemical Biology},
	volume = {12},
	number = {12},
	year = {2016},
	note = {cited By 40},
	pages = {1037-1045},
	abstract = {Viruses lack the basic machinery needed to replicate and therefore must hijack the host{\textquoteright}s metabolism to propagate. Virus-induced metabolic changes have yet to be systematically studied in the context of host transcriptional regulation, and such studies shoul offer insight into host-pathogen metabolic interplay. In this work we identified hepatitis C virus (HCV)-responsive regulators by coupling system-wide metabolic-flux analysis with targeted perturbation of nuclear receptors in primary human hepatocytes. We found HCV-induced upregulation of glycolysis, ketogenesis and drug metabolism, with glycolysis controlled by activation of HNF4α, ketogenesis by PPARα and FXR, and drug metabolism by PXR. Pharmaceutical inhibition of HNF4α reversed HCV-induced glycolysis, blocking viral replication while increasing apoptosis in infected cells showing virus-induced dependence on glycolysis. In contrast, pharmaceutical inhibition of PPARα or FXR reversed HCV-induced ketogenesis but increased viral replication, demonstrating a novel host antiviral response. Our results show that virus-induced changes to a host{\textquoteright}s metabolism can be detrimental to its life cycle, thus revealing a biologically complex relationship between virus and host. {\textcopyright} Nature America, Inc.},
	doi = {10.1038/nchembio.2193},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84990886692\&doi=10.1038\%2fnchembio.2193\&partnerID=40\&md5=dced0fd6d785b11bab6bda0b26c7d576},
	author = {Levy, G. and Habib, N. and Guzzardi, M.A. and Kitsberg, D. and Bomze, D. and Ezra, E. and Uygun, B.E. and Uygun, K. and Trippler, M. and Schlaak, J.F. and Shibolet, O. and Sklan, E.H. and Cohen, M. and Timm, J. and Friedman, N. and Nahmias, Y.}
}
@article {Bavli2016,
	title = {One step antibody-mediated isolation and patterning of multiple cell types in microfluidic devices},
	journal = {Biomicrofluidics},
	volume = {10},
	number = {2},
	year = {2016},
	note = {cited By 0},
	abstract = {Cell-cell interactions play a key role in regeneration, differentiation, and basic tissue function taking place under physiological shear forces. However, current solutions to mimic such interactions by micro-patterning cells within microfluidic devices have low resolution, high fabrication complexity, and are limited to one or two cell types. Here, we present a microfluidic platform capable of laminar patterning of any biotinlabeled peptide using streptavidin-based surface chemistry. The design permits the generation of arbitrary cell patterns from heterogeneous mixtures in microfluidic devices. We demonstrate the robust co-patterning of α-CD24, α-ASGPR-1, and α- Tie2 antibodies for rapid isolation and co-patterning of mixtures of hepatocytes and endothelial cells. In addition to one-step isolation and patterning, our design permits step-wise patterning of multiple cell types and empty spaces to create complex cellular geometries in vitro. In conclusion, we developed a microfluidic device that permits the generation of perfusable tissue-like patterns in microfluidic devices by directly injecting complex cell mixtures such as differentiated stem cells or tissue digests with minimal sample preparation. {\textcopyright} 2016 AIP Publishing LLC.},
	doi = {10.1063/1.4944741},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84961584087\&doi=10.1063\%2f1.4944741\&partnerID=40\&md5=76cf81bbbfe5337ba93e477f1239fd34},
	author = {Bavli, D. and Ezra, E. and Kitsberg, D. and Vosk-Artzi, M. and Murthy, S.K. and Nahmias, Y.}
}
@article {Bavli2016E2231,
	title = {Real-time monitoring of metabolic function in liver-onchip microdevices tracks the dynamics of Mitochondrial dysfunction},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {113},
	number = {16},
	year = {2016},
	note = {cited By 262},
	pages = {E2231-E2240},
	abstract = {Microfluidic organ-on-a-chip technology aims to replace animal toxicity testing, but thus far has demonstrated few advantages over traditional methods. Mitochondrial dysfunction plays a critical role in the development of chemical and pharmaceutical toxicity, as well as pluripotency and disease processes. However, current methods to evaluate mitochondrial activity still rely on end-point assays, resulting in limited kinetic and prognostic information. Here, we present a liveron-chip device capable of maintaining human tissue for over a month in vitro under physiological conditions. Mitochondrial respiration was monitored in real time using two-frequency phase modulation of tissue-embedded phosphorescent microprobes. A computer-controlled microfluidic switchboard allowed contiguous electrochemical measurements of glucose and lactate, providing real-time analysis of minute shifts from oxidative phosphorylation to anaerobic glycolysis, an early indication of mitochondrial stress. We quantify the dynamics of cellular adaptation to mitochondrial damage and the resulting redistribution of ATP production during rotenone-induced mitochondrial dysfunction and troglitazone (Rezulin)-induced mitochondrial stress. We show troglitazone shifts metabolic fluxes at concentrations previously regarded as safe, suggesting a mechanism for its observed idiosyncratic effect. Our microfluidic platform reveals the dynamics and strategies of cellular adaptation to mitochondrial damage, a unique advantage of organ-on-chip technology.},
	doi = {10.1073/pnas.1522556113},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84964343834\&doi=10.1073\%2fpnas.1522556113\&partnerID=40\&md5=a38dfd1d6c87889fcc39fe067041a7c1},
	author = {Bavli, D. and Prill, S. and Ezra, E. and Levy, G. and Cohen, M. and Vinken, M. and Vanfleteren, J. and Jaeger, M. and Nahmias, Y.}
}
@article {Prill20161181,
	title = {Real-time monitoring of oxygen uptake in hepatic bioreactor shows CYP450-independent mitochondrial toxicity of acetaminophen and amiodarone},
	journal = {Archives of Toxicology},
	volume = {90},
	number = {5},
	year = {2016},
	note = {cited By 57},
	pages = {1181-1191},
	abstract = {Prediction of drug-induced toxicity is complicated by the failure of animal models to extrapolate human response, especially during assessment of repeated dose toxicity for cosmetic or chronic drug treatments. In this work, we present a 3D microreactor capable of maintaining metabolically active HepG2/C3A spheroids for over 28~days in vitro under stable oxygen gradients mimicking the in vivo microenvironment. Mitochondrial respiration was monitored using two-frequency phase modulation of phosphorescent microprobes embedded in the tissue. Phase modulation is focus independent and unaffected by cell death or migration. This sensitive measurement of oxygen dynamics revealed important information on the drug mechanism of action and transient subthreshold effects. Specifically, exposure to antiarrhythmic agent, amiodarone, showed that both respiration and the time to onset of mitochondrial damage were dose dependent showing a TC50 of 425~μm. Analysis showed significant induction of both phospholipidosis and microvesicular steatosis during long-term exposure. Importantly, exposure to widely used analgesic, acetaminophen, caused an immediate, reversible, dose-dependent loss of oxygen uptake followed by a slow, irreversible, dose-independent death, with a TC50 of 12.3~mM. Transient loss of mitochondrial respiration was also detected below the threshold of acetaminophen toxicity. The phenomenon was repeated in HeLa cells that lack CYP2E1 and 3A4, and was blocked by preincubation with ascorbate and TMPD. These results mark the importance of tracing toxicity effects over time, suggesting a NAPQI-independent targeting of mitochondrial complex III might be responsible for acetaminophen toxicity in extrahepatic tissues. {\textcopyright} 2015, Springer-Verlag Berlin Heidelberg.},
	doi = {10.1007/s00204-015-1537-2},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84930370310\&doi=10.1007\%2fs00204-015-1537-2\&partnerID=40\&md5=a754886ab7f6d333314840f0a3bcd416},
	author = {Prill, S. and Bavli, D. and Levy, G. and Ezra, E. and Schm{\"a}lzlin, E. and Jaeger, M.S. and Schwarz, M. and Duschl, C. and Cohen, M. and Nahmias, Y.}
}
@article {Drori2016215,
	title = {When Every Second Counts: Novel Device to Shorten Chest Tube Insertion Time in a Pre-hospital Setting},
	journal = {Pulmonary Therapy},
	volume = {2},
	number = {2},
	year = {2016},
	note = {cited By 0},
	pages = {215-219},
	abstract = {Tension pneumothorax is a life-threatening medical emergency mostly associated with chest trauma. It is considered a leading cause of death due to injury and represents a substantial portion of potentially preventable deaths in the battlefield. The accepted therapeutic approach is manual thoracostomy with chest tube insertion. This is a relatively simple procedure when performed by skilled hands and in optimal conditions. In the battlefield and in other pre-hospital settings or when performed by unprofessional personnel, it may become complicated and time-consuming. We describe a novel technique for the treatment of pneumothorax in the pre-hospital setting, utilizing a quick, one-handed, easy-to-apply approach. {\textcopyright} 2016, The Author(s).},
	doi = {10.1007/s41030-016-0020-4},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85103368678\&doi=10.1007\%2fs41030-016-0020-4\&partnerID=40\&md5=4615e53dc84f1d74ecd1ca26f5ea3a52},
	author = {Drori, A. and Kan-tor, Y. and Nadorp, B. and Goldstein, C. and Buxboim, A. and Nahmias, Y. and Levy, L.}
}
@article {Ezra201517,
	title = {Delivering advanced methods in mathematical programming to students of all disciplines using abstraction, modularity and open-ended assignments},
	journal = {Eurasia Journal of Mathematics, Science and Technology Education},
	volume = {11},
	number = {1},
	year = {2015},
	note = {cited By 2},
	pages = {17-23},
	abstract = {The advent of integrated multidisciplinary research has given rise to some of the most important breakthroughs of our time, but has also set significant challenges to the current educational paradigm. Current academic education often limits cross-discipline discussion, depends on close-ended problems, and restricts utilization of interdisciplinary methods. "Advanced Methods in Mathematical Programming" is a new course developed at the Hebrew University of Jerusalem. We used MATLAB as the course platform, exploiting the software{\textquoteright}s high levels of abstraction and modularity to teach network analysis, signal processing, module-oriented design, and mathematical modeling to students of all disciplines. Enrollment included students from different disciplines ranging from computer science to psychology. In their final projects, students presented novel ways of approaching classic disciplinary problems. {\textcopyright} 2015 by iSER, International Society of Educational Research.},
	doi = {10.12973/eurasia.2015.1302a},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84923066160\&doi=10.12973\%2feurasia.2015.1302a\&partnerID=40\&md5=84a45b21fe515d0fe88cba8cf02cd965},
	author = {Ezra, E. and Nahmias, Y.}
}
@article {Ordov{\'a}s2015918,
	title = {Efficient recombinase-mediated cassette exchange in hPSCs to study the hepatocyte lineage reveals AAVS1 locus-mediated transgene inhibition},
	journal = {Stem Cell Reports},
	volume = {5},
	number = {5},
	year = {2015},
	note = {cited By 103},
	pages = {918-931},
	abstract = {Tools for rapid and efficient transgenesis in "safe harbor" loci in an isogenic context remain important to exploit the possibilities of human pluripotent stem cells (hPSCs). We created hPSC master cell lines suitable for FLPe recombinase-mediated cassette exchange (RMCE) in the AAVS1 locus that allow generation of transgenic lines within 15 days with 100\% efficiency and without random integrations. Using RMCE, we successfully incorporated several transgenes useful for lineage identification, cell toxicity studies, and gene overexpression to study the hepatocyte lineage. However, we observed unexpected and variable transgene expression inhibition in vitro, due to DNA methylation and other unknown mechanisms, both in undifferentiated hESC and differentiating hepatocytes. Therefore, the AAVS1 locus cannot be considered a universally safe harbor locus for reliable transgene expression in vitro, and using it for transgenesis in hPSC will require careful assessment of the function of individual transgenes. {\textcopyright} 2015 The Authors.},
	doi = {10.1016/j.stemcr.2015.09.004},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84946714665\&doi=10.1016\%2fj.stemcr.2015.09.004\&partnerID=40\&md5=a12856fa562f6d898ce16ca1b0bb3c34},
	author = {Ordov{\'a}s, L. and Boon, R. and Pistoni, M. and Chen, Y. and Wolfs, E. and Guo, W. and Sambathkumar, R. and Bobis-Wozowicz, S. and Helsen, N. and Vanhove, J. and Berckmans, P. and Cai, Q. and Vanuytsel, K. and Eggermont, K. and Vanslembrouck, V. and Schmidt, B.Z. and Raitano, S. and Van Den Bosch, L. and Nahmias, Y. and Cathomen, T. and Struys, T. and Verfaillie, C.M.}
}
@article {Moussaieff2015392,
	title = {Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells},
	journal = {Cell Metabolism},
	volume = {21},
	number = {3},
	year = {2015},
	note = {cited By 504},
	pages = {392-402},
	abstract = {Loss of pluripotency is a gradual event whose initiating factors are largely unknown. Here we report the earliest metabolic changes induced during the first hours of differentiation. High-resolution NMR identified 44 metabolites and a distinct metabolic transition occurring during early differentiation. Metabolic and transcriptional analyses showed that pluripotent cells produced acetyl-CoA through glycolysis and rapidly lost this function during differentiation. Importantly, modulation of glycolysis blocked histone deacetylation and differentiation in human and mouse embryonic stem cells. Acetate, a precursor of acetyl-CoA, delayed differentiation and blocked early histone deacetylation in a dose-dependent manner. Inhibitors upstream of acetyl-CoA caused differentiation of pluripotent cells, while those downstream delayed differentiation. Our results show a metabolic switch causing a loss of histone acetylation and pluripotent state during the first hours of differentiation. Our data highlight the important role metabolism plays in pluripotency and suggest that a glycolytic switch controlling histone acetylation can release stem cells from pluripotency. {\textcopyright} 2015 Elsevier Inc.},
	doi = {10.1016/j.cmet.2015.02.002},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84924369505\&doi=10.1016\%2fj.cmet.2015.02.002\&partnerID=40\&md5=a4ea30058a0c4597f967ecb6ad53f490},
	author = {Moussaieff, A. and Rouleau, M. and Kitsberg, D. and Cohen, M. and Levy, G. and Barasch, D. and Nemirovski, A. and Shen-Orr, S. and Laevsky, I. and Amit, M. and Bomze, D. and Elena-Herrmann, B. and Scherf, T. and Nissim-Rafinia, M. and Kempa, S. and Itskovitz-Eldor, J. and Meshorer, E. and Aberdam, D. and Nahmias, Y.}
}
@article {Levy2015377,
	title = {In vitro cell culture models of hepatic steatosis},
	journal = {Methods in Molecular Biology},
	volume = {1250},
	year = {2015},
	note = {cited By 3},
	pages = {377-390},
	abstract = {The liver is the systemic hub of lipid metabolism. The excessive accumulation of lipids in hepatocytes, steatosis, is a major clinical concern, whose progressive forms lead to end-stage liver disease. Currently, animal studies are the gold standard in toxicological risk assessment. Fueled by an integration of modernomics technologies, in silico models and in vitro system optimization, a new paradigm in the basis for toxicological risk assessment is emerging away from the use of animals. In recent years, in vitro assays have been developed for the early screening of the steatogenic potential of compounds. The present chapter describes an assay for the intracellular detection of lipids, a high-content screen for the distinction between steatosis and phospholipidosis, a multiparametric high-content screen for steatogenic potential and a liver X receptor reporter cell line. {\textcopyright} Springer Science+Business Media New York 2015.},
	doi = {10.1007/978-1-4939-2074-7_29},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84959235898\&doi=10.1007\%2f978-1-4939-2074-7_29\&partnerID=40\&md5=47c17978a0a09661951d615c5b7c7602},
	author = {Levy, G. and Cohen, M. and Nahmias, Y.}
}
@article {Levy20151264,
	title = {Long-term culture and expansion of primary human hepatocytes},
	journal = {Nature Biotechnology},
	volume = {33},
	number = {12},
	year = {2015},
	note = {cited By 128},
	pages = {1264-1271},
	abstract = {Hepatocytes have a critical role in metabolism, but their study is limited by the inability to expand primary hepatocytes in vitro while maintaining proliferative capacity and metabolic function. Here we describe the oncostatin M (OSM)-dependent expansion of primary human hepatocytes by low expression of the human papilloma virus (HPV) genes E6 and E7 coupled with inhibition of epithelial-to-mesenchymal transition. We show that E6 and E7 expression upregulates the OSM receptor gp130 and that OSM stimulation induces hepatocytes to expand for up to 40 population doublings, producing 1013 to 1016 cells from a single human hepatocyte isolate. OSM removal induces differentiation into metabolically functional, polarized hepatocytes with functional bile canaliculi. Differentiated hepatocytes show transcriptional and toxicity profiles and cytochrome P450 induction similar to those of primary human hepatocytes. Replication and infectivity of hepatitis C virus (HCV) in differentiated hepatocytes are similar to those of Huh7.5.1 human hepatoma cells. These results offer a means of expanding human hepatocytes of different genetic backgrounds for research, clinical applications and pharmaceutical development. {\textcopyright} 2015 Nature America, Inc.},
	doi = {10.1038/nbt.3377},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84949784001\&doi=10.1038\%2fnbt.3377\&partnerID=40\&md5=41e826c78b54bf3cc0bbcf9e40d5d78e},
	author = {Levy, G. and Bomze, D. and Heinz, S. and Ramachandran, S.D. and Noerenberg, A. and Cohen, M. and Shibolet, O. and Sklan, E. and Braspenning, J. and Nahmias, Y.}
}
@article {Avior2015265,
	title = {Microbial-Derived Lithocholic Acid and Vitamin K2 Drive the Metabolic Maturation of Pluripotent Stem Cells-Derived and Fetal Hepatocytes},
	journal = {Hepatology},
	volume = {62},
	number = {1},
	year = {2015},
	note = {cited By 71},
	pages = {265-278},
	abstract = {The liver is the main organ responsible for the modification, clearance, and transformational toxicity of most xenobiotics owing to its abundance in cytochrome P450 (CYP450) enzymes. However, the scarcity and variability of primary hepatocytes currently limits their utility. Human pluripotent stem cells (hPSCs) represent an excellent source of differentiated hepatocytes; however, current protocols still produce fetal-like hepatocytes with limited mature function. Interestingly, fetal hepatocytes acquire mature CYP450 expression only postpartum, suggesting that nutritional cues may drive hepatic maturation. We show that vitamin K2 and lithocholic acid, a by-product of intestinal flora, activate pregnane X receptor (PXR) and subsequent CYP3A4 and CYP2C9 expression in hPSC-derived and isolated fetal hepatocytes. Differentiated cells produce albumin and apolipoprotein B100 at levels equivalent to primary human hepatocytes, while demonstrating an 8-fold induction of CYP450 activity in response to aryl hydrocarbon receptor (AhR) agonist omeprazole and a 10-fold induction in response to PXR agonist rifampicin. Flow cytometry showed that over 83\% of cells were albumin and hepatocyte nuclear factor 4 alpha (HNF4α) positive, permitting high-content screening in a 96-well plate format. Analysis of 12 compounds showed an R2 correlation of 0.94 between TC50 values obtained in stem cell-derived hepatocytes and primary cells, compared to 0.62 for HepG2 cells. Finally, stem cell-derived hepatocytes demonstrate all toxicological endpoints examined, including steatosis, apoptosis, and cholestasis, when exposed to nine known hepatotoxins. Conclusion: Our work provides fresh insights into liver development, suggesting that microbial-derived cues may drive the maturation of CYP450 enzymes postpartum. Addition of these cues results in the first functional, inducible, hPSC-derived hepatocyte for predictive toxicology. {\textcopyright} 2015 by the American Association for the Study of Liver Diseases.},
	doi = {10.1002/hep.27803},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84933181542\&doi=10.1002\%2fhep.27803\&partnerID=40\&md5=7617b9edeb504ea499772f0481aa4039},
	author = {Avior, Y. and Levy, G. and Zimerman, M. and Kitsberg, D. and Schwartz, R. and Sadeh, R. and Moussaieff, A. and Cohen, M. and Itskovitz-Eldor, J. and Nahmias, Y.}
}
@article {Ezra2015,
	title = {Microprocessor-based integration of microfluidic control for the implementation of automated sensor monitoring and multithreaded optimization algorithms},
	journal = {Biomedical Microdevices},
	volume = {17},
	number = {4},
	year = {2015},
	note = {cited By 9},
	abstract = {Microfluidic applications range from combinatorial synthesis to high throughput screening, with platforms integrating analog perfusion components, digitally controlled micro-valves and a range of sensors that demand a variety of communication protocols. Currently, discrete control units are used to regulate and monitor each component, resulting in scattered control interfaces that limit data integration and synchronization. Here, we present a microprocessor-based control unit, utilizing the MS Gadgeteer open framework that integrates all aspects of microfluidics through a high-current electronic circuit that supports and synchronizes digital and analog signals for perfusion components, pressure elements, and arbitrary sensor communication protocols using a plug-and-play interface. The control unit supports an integrated touch screen and TCP/IP interface that provides local and remote control of flow and data acquisition. To establish the ability of our control unit to integrate and synchronize complex microfluidic circuits we developed an equi-pressure combinatorial mixer. We demonstrate the generation of complex perfusion sequences, allowing the automated sampling, washing, and calibrating of an electrochemical lactate sensor continuously monitoring hepatocyte viability following exposure to the pesticide rotenone. Importantly, integration of an optical sensor allowed us to implement automated optimization protocols that require different computational challenges including: prioritized data structures in a genetic algorithm, distributed computational efforts in multiple-hill climbing searches and real-time realization of probabilistic models in simulated annealing. Our system offers a comprehensive solution for establishing optimization protocols and perfusion sequences in complex microfluidic circuits. {\textcopyright} 2015, Springer Science+Business Media New York.},
	doi = {10.1007/s10544-015-9989-y},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84938328469\&doi=10.1007\%2fs10544-015-9989-y\&partnerID=40\&md5=f25f6eef73883a3ef859ef83857555a7},
	author = {Ezra, E. and Maor, I. and Bavli, D. and Shalom, I. and Levy, G. and Prill, S. and Jaeger, M.S. and Nahmias, Y.}
}
@article {Keinan2015,
	title = {Opposing shear-induced forces dominate inertial focusing in curved channels and high Reynolds numbers},
	journal = {Applied Physics Letters},
	volume = {107},
	number = {19},
	year = {2015},
	note = {cited By 7},
	abstract = {Inertial focusing is the migration of particles in fluid toward equilibrium, where current theory predicts that shear-induced and wall-induced lift forces are balanced. First reported in 1961, this Segre-Silberberg effect is particularly useful for microfluidic isolation of cells and particles. Interestingly, recent work demonstrated particle focusing at high Reynolds numbers that cannot be explained by current theory. In this work, we show that non-monotonous velocity profiles, such as those developed in curved channels, create peripheral velocity maxima in which opposing shear-induced forces dominate over wall effects. Similarly, entry effects amplified in high Reynolds flow produce an equivalent trapping mechanism in short, straight channels. This focusing mechanism in the developing flow regime enables a 10-fold miniaturization of inertial focusing devices, while our model corrects long-standing misconceptions about the nature of mechanical forces governing inertial focusing in curved channels. {\textcopyright} 2015 AIP Publishing LLC.},
	doi = {10.1063/1.4935466},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84947474592\&doi=10.1063\%2f1.4935466\&partnerID=40\&md5=eed21ee9f6d6c3e652184be009533a8c},
	author = {Keinan, E. and Ezra, E. and Nahmias, Y.}
}
@article {Bartok20151538,
	title = {The transcription factor Cabut coordinates energy metabolism and the circadian clock in response to sugar sensing},
	journal = {EMBO Journal},
	volume = {34},
	number = {11},
	year = {2015},
	note = {cited By 42},
	pages = {1538-1553},
	abstract = {Nutrient sensing pathways adjust metabolism and physiological functions in response to food intake. For example, sugar feeding promotes lipogenesis by activating glycolytic and lipogenic genes through the Mondo/ChREBP-Mlx transcription factor complex. Concomitantly, other metabolic routes are inhibited, but the mechanisms of transcriptional repression upon sugar sensing have remained elusive. Here, we characterize cabut (cbt), a transcription factor responsible for the repressive branch of the sugar sensing transcriptional network in Drosophila. We demonstrate that cbt is rapidly induced upon sugar feeding through direct regulation by Mondo-Mlx. We found that CBT represses several metabolic targets in response to sugar feeding, including both isoforms of phosphoenolpyruvate carboxykinase (pepck). Deregulation of pepck1 (CG17725) in mlx mutants underlies imbalance of glycerol and glucose metabolism as well as developmental lethality. Furthermore, we demonstrate that cbt provides a regulatory link between nutrient sensing and the circadian clock. Specifically, we show that a subset of genes regulated by the circadian clock are also targets of CBT. Moreover, perturbation of CBT levels leads to deregulation of the circadian transcriptome and circadian behavioral patterns. Synopsis Sugar feeding in flies induces specific gene expression but also triggers a repressive branch via transcription factor Cabut. Induction of Cabut alters accumulation of the metabolic enzyme PEPCK and provides a regulatory link between nutrient sensing and the circadian clock. Transcriptional regulator Cabut is directly activated by Mondo-Mlx upon sugar feeding. Cabut represses metabolic genes upon sugar feeding. Cabut represses the expression of both isoforms of the phosphoenolpyruvate carboxykinase PEPCK. Deregulation of PEPCK1 contributes to the metabolic imbalance and lethality of mlx mutant animals. Cabut represses the cycling of metabolic target genes of the circadian clock. Sugar feeding in flies induces specific gene expression but also triggers a repressive branch via transcription factor Cabut. Induction of Cabut alters accumulation of the metabolic enzyme PEPCK and provides a regulatory link between nutrient sensing and the circadian clock. {\textcopyright} 2015 The Authors.},
	doi = {10.15252/embj.201591385},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84937191093\&doi=10.15252\%2fembj.201591385\&partnerID=40\&md5=81ead9cc7e7c99584f6a25616eaf9f33},
	author = {Bartok, O. and Teesalu, M. and Ashwall-Fluss, R. and Pandey, V. and Hanan, M. and Rovenko, B.M. and Poukkula, M. and Havula, E. and Moussaieff, A. and Vodala, S. and Nahmias, Y. and Kadener, S. and Hietakangas, V.}
}
@article {Cohen2014161,
	title = {Coculture and long-term maintenance of hepatocytes},
	journal = {Methods in Molecular Biology},
	volume = {1250},
	year = {2014},
	note = {cited By 10},
	pages = {161-173},
	abstract = {The liver is the largest internal organ in mammals, serving a wide spectrum of vital functions. Loss of liver function due to drug toxicity, progressive fatty liver disease, or viral infection is a major cause of death in the United States of America. Pharmaceutical and cosmetic toxicity screening, basic research and the development of bioartificial liver devices require long-term hepatocyte culture techniques that sustain hepatocyte morphology and function. In recent years, several techniques have been developed that can support high levels of liver-specific gene expression, metabolic function, and synthetic activity for several weeks in culture. These include the collagen double gel configuration, hepatocyte spheroids, coculture with nonparenchymal cells, and micropatterned cocultures. This chapter will cover the current status of hepatocyte culture techniques, including media formulation, oxygen supply, and heterotypic cell-cell interactions. {\textcopyright} Springer Science+Business Media New York 2015.},
	doi = {10.1007/978-1-4939-2074-7_11},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84955373146\&doi=10.1007\%2f978-1-4939-2074-7_11\&partnerID=40\&md5=f33f4b3a4812787ab1eb5a1d1619557d},
	author = {Cohen, M. and Levy, G. and Nahmias, Y.}
}
@article {Cohen2014,
	title = {Live imaging of GLUT2 glucosedependent trafficking and its inhibition in polarized epithelial cysts},
	journal = {Open Biology},
	volume = {4},
	number = {JULY},
	year = {2014},
	note = {cited By 47},
	abstract = {GLUT2 is a facilitative glucose transporter, expressed in polarized epithelial cells of the liver, intestine, kidney and pancreas, where it plays a critical role in glucose homeostasis. Togetherwith SGLT1/2, it mediates glucose absorption in metabolic epithelial tissues, where it can be translocated apically upon high glucose exposure. To track the subcellular localization and dynamics of GLUT2, we created an mCherry-hGLUT2 fusion protein and expressed it in multicellular kidney cysts, a major site of glucose reabsorption. Live imaging of GLUT2 enabled us to avoid the artefactual localization of GLUT2 in fixed cells and to confirm the apical GLUT2 model. Live cell imaging showed a rapid 15{\textpm}3 min PKC-dependent basal-to-apical translocation of GLUT2 in response to glucose stimulation and a fourfold slower basolateral translocation under starvation. These results mark the physiological importance of responding quickly to rising glucose levels. Importantly, we show that phloretin, an apple polyphenol, inhibits GLUT2 translocation in both directions, suggesting that it exerts its effect by PKC inhibition. Subcellular localization studies demonstrated that GLUT2 is endocytosed through a caveolae-dependent mechanism, and that it is at least partly recovered in Rab11A-positive recycling endosome. Our work illuminates GLUT2 dynamics, providing a platform for drug development for diabetes and hyperglycaemia. {\textcopyright} 2014 The Authors.},
	doi = {10.1098/rsob.140091},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84904797805\&doi=10.1098\%2frsob.140091\&partnerID=40\&md5=1168b1a0f55e87452aac50215b665b28},
	author = {Cohen, M. and Kitsberg, D. and Tsytkin, S. and Shulman, M. and Aroeti, B. and Nahmias, Y.}
}
@article {Zhu20141354,
	title = {Microfluidic isolation of CD34-positive skin cells enables regeneration of hair and sebaceous glands in vivo},
	journal = {Stem Cells Translational Medicine},
	volume = {3},
	number = {11},
	year = {2014},
	note = {cited By 15},
	pages = {1354-1363},
	abstract = {Skin stem cells resident in the bulge area of hair follicles and at the basal layer of the epidermis are multipotent and able to self-renew when transplanted into full-thickness defects in nude mice. Based on cell surface markers such as CD34 and thea6-integrin, skin stem cells can be extracted from tissuederived cell suspensions for engraftment using the gold standard cell separation technique of fluorescence-activated cell sorting (FACS). This paper describes an alternative separation method using microfluidic devices coated with degradable antibody-functionalized hydrogels. The microfluidic method allows direct injection of tissue digestate (no preprocessing tagging of cells is needed), is fast (45 minutes from injected sample to purified cells), and scalable. This method is used in this study to isolate CD34-positive (CD34+) cells from murine skin tissue digestate, and the functional capability of these cells is demonstrated by transplantation into nude mice using protocols developed by other groups for FACS-sorted cells. Specifically, the transplantation of microfluidic isolated CD34+ cells along with dermal and epidermal cells was observed to generate significant levels of hair follicles and sebaceous glands consistent with those observed previously with FACS-sorted cells. {\textcopyright} AlphaMed Press.},
	doi = {10.5966/sctm.2014-0098},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84908380334\&doi=10.5966\%2fsctm.2014-0098\&partnerID=40\&md5=cc99cb7404ccc36f2345e7e53ca1c98e},
	author = {Zhu, B. and Nahmias, Y. and Yarmush, M.L. and Murthy, S.K.}
}
@article {Harrison2014,
	title = {A Tetraploid Intermediate Precedes Aneuploid Formation in Yeasts Exposed to Fluconazole},
	journal = {PLoS Biology},
	volume = {12},
	number = {3},
	year = {2014},
	note = {cited By 128},
	abstract = {Candida albicans, the most prevalent human fungal pathogen, is generally diploid. However, 50\% of isolates that are resistant to fluconazole (FLC), the most widely used antifungal, are aneuploid and some aneuploidies can confer FLC resistance. To ask if FLC exposure causes or only selects for aneuploidy, we analyzed diploid strains during exposure to FLC using flow cytometry and epifluorescence microscopy. FLC exposure caused a consistent deviation from normal cell cycle regulation: nuclear and spindle cycles initiated prior to bud emergence, leading to "trimeras," three connected cells composed of a mother, daughter, and granddaughter bud. Initially binucleate, trimeras underwent coordinated nuclear division yielding four daughter nuclei, two of which underwent mitotic collapse to form a tetraploid cell with extra spindle components. In subsequent cell cycles, the abnormal number of spindles resulted in unequal DNA segregation and viable aneuploid progeny. The process of aneuploid formation in C. albicans is highly reminiscent of early stages in human tumorigenesis in that aneuploidy arises through a tetraploid intermediate and subsequent unequal DNA segregation driven by multiple spindles coupled with a subsequent selective advantage conferred by at least some aneuploidies during growth under stress. Finally, trimera formation was detected in response to other azole antifungals, in related Candida species, and in an in vivo model for Candida infection, suggesting that aneuploids arise due to azole treatment of several pathogenic yeasts and that this can occur during the infection process. {\textcopyright} 2014 Harrison et al.},
	doi = {10.1371/journal.pbio.1001815},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84898956673\&doi=10.1371\%2fjournal.pbio.1001815\&partnerID=40\&md5=d157d88a59e29be330540de7c682915b},
	author = {Harrison, B.D. and Hashemi, J. and Bibi, M. and Pulver, R. and Bavli, D. and Nahmias, Y. and Wellington, M. and Sapiro, G. and Berman, J.}
}
@article {Uzi2013495,
	title = {CHOP is a critical regulator of acetaminophen-induced hepatotoxicity},
	journal = {Journal of Hepatology},
	volume = {59},
	number = {3},
	year = {2013},
	note = {cited By 155},
	pages = {495-503},
	abstract = {Background \& Aims The liver is a major site of drug metabolism and elimination and as such is susceptible to drug toxicity. Drug induced liver injury is a leading cause of acute liver injury, of which acetaminophen (APAP) is the most frequent causative agent. APAP toxicity is initiated by its toxic metabolite NAPQI. However, downstream mechanisms underlying APAP induced cell death are still unclear. Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have recently emerged as major regulators of metabolic homeostasis. UPR regulation of the transcription repressor CHOP promotes cell death. We analyzed the role of UPR and CHOP in mediating APAP hepatotoxicity. Methods A toxic dose of APAP was orally administered to wild type (wt) and CHOP knockout (KO) mice and damage mechanisms were assessed. Results CHOP KO mice were protected from APAP induced damage and exhibited decreased liver necrosis and increased survival. APAP metabolism in CHOP KO mice was undisturbed and glutathione was depleted at similar kinetics to wt. ER stress and UPR activation were overtly seen 12 h following APAP administration, a time that coincided with strong upregulation of CHOP. Remarkably, CHOP KO but not wt mice exhibited hepatocyte proliferation at sites of necrosis. In vitro, large T immortalized CHOP KO hepatocytes were protected from APAP toxicity in comparison to wt control cells. Conclusions CHOP upregulation during APAP induced liver injury compromises hepatocyte survival in various mechanisms, in part by curtailing the regeneration phase following liver damage. Thus, CHOP plays a pro-damage role in response to APAP intoxication. {\textcopyright} 2013 European Association for the Study of the Liver.},
	doi = {10.1016/j.jhep.2013.04.024},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84882855544\&doi=10.1016\%2fj.jhep.2013.04.024\&partnerID=40\&md5=9ff8e3e38bbafeadc688d03a0fbd80be},
	author = {Uzi, D. and Barda, L. and Scaiewicz, V. and Mills, M. and Mueller, T. and Gonzalez-Rodriguez, A. and Valverde, A.M. and Iwawaki, T. and Nahmias, Y. and Xavier, R. and Chung, R.T. and Tirosh, B. and Shibolet, O.}
}
@article {Roelandt2013199,
	title = {Erratum: Human pluripotent stem cell-derived hepatocytes support complete replication of hepatitis C virus (Journal of Hepatology (2012) 57 (246-251))},
	journal = {Journal of Hepatology},
	volume = {58},
	number = {1},
	year = {2013},
	note = {cited By 0},
	pages = {199-200},
	doi = {10.1016/j.jhep.2012.08.021},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84871242530\&doi=10.1016\%2fj.jhep.2012.08.021\&partnerID=40\&md5=b1d9dd18e5eaca79409e80adbb14c81b},
	author = {Roelandt, P. and Obeid, S. and Paeshuyse, J. and Vanhove, J. and Van Lommel, A. and Nahmias, Y. and Nevens, F. and Neyts, J. and Verfaillie, C.M.}
}
@article {Avior2013831,
	title = {Flavonoids as dietary regulators of nuclear receptor activity},
	journal = {Food and Function},
	volume = {4},
	number = {6},
	year = {2013},
	note = {cited By 49},
	pages = {831-844},
	abstract = {Metabolic diseases such as obesity, type II diabetes, and dyslipidemia are a rising cause of mortality worldwide. The progression of many metabolic diseases is fundamentally regulated on the transcriptional level by a family of ligand-activated transcription factors, called nuclear receptors, which detect and respond to metabolic changes. Their role in maintaining metabolic homeostasis makes nuclear receptors an important pharmaceutical and dietary target. This review will present the growing evidence that flavonoids, natural secondary plant metabolites, are important regulators of nuclear receptor activity. Structural similarities between flavonoids and cholesterol derivatives combined with the promiscuous nature of most nuclear receptors provide a wealth of possibilities for pharmaceutical and dietary modulation of metabolism. While the challenges of bringing flavonoid-derived therapeutics to the market are significant, we consider this rapidly growing field to be an essential aspect of the functional food initiative and an important mine for pharmaceutical compounds. {\textcopyright} The Royal Society of Chemistry.},
	doi = {10.1039/c3fo60063g},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84878704614\&doi=10.1039\%2fc3fo60063g\&partnerID=40\&md5=749f6e9dcf2d7d0ca01db9a12edc3f7f},
	author = {Avior, Y. and Bomze, D. and Ramon, O. and Nahmias, Y.}
}
@article {Keinan2013,
	title = {Frame rate free image velocimetry for microfluidic devices},
	journal = {Applied Physics Letters},
	volume = {103},
	number = {6},
	year = {2013},
	note = {cited By 6},
	abstract = {Here, we introduce Streamline Image Velocimetry, a method to derive fluid velocity fields in fully developed laminar flow from long-exposure images of streamlines. Streamlines confine streamtubes, in which the volumetric flow is constant for incompressible fluid. Using an explicit analytical solution as a boundary condition, velocity fields and emerging properties such as shear force and pressure can be quantified throughout. Numerical and experimental validations show a high correlation between anticipated and measured results, with R2 \&gt; 0.91. We report spatial resolution of 2 μm in a flow rate of 0.15 m/s, resolution that can only be achieved with 75 kHz frame rate in traditional particle tracking velocimetry. {\textcopyright} 2013 AIP Publishing LLC.},
	doi = {10.1063/1.4818142},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84881631478\&doi=10.1063\%2f1.4818142\&partnerID=40\&md5=4a975e07445dd092a2dd4296e3ac7c3b},
	author = {Keinan, E. and Ezra, E. and Nahmias, Y.}
}
@article {Shulman2013287,
	title = {Long-term culture and coculture of primary rat and human hepatocytes},
	journal = {Methods in Molecular Biology},
	volume = {945},
	year = {2013},
	note = {cited By 94},
	pages = {287-302},
	abstract = {The liver is the largest internal organ in mammals, serving a wide spectrum of vital functions. Loss of liver function due to drug toxicity or viral infection is a major cause of death in the United States. The development of Bioartificial Liver (BAL) devices and the demand for pharmaceutical and cosmetic toxicity screening require the development of long-term hepatocyte culture techniques. However, primary hepatocytes rapidly lose their cuboidal morphology and liver-specific functions over a few days in culture. Accumulation of stress fibers, loss of metabolic function, and cell death are known phenomena. In recent years, several techniques were developed that can support high levels of liver-specific gene expression, metabolic and synthetic function for several weeks in culture. These include the collagen double-gel configuration, hepatocyte spheroids, coculture with endothelial cells, and micropatterned cocultures with 3T3-J2 fibroblasts. This chapter covers the current status of hepatocyte culture techniques, including: hepatocyte isolation, media formulation, oxygen supply, heterotypic cell-cell interactions, and basic functional assays. {\textcopyright} 2013 Springer Science+Business Media, LLC.},
	doi = {10.1007/978-1-62703-125-7_17},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84870558580\&doi=10.1007\%2f978-1-62703-125-7_17\&partnerID=40\&md5=3a618117c614d830bd225e8eb6332564},
	author = {Shulman, M. and Nahmias, Y.}
}
@article {Zhu2013765,
	title = {Microfluidic enrichment of mouse epidermal stem cells and validation of stem cell proliferation in vitro},
	journal = {Tissue Engineering - Part C: Methods},
	volume = {19},
	number = {10},
	year = {2013},
	note = {cited By 15},
	pages = {765-773},
	abstract = {Bulge stem cells reside in the lowest permanent portion of hair follicles and are responsible for the renewal of these follicles along with the repair of the epidermis during wound healing. These cells are identified by surface expression of CD34 and the α6-integrin. When CD34 and α6 double-positive cells are isolated and implanted into murine skin, they give rise to epidermis and hair follicle structures. The current gold standard for isolation of these stem cells is fluorescence-activated cell sorting (FACS) based on cell surface markers. Here, we describe an alternative method for CD34 bulge stem cell isolation: a microfluidic platform that captures stem cells based on cell surface markers. This method is relatively fast, requiring 30 min of time from direct introduction of murine skin tissue digestate into a two-stage microfluidic device to one-pass elution of CD34+ enriched cells with a purity of 55.8\%{\textpm}5.1\%. The recovered cells remain viable and formed colonies with characteristic morphologies. When grown in culture, enriched cells contain a larger α6+ population than un-enriched cells. {\textcopyright} 2013, Mary Ann Liebert, Inc.},
	doi = {10.1089/ten.tec.2012.0638},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84883037125\&doi=10.1089\%2ften.tec.2012.0638\&partnerID=40\&md5=b8b8776149965739eb85d5c16777d3e7},
	author = {Zhu, B. and Smith, J. and Yarmush, M.L. and Nahmias, Y. and Kirby, B.J. and Murthy, S.K.}
}
@article {Ezra2013474,
	title = {Non-dimensional analysis of retinal microaneurysms: Critical threshold for treatment},
	journal = {Integrative Biology (United Kingdom)},
	volume = {5},
	number = {3},
	year = {2013},
	note = {cited By 22},
	pages = {474-480},
	abstract = {Fluid dynamics play a fundamental role in the development of diabetic retinopathy, one of the leading causes of blindness in the Western world, affecting over 4 million people in the US alone. The disease is defined by microaneurysms, local expansions of capillaries that disturb the hemodynamic forces experienced by the endothelium leading to dysfunction, leakage and edema. Here we present a method to identify microaneurysms with a high risk of leakage based on a critical ratio of microaneurysm to vessel diameter. We derive this non-dimensional parameter from an analytical solution and generalize it using experimentally validated numerical methods. We show that this non-dimensional parameter defines the shear force experienced by endothelial cells, below which endothelial dysfunction is evident in vivo. Our results demonstrate the involvement of vWF in diabetic retinopathy, and explain a perceived disconnect between microaneurysm size and leakage. This method will allow experts to treat microaneurysms poising a high-risk of leakage, prior to edema, minimizing damage and saving vision. {\textcopyright} 2013 The Royal Society of Chemistry.},
	doi = {10.1039/c3ib20259c},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84874810411\&doi=10.1039\%2fc3ib20259c\&partnerID=40\&md5=ad81313769a443f9260456a7f715e8a5},
	author = {Ezra, E. and Keinan, E. and Mandel, Y. and Boulton, M.E. and Nahmias, Y.}
}
@article {Bao2013299,
	title = {Serum-free medium and mesenchymal stromal cells enhance functionality and stabilize integrity of rat hepatocyte spheroids},
	journal = {Cell Transplantation},
	volume = {22},
	number = {2},
	year = {2013},
	note = {cited By 28},
	pages = {299-308},
	abstract = {Long-term culture of hepatocyte spheroids with high ammonia clearance is valuable for therapeutic applications, especially the bioartificial liver. However, the optimal conditions are not well studied. We hypothesized that liver urea cycle enzymes can be induced by high protein diet and maintain on a higher expression level in rat hepatocyte spheroids by serum-free medium (SFM) culture and coculture with mesenchymal stromal cells (MSCs). Rats were feed normal protein diet (NPD) or high protein diet (HPD) for 7 days before liver digestion and isolation of hepatocytes. Hepatocyte spheroids were formed and maintained in a rocked suspension culture with or without MSCs in SFM or 10\% serum-containing medium (SCM). Spheroid viability, kinetics of spheroid formation, hepatic functions, gene expression, and biochemical activities of rat hepatocyte spheroids were tested over 14 days of culture. We observed that urea cycle enzymes of hepatocyte spheroids can be induced by high protein diet. SFM and MSCs enhanced ammonia clearance and ureagenesis and stabilized integrity of hepatocyte spheroids compared to control conditions over 14 days. Hepatocytes from high protein diet-fed rats formed spheroids and maintained a high level of ammonia detoxification for over 14 days in a novel SFM. Hepatic functionality and spheroid integrity were further stabilized by coculture of hepatocytes with MSCs in the spheroid microenvironment. These findings have direct application to development of the spheroid reservoir bioartificial liver. {\textcopyright} 2013 Cognizant Comm. Corp.},
	doi = {10.3727/096368912X656054},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84874376590\&doi=10.3727\%2f096368912X656054\&partnerID=40\&md5=68fdfd8280305594c055a97aaadc754d},
	author = {Bao, J. and Fisher, J.E. and Lillegard, J.B. and Wang, W. and Amiot, B. and Yu, Y. and Dietz, A.B. and Nahmias, Y. and Nyberg, S.L.}
}
@article {Spokoini2012738,
	title = {Confinement to Organelle-Associated Inclusion Structures Mediates Asymmetric Inheritance of Aggregated Protein in Budding Yeast},
	journal = {Cell Reports},
	volume = {2},
	number = {4},
	year = {2012},
	note = {cited By 159},
	pages = {738-747},
	abstract = {The division of the S. cerevisiae budding yeast, which produces one mother cell and one daughter cell, is asymmetric with respect to aging. Remarkably, the asymmetry of yeast aging coincides with asymmetric inheritance of damaged and aggregated proteins by the mother cell. Here, we show that misfolded proteins are retained in the mother cell by being sequestered in juxtanuclear quality control compartment (JUNQ) and insoluble protein deposit (IPOD) inclusions, which are attached to organelles. Upon exposure to stress, misfolded proteins accumulate in stress foci that must be disaggregated by Hsp104 in order to be degraded or processed to JUNQ and IPOD. Cells that fail to deliver aggregates to an inclusion pass on aggregates to subsequent generations. The ability of cells to asymmetrically segregate aggregates during division has become an increasingly fascinating topic in the field of aggregation and aging. In this study, Kaganovich and colleagues advance our cellular understanding of aging by showing that confinement of aggregated proteins is precisely regulated by compartmentalization in inclusions and is key to preventing generational transfer of aggregated proteins. The authors provide mechanistic insight that enables control of asymmetric aggregate inheritance. {\textcopyright} 2012 The Authors.},
	doi = {10.1016/j.celrep.2012.08.024},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84868149498\&doi=10.1016\%2fj.celrep.2012.08.024\&partnerID=40\&md5=0faadae4112a59e539ada615214e2d61},
	author = {Spokoini, R. and Moldavski, O. and Nahmias, Y. and England, J. and Schuldiner, M. and Kaganovich, D.}
}
@article {Roelandt2012246,
	title = {Human pluripotent stem cell-derived hepatocytes support complete replication of hepatitis C virus},
	journal = {Journal of Hepatology},
	volume = {57},
	number = {2},
	year = {2012},
	note = {cited By 92},
	pages = {246-251},
	abstract = {Background \& Aims: Worldwide, about 180 million people are chronically infected with the hepatitis C virus (HCV). Current in vitro culture systems for HCV depend chiefly on human hepatoma cell lines. Although primary human hepatocytes support HCV infection in vitro, and immunodeficient mice repopulated with human hepatocytes support HCV infection in vivo, these models are limited because of shortage of human livers to isolate hepatocytes. Therefore, there is significant interest in the establishment from of a HCV culture system in human stem cell-derived hepatocyte-like cells. Methods: Human embryonic stem cell (hESC)-derived hepatocytes were infected with HCV in the presence or absence of direct acting antivirals. After inoculation, replication of HCV was analyzed extensively. Results: We demonstrate that hESC-derived hepatocytes can be infected with the HCV JFH1 genotype 2a, resulting in the production of viral RNA in the stem cell progeny. Viral replication is inhibited by a non-nucleoside HCV polymerase-inhibitor (HCV-796), a cyclophilin binding molecule (Debio 025-Alisporivir) and the protease inhibitor VX-950 (Telaprevir). Stem cell-derived hepatocytes produced, for more than 10 days, the HCV core protein as well as virions that were capable of re-infecting hepatoma cells. Conclusions: Hepatocytes derived from hESC support the complete HCV replication cycle (including the production of infectious virus), and viral replication in these cells is efficiently inhibited by selective inhibitors of HCV replication. {\textcopyright} 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.},
	doi = {10.1016/j.jhep.2012.03.030},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84863982020\&doi=10.1016\%2fj.jhep.2012.03.030\&partnerID=40\&md5=c9dd1d3c569f8b3298b0e34f058891e9},
	author = {Roelandt, P. and Obeid, S. and Paeshuyse, J. and Vanhove, J. and Van Lommel, A. and Nahmias, Y. and Nevens, F. and Neyts, J. and Verfaillie, C.M.}
}
@article {Nevo-Yassaf20126491,
	title = {Role for TBC1D20 and Rab1 in hepatitis C virus replication via interaction with lipid droplet-bound nonstructural protein 5A},
	journal = {Journal of Virology},
	volume = {86},
	number = {12},
	year = {2012},
	note = {cited By 50},
	pages = {6491-6502},
	abstract = {Replication and assembly of hepatitis C virus (HCV) depend on the host{\textquoteright}s secretory and lipid-biosynthetic machinery. Viral replication occurs on endoplasmic reticulum (ER)-derived modified membranes, while viral assembly is thought to occur on lipid droplets (LDs). A physical association and coordination between the viral replication and assembly complexes are prerequisites for efficient viral production. Nonstructural protein 5A (NS5A), which localizes both to the ER and LDs, is an ideal candidate for this function. Here, the interaction of NS5A with host cell membranes and binding partners was characterized in living cells. The binding of NS5A to LDs is apparently irreversible, both in HCV-infected cells and when ectopically expressed. In HCV-infected cells, NS5A fluorescence was observed around the LDs and in perinuclear structures that were incorporated into a highly immobile platform superimposed over the ER membrane. Moreover, TBC1D20 and its cognate GTPase Rab1 are recruited by NS5A to LDs. The NS5A-TBC1D20 interaction was shown to be essential for the viral life cycle. In cells, expression of the Rab1 dominant negative (Rab1DN) GTPase mutant abolished steady-state LDs. In infected cells, Rab1DN induced the elimination of NS5A from viral replication sites. Our results demonstrate the significance of the localization of NS5A to LDs and support a model whereby its interaction with TBC1D20 and Rab1 affects lipid droplet metabolism to promote the viral life cycle. {\textcopyright} 2012, American Society for Microbiology.},
	doi = {10.1128/JVI.00496-12},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84864007958\&doi=10.1128\%2fJVI.00496-12\&partnerID=40\&md5=cbe8b14de7c28d85a0bd8ae36b6babd4},
	author = {Nevo-Yassaf, I. and Yaffe, Y. and Asher, M. and Ravid, O. and Eizenberg, S. and Henis, Y.I. and Nahmias, Y. and Hirschberg, K. and Sklan, E.H.}
}
@article {Shulman2011,
	title = {Enhancement of naringenin bioavailability by complexation with hydroxypropoyl-β-cyclodextrin},
	journal = {PLoS ONE},
	volume = {6},
	number = {4},
	year = {2011},
	note = {cited By 154},
	abstract = {The abundant flavonoid aglycone, naringenin, which is responsible for the bitter taste in grapefruits, has been shown to possess hypolipidemic and anti-inflammatory effects both in vitro and in vivo. Recently, our group demonstrated that naringenin inhibits hepatitis C virus (HCV) production, while others demonstrated its potential in the treatment of hyperlipidemia and diabetes. However, naringenin suffers from low oral bioavailability critically limiting its clinical potential. In this study, we demonstrate that the solubility of naringenin is enhanced by complexation with β-cyclodextrin, an FDA approved excipient. Hydroxypropoyl-β-cyclodextrin (HPβCD), specifically, increased the solubility of naringenin by over 400-fold, and its transport across a Caco-2 model of the gut epithelium by 11-fold. Complexation of naringenin with HPβCD increased its plasma concentrations when fed to rats, with AUC values increasing by 7.4-fold and Cmax increasing 14.6-fold. Moreover, when the complex was administered just prior to a meal it decreased VLDL levels by 42\% and increased the rate of glucose clearance by 64\% compared to naringenin alone. These effects correlated with increased expression of the PPAR co-activator, PGC1α in both liver and skeletal muscle. Histology and blood chemistry analysis indicated this route of administration was not associated with damage to the intestine, kidney, or liver. These results suggest that the complexation of naringenin with HPβCD is a viable option for the oral delivery of naringenin as a therapeutic entity with applications in the treatment of dyslipidemia, diabetes, and HCV infection. {\textcopyright} 2011 Shulman et al.},
	doi = {10.1371/journal.pone.0018033},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-79953748950\&doi=10.1371\%2fjournal.pone.0018033\&partnerID=40\&md5=bda9aba4a076379ad0c2544079f1ab94},
	author = {Shulman, M. and Cohen, M. and Soto-Gutierrez, A. and Yagi, H. and Wang, H. and Goldwasser, J. and Lee-Parsons, C.W. and Benny-Ratsaby, O. and Yarmush, M.L. and Nahmias, Y.}
}
@article {Merquiol2011,
	title = {HCV causes chronic endoplasmic reticulum stress leading to adaptation and interference with the unfolded protein response},
	journal = {PLoS ONE},
	volume = {6},
	number = {9},
	year = {2011},
	note = {cited By 95},
	abstract = {Background: The endoplasmic reticulum (ER) is the cellular site for protein folding. ER stress occurs when protein folding capacity is exceeded. This stress induces a cyto-protective signaling cascades termed the unfolded protein response (UPR) aimed at restoring homeostasis. While acute ER stress is lethal, chronic sub-lethal ER stress causes cells to adapt by attenuation of UPR activation. Hepatitis C virus (HCV), a major human pathogen, was shown to cause ER stress, however it is unclear whether HCV induces chronic ER stress, and if so whether adaptation mechanisms are initiated. We wanted to characterize the kinetics of HCV-induced ER stress during infection and assess adaptation mechanisms and their significance. Methods and Findings: The HuH7.5.1 cellular system and HCV-transgenic (HCV-Tg) mice were used to characterize HCV-induced ER stress/UPR pathway activation and adaptation. HCV induced a wave of acute ER stress peaking 2-5 days post-infection, which rapidly subsided thereafter. UPR pathways were activated including IRE1 and EIF2α phosphorylation, ATF6 cleavage and XBP-1 splicing. Downstream target genes including GADD34, ERdj4, p58ipk, ATF3 and ATF4 were upregulated. CHOP, a UPR regulated protein was activated and translocated to the nucleus. Remarkably, UPR activity did not return to baseline but remained elevated for up to 14 days post infection suggesting that chronic ER stress is induced. At this time, cells adapted to ER stress and were less responsive to further drug-induced ER stress. Similar results were obtained in HCV-Tg mice. Suppression of HCV by Interferon-α 2a treatment, restored UPR responsiveness to ER stress tolerant cells. Conclusions: Our study shows, for the first time, that HCV induces adaptation to chronic ER stress which was reversed upon viral suppression. These finding represent a novel viral mechanism to manipulate cellular response pathways. {\textcopyright} 2011 Merquiol et al.},
	doi = {10.1371/journal.pone.0024660},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-80052899192\&doi=10.1371\%2fjournal.pone.0024660\&partnerID=40\&md5=0aa97c0fe41e766ee1be6c247ae9371c},
	author = {Merquiol, E. and Uzi, D. and Mueller, T. and Goldenberg, D. and Nahmias, Y. and Xavier, R.J. and Tirosh, B. and Shibolet, O.}
}
@article {Izamis2011839,
	title = {In situ metabolic flux analysis to quantify the liver metabolic response to experimental burn injury},
	journal = {Biotechnology and Bioengineering},
	volume = {108},
	number = {4},
	year = {2011},
	note = {cited By 24},
	pages = {839-852},
	abstract = {Trauma such as burns induces a hypermetabolic response associated with altered central carbon and nitrogen metabolism. The liver plays a key role in these metabolic changes; however, studies to date have evaluated the metabolic state of liver using ex vivo perfusions or isotope labeling techniques targeted to specific pathways. Herein, we developed a unique mass balance approach to characterize the metabolic state of the liver in situ, and used it to quantify the metabolic changes to experimental burn injury in rats. Rats received a sham (control uninjured), 20\% or 40\% total body surface area (TBSA) scald burn, and were allowed to develop a hypermetabolic response. One day prior to evaluation, all animals were fasted to deplete glycogen stores. Four days post-burn, blood flow rates in major vessels of the liver were measured, and blood samples harvested. We combined measurements of metabolite concentrations and flow rates in the major vessels entering and leaving the liver with a steady-state mass balance model to generate a quantitative picture of the metabolic state of liver. The main findings were: (1) Sham-burned animals exhibited a gluconeogenic pattern, consistent with the fasted state; (2) the 20\% TBSA burn inhibited gluconeogenesis and exhibited glycolytic-like features with very few other significant changes; (3) the 40\% TBSA burn, by contrast, further enhanced gluconeogenesis and also increased amino acid extraction, urea cycle reactions, and several reactions involved in oxidative phosphorylation. These results suggest that increasing the severity of injury does not lead to a simple dose-dependent metabolic response, but rather leads to qualitatively different responses. {\textcopyright} 2010 Wiley Periodicals, Inc.},
	doi = {10.1002/bit.22998},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-79952586611\&doi=10.1002\%2fbit.22998\&partnerID=40\&md5=0134741c98bc67e45a9f29049182f7c5},
	author = {Izamis, M.-L. and Sharma, N.S. and Uygun, B. and Bieganski, R. and Saeidi, N. and Nahmias, Y. and Uygun, K. and Yarmush, M.L. and Berthiaume, F.}
}
@article {Goldwasser2011963,
	title = {Naringenin inhibits the assembly and long-term production of infectious hepatitis C virus particles through a PPAR-mediated mechanism},
	journal = {Journal of Hepatology},
	volume = {55},
	number = {5},
	year = {2011},
	note = {cited By 128},
	pages = {963-971},
	abstract = {Background \& Aims: Hepatitis C virus (HCV) infection affects 3\% of the world population and is the leading cause of chronic liver disease worldwide. Current standard of care is effective in only 50\% of the patients, poorly tolerated, and associated with significant side effects and viral resistance. Recently, our group and others demonstrated that the HCV lifecycle is critically dependent on host lipid metabolism and that its production is metabolically modulated. Methods: The JFH1/Huh7.5.1 full lifecycle model of HCV was used to study the antiviral effects of naringenin on viral replication, assembly, and production. Activation of PPARα was elucidated using GAL4-PPARα fusion reporters, PPRE reporters, qRT-PCR, and metabolic studies. Metabolic results were confirmed in primary human hepatocytes. Results: We demonstrate that the grapefruit flavonoid naringenin dose-dependently inhibits HCV production without affecting intracellular levels of the viral RNA or protein. We show that naringenin blocks the assembly of intracellular infectious viral particles, upstream of viral egress. This antiviral effect is mediated in part by the activation of PPARα, leading to a decrease in VLDL production without causing hepatic lipid accumulation in Huh7.5.1 cells and primary human hepatocytes. Long-term treatment with naringenin leads to a rapid 1.4 log reduction in HCV, similar to 1000 U of interferon. During the washout period, HCV levels returned to normal, consistent with our proposed mechanism of action. Conclusions: The data demonstrates that naringenin is a non-toxic assembly inhibitor of HCV and that other PPARα agonists play a similar role in blocking viral production. The combination of naringenin with STAT-C agents could potentially bring a rapid reduction in HCV levels during the early treatment phase, an outcome associated with sustained virological response. {\textcopyright} 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.},
	doi = {10.1016/j.jhep.2011.02.011},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-80054728029\&doi=10.1016\%2fj.jhep.2011.02.011\&partnerID=40\&md5=b14436609bb50d976801c6bae3afb0d2},
	author = {Goldwasser, J. and Cohen, P.Y. and Lin, W. and Kitsberg, D. and Balaguer, P. and Polyak, S.J. and Chung, R.T. and Yarmush, M.L. and Nahmias, Y.}
}
@article {Koria20111034,
	title = {Self-assembling elastin-like peptides growth factor chimeric nanoparticles for the treatment of chronic wounds},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {108},
	number = {3},
	year = {2011},
	note = {cited By 158},
	pages = {1034-1039},
	abstract = {Chronic wounds are associated with poor epidermal and dermal remodeling. Previous work has shown the efficacy of keratinocyte growth factor (KGF) in reepithelialization and elastin in dermal wound healing. Here we demonstrate the fabrication of a fusion protein comprising of elastin-like peptides and KGF. This fusion protein retains the performance characteristics of KGF and elastin as evidenced by its enhancement of keratinocyte and fibroblast proliferation. It also preserved the characteristic elastin-like peptides inverse phase transitioning allowing the recombinant protein to be expressed in bacterial hosts (such as Escherichia coli) and purified rapidly and easily using inverse temperature cycling. The fusion protein self-assembled into nanoparticles at physiological temperatures. Whenapplied to full thickness,woundsin Lepr db diabetic mice these particles enhanced reepithelialization and granulation, by 2- and 3-fold respectively, when compared to the controls. The data strongly suggests that these self-assembled nanoparticles may be beneficial in the treatment of chronic wounds resulting from diabetes or other underlying circulatory conditions.},
	doi = {10.1073/pnas.1009881108},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-79551645570\&doi=10.1073\%2fpnas.1009881108\&partnerID=40\&md5=b0751772cab0c7d79a58b7d106d0a876},
	author = {Koria, P. and Yagi, H. and Kitagawa, Y. and Megeed, Z. and Nahmias, Y. and Sheridan, R. and Yarmush, M.L.}
}
@article {Soto-Gutierrez2010815,
	title = {Engineering of an hepatic organoid to develop liver assist devices},
	journal = {Cell Transplantation},
	volume = {19},
	number = {6-7},
	year = {2010},
	note = {cited By 44},
	pages = {815-822},
	abstract = {Cell-based technologies to support/restore liver function represent one of the most promising opportunities in the treatment of acute liver failure. However, the understanding of the constituent cell types that interact to achieve liver-specific structure and function has not been achieved in the development of liver assist devices (LADs). Here we show that hepatocytes migrated toward and adhered and formed sinusoids-like structures in conjunction with liver nonparenchymal cells, and that this liver organoid formed sophisticated tissue after 7 days in an implanted LAD in rodents. Hepatocytes only or in combination with human nonparenchymal liver cell lines (endothelial, cholangiocytes, and stellate cells) were cultured in Matrigel. Ultrastructural analysis showed that the hepatocyte-decorated endothelial vascular structures resemble in vivo sinusoids containing plate-like structures, bile canaliculi, and lumen. The sinusoid-like structures retained albumin secretion and drug metabolism capabilities. In addition, LADs containing cocultures of human liver nonparenchymal cells were transplanted in animals for a week; the liver tissue formed sophisticated structures resembling the liver. These results demonstrate the importance of nonparenchymal cells in the cellular composition of LADs. The novelty of the culture{\textquoteright}s sinusoid-like organization and function strongly support the integration of liver nonparenchymal units into hepatocyte coculture-based LADs as a potential destination therapy for liver failure. Copyright {\textcopyright} 2010 Cognizant Comm. Corp.},
	doi = {10.3727/096368910X508933},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-77958560067\&doi=10.3727\%2f096368910X508933\&partnerID=40\&md5=bed2a83c50de202aa3456c621ee701e2},
	author = {Soto-Gutierrez, A. and Navarro-Alvarez, N. and Yagi, H. and Nahmias, Y. and Yarmush, M.L. and Kobayashi, N.}
}
@article {VanPoll2010783,
	title = {Human immune reactivity against liver sinusoidal endothelial cells from GalTα(1,3)GalT-deficient pigs},
	journal = {Cell Transplantation},
	volume = {19},
	number = {6-7},
	year = {2010},
	note = {cited By 11},
	pages = {783-789},
	abstract = {Elimination of galactose-α(1,3)galactose (Gal) expression in pig organs has been previously shown to prevent hyperacute xenograft rejection. However, naturally present antibodies to non-Gal epitopes activate endothelial cells, leading to acute humoral xenograft rejection. Still, it is unknown whether xenogeneic pig liver sinusoidal endothelial cells (LSECs) from α(1,3)galactosyltransferase (GalT)-deficient pigs are damaged by antibody and complement-mediated mechanisms. The present study examined the xeno-antibody response of LSECs from GalT-deficient and wild pigs. Isolated LSEC from wild-type and GalT pigs were expose to human and baboon sera; IgM and IgG binding was analyzed by flow cytometry. Complement activation (C3a and CH50) was quantified in vitro from serum-exposed LSEC cultures using Enzyme-Linked Immuno-Sorbent assay (ELISA). Levels of complement-activated cytotoxicity (CAC) were also determined by a fluorescent Live-Dead Assay and by the quantification of LDH release. IgM binding to GalT knockout (KO) LSECs was significantly lower (80\% human and 87\% baboon) compare to wild-type pig LSEC. IgG binding was low in all groups. Moreover, complement activation (C3a and CH50) levels released following exposure to human or baboon sera were importantly reduced (42\% human and 52\% baboon), CAC in GalT KO LSECs was reduced by 60\% in human serum and by 72\% in baboon serum when compared to wildtype LSECs, and LDH release levels were reduced by 37\% and 57\%, respectively. LSECs from GalT KO pigs exhibit a significant protection to humoral-induced cell damage compared to LSECs from wild pigs when exposed to human serum. Although insufficient to inhibit xenogeneic reactivity completely, transgenic GalT KO expression on pig livers might contribute to a successful application of clinical xenotransplantation in combination with other protective strategies. Copyright {\textcopyright} 2010 Cognizant Comm. Corp.},
	doi = {10.3727/096368910X508898},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-77958524721\&doi=10.3727\%2f096368910X508898\&partnerID=40\&md5=224ba0e16aca2fdd8559678f4c9f7c5f},
	author = {Van Poll, D. and Nahmias, Y. and Soto-Gutierrez, A. and Ghasemi, M. and Yagi, H. and Kobayashi, N. and Yarmush, M.L. and Hertl, M.}
}
@article {Wagoner20101912,
	title = {Multiple effects of silymarin on the hepatitis C virus lifecycle},
	journal = {Hepatology},
	volume = {51},
	number = {6},
	year = {2010},
	note = {cited By 202},
	pages = {1912-1921},
	abstract = {Silymarin, an extract from milk thistle (Silybum marianum), and its purified flavonolignans have been recently shown to inhibit hepatitis C virus (HCV) infection, both in vitro and in vivo. In the current study, we further characterized silymarin{\textquoteright}s antiviral actions. Silymarin had antiviral effects against hepatitis C virus cell culture (HCVcc) infection that included inhibition of virus entry, RNA and protein expression, and infectious virus production. Silymarin did not block HCVcc binding to cells but inhibited the entry of several viral pseudoparticles (pp), and fusion of HCVpp with liposomes. Silymarin but not silibinin inhibited genotype 2a NS5B RNA-dependent RNA polymerase (RdRp) activity at concentrations 5 to 10 times higher than required for anti-HCVcc effects. Furthermore, silymarin had inefficient activity on the genotype 1b BK and four 1b RDRPs derived from HCV-infected patients. Moreover, silymarin did not inhibit HCV replication in five independent genotype 1a, 1b, and 2a replicon cell lines that did not produce infectious virus. Silymarin inhibited microsomal triglyceride transfer protein activity, apolipoprotein B secretion, and infectious virion production into culture supernatants. Silymarin also blocked cell-to-cell spread of virus. Conclusion: Although inhibition of in vitro NS5B polymerase activity is demonstrable, the mechanisms of silymarin{\textquoteright}s antiviral action appear to include blocking of virus entry and transmission, possibly by targeting the host cell. Copyright {\textcopyright} 2010 by the American Association for the Study of Liver Diseases.},
	doi = {10.1002/hep.23587},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-77950530324\&doi=10.1002\%2fhep.23587\&partnerID=40\&md5=710c422b625fca4d15125aa20f26655c},
	author = {Wagoner, J. and Negash, A. and Kane, O.J. and Martinez, L.E. and Nahmias, Y. and Bourne, N. and Owen, D.M. and Grove, J. and Brimacombe, C. and McKeating, J.A. and P{\'e}cheur, E.-I. and Graf, T.N. and Oberlies, N.H. and Lohmann, V. and Cao, F. and Tavis, J.E. and Polyak, S.J.}
}
@article {Uygun2010814,
	title = {Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix},
	journal = {Nature Medicine},
	volume = {16},
	number = {7},
	year = {2010},
	note = {cited By 1180},
	pages = {814-820},
	abstract = {Orthotopic liver transplantation is the only available treatment for severe liver failure, but it is currently limited by organ shortage. One technical challenge that has thus far limited the development of a tissue-engineered liver graft is oxygen and nutrient transport. Here we demonstrate a novel approach to generate transplantable liver grafts using decellularized liver matrix. The decellularization process preserves the structural and functional characteristics of the native microvascular network, allowing efficient recellularization of the liver matrix with adult hepatocytes and subsequent perfusion for in vitro culture. The recellularized graft supports liver-specific function including albumin secretion, urea synthesis and cytochrome P450 expression at comparable levels to normal liver in vitro. The recellularized liver grafts can be transplanted into rats, supporting hepatocyte survival and function with minimal ischemic damage. These results provide a proof of principle for the generation of a transplantable liver graft as a potential treatment for liver disease. {\textcopyright} 2010 Nature America, Inc. All rights reserved.},
	doi = {10.1038/nm.2170},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-77954533642\&doi=10.1038\%2fnm.2170\&partnerID=40\&md5=8075f94b877bcbcf720c7ad6c38ad03d},
	author = {Uygun, B.E. and Soto-Gutierrez, A. and Yagi, H. and Izamis, M.-L. and Guzzardi, M.A. and Shulman, C. and Milwid, J. and Kobayashi, N. and Tilles, A. and Berthiaume, F. and Hertl, M. and Nahmias, Y. and Yarmush, M.L. and Uygun, K.}
}
@article {Yagi20101857,
	title = {Reactive bone marrow stromal cells attenuate systemic inflammation via sTNFR1},
	journal = {Molecular Therapy},
	volume = {18},
	number = {10},
	year = {2010},
	note = {cited By 143},
	pages = {1857-1864},
	abstract = {Excessive systemic inflammation following trauma, sepsis, or burn could lead to distant organ damage. The transplantation of bone marrow stromal cells or mesenchymal stem cells (MSCs) has been reported to be an effective treatment for several immune disorders by modulating the inflammatory response to injury. We hypothesized that MSCs can dynamically secrete systemic factors that can neutralize the activity of inflammatory cytokines. In this study, we showed that cocultured MSCs are able to decrease nuclear factor -B (NFB) activation in target epithelial cells incubated in inflammatory serum conditions. Proteomic screening revealed a responsive secretion of soluble tumor necrosis factor (TNF) receptor 1 (sTNFR1) when MSCs were exposed to lipopolysaccharide (LPS)-stimulated rat serum. The responsive effect was eliminated when NFB activation was blocked in MSCs. Intramuscular transplantation of MSCs in LPS-endotoxic rats decreased a panel of inflammatory cytokines and inflammatory infiltration of macrophages and neutrophils in lung, kidney, and liver when compared to controls. These results suggest that improvements of inflammatory responses in animal models after local transplantation of MSCs are at least, in part, explained by the NFB-dependent secretion of sTNFR1 by MSCs. {\textcopyright} The American Society of Gene \& Cell Therapy.},
	doi = {10.1038/mt.2010.155},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-77957580211\&doi=10.1038\%2fmt.2010.155\&partnerID=40\&md5=0dbd801664d3959827937c3488645543},
	author = {Yagi, H. and Soto-Gutierrez, A. and Navarro-Alvarez, N. and Nahmias, Y. and Goldwasser, Y. and Kitagawa, Y. and Tilles, A.W. and Tompkins, R.G. and Parekkadan, B. and Yarmush, M.L.}
}
@article {Goldwasser2010,
	title = {Transcriptional regulation of human and rat hepatic lipid metabolism by the grapefruit flavonoid naringenin: Role of PPARα, PPARγ and LXRα},
	journal = {PLoS ONE},
	volume = {5},
	number = {8},
	year = {2010},
	note = {cited By 198},
	abstract = {Disruption of lipid and carbohydrate homeostasis is an important factor in the development of prevalent metabolic diseases such as diabetes, obesity, and atherosclerosis. Therefore, small molecules that could reduce insulin dependence and regulate dyslipidemia could have a dramatic effect on public health. The grapefruit flavonoid naringenin has been shown to normalize lipids in diabetes and hypercholesterolemia, as well as inhibit the production of HCV. Here, we demonstrate that naringenin regulates the activity of nuclear receptors PPARα, PPARγ, and LXRα. We show it activates the ligand-binding domain of both PPARα and PPARγ, while inhibiting LXRα in GAL4-fusion reporters. Using TR-FRET, we show that naringenin is a partial agonist of LXRα, inhibiting its association with Trap220 co-activator in the presence of TO901317. In addition, naringenin induces the expression of PPARα co-activator, PGC1α. The flavonoid activates PPAR response element (PPRE) while suppressing LXRα response element (LXRE) in human hepatocytes, translating into the induction of PPAR-regulated fatty acid oxidation genes such as CYP4A11, ACOX, UCP1 and ApoAI, and inhibition of LXRα-regulated lipogenesis genes, such as FAS, ABCA1, ABCG1, and HMGR. This effect results in the induction of a fasted-like state in primary rat hepatocytes in which fatty acid oxidation increases, while cholesterol and bile acid production decreases. Our findings explain the myriad effects of naringenin and support its continued clinical development. Of note, this is the first description of a non-toxic, naturally occurring LXRα inhibitor. {\textcopyright} 2010 Goldwasser et al.},
	doi = {10.1371/journal.pone.0012399},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-77957871769\&doi=10.1371\%2fjournal.pone.0012399\&partnerID=40\&md5=f73e229341b6c6a54785cb84e34a4e53},
	author = {Goldwasser, J. and Cohen, P.Y. and Yang, E. and Balaguer, P. and Yarmush, M.L. and Nahmias, Y.}
}
@article {Jindal20092288,
	title = {Amino acid-mediated heterotypic interaction governs performance of a hepatic tissue model},
	journal = {FASEB Journal},
	volume = {23},
	number = {7},
	year = {2009},
	note = {cited By 37},
	pages = {2288-2298},
	abstract = {Tissue-engineered models that mimic in vivo tissue organization offer the potential of capturing complex signaling pathways in vitro. In the liver, hepatocytes and endothelial cells are closely associated but separated by the extracellular matrix of the space of Disse. This unique configuration was mimicked by embedding primary hepatocytes in collagen gel and overlaying the matrix with endothelial cells. We demonstrate that during the first few days of culture, the secretion of albumin and fibrinogen was 2-fold higher in cocultures compared to hepatocytes alone. Hepatocyte function in both cultures stabilized to a similar level during the second week, suggesting that endothelial cells can induce the early recovery of hepatocytes after isolation and seeding. Endothelial cell-conditioned medium reproduced the effect of coculture in a dose-dependent fashion, suggesting a role for endothelial cell-derived soluble factors. Endothelial cell-conditioned medium increased mRNA levels of various acute-phase proteins such as albumin, fibrinogen, transferrin, and α-macroglobulin in hepatocytes. Surprisingly, the effect of endothelial cell-conditioned medium was not mediated by growth factors or cytokines, or by secreted extracellular matrix, but by the release of the amino acid proline, which mediates endogenous collagen synthesis by hepatocytes. These findings suggest an important role for proline secretion by endothelial cells as a paracrine factor regulating hepatocyte function. {\textcopyright} FASEB.},
	doi = {10.1096/fj.08-114934},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-68549135298\&doi=10.1096\%2ffj.08-114934\&partnerID=40\&md5=1ecb96aa5413b1eb7a40084f2a3497f6},
	author = {Jindal, R. and Nahmias, Y. and Tilles, A.W. and Berthiaume, F. and Yarmush, M.L.}
}
@article {Maguire20091192,
	title = {Design and application of microfluidic systems for in vitro pharmacokinetic evaluation of drug candidates},
	journal = {Current Drug Metabolism},
	volume = {10},
	number = {10},
	year = {2009},
	note = {cited By 45},
	pages = {1192-1199},
	abstract = {One of the fundamental challenges facing the development of new chemical entities within the pharmaceutical industry is the extrapolation of key in vivo parameters from in vitro cell culture assays and animal studies. Development of microscale devices and screening assays incorporating primary human cells can potentially provide better, faster and more efficient prediction of in vivo toxicity and clinical drug performance. With this goal in mind, large strides have been made in the area of microfluidics to provide in vitro surrogates that are designed to mimic the physiological architecture and dynamics. More recent advancements have been made in the development of in vitro analogues to physiologically-based pharmacokinetic (PBPK) models - a mathematical model that represents the body as interconnected compartments specific for a particular organ. In this review we highlight recent advancements in human hepatocyte microscale culture, and describe the next generation of integrated devices, whose potential allows for the high throughput assessment of drug metabolism, distribution and pharmacokinetics. {\textcopyright} 2009 Bentham Science Publishers Ltd.},
	doi = {10.2174/138920009790820093},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-77649131395\&doi=10.2174\%2f138920009790820093\&partnerID=40\&md5=34f5cfd4e030de41b60b8c7078d313a9},
	author = {Maguire, T.J. and Novik, E. and Chao, P. and Barminko, J. and Nahmias, Y. and Yarmush, M.L. and Cheng, K.-C.}
}
@article {Song200987,
	title = {Low power laser irradiation stimulates the proliferation of adult human retinal pigment epithelial cells in culture},
	journal = {Cellular and Molecular Bioengineering},
	volume = {2},
	number = {1},
	year = {2009},
	note = {cited By 9},
	pages = {87-103},
	abstract = {We investigated the effects of low power laser irradiation on the proliferation of retinal pigment epithelial (RPE) cells. Adult human RPE cells were artificially pigmented by preincubation with sepia melanin, and exposed to a single sublethal laser pulse (590 nm, 1 μs, \&lt;200 mJ/cm2). DNA synthesis, cell number, and growth factor activity in irradiated RPE cells were subsequently monitored. The effect of sublethal laser irradiation on the "wound" healing response of an RPE monolayer in an in vitro scratch assay was also investigated. Single pulsed laser irradiation increased DNA synthesis in pigmented RPE cells measured 6 h post-treatment. In the scratch assay, laser irradiation increased the rates of cell proliferation and wound closure. Conditioned medium, collected 48 h following laser treatment, increased cell proliferation of unirradiated cells. Irradiation increased RPE cell secretion of platelet-derived growth factor (PDGF)-B chain, and increased mRNA levels of several growth factors and their receptors, including PDGF, transforming growth factor-β1, basic fibroblast growth factor, epidermal growth factor, insulin-like growth factor, as well as heat shock proteins. This demonstrates, for the first time, that low power single pulsed laser irradiation stimulates the proliferation of RPE cells, and upregulates growth factors that are mitogenic for RPE cells. {\textcopyright} 2008 Biomedical Engineering Society.},
	doi = {10.1007/s12195-008-0041-7},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-65549163882\&doi=10.1007\%2fs12195-008-0041-7\&partnerID=40\&md5=f1b0bdb9d4a60dd1c2b24c4506c3b338},
	author = {Song, Q. and Uygun, B. and Banerjee, I. and Nahmias, Y. and Zhang, Q. and Berthiaume, F. and Latina, M. and Yarmush, M.L.}
}
@article {Kidambi200915714,
	title = {Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {106},
	number = {37},
	year = {2009},
	note = {cited By 177},
	pages = {15714-15719},
	abstract = {The liver is a major site for the metabolism of xenobiotic compounds due to its abundant level of phase I/II metabolic enzymes. With the cost of drug development escalating to over $400 million/ drug there is an urgent need for the development of rigorous models of hepatic metabolism for preclinical screening of drug clearance and hepatotoxicity. Here, we present a microenvironment in which primary human and rat hepatocytes maintain a high level of metabolic competence without a long adaptation period. We demonstrate that co-cultures of hepatocytes and endothelial cells in serum-free media seeded under 95\% oxygen maintain functional apical and basal polarity, high levels of cytochrome P450 activity, and gene expression profiles on par with freshly isolated hepatocytes. These oxygenated co-cultures demonstrate a remarkable ability to predict in vivo drug clearance rates of both rapid and slow clearing drugs with an R2 of 0.92. Moreover, as the metabolic function of oxygenated co-cultures stabilizes overnight, preclinical testing can be carried out days or even weeks before other culture methods, significantly reducing associated labor and cost. These results are readily extendable to other culture configurations including three-dimensional culture, bioreactor studies, as well as microfabricated co-cultures.},
	doi = {10.1073/pnas.0906820106},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-70349466841\&doi=10.1073\%2fpnas.0906820106\&partnerID=40\&md5=f7b505920ce2e1c7edf6973040db1a1d},
	author = {Kidambi, S. and Yarmush, R.S. and Novik, E. and Chao, P. and Yarmush, M.L. and Nahmias, Y.}
}
@article {Kidambi2009657,
	title = {Propofol induces ERK-dependant expression of c-Fos and Egr-1 in neuronal cells},
	journal = {NeuroReport},
	volume = {20},
	number = {7},
	year = {2009},
	note = {cited By 8},
	pages = {657-662},
	abstract = {This study explored the effects of propofol on c-Fos and Egr-1 in neuroblastoma (N2A) cells. We demonstrate that propofol induced the expression of c-Fos and Egr-1 within 30 and 60min of exposure time. At 16.8μM concentration, propofol induced a 6 and 2.5-fold expression of c-Fos and Egr-1, respectively. However, at concentrations above 100μM, propofol failed to induce expression of c-Fos or Egr-1. Propofol-induced c-Fos and Egr-1 transcription was unaffected by bicuculline, a γ-aminobutyric acid-A receptor antagonist, but was abolished by PD98059, a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor. Our study shows that clinically relevant concentrations of propofol induce c-Fos and Egr-1 expression through an extracellular signal-regulated kinase mediated and γ-aminobutyric acid-A independent pathway. {\textcopyright} 2009 Wolters Kluwer Health | Lippincott Williams \& Wilkins.},
	doi = {10.1097/WNR.0b013e328329a449},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-67049171035\&doi=10.1097\%2fWNR.0b013e328329a449\&partnerID=40\&md5=1e3405c2cf5efb41a094042f8802428b},
	author = {Kidambi, S. and Yarmush, J. and Fong, W. and Kamath, S. and Schianodicola, J. and Nahmias, Y.}
}
@article {Tolboom2009170,
	title = {Recovery of warm ischemic rat liver grafts by normothermic extracorporeal perfusion},
	journal = {Transplantation},
	volume = {87},
	number = {2},
	year = {2009},
	note = {cited By 78},
	pages = {170-177},
	abstract = {Liver transplantation is currently the only established treatment of end-stage liver disease, but it is limited by a severe shortage of viable donor livers. Donors after cardiac death (DCD) are an untapped source that could significantly increase the pool of available livers. Preservation of these DCD livers by conventional static cold storage (SCS) is associated with an unacceptable risk of primary nonfunction and delayed graft failure. Normothermic extracorporeal liver perfusion (NELP) has been suggested as an improvement over SCS. Livers recovered from male Lewis rats were subjected to 1 hr of warm ischemia and preserved with 5 hr of SCS or NELP, and transplanted into syngeneic recipients. As additional controls, non-ischemic livers preserved with 6 hr of SCS or NELP and unpreserved ischemic livers were transplanted. After NELP, ischemically damaged livers could be orthotopically transplanted into syngeneic recipients with 92\% survival (n=13) after 4 weeks, which was comparable with control animals that received healthy livers preserved by SCS (n=9) or NELP (n=11) for 6 hr. On the other hand, animals from ischemia/SCS control group all died within 12 hr postoperatively (n=6). Similarly, animals that received ischemic livers without preservation all died within 24 hr after transplantation (n=6). These results suggest that NELP has the potential to reclaim warm ischemic livers that would not be transplantable otherwise. The rat model in this study is a useful platform to further optimize NELP as a method of recovery and preservation of DCD livers.},
	doi = {10.1097/TP.0b013e318192df6b},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-59649091509\&doi=10.1097\%2fTP.0b013e318192df6b\&partnerID=40\&md5=58e8d00437f9ff703d8927135d2871d5},
	author = {Tolboom, H. and Pouw, R.E. and Izamis, M.-L. and Milwid, J.M. and Sharma, N. and Soto-Gutierrez, A. and Nahmias, Y. and Uygun, K. and Berthiaume, F. and Yarmush, M.L.}
}
@book {Nahmias2009855,
	title = {Tissue engineering application in general surgery},
	series = {Fundamentals of Tissue Engineering and Regenerative Medicine},
	year = {2009},
	note = {cited By 2},
	pages = {855-867},
	abstract = {The field of tissue engineering encompasses efforts to construct functional biological elements using cells, biomaterials, or their combination [1]. While most definitions of tissue engineering cover a broad range of applications, in practice the term is closely associated with efforts to repair or replace tissue function that was lost due to trauma, disease, or genetic disorder. The term has also been applied to efforts to construct extracorporeal support systems such as kidney dialysis or bioartificial liver [2, 3]. The term regenerative medicine is sometimes used synonymously with tissue engineering, although the former term emphasizes the use of stem and progenitor cells to produce tissues. Finally, cellular therapies are closely related approaches which rely on the ability of individual cells to engraft and adapt to the host microenvironment without the support of biomaterials or a well-defined architecture. This chapter aims to review current tissue engineering applications which found their way into clinical practice. We will begin with a short historical review of the field and continue by describing tissue engineering applications in clinical practice. This work will examine applications in the cardiovascular system, musculoskeletal system, skin, and finally the digestive system. We will conclude this work by summarizing the current challenges and expanding opportunities of the field of tissue engineering. {\textcopyright} 2009 Springer Berlin Heidelberg.},
	doi = {10.1007/978-3-540-77755-7_59},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84861816167\&doi=10.1007\%2f978-3-540-77755-7_59\&partnerID=40\&md5=f1ae47f279865e035cc4914055279b35},
	author = {Nahmias, Y. and Yarmush, M.L.}
}
@article {Parashurama2008474,
	title = {Activin alters the kinetics of endoderm induction in embryonic stem cells cultured on collagen gels},
	journal = {Stem Cells},
	volume = {26},
	number = {2},
	year = {2008},
	note = {cited By 19},
	pages = {474-484},
	abstract = {Embryonic stem cell-derived endoderm is critical for the development of cellular therapies for the treatment of disease such as diabetes, liver cirrhosis, or pulmonary emphysema. Here, we describe a novel approach to induce endoderm from mouse embryonic stem (mES) cells using fibronectin-coated collagen gels. This technique results in a homogeneous endoderm-like cell population, demonstrating endoderm-specific gene and protein expression, which remains committed following in vivo transplantation. In this system, activin, normally an endoderm inducer, caused an 80\% decrease in the Foxa2-positive endoderm fraction, whereas follistatin increased the Foxa2-positive endoderm fraction to 78\%. Our work suggests that activin delays the induction of endoderm through its transient precursors, the epiblast and mesendoderm. Long-term differentiation displays a twofold reduction in hepatic gene expression and threefold reduction in hepatic protein expression of activintreated cells compared with follistatin-treated cells. Moreover, subcutaneous transplantation of activin-treated cells in a syngeneic mouse generated a heterogeneous teratoma-like mass, suggesting that these were a more primitive population. In contrast, follistatin-treated cells resulted in an encapsulated epithelial-like mass, suggesting that these cells remained committed to the endoderm lineage. In conclusion, we demonstrate a novel technique to induce the direct differentiation of endoderm from mES cells without cell sorting. In addition, our work suggests a new role for activin in induction of the precursors to endoderm and a new endoderm-enrichment technique using follistatin. {\textcopyright}AlphaMed Press.},
	doi = {10.1634/stemcells.2007-0303},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-41049100546\&doi=10.1634\%2fstemcells.2007-0303\&partnerID=40\&md5=ede4109f79651bb3ebc0ea9e4d615438},
	author = {Parashurama, N. and Nahmias, Y. and Cho, C.H. and Van Poll, D. and Tilles, A.W. and Berthiaume, F. and Yarmush, M.L.}
}
@article {Nahmias20081437,
	title = {Apolipoprotein B-dependent hepatitis C virus secretion is inhibited by the grapefruit flavonoid naringenin},
	journal = {Hepatology},
	volume = {47},
	number = {5},
	year = {2008},
	note = {cited By 244},
	pages = {1437-1445},
	abstract = {Hepatitis C virus (HCV) infects over 3\% of the world population and is the leading cause of chronic liver disease worldwide. HCV has long been known to associate with circulating lipoproteins, and its interactions with the cholesterol and lipid pathways have been recently described. In this work, we demonstrate that HCV is actively secreted by infected cells through a Golgi-dependent mechanism while bound to very low density lipoprotein (vLDL). Silencing apolipoprotein B (ApoB) messenger RNA in infected cells causes a 70\% reduction in the secretion of both ApoB-100 and HCV. More importantly, we demonstrate that the grapefruit flavonoid naringenin, previously shown to inhibit vLDL secretion both in vivo and in vitro, inhibits the microsomal triglyceride transfer protein activity as well as the transcription of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and acyl-coenzyme Archolesterol acyltransferase 2 in infected cells. Stimulation with naringenin reduces HCV secretion in infected cells by 80\%. Moreover, we find that naringenin is effective at concen-trations that are an order of magnitude below the toxic threshold in primary human hepatocytes and in mice. Conclusion: These results suggest a novel therapeutic approach for the treatment of HCV infection. Copyright {\textcopyright} 2008 by the American Association for the Study of Liver Diseases.},
	doi = {10.1002/hep.22197},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-43949087893\&doi=10.1002\%2fhep.22197\&partnerID=40\&md5=5a0f5fea37be08fdf631ac24ce48aaf1},
	author = {Nahmias, Y. and Goldwasser, J. and Casali, M. and Van Poll, D. and Wakita, T. and Chung, R.T. and Yarmush, M.L.}
}
@conference {Jindal2008,
	title = {Endothelial cells augment hepatocytes function in an organotypical model of liver},
	booktitle = {AIChE Annual Meeting, Conference Proceedings},
	year = {2008},
	note = {cited By 0},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-79952295669\&partnerID=40\&md5=9d946013a81177df32459c29a471f7ad},
	author = {Jindal, R. and Nahmias, Y. and Tilles, A.W. and Berthiaume, F. and Yarmush, M.}
}
@article {Cho2008898,
	title = {Homogeneous differentiation of hepatocyte-like cells from embryonic stem cells: Applications for the treatment of liver failure},
	journal = {FASEB Journal},
	volume = {22},
	number = {3},
	year = {2008},
	note = {cited By 65},
	pages = {898-909},
	abstract = {One of the major hurdles of cellular therapies for the treatment of liver failure is the low availability of functional human hepatocytes. While embryonic stem (ES) cells represent a potential cell source for therapy, current methods for differentiation result in mixed cell populations or low yields of the cells of interest. Here we describe a rapid, direct differentiation method that yields a homogeneous population of endoderm-like cells with 95\% purity. Mouse ES cells cultured on top of collagen-sandwiched hepatocytes differentiated and proliferated into a uniform and homogeneous cell population of endoderm-like cells. The endoderm-like cell population was positive for Foxa2, Sox17, and AFP and could be further differentiated into hepatocyte-like cells, demonstrating hepatic morphology, functionality, and gene and protein expression. Incorporating the hepatocyte-like cells into a bioartificial liver device to treat fulminant hepatic failure improved animal survival, thereby underscoring the therapeutic potential of these cells. {\textcopyright} FASEB.},
	doi = {10.1096/fj.06-7764com},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-40449118677\&doi=10.1096\%2ffj.06-7764com\&partnerID=40\&md5=24702a80d10bda505dcd8bde707685a7},
	author = {Cho, C.H. and Parashurama, N. and Park, E.Y.H. and Suganuma, K. and Nahmias, Y. and Park, J. and Tilles, A.W. and Berthiaume, F. and Yarmush, M.L.}
}
@article {VanPoll20081634,
	title = {Mesenchymal stem cell-derived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo},
	journal = {Hepatology},
	volume = {47},
	number = {5},
	year = {2008},
	note = {cited By 473},
	pages = {1634-1643},
	abstract = {Orthotopic liver transplantation is the only proven effective treatment for fulminant hepatic failure (FHF), but its use is limited because of organ donor shortage, associated high costs, and the requirement for lifelong immunosuppression. FHF is usually accompanied by massive hepatocellular death with compensatory liver regeneration that fails to meet the cellular losses. Therefore, therapy aimed at inhibiting cell death and stimulating endogenous repair pathways could offer major benefits in the treatment of FHF. Recent studies have demonstrated that mesenchymal stem cell (MSC) therapy can prevent parenchymal cell loss and promote tissue repair in models of myocardial infarction, acute kidney failure, and stroke through the action of trophic secreted molecules. In this study, we investigated whether MSC therapy can protect the acutely injured liver and stimulate regeneration. In a D-galactosamine-induced rat model of acute liver injury, we show that systemic infusion of MSC-conditioned medium (MSC-CM) provides a significant survival benefit and prevents the release of liver injury biomarkers. Furthermore, MSC-CM therapy resulted in a 90\% reduction of apoptotic hepatocellular death and a three-fold increment in the number of proliferating hepatocytes. This was accompanied by a dramatic increase in the expression levels of 10 genes known to be up-regulated during hepatocyte replication. Direct antiapoptotic and premitotic effects of MSC-CM on hepatocytes were demonstrated using in vitro assays. Conclusion: These data provide the first clear evidence that MSC-CM therapy provides trophic support to the injured liver by inhibiting hepatocellular death and stimulating regeneration, potentially creating new avenues for the treatment of FHF. Copyright {\textcopyright} 2008 by the American Association for the Study of Liver Diseases.},
	doi = {10.1002/hep.22236},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-43949143205\&doi=10.1002\%2fhep.22236\&partnerID=40\&md5=1c4b2b1a3fe4b0b9448821d243125617},
	author = {Van Poll, D. and Parekkadan, B. and Cho, C.H. and Berthiaume, F. and Nahmias, Y. and Tilles, A.W. and Yarmush, M.L.}
}
@article {Benny2008799,
	title = {An orally delivered small-molecule formulation with antiangiogenic and anticancer activity},
	journal = {Nature Biotechnology},
	volume = {26},
	number = {7},
	year = {2008},
	note = {cited By 165},
	pages = {799-807},
	abstract = {Targeting angiogenesis, the formation of blood vessels, is an important modality for cancer therapy. TNP-470, a fumagillin analog, is among the most potent and broad-spectrum angiogenesis inhibitors. However, a major clinical limitation is its poor oral availability and short half-life, necessitating frequent, continuous parenteral administration. We have addressed these issues and report an oral formulation of TNP-470, named Lodamin. TNP-470 was conjugated to monomethoxy-polyethylene glycol-polylactic acid to form nanopolymeric micelles. This conjugate can be absorbed by the intestine and selectively accumulates in tumors. Lodamin significantly inhibits tumor growth, without causing neurological impairment in tumor-bearing mice. Using the oral route of administration, it first reaches the liver, making it especially efficient in preventing the development of liver metastasis in mice. We show that Lodamin is an oral nontoxic antiangiogenic drug that can be chronically administered for cancer therapy or metastasis prevention. {\textcopyright} 2008 Nature Publishing Group.},
	doi = {10.1038/nbt1415},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-46949110744\&doi=10.1038\%2fnbt1415\&partnerID=40\&md5=d3addc42a73d156cb88910c105f1999c},
	author = {Benny, O. and Fainaru, O. and Adini, A. and Cassiola, F. and Bazinet, L. and Adini, I. and Pravda, E. and Nahmias, Y. and Koirala, S. and Corfas, G. and D{\textquoteright}Amato, R.J. and Folkman, J.}
}
@conference {Kidambi2008,
	title = {Propofol induces a GABA-independent expression of C-Fos and Egr-1 in neuronal cells},
	booktitle = {AIChE Annual Meeting, Conference Proceedings},
	year = {2008},
	note = {cited By 0},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-79952305867\&partnerID=40\&md5=03aa751fc4ac968e58ee7d624ef00178},
	author = {Kidambi, S. and Yarmush, J. and Fong, W. and Kamath, S. and Schianodicola, J. and Nahmias, Y.}
}
@article {Nahmias20082142,
	title = {Reply},
	journal = {Hepatology},
	volume = {47},
	number = {6},
	year = {2008},
	note = {cited By 0},
	pages = {2142-2143},
	doi = {10.1002/hep.22340},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-46749084699\&doi=10.1002\%2fhep.22340\&partnerID=40\&md5=e04aa463eefc2feb99bc2dbf5c486067},
	author = {Nahmias, Y. and Yarmush, M.L. and Chung, R.T.}
}
@article {Song200810518,
	title = {Selective targeting of pigmented retinal pigment epithelial (RPE) cells by a single pulsed laser irradiation: An in vitro study},
	journal = {Optics Express},
	volume = {16},
	number = {14},
	year = {2008},
	note = {cited By 8},
	pages = {10518-10528},
	abstract = {This work describes the selective targeting of pigmented retinal pigment epithelial (RPE) cells by a single pulsed laser irradiation. We observed: (1) single pulsed laser irradiation caused cellular damages on pigmented, and not on non-pigmented RPE cells at laser radiant exposure up to 2550 mJ/cm2; (2) in the mixture of pigmented and non-pigmented RPE cells, single pulsed laser-induced damage was confined to pigmented RPE cells. This study demonstrates that the pigmented RPE cells can be selectively damaged, using a single pulsed laser irradiation, without thermal coagulation to adjacent non-pigmented RPE cells. {\textcopyright} 2008 Optical Society of America.},
	doi = {10.1364/OE.16.010518},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-47249097946\&doi=10.1364\%2fOE.16.010518\&partnerID=40\&md5=b0c580d128416ddaafca5c1287e91d86},
	author = {Song, Q. and Risco, R. and Latina, M. and Berthiaume, F. and Nahmias, Y. and Yarmush, M.L.}
}
@article {Nahmias20061627,
	title = {Endothelium-mediated hepatocyte recruitment in the establishment of liver-like tissue in vitro},
	journal = {Tissue Engineering},
	volume = {12},
	number = {6},
	year = {2006},
	note = {cited By 71},
	pages = {1627-1638},
	abstract = {A major goal of liver tissue engineering is to understand how the constituent cell types interact to achieve liver-specific structure and function. Here we show that hepatocytes migrate toward and adhere to endothelial vascular structures formed on Matrigel in vitro, and that hepatocyte recruitment is dependent on endothelium-derived hepatocyte growth factor. The hepatocyte-decorated endothelial vascular structures resemble in vivo sinusoids containing plate-like structures, bile canaliculi, and a lumen. The sinusoid-like structures retained cytochrome P450 expression and activity, in addition to stable albumin expression and secretion rate for over 2 months in vitro. The stability of the sinusoid-like structures was dependent on the presence of vimentin-positive fibroblasts in culture. The sinusoid-like structures formed by hepatocytes and pure populations of endothelial cells collapsed after 10 days in culture. In contrast, culture of hepatocytes with fibroblast-contaminated human dermal microvascular endothelial cells or a combination of human umbilical vein endothelial cells and normal human dermal fibroblasts resulted in stable sinusoid-like structures surrounded by a fibroblastic capsule that maintained liver specific functions for several months in vitro. These results demonstrate that specification of endothelial cell position ultimately determines hepatocyte position in vitro, suggesting that similar interactions might occur in vivo. The novelty of the culture{\textquoteright}s sinusoid-like organization and long-term function suggest a new model for the study of liver toxicity, iscaemia/reperfusion injury, and fibrosis. {\textcopyright} Mary Ann Liebert, Inc.},
	doi = {10.1089/ten.2006.12.1627},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-33746841799\&doi=10.1089\%2ften.2006.12.1627\&partnerID=40\&md5=d41eb89c0c0a091df4d4921786259a9f},
	author = {Nahmias, Y. and Schwartz, R.E. and Hu, W.-S. and Verfaillie, C.M. and Odde, D.J.}
}
@article {Nahmias2006309,
	title = {Integration of technologies for hepatic tissue engineering},
	journal = {Advances in Biochemical Engineering/Biotechnology},
	volume = {103},
	year = {2006},
	note = {cited By 137},
	pages = {309-329},
	abstract = {The liver is the largest internal organ in the body, responsible for over 500 metabolic, regulatory, and immune functions. Loss of liver function leads to liver failure which causes over 25 000 deaths/year in the United States. Efforts in the field of hepatic tissue engineering include the design of bioartificial liver systems to prolong patient{\textquoteright}s lives during liver failure, for drug toxicity screening and for the study of liver regeneration, ischemia/reperfusion injury, fibrosis, viral infection, and inflammation. This chapter will overview the current state-of-the-art in hepatology including isolated perfused liver, culture of liver slices and tissue explants, hepatocyte culture on collagen "sandwich" and spheroids, coculture of hepatocytes with non-parenchymal cells, and the integration of these culture techniques with microfluidics and reactor design. This work will discuss the role of oxygen and medium composition in hepatocyte culture and present promising new technologies for hepatocyte proliferation and function. We will also discuss liver development, architecture, and function as they relate to these culture techniques. Finally, we will review current opportunities and major challenges in integrating cell culture, bioreactor design, and microtechnology to develop new systems for novel applications. {\textcopyright} Springer-Verlag 2006.},
	doi = {10.1007/10_029},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-33750338674\&doi=10.1007\%2f10_029\&partnerID=40\&md5=a2b8e2a723012777a84b890383e9328a},
	author = {Nahmias, Y. and Berthiaume, F. and Yarmush, M.L.}
}
@article {Nahmias2006257,
	title = {Liver endothelial cells promote LDL-R expression and the uptake of HCV-like particles in primary rat and human hepatocytes},
	journal = {Hepatology},
	volume = {43},
	number = {2},
	year = {2006},
	note = {cited By 67},
	pages = {257-265},
	abstract = {Low-density lipoprotein (LDL) is an important carrier of plasma cholesterol and triglycerides whose concentration is regulated by the liver parenchymal cells. Abnormal LDL regulation is thought to cause atherosclerosis, while viral binding to LDL has been suggested to facilitate hepatitis C infection. Primary hepatocytes quickly lose the ability to clear LDL during in vitro culture. Here we show that the coculture of hepatocytes with liver sinusoidal endothelial cells (LSEC) significantly increases the ability of hepatocytes to uptake LDL in vitro. LDL uptake does not increase when hepatocytes are cocultured with other cell types such as fibroblasts or umbilical vein endothelial cells. We find that LSECs induce the hepatic expression of the LDL receptor and the epidermal growth factor receptor. In addition, while hepatocytes in single culture did not take up hepatitis C virus (HCV)-like particles, the hepatocytes cocultured with LSECs showed a high level of HCV-like particle uptake. We suggest that coculture with LSECs induces the emergence of a sinusoidal surface in primary hepatocytes conducive to the uptake of HCV-like particles. In conclusion, our findings describe a novel model of polarized hepatocytes in vitro that can be used for the study of LDL metabolism and hepatitis C infection. Copyright {\textcopyright} 2006 by the American Association for the Study of Liver Diseases.},
	doi = {10.1002/hep.21016},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-33644501855\&doi=10.1002\%2fhep.21016\&partnerID=40\&md5=c2c5977c9f21f02214e239f67d692ec3},
	author = {Nahmias, Y. and Casali, M. and Barbe, L. and Berthiaume, F. and Yarmush, M.L.}
}
@article {Nahmias20062288,
	title = {Micropatterning of living cells by laser-guided direct writing: Application to fabrication of hepatic-endothelial sinusoid-like structures},
	journal = {Nature Protocols},
	volume = {1},
	number = {5},
	year = {2006},
	note = {cited By 110},
	pages = {2288-2296},
	abstract = {Here, we describe a simple protocol for the design and construction of a laser-guided direct writing (LGDW) system able to micropattern the self-assembly of liver sinusoid-like structures with micrometer resolution in vitro. To the best of our knowledge, LGDW is the only technique able to pattern cells "on the fly" with micrometer precision on arbitrary matrices, including soft gels such as Matrigel. By micropatterning endothelial cells on Matrigel, one can control the self-assembly of vascular structures and associated liver tissue. LGDW is therefore uniquely suited for studying the role of tissue architecture and mechanical properties at the single-cell resolution, and for studying the effects of heterotypic cell-cell interactions underlying processes such as liver morphogenesis, differentiation and angiogenesis. The total time required to carry out this protocol is typically 7 h.},
	doi = {10.1038/nprot.2006.386},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-34548093866\&doi=10.1038\%2fnprot.2006.386\&partnerID=40\&md5=046b45a1dc2c6c70c95520378f23e3f9},
	author = {Nahmias, Y. and Odde, D.J.}
}
@article {Nahmias2006,
	title = {A novel formulation of oxygen-carrying matrix enhances liver-specific function of cultured hepatocytes},
	journal = {FASEB Journal},
	volume = {20},
	number = {14},
	year = {2006},
	note = {cited By 75},
	pages = {E1828-E1836},
	abstract = {Oxygen is an important component of the cellular microenvironment, mediating cell survival, differentiation, and function. Oxygen supply is a limiting factor during culture of highly metabolic cells such as hepatocytes. Here we present a simple formulation of a fluorocarbon-based oxygen carrier embedded in collagen gel that increases oxygen concentration in culture 6-fold. Rat hepatocytes cultured on oxygen carrier-collagen showed a significant increase in viability and function. Cytochrome P450IA1 activity was increased by 140\% in serum-free cultures and by 820\% in serum-containing cultures. The significantly higher hepatocellular function on oxygen carrier-collagen matrix persisted and increased during long-term culture. Long-term albumin secretion was increased by 350\% in serum-free cultures and by 166\% in serum-containing culture. Long-term urea secretion was increased by 79\% in serum-free cultures and by 76\% in serum-containing cultures. We conclude that oxygen supply may limit hepatocyte function in vitro. This limitation can be overcome by addition of an oxygen carrier to the extracellular matrix. Culture of hepatocytes on oxygen-carrying matrix mimics the oxygen-rich environment of the liver and provides a simple method for enhanced long-term function. {\textcopyright} FASEB.},
	doi = {10.1096/fj.06-6192fje},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-33845610506\&doi=10.1096\%2ffj.06-6192fje\&partnerID=40\&md5=1273848f4f2ece617af4bfd996085e6f},
	author = {Nahmias, Y. and Kramvis, Y. and Barbe, L. and Casali, M. and Berthiaume, F. and Yarmush, M.L.}
}
@article {Nahmias2005701,
	title = {Cell patterning on biological gels via cell spraying through a mask},
	journal = {Tissue Engineering},
	volume = {11},
	number = {5-6},
	year = {2005},
	note = {cited By 45},
	pages = {701-708},
	abstract = {We present an easily applicable and inexpensive method for patterning cells on arbitrary surfaces including biological gels with little loss of viability or function. Single-cell suspensions of human umbilical vein endothelial cells and NIH 3T3 fibroblasts were sprayed with an off-the-shelf airbrush through a mask to create 100-μm scale patterns on collagen gels. Three-dimensional patterns were created by layering a collagen gel on top of the first pattern and patterning the top gel. Coculture of rat hepatocytes with NIH 3T3 patterns on collagen gels resulted in localized increased activity of cytochrome P-450 along the pattern. These results suggest that cell spraying is a useful tool for the study of heterotypic cellular interactions and tissue-engineering applications on biologically relevant matrices, and for the creation of three-dimensional cell patterns in vitro. {\textcopyright} Mary Ann Liebert, Inc.},
	doi = {10.1089/ten.2005.11.701},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-21844469731\&doi=10.1089\%2ften.2005.11.701\&partnerID=40\&md5=be88d8ea0cf7133b35e457ace216e7a0},
	author = {Nahmias, Y. and Arneja, A. and Tower, T.T. and Renn, M.J. and Odde, D.J.}
}
@conference {Barbe20058927,
	title = {In-vitro model of hepatic ischemia/reperfusion injury},
	booktitle = {AIChE Annual Meeting, Conference Proceedings},
	year = {2005},
	note = {cited By 0},
	pages = {8927},
	abstract = {Ischemia-reperfusion (I/R) injury is the main cause of primary dysfunction or nonfunction after liver transplantation. Steatotic (i.e. fatty) livers comprise up to 25\% of the liver donor pool. Steatotic livers are more susceptible to cold or warm ischemia, suffer greater hepatocellular damage during reperfusion, and have impaired regeneration. These factors contribute to the increased postoperative complications and poor survival rates after transplantation or after resection surgery in experimental animals and humans with fatty livers. For example, patients receiving livers with mild-to-moderate steatosis, which are usually considered "marginally acceptable," have a 77\% survival 2 years posttransplantation compared with a 91\% survival in patients receiving nonsteatotic livers. The mechanisms underlying the high sensitivity of fatty livers to I/R injury are poorly understood. The motivation of this work is to develop an in vitro model of hepatic I/R so that the many potential factors involved can be decoupled. We cultured rat hepatocytes in the collagen sandwich configuration and made them fatty by exposure to fatty acid-supplemented culture medium. Cultures were exposed to defined periods of ischemia followed by normoxia and cell viability was determined. In some experiments, we co-cultured hepatocytes with nonparenchymal cells (NPCs) to determine the impact of these cells on the response. Results with cultured hepatocytes were consistent with in vivo studies. Fatty hepatocytes were more sensitive to I/R injury, as indicated by higher lactate dehydrogenase release when compared to lean hepatocytes. Hepatocyte damage increased as a function of duration of the ischemic period, and was highest during the reperfusion phase. Co-culture with Kupffer cells, which are known to be activated during I/R in vivo, exacerbated the damaging effect of I/R. This cell culture model will be useful to elucidate the mechanisms of I/R in the liver at the cellular level. Furthermore, this system may be a useful platform for high-throughput screening of treatments which could enhance the resistance of lean and fatty liver cells to I/R.},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-33645636548\&partnerID=40\&md5=50b4d7409fb38ac47519c649ebd8ae5e},
	author = {Barbe, L. and Tolboom, H. and Nahmias, Y. and Berthiaume, F. and Yarmush, M.}
}
@article {Nahmias2005129,
	title = {Laser-guided direct writing for three-dimensional tissue engineering},
	journal = {Biotechnology and Bioengineering},
	volume = {92},
	number = {2},
	year = {2005},
	note = {cited By 238},
	pages = {129-136},
	abstract = {One of the principal limitations to the size of an engineered tissue is oxygen and nutrient transport. Lacking a vascular bed, cells embedded in an engineered tissue will consume all available oxygen within hours while out branching blood vessels will take days to vascularize the implanted tissue. One possible solution is to directly write vascular structures within the engineered tissue prior to implantation, reconstructing the tissue according to its native architecture. The cell patterning technique, laser-guided direct writing (LGDW), can pattern multiple cells types with micrometer resolution on arbitrary surfaces, including biological gels. Here we show that LGDW can pattern human umbilical vein endothelial cells (HUVEC) in two- and three-dimensions with micrometer accuracy. By patterning HUVEC on Matrigel, we can direct their self-assembly into vascular structures along the desired pattern. Finally, co-culturing the vascular structures with hepatocytes resulted in an aggregated tubular structure similar in organization to a hepatic sinusoid. This capability can facilitate studies of tissue architecture at the single cell level, and of heterotypic interactions underlying processes such as liver and pancreas morphogenesis, differentiation, and angiogenesis. {\textcopyright} 2005 Wiley Periodicals, Inc.},
	doi = {10.1002/bit.20585},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-27744553784\&doi=10.1002\%2fbit.20585\&partnerID=40\&md5=be64928f18ac0071932ff97287504cfc},
	author = {Nahmias, Y. and Schwartz, R.E. and Verfaillie, C.M. and Odde, D.J.}
}
@article {Nahmias20043999,
	title = {Dimensionless parameters for the design of optical traps and laser guidance systems},
	journal = {Applied Optics},
	volume = {43},
	number = {20},
	year = {2004},
	note = {cited By 44},
	pages = {3999-4006},
	abstract = {Optical traps are routinely used for the manipulation of neutral particles. However, optical trap design is limited by the lack of an accurate theory. The generalized Lorenz-Mie theory (GLMT) solves the scattering problem for arbitrary particle size and predicts radial forces accurately. Here we show that the GLMT predicts the observed radial and axial forces in a variety of optical manipulators. We also present a dimensionless parameter β for the prediction of axial forces. Coupled with our correlation for radial escape forces, we now have a set of two simple correlations for the practical design of radiationforce-based systems. {\textcopyright} 2004 Optical Society of America.},
	doi = {10.1364/AO.43.003999},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-3142664585\&doi=10.1364\%2fAO.43.003999\&partnerID=40\&md5=8e2a1c2d7597c9d37dfc0a7cdc23d4ad},
	author = {Nahmias, Y.K. and Gao, B.Z. and Odde, D.J.}
}
@article {Nahmias2002131,
	title = {Analysis of radiation forces in laser trapping and laser-guided direct writing applications},
	journal = {IEEE Journal of Quantum Electronics},
	volume = {38},
	number = {2},
	year = {2002},
	note = {cited By 46},
	pages = {131-141},
	abstract = {Radiation forces allow the remote manipulation of physical objects. Two radiation force-based systems have been used, in particular: 1) laser trapping, which uses a strongly convergent beam to form a micrometer-sized focal point in which particles can be trapped and manipulated in three dimensions, and 2) laser guidance, which uses a weakly convergent beam to achieve radial confinement of particles about the beam axis coupled with pushing along the beam axis, which allows the high precision delivery of particles over hundreds of micrometers. Biological applications of laser trapping include high-precision molecular motor force measurement, and those of laser guidance include the direct writing of living cells in two and three dimensions for tissue engineering applications. The results presented here show that a general electromagnetic theory, the Generalized Lorenz-Mie Theory, is able to accurately predict experimental results for both schemes without any assumptions regarding the size of the particle relative to the wavelength of the radiation. In addition, radial forces are found to be directly correlated to the dimensionless particle size (a/ω) where the particle radius (a) is normalized over the beam radius (ω). The dimensionless particle size can be used to theoretically estimate radiation forces in any arbitrary setup, and facilitate the design of radiation force-based systems for a variety of applications in biology and medicine.},
	doi = {10.1109/3.980265},
	url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-0036477443\&doi=10.1109\%2f3.980265\&partnerID=40\&md5=4ab5df7db76a1e2a2569086021f9ffd9},
	author = {Nahmias, Y.K. and Odde, D.J.}
}
