Diabetes cell replacement therapy has the potential to be transformed by human pluripotent stem cell-derived β cells (SC-β cells). However, the precise identity of SC-β cells in relationship to ...primary fetal and adult β-cells remains unclear. Here, we used single-cell sequencing datasets to characterize the transcriptional identity of islets from in vitro differentiation, fetal islets, and adult islets. Our analysis revealed that SC-β cells share a core β-cell transcriptional identity with human adult and fetal β-cells, however SC-β cells possess a unique transcriptional profile characterized by the persistent expression and activation of progenitor and neural-biased gene networks. These networks are present in SC-β cells, irrespective of the derivation protocol used. Notably, fetal β-cells also exhibit this neural signature at the transcriptional level. Our findings offer insights into the transcriptional identity of SC-β cells and underscore the need for further investigation of the role of neural transcriptional networks in their development.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Growth differentiation factor 15 (GDF15), a distant member of the transforming growth factor (TGF)-β family, is a secreted protein that circulates as a 25-kDa dimer. In humans, elevated GDF15 ...correlates with weight loss, and the administration of GDF15 to mice with obesity reduces body weight, at least in part, by decreasing food intake. The mechanisms through which GDF15 reduces body weight remain poorly understood, because the cognate receptor for GDF15 is unknown. Here we show that recombinant GDF15 induces weight loss in mice fed a high-fat diet and in nonhuman primates with spontaneous obesity. Furthermore, we find that GDF15 binds with high affinity to GDNF family receptor α-like (GFRAL), a distant relative of receptors for a distinct class of the TGF-β superfamily ligands. Gfral is expressed in neurons of the area postrema and nucleus of the solitary tract in mice and humans, and genetic deletion of the receptor abrogates the ability of GDF15 to decrease food intake and body weight in mice. In addition, diet-induced obesity and insulin resistance are exacerbated in GFRAL-deficient mice, suggesting a homeostatic role for this receptor in metabolism. Finally, we demonstrate that GDF15-induced cell signaling requires the interaction of GFRAL with the coreceptor RET. Our data identify GFRAL as a new regulator of body weight and as the bona fide receptor mediating the metabolic effects of GDF15, enabling a more comprehensive assessment of GDF15 as a potential pharmacotherapy for the treatment of obesity.
Insulin-producing β cells created from human pluripotent stem cells have potential as a therapy for insulin-dependent diabetes, but human pluripotent stem cell-derived islets (SC-islets) still differ ...from their in vivo counterparts. To better understand the state of cell types within SC-islets and identify lineage specification deficiencies, we used single-nucleus multi-omic sequencing to analyse chromatin accessibility and transcriptional profiles of SC-islets and primary human islets. Here we provide an analysis that enabled the derivation of gene lists and activity for identifying each SC-islet cell type compared with primary islets. Within SC-islets, we found that the difference between β cells and awry enterochromaffin-like cells is a gradient of cell states rather than a stark difference in identity. Furthermore, transplantation of SC-islets in vivo improved cellular identities overtime, while long-term in vitro culture did not. Collectively, our results highlight the importance of chromatin and transcriptional landscapes during islet cell specification and maturation.
Diabetes cell replacement therapy has the potential to be transformed by human pluripotent stem cell-derived beta cells (SC-beta cells). However, the precise identity of SC-beta cells in relationship ...to primary fetal and adult beta-cells remains unclear. Here, we used single-cell sequencing datasets to characterize the transcriptional identity of islets from in vitro differentiation, fetal islets, and adult islets. Our analysis revealed that SC-beta cells share a core beta-cell transcriptional identity with human adult and fetal beta-cells, however SC-beta cells possess a unique transcriptional profile characterized by the persistent expression and activation of progenitor and neural-biased gene networks. These networks are present in SC-beta cells, irrespective of the derivation protocol used. Notably, fetal beta-cells also exhibit this neural signature at the transcriptional level. Our findings offer insights into the transcriptional identity of SC-beta cells and underscore the need for further investigation of the role of neural transcriptional networks in their development.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A major challenge for the development of a highly effective AIDS vaccine is the identification of mechanisms of protective immunity. To address this question, we used a nonhuman primate challenge ...model with simian immunodeficiency virus (SIV). We show that antibodies to the SIV envelope are necessary and sufficient to prevent infection. Moreover, sequencing of viruses from breakthrough infections revealed selective pressure against neutralization-sensitive viruses; we identified a two-amino-acid signature that alters antigenicity and confers neutralization resistance. A similar signature confers resistance of human immunodeficiency virus (HIV)-1 to neutralization by monoclonal antibodies against variable regions 1 and 2 (V1V2), suggesting that SIV and HIV share a fundamental mechanism of immune escape from vaccine-elicited or naturally elicited antibodies. These analyses provide insight into the limited efficacy seen in HIV vaccine trials.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The emergence of highly transmissible SARS-CoV-2 variants of concern (VOCs) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. ...We identified four receptor binding domain-targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 23 variants, including the B.1.1.7, B.1.351, P.1, B.1.429, B.1.526, and B.1.617 VOCs. Two antibodies are ultrapotent, with subnanomolar neutralization titers half-maximal inhibitory concentration (IC
) 0.3 to 11.1 nanograms per milliliter; IC
1.5 to 34.5 nanograms per milliliter). We define the structural and functional determinants of binding for all four VOC-targeting antibodies and show that combinations of two antibodies decrease the in vitro generation of escape mutants, suggesting their potential in mitigating resistance development.
Massively parallel DNA sequencing technologies provide an unprecedented ability to screen entire genomes for genetic changes associated with tumour progression. Here we describe the genomic analyses ...of four DNA samples from an African-American patient with basal-like breast cancer: peripheral blood, the primary tumour, a brain metastasis and a xenograft derived from the primary tumour. The metastasis contained two de novo mutations and a large deletion not present in the primary tumour, and was significantly enriched for 20 shared mutations. The xenograft retained all primary tumour mutations and displayed a mutation enrichment pattern that resembled the metastasis. Two overlapping large deletions, encompassing CTNNA1, were present in all three tumour samples. The differential mutation frequencies and structural variation patterns in metastasis and xenograft compared with the primary tumour indicate that secondary tumours may arise from a minority of cells within the primary tumour.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Compositional variations of peridotites from the Cretaceous ophiolites in southern Turkey and Northern Cyprus are presented to document the nature of partial melting and possible effects of reactive ...dissolution of primary mantle phases during fore-arc spreading. The peridotites overall exhibit a range of 187Os/188Os ratios from 0.1171 to 0.1266 and appear to represent a mantle region that preserves a record of ancient melt depletion. The samples are depleted in 187Os/188Os compared to the ambient oceanic upper mantle (187Os/188Os ~0.127), suggesting that they are representatives of a shallow fore-arc mantle where transport of radiogenic 187Os during slab dehydration was limited. Chemical variations of primary mantle minerals indicate that the peridotites are the residues of moderate to high degrees (>16%) of partial melting and have experienced significant modal and chemical compositional modification through interaction with oxidizing hydrous basaltic melts. Interacting melts, which appear to be similar in composition to primitive arc tholeiite, are likely to have originated from sub-lithospheric lower part of the mantle wedge during early stages of fore-arc spreading and migrated upward to react with variably depleted harzburgites to induce further melting in the overlying lithospheric mantle through open-system reactive flow. This second stage melting resulted in (1) common occurrence of reactive harzburgites and dunites by incongruent melting of orthopyroxene and crystallization of olivine through interaction with olivine saturated melt; and (2) local development of refertilized peridotites by shallower melt impregnation that involves interaction with olivine + clinopyroxene saturated melt. The dissolution of orthopyroxene caused the reacting melt to be enriched in silica and diluted in incompatible elements which led to the production of the final melts similar in composition to fore arc basalt and boninite. Involvement of compositionally variable mantle and melt components with different rates of melt influx therefore appears to explain the generation of fore-arc crust with a range of diverse rock suites including temporally and spatially associated arc tholeiites and boninites with significant depletion in incompatible elements.
•Peridotites from the Eastern Mediterranean ophiolites have depleted 187Os/188Os.•Geochemical variations reflect lithosphere evolution in fore-arc setting.•Mineral chemistry indicate significant effects of reactive melt inflow.•Reactive melting leads to the formation of incompatible element depleted melt.•Reactive dissolution of orthopyroxene produces fore-arc basalts.
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