Readily releasable β cells with tight Ca-exocytosis coupling dictate biphasic glucose-stimulated insulin secretion.

Biphasic glucose-stimulated insulin secretion (GSIS) is essential for blood glucose regulation, but a mechanistic model incorporating the recently identified islet β cell heterogeneity remains elusive. Here, we show that insulin secretion is spatially and dynamically heterogeneous across the islet. Using a zinc-based fluorophore with spinning-disc confocal microscopy, we reveal that approximately 40% of islet cells, which we call readily releasable β cells (RRβs), are responsible for 80% of insulin exocytosis events.

Pluripotency state transition of embryonic stem cells requires the turnover of histone chaperone FACT on chromatin.

The differentiation of embryonic stem cells (ESCs) begins with the transition from the naive to the primed state. The formative state was recently established as a critical intermediate between the two states. Here, we demonstrate the role of the histone chaperone FACT in regulating the naive-to-formative transition.

Intelligent prognosis evaluation system for stage I-III resected non-small-cell lung cancer patients on CT images: a multi-center study.

Background: Prognosis is crucial for personalized treatment and surveillance suggestion of the resected non-small-cell lung cancer (NSCLC) patients in stage I-III. Although the tumor-node-metastasis (TNM) staging system is a powerful predictor, it is not perfect enough to accurately distinguish all the patients, especially within the same TNM stage. In this study, we developed an intelligent prognosis evaluation system (IPES) using pre-therapy CT images to assist the traditional TNM staging system for more accurate prognosis prediction of resected NSCLC patients.

The N-terminus of Spt16 anchors FACT to MCM2-7 for parental histone recycling.

Parental histone recycling is vital for maintaining chromatin-based epigenetic information during replication, yet its underlying mechanisms remain unclear. Here, we uncover an unexpected role of histone chaperone FACT and its N-terminus of the Spt16 subunit during parental histone recycling and transfer in budding yeast. Depletion of Spt16 and mutations at its middle domain that impair histone binding compromise parental histone recycling on both the leading and lagging strands of DNA replication forks.

Determining subunit-subunit interaction from statistics of cryo-EM images: observation of nearest-neighbor coupling in a circadian clock protein complex.

Biological processes are typically actuated by dynamic multi-subunit molecular complexes. However, interactions between subunits, which govern the functions of these complexes, are hard to measure directly. Here, we develop a general approach combining cryo-EM imaging technology and statistical modeling and apply it to study the hexameric clock protein KaiC in Cyanobacteria.

Synthesis towards Phainanoid F: Photo-induced 6π-Electrocyclization for Constructing Contiguous All-Carbon Quaternary Centers.

In this paper, we report an efficient strategy for synthesizing the DEFGH rings of phainanoid F. The key to the construction of the 13,30-cyclodammarane skeleton of the molecule was a photo-induced 6π-electrocyclization and a homoallylic elimination. Notably, this is a rare example of using electrocyclization reaction to simultaneously construct two vicinal quaternary carbons in total synthesis.

Investigation of Peptide Labeling with -Phthalaldehyde and 2-Acylbenzaldehyde.

-Phthalaldehyde (OPA) with high reactivity to the amine group has been widely used to modify proteins. We discovered new modifications of OPA and 2-acylbenzaldehyde and proposed the reaction mechanism. Using isotope labeling mass spectrometry-based experiment, we identified new cross-linking properties of OPA and 2-acylbenzaldehyde.

Establishment of Digital PCR Method and Reference Material for Adenoviruses 40 and 41.

Coinfection with human adenovirus (HAdV) and SARS-CoV-2 has been associated with acute hepatitis in children with unknown etiology. Similar cases have been reported in many countries, and HAdV 40 and HAdV 41 have been identified. The quantification method is established based on digital PCR (dPCR) for HAdV 40/41, which is more convenient for low-concentration virus detection.

Deciphering a global source of non-genetic heterogeneity in cancer cells.

Cell-to-cell variability within a clonal population, also known as non-genetic heterogeneity, has created significant challenges for intervening with diseases such as cancer. While non-genetic heterogeneity can arise from the variability in the expression of specific genes, it remains largely unclear whether and how clonal cells could be heterogeneous in the expression of the entire transcriptome. Here, we showed that gene transcriptional activity is globally modulated in individual cancer cells, leading to non-genetic heterogeneity in the global transcription rate.

Deep-learning-enabled protein-protein interaction analysis for prediction of SARS-CoV-2 infectivity and variant evolution.

Host-pathogen interactions and pathogen evolution are underpinned by protein-protein interactions between viral and host proteins. An understanding of how viral variants affect protein-protein binding is important for predicting viral-host interactions, such as the emergence of new pathogenic SARS-CoV-2 variants. Here we propose an artificial intelligence-based framework called UniBind, in which proteins are represented as a graph at the residue and atom levels.

Structural basis of human Slo2.2 channel gating and modulation.

The sodium-activated Slo2.2 channel is abundantly expressed in the brain, playing a critical role in regulating neuronal excitability. The Na-binding site and the underlying mechanisms of Na-dependent activation remain unclear.

Total Synthesis of (+)-Haperforin G.

(+)-Haperforin G was synthesized in 20 steps from commercially available starting materials. A Co-catalyzed intramolecular Pauson-Khand reaction was used for stereoselective construction of cyclopentanone bearing an all-carbon quaternary stereogenic center at the bridge-head position. Light-initiated photocatalysis was used for convergent and asymmetric cross-coupling of the unstabilized C(sp) radical with an enone.

Microfluidic Approach for Modeling Coupled Circadian Clock.

In mammals, it is believed that the intercellular coupling mechanism between neurons in the suprachiasmatic nucleus (SCN) confers circadian robustness and distinguishes the central clock from peripheral circadian oscillators. Current in vitro culturing methods mainly work with Petri dishes to study intercellular coupling by exogenous factors and invariably cause perturbations, such as simple exchanges of media. Here, a microfluidic device is designed to quantitatively study the intercellular coupling mechanism of circadian clock at the single-cell level and to demonstrate that the vasoactive intestinal peptide (VIP)-induced coupling in clock mutant Cry1-/- mouse adult fibroblasts (MAF), which are engineered to express the VIP receptor (i.

Free energy dissipation enhances spatial accuracy and robustness of self-positioned Turing pattern in small biochemical systems.

Accurate and robust spatial orders are ubiquitous in living systems. In 1952, Turing proposed a general mechanism for pattern formation exemplified by a reaction-diffusion model with two chemical species in a large system. However, in small biological systems such as a cell, the existence of multiple Turing patterns and strong noise can lower the spatial order.

C-H Glycosylation of Native Carboxylic Acids: Discovery of Antidiabetic SGLT-2 Inhibitors.

-Glycosides are critical motifs embedded in many bioactive natural products. The inert -glycosides are privileged structures for developing therapeutic agents owing to their high chemical and metabolic stability. Despite the comprehensive strategies and tactics established in the past few decades, highly efficient -glycoside syntheses via C-C coupling with excellent regio-, chemo-, and stereoselectivity are still needed.

NFAT and NF-κB dynamically co-regulate TCR and CAR signaling responses in human T cells.

While it has been established that the responses of T cells to antigens are combinatorially regulated by multiple signaling pathways, it remains elusive what mechanisms cells utilize to quantitatively modulate T cell responses during pathway integration. Here, we show that two key pathways in T cell signaling, calcium/nuclear factor of activated T cells (NFAT) and protein kinase C (PKC)/nuclear factor κB (NF-κB), integrate through a dynamic and combinatorial strategy to fine-tune T cell response genes. At the cis-regulatory level, the two pathways integrate through co-binding of NFAT and NF-κB to immune response genes.

Deciphering molecular mechanisms of phase separation in RNA biology by single-molecule biophysical technologies.

Ribonucleic acid (RNA) biology has emerged as one of the most important areas in modern biology and biomedicine. RNA and RNA-binding proteins (RBPs) are involved in forming biomolecular condensates, which are crucial for RNA metabolism. To quantitively decipher the molecular mechanisms of RNP granules, researchers have turned to single-molecule biophysical techniques, such as single-molecule Förster resonance energy transfer (smFRET), single-molecule imaging technique with single particle tracking (SPT), DNA Curtains, optical tweezers, and atomic force microscopy (AFM).

Single-Molecule Force Spectroscopy Reveals Cation-π Interactions in Aqueous Media Are Highly Affected by Cation Dehydration.

Cation-π interactions underlie many important processes in biology and materials science. However, experimental investigations of cation-π interactions in aqueous media remain challenging. Here, we studied the cation-π binding strength and mechanism by pulling two hydrophobic polymers with distinct cation binding properties, i.

Homozygous Missense Variant in the N-Terminal Region of ANK3 Gene Is Associated with Developmental Delay, Seizures, Speech Abnormality, and Aggressive Behavior.

Introduction: Intellectual disability (ID) is a lifelong disability that affects an individual‧s learning capacity and adaptive behavior. Such individuals depend on their families for day-to-day survival and pose a significant challenge to the healthcare system, especially in developing countries. ID is a heterogeneous condition, and genetic studies are essential to unravel the underlying cellular pathway for brain development and functioning.

The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system.

Amyloid-like aggregates of the microtubule-associated protein Tau are associated with several neurodegenerative disorders including Alzheimer's disease. The existence of cellular machinery for the removal of such aggregates has remained unclear, as specialized disaggregase chaperones are thought to be absent in mammalian cells. Here we show in cell culture and in neurons that the hexameric ATPase valosin-containing protein (VCP) is recruited to ubiquitylated Tau fibrils, resulting in their efficient disaggregation.

Clinical genetics of spondylocostal dysostosis: A mini review.

Spondylocostal dysostosis is a genetic defect associated with severe rib and vertebrae malformations. In recent years, extensive clinical and molecular diagnosis advancements enabled us to identify disease-causing variants in different genes for such severe conditions. The identification of novel candidate genes enabled us to understand the developmental biology and molecular and cellular mechanisms involved in the etiology of these rare diseases.

A Complete Endocannabinoid Signaling System Modulates Synaptic Transmission between Human Induced Pluripotent Stem Cell-Derived Neurons.

The endocannabinoid system (ECS) modulates synaptic function to regulate many aspects of neurophysiology. It adapts to environmental changes and is affected by disease. Thus, the ECS presents an important target for therapeutic development.