DAXX is associated with early recurrence of pancreatic neuroendocrine tumors after R0 resection.

Introduction: ATRX, DAXX, MEN1, and PTEN mutations are proposed drivers of pancreatic neuroendocrine tumor tumorigenesis and independent prognostic factors for metastasis and mortality. However, their implications after R0 resection remain debated. Thus, we sought to identify genomic signatures of pancreatic neuroendocrine tumor disease-specific mortality and recurrence after surgery for curative intent.

Single-cell transcriptomic profiling of human pancreatic islets reveals genes responsive to glucose exposure over 24 h.

Aims/hypothesis: Disruption of pancreatic islet function and glucose homeostasis can lead to the development of sustained hyperglycaemia, beta cell glucotoxicity and subsequently type 2 diabetes. In this study, we explored the effects of in vitro hyperglycaemic conditions on human pancreatic islet gene expression across 24 h in six pancreatic cell types: alpha; beta; gamma; delta; ductal; and acinar. We hypothesised that genes associated with hyperglycaemic conditions may be relevant to the onset and progression of diabetes.

Functional interrogation of twenty type 2 diabetes-associated genes using isogenic human embryonic stem cell-derived β-like cells.

Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional roles of many loci remain unexplored. Here, we engineered isogenic knockout human embryonic stem cell lines for 20 genes associated with T2D risk. We examined the impacts of each knockout on β cell differentiation, functions, and survival.

Functional interrogation of twenty type 2 diabetes-associated genes using isogenic hESC-derived β-like cells.

Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional role of many loci has remained unexplored. In this study, we engineered isogenic knockout human embryonic stem cell (hESC) lines for 20 genes associated with T2D risk. We systematically examined β-cell differentiation, insulin production and secretion, and survival.

A multi-organoid platform identifies CIART as a key factor for SARS-CoV-2 infection.

COVID-19 is a systemic disease involving multiple organs. We previously established a platform to derive organoids and cells from human pluripotent stem cells to model SARS-CoV-2 infection and perform drug screens. This provided insight into cellular tropism and the host response, yet the molecular mechanisms regulating SARS-CoV-2 infection remain poorly defined.

Two-Dimensional Detergent Expansion Strategy for Membrane Protein Studies.

Detergents are the most frequently applied reagents in membrane protein (MP) studies. The limited diversity of one-head-one-tailed traditional detergents, however, is far from sufficient for structurally distinct MPs. Expansion of detergent repertoire has a continuous momentum.

Ugi Reaction Mediated Detergent Assembly for Membrane Protein Studies.

Despite the continuous efforts, the current repertoire of detergents is still far from sufficient for the biophysics studies of membrane proteins (MPs). Toward the rapid expansion of detergent diversity, we herein report a new strategy based on Ugi reaction mediated modular assembly. Structural varieties, including hydrophobic tails and hydrophilic heads, could be conveniently introduced from the multiple reaction components.

Structure-Activity Relationship Studies of Hydantoin-Cored Ligands for Smoothened Receptor.

An underside binding site was recently identified in the transmembrane domain of smoothened receptor (SMO). Herein, we report efforts in the exploration of new insights into the interactions between the ligand and SMO. The hydantoin core in the middle of the parent compound was found to be highly conservative in chirality, ring size, and substituents.

Elucidation of Distinct Modular Assemblies of Smoothened Receptor by Bitopic Ligand Measurement.

Class F G protein-coupled receptors are characterized by a large extracellular domain (ECD) in addition to the common transmembrane domain (TMD) with seven α-helixes. For smoothened receptor (SMO), structural studies revealed dissected ECD and TMD, and their integrated assemblies. However, distinct assemblies were reported under different circumstances.

Rational Remodeling of Atypical Scaffolds for the Design of Photoswitchable Cannabinoid Receptor Tools.

Azobenzene-embedded photoswitchable ligands are the widely used chemical tools in photopharmacological studies. Current approaches to azobenzene introduction rely mainly on the isosteric replacement of typical azologable groups. However, atypical scaffolds may offer more opportunities for photoswitch remodeling, which are chemically in an overwhelming majority.

Catalytically Cleavable Detergent for Membrane Protein Studies.

Throughout the studies of membrane proteins (MPs), proper detergents are essential for the preparation of stable aqueous samples. To date, universally applicable detergents have not yet been reported to accommodate the distinct requirements for the highly diversified MPs and at the different stages of MP manipulation. Detergent exchange often has to be performed.

SARS-CoV-2 infection induces beta cell transdifferentiation.

Recent clinical data have suggested a correlation between coronavirus disease 2019 (COVID-19) and diabetes. Here, we describe the detection of SARS-CoV-2 viral antigen in pancreatic beta cells in autopsy samples from individuals with COVID-19. Single-cell RNA sequencing and immunostaining from ex vivo infections confirmed that multiple types of pancreatic islet cells were susceptible to SARS-CoV-2, eliciting a cellular stress response and the induction of chemokines.

Disulfide-Containing Detergents (DCDs) for the Structural Biology of Membrane Proteins.

Disulfide-containing detergents (DCDs) are introduced, which contain a disulfide bond in the hydrophobic tail. DCDs form smaller micelles than corresponding detergents with linear hydrocarbon chains, while providing good solubilization and reconstitution of membrane proteins. The use of this new class of detergents in structural biology is illustrated with solution NMR spectra of the human G protein-coupled receptor A AR, which is an α-helical protein, and the β-barrel protein OmpX from E.

The structure-based traceless specific fluorescence labeling of the smoothened receptor.

The smoothened receptor (SMO) mediates the hedgehog (Hh) signaling pathway and plays a vital role in embryonic development and tumorigenesis. The visualization of SMO has the potential to provide new insights into its enigmatic mechanisms and associated disease pathogenesis. Based on recent progress in structural studies of SMO, we have designed and characterized a group of affinity probes to facilitate the turn-on fluorescence labeling of SMO at the ε-amine of K395.

A Chemical Strategy for Amphiphile Replacement in Membrane Protein Research.

Membrane mimics are indispensable tools in the structural and functional understanding of membrane proteins (MPs). Given stringent requirements of integral MP manipulations, amphiphile replacement is often required in sample preparation for various biophysical purposes. Current protocols generally rely on physical methodologies and rarely reach complete replacement.

A structurally guided dissection-then-evolution strategy for ligand optimization of smoothened receptor.

We present herein a novel dissection-then-evolution strategy for ligand optimization. Using the co-crystal structure of the smoothened receptor (SMO) as a guide, we studied the modular contribution of LY2940680 by systematically "silencing" the specific interaction between the individual residue(s) and the fragment in the ligand. Following evolution by focusing on the benzoyl part finally yielded an improved ligand .