Mitigating Ischemic Injury of Stem Cell-Derived Insulin-Producing Cells after Transplant.

The advent of large-scale in vitro differentiation of human stem cell-derived insulin-producing cells (SCIPC) has brought us closer to treating diabetes using stem cell technology. However, decades of experiences from islet transplantation show that ischemia-induced islet cell death after transplant severely limits the efficacy of the therapy. It is unclear to what extent human SCIPC are susceptible to ischemia. In this study, we show that more than half of SCIPC die shortly after transplantation. Nutrient deprivation and hypoxia acted synergistically to kill SCIPC in vitro. Amino acid supplementation rescued SCIPC from nutrient deprivation, likely by providing cellular energy. Generating SCIPC under physiological oxygen tension of 5% conferred hypoxia resistance without affecting their differentiation or function. A two-pronged strategy of physiological oxygen acclimatization during differentiation and amino acid supplementation during transplantation significantly improved SCIPC survival after transplant

Tunneling electroresistance effect in ferroelectric tunnel junctions at the nanoscale

Stable and switchable polarization of ferroelectric materials opens a possibility to electrically control their functional behavior. A particularly promising approach is to employ ferroelectric tunnel junctions where the polarization reversal in a ferroelectric barrier changes the tunneling current across the junction. Here, we demonstrate the reproducible tunneling electroresistance effect using a combination of Piezoresponse Force Microscopy (PFM) and Conducting Atomic Force Microscopy (C-AFM) techniques on nanometer-thick epitaxial BaTiO3 single crystal thin films on SrRuO3 bottom electrodes. Correlation between ferroelectric and electronic transport properties is established by the direct nanoscale visualization and control of polarization and tunneling current in BaTiO3 films. The obtained results show a change in resistance by about two orders of magnitude upon polarization reversal on a lateral scale of 20 nm at room temperature. These results are promising for employing ferroelectric tunnel junctions in non-volatile memory and logic devices, not involving charge as a state variable.Comment: 18 pages, 4 figure

Controlled induction of human pancreatic progenitors produces functional beta‐like cells in vitro

Directed differentiation of human pluripotent stem cells into functional insulin‐producing beta‐like cells holds great promise for cell replacement therapy for patients suffering from diabetes. This approach also offers the unique opportunity to study otherwise inaccessible aspects of human beta cell development and function in vitro. Here, we show that current pancreatic progenitor differentiation protocols promote precocious endocrine commitment, ultimately resulting in the generation of non‐functional polyhormonal cells. Omission of commonly used BMP inhibitors during pancreatic specification prevents precocious endocrine formation while treatment with retinoic acid followed by combined EGF/KGF efficiently generates both PDX1+ and subsequent PDX1+/NKX6.1+ pancreatic progenitor populations, respectively. Precise temporal activation of endocrine differentiation in PDX1+/NKX6.1+ progenitors produces glucose‐responsive beta‐like cells in vitro that exhibit key features of bona fide human beta cells, remain functional after short‐term transplantation, and reduce blood glucose levels in diabetic mice. Thus, our simplified and scalable system accurately recapitulates key steps of human pancreas development and provides a fast and reproducible supply of functional human beta‐like cells.SynopsisFocusing on developmental mechanisms, the results of this study further accelerate successful differentiation of human ESCs into functional pancreatic beta cells.Exclusion of commonly used BMP inhibitors during human embryonic stem cell to pancreatic progenitor differentiation prevents precocious endocrine induction.Sequential exposure of foregut cells to retinoic acid followed by combined EGF/KGF treatment establishes highly pure PDX1+ and PDX1+/NKX6.1+ progenitor populations, respectively.Precise temporal induction of endocrine differentiation in PDX1+/NKX6.1+ progenitors, but not in PDX1+/NKX6.1− progenitors, results in the generation of functional beta‐like cells in vitro.Beta‐like cells exhibit key features of bona fide human beta cells, remain functional after short‐term transplantation, and reduce blood glucose levels in diabetic mice.Focusing on developmental mechanisms, the results of this study further accelerate successful differentiation of human ESCs into functional pancreatic beta cells.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111932/1/embj201591058.reviewer_comments.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/111932/2/embj201591058.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/111932/3/embj201591058-sup-0001-FigsS1-S4.pd

Topological crystalline insulator states in Pb(1-x)Sn(x)Se

Topological insulators are a novel class of quantum materials in which time-reversal symmetry, relativistic (spin-orbit) effects and an inverted band structure result in electronic metallic states on the surfaces of bulk crystals. These helical states exhibit a Dirac-like energy dispersion across the bulk bandgap, and they are topologically protected. Recent theoretical proposals have suggested the existence of topological crystalline insulators, a novel class of topological insulators in which crystalline symmetry replaces the role of time-reversal symmetry in topological protection [1,2]. In this study, we show that the narrow-gap semiconductor Pb(1-x)Sn(x)Se is a topological crystalline insulator for x=0.23. Temperature-dependent magnetotransport measurements and angle-resolved photoelectron spectroscopy demonstrate that the material undergoes a temperature-driven topological phase transition from a trivial insulator to a topological crystalline insulator. These experimental findings add a new class to the family of topological insulators. We expect these results to be the beginning of both a considerable body of additional research on topological crystalline insulators as well as detailed studies of topological phase transitions.Comment: v2: published revised manuscript (6 pages, 3 figures) and supplementary information (5 pages, 8 figures

Anti-cancer drug validation: the contribution of tissue engineered models

Abstract Drug toxicity frequently goes concealed until clinical trials stage, which is the most challenging, dangerous and expensive stage of drug development. Both the cultures of cancer cells in traditional 2D assays and animal studies have limitations that cannot ever be unraveled by improvements in drug-testing protocols. A new generation of bioengineered tumors is now emerging in response to these limitations, with potential to transform drug screening by providing predictive models of tumors within their tissue context, for studies of drug safety and efficacy. Considering the NCI60, a panel of 60 cancer cell lines representative of 9 different cancer types: leukemia, lung, colorectal, central nervous system (CNS), melanoma, ovarian, renal, prostate and breast, we propose to review current Bstate of art^ on the 9 cancer types specifically addressing the 3D tissue models that have been developed and used in drug discovery processes as an alternative to complement their studyThis article is a result of the project FROnTHERA (NORTE-01-0145-FEDER-000023), supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). This article was also supported by the EU Framework Programme for Research and Innovation HORIZON 2020 (H2020) under grant agreement n° 668983 — FoReCaST. FCT distinction attributed to Joaquim M. Oliveira (IF/00423/2012) and Vitor M. Correlo (IF/01214/2014) under the Investigator FCT program is also greatly acknowledged.info:eu-repo/semantics/publishedVersio

Metabolic Regulation in Progression to Autoimmune Diabetes

Recent evidence from serum metabolomics indicates that specific metabolic disturbances precede β-cell autoimmunity in humans and can be used to identify those children who subsequently progress to type 1 diabetes. The mechanisms behind these disturbances are unknown. Here we show the specificity of the pre-autoimmune metabolic changes, as indicated by their conservation in a murine model of type 1 diabetes. We performed a study in non-obese prediabetic (NOD) mice which recapitulated the design of the human study and derived the metabolic states from longitudinal lipidomics data. We show that female NOD mice who later progress to autoimmune diabetes exhibit the same lipidomic pattern as prediabetic children. These metabolic changes are accompanied by enhanced glucose-stimulated insulin secretion, normoglycemia, upregulation of insulinotropic amino acids in islets, elevated plasma leptin and adiponectin, and diminished gut microbial diversity of the Clostridium leptum group. Together, the findings indicate that autoimmune diabetes is preceded by a state of increased metabolic demands on the islets resulting in elevated insulin secretion and suggest alternative metabolic related pathways as therapeutic targets to prevent diabetes

Wild vascular plants gathered for consumption in the Polish countryside: a review

BACKGROUND: This paper is an ethnobotanical review of wild edible plants gathered for consumption from the end of the 18(th )century to the present day, within the present borders of Poland. METHODS: 42 ethnographic and botanical sources documenting the culinary use of wild plants were analyzed. RESULTS: The use of 112 species (3.7% of the flora) has been recorded. Only half of them have been used since the 1960s. Three species: Cirsium rivulare, Euphorbia peplus and Scirpus sylvaticus have never before been reported as edible by ethnobotanical literature. The list of wild edible plants which are still commonly gathered includes only two green vegetables (Rumex acetosa leaves for soups and Oxalis acetosella as children's snack), 15 folk species of fruits and seeds (Crataegus spp., Corylus avellana, Fagus sylvatica, Fragaria vesca, Malus domestica, Prunus spinosa, Pyrus spp., Rosa canina, Rubus idaeus, Rubus sect. Rubus, Sambucus nigra, Vaccinium myrtillus, V. oxycoccos, V. uliginosum, V. vitis-idaea) and four taxa used for seasoning or as preservatives (Armoracia rusticana root and leaves, Carum carvi seeds, Juniperus communis pseudo-fruits and Quercus spp. leaves). The use of other species is either forgotten or very rare. In the past, several species were used for food in times of scarcity, most commonly Chenopodium album, Urtica dioica, U. urens, Elymus repens, Oxalis acetosella and Cirsium spp., but now the use of wild plants is mainly restricted to raw consumption or making juices, jams, wines and other preserves. The history of the gradual disappearance of the original barszcz, Heracleum sphondylium soup, from Polish cuisine has been researched in detail and two, previously unpublished, instances of its use in the 20(th )century have been found in the Carpathians. An increase in the culinary use of some wild plants due to media publications can be observed. CONCLUSION: Poland can be characterized as a country where the traditions of culinary use of wild plants became impoverished very early, compared to some parts of southern Europe. The present use of wild plants, even among the oldest generation, has been almost entirely restricted to fruits

National Institutes of Health–Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities

Eight manufacturing facilities participating in the National Institutes of Health–sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for the manufacture of allogeneic purified human pancreatic islet (PHPI) product evaluated in a phase 3 trial in subjects with type 1 diabetes. Manufacturing was controlled by a common master production batch record, standard operating procedures that included acceptance criteria for deceased donor organ pancreata and critical raw materials, PHPI product specifications, certificate of analysis, and test methods. The process was compliant with Current Good Manufacturing Practices and Current Good Tissue Practices. This report describes the manufacturing process for 75 PHPI clinical lots and summarizes the results, including lot release. The results demonstrate the feasibility of implementing a harmonized process at multiple facilities for the manufacture of a complex cellular product. The quality systems and regulatory and operational strategies developed by the CIT Consortium yielded product lots that met the prespecified characteristics of safety, purity, potency, and identity and were successfully transplanted into 48 subjects. No adverse events attributable to the product and no cases of primary nonfunction were observed

Women's Education Level, Maternal Health Facilities, Abortion Legislation and Maternal Deaths: A Natural Experiment in Chile from 1957 to 2007

The aim of this study was to assess the main factors related to maternal mortality reduction in large time series available in Chile in context of the United Nations' Millennium Development Goals (MDGs).Time series of maternal mortality ratio (MMR) from official data (National Institute of Statistics, 1957-2007) along with parallel time series of education years, income per capita, fertility rate (TFR), birth order, clean water, sanitary sewer, and delivery by skilled attendants were analysed using autoregressive models (ARIMA). Historical changes on the mortality trend including the effect of different educational and maternal health policies implemented in 1965, and legislation that prohibited abortion in 1989 were assessed utilizing segmented regression techniques.During the 50-year study period, the MMR decreased from 293.7 to 18.2/100,000 live births, a decrease of 93.8%. Women's education level modulated the effects of TFR, birth order, delivery by skilled attendants, clean water, and sanitary sewer access. In the fully adjusted model, for every additional year of maternal education there was a corresponding decrease in the MMR of 29.3/100,000 live births. A rapid phase of decline between 1965 and 1981 (-13.29/100,000 live births each year) and a slow phase between 1981 and 2007 (-1.59/100,000 live births each year) were identified. After abortion was prohibited, the MMR decreased from 41.3 to 12.7 per 100,000 live births (-69.2%). The slope of the MMR did not appear to be altered by the change in abortion law.Increasing education level appears to favourably impact the downward trend in the MMR, modulating other key factors such as access and utilization of maternal health facilities, changes in women's reproductive behaviour and improvements of the sanitary system. Consequently, different MDGs can act synergistically to improve maternal health. The reduction in the MMR is not related to the legal status of abortion