Human umbilical cord-derived mesenchymal stem cells alleviate oxidative stress-induced islet impairment via the Nrf2/HO-1 axis

Hyperglycaemia-induced oxidative stress may disrupt insulin secretion andβ-cell survival in diabetes mellitus by overproducing reactive oxygen species.Human umbilical cord-derived mesenchymal stem cells(hUC-MSCs)exhibit antioxidant properties.However,the mechanisms by which hUC-MSCs protectβ-cells from high glucose-induced oxidative stress remain underexplored.In this study,we showed that intravenously injected hUC-MSCs engrafted into the injured pancreas and promoted pancreaticβ-cell function in a mouse model of type 1 diabetes mellitus.The in vitro study revealed that hUC-MSCs attenuated high glucoseinduced oxidative stress and preventedβ-cell impairment via the Nrf2/HO-1 signalling pathway.Nrf2 knockdown partially blocked the anti-oxidative effect of hUC-MSCs,resulting inβ-cell decompensation in a high-glucose environment.Overall,these findings provide novel insights into how hUC-MSCs protectβ-cells from high glucose-induced oxidative stress.

Peripheral actions and direct central-local communications of melanocortin 4 receptor signaling

Melanocortin 4 receptor(MC4R),the most important monogenetic cause of human metabolic disorders,has been of great interest to many researchers in the field of energy homeostasis and public health.Because MC4R is a vital pharmaceutical target for maintaining controllable appetite and body weight for professional athletes,previous studies have mainly focused on the central,rather than the peripheral,roles of MC4R.Thus,the local expression of MC4R and its behavioral regulation remain unclear.In an attempt to shed light on different directions for future studies of MC4R signaling,we review a series of recent and important studies exploring the peripheral functions of MC4R and the direct physiological interaction between peripheral organs and central MC4R neurons in this article.

Privacy-preserving integration of multiple institutional data for single-cell type identification with scPrivacy

The rapid accumulation of large-scale single-cell RNA-seq datasets from multiple institutions presents remarkable opportunities for automatically cell annotations through integrative analyses.However,the privacy issue has existed but being ignored,since we are limited to access and utilize all the reference datasets distributed in different institutions globally due to the prohibited data transmission across institutions by data regulation laws.To this end,we present scPrivacy,which is the first and generalized automatically single-cell type identification prototype to facilitate single cell annotations in a data privacy-preserving collaboration manner.We evaluated scPrivacy on a comprehensive set of publicly available benchmark datasets for single-cell type identification to stimulate the scenario that the reference datasets are rapidly generated and distributed in multiple institutions,while they are prohibited to be integrated directly or exposed to each other due to the data privacy regulations,demonstrating its effectiveness,time efficiency and robustness for privacy-preserving integration of multiple institutional datasets in single cell annotations.

DJ-1 is dispensable for human stem cell homeostasis

Dear Editor,Safeguard!ng cellular redox homeostasis is crucial for maintaining organism health and preventing diseases.Oxidative stress,often characterized by decreased mitochondrial integrity and increased reactive oxygen species(ROS)product!on,disrupts proteostasis and genomic stability,which may eventually lead to cellular decomposition(Oh et al.,2014).Stem cells(such as mesenchymal stem cells,MSCs,and neural stem cells,NSCs)are susceptible to various external and internal stresses,and their dysfunction con tributes to aging and agin g-related diseases.Thus,it is of importance to elucidate the complex signaling networks regulated by oxidative stress in stem cells.Although redox signaling has been implicated in multiple cellular processes,how the redox system functions in various human stem cells is unclear.

The expanded development and application of CRISPR system for sensitive nucleotide detection

CRISPR/Cas system,originally developed as genetic editing tool,also shows great potentials for nucleotide detection.A recent study published in Molecular Cell(Freije et al.,2019)developed a Cas13a-based CARVER(Cas13-assisted restriction of viral expression and readout)to detect RNA viruses such as lymphocytic choriomeningitis,influenza A and vesicular stomatitis,which provided a potential expanded application for the detection of a broad range of viral nucleotides in disease diagnosis.

MEMOIR: A Novel System for Neural Lineage Tracing

Memory by Engineered Mutagenesis with Optical In situ Readout（MEMOIR）is a novel strategy for lineage tracing that combines Cas9/g RNA and sequential multiplexed single-molecule RNA fluorescence hybridization（seqFISH）[1],which was created by Cai Long et al.at the California Institute of Technology[2].In MEMOIR,dynamic cellular event histories are recorded,then read out in single cells using seq FISH.Here,we introduce the

Systematic Exploration of Optimized Base Editing gRNA Design and Pleiotropic Effects with BExplorer

Base editing technology is being increasingly applied in genome engineering,but the current strategy for designing guide RNAs(gRNAs)relies substantially on empirical experience rather than a dependable and efficient in silico design.Furthermore,the pleiotropic effect of base editing on disease treatment remains unexplored,which prevents its further clinical usage.Here,we presented BExplorer,an integrated and comprehensive computational pipeline to optimize the design of gRNAs for 26 existing types of base editors in silico.Using BExplorer,we described its results for two types of mainstream base editors,BE3 and ABE7.10,and evaluated the pleiotropic effects of the corresponding base editing loci.BExplorer revealed 524 and 900 editable pathogenic single nucleotide polymorphism(SNP)loci in the human genome together with the selected optimized gRNAs for BE3 and ABE7.10,respectively.In addition,the impact of 707 edited pathogenic SNP loci following base editing on 131 diseases was systematically explored by revealing their pleiotropic effects,indicating that base editing should be carefully utilized given the potential pleiotropic effects.Collectively,the systematic exploration of optimized base editing gRNA design and the corresponding pleiotropic effects with BExplorer provides a computational basis for applying base editing in disease treatment.

Bilineage embryo-like structure from EPS cells can produce live mice with tetraploid trophectoderm

Self-organized blastoids from extended pluripotent stem(EPs)cells possess enormous potential for investigating postimplantation embryo development and related diseases.However,the limited ability of postimplantation development of Eps-blastoids hinders its further application.In this study,single-cell transcriptomic analysis indicated that the“trophectoderm(TE)-like structure”of EPSblastoids was primarily composed of primitive endoderm(PrE)-related cells instead of TE-related cells.We further identified PrE-like cells in EPS cell culture that contribute to the blastoid formation with TE-like structure.Inhibition of PrE cell differentiation by inhibiting MEK signaling or knockout of Gata6 in EPS cells markedly suppressed EPS-blastoid formation.Furthermore,we demonstrated that blastocyst-like structures reconstituted by combining the EPs-derived bilineage embryo-like structure(BLEs)with either tetraploid embryos or tetraploid TE cells could implant normally and develop into live fetuses.In summary,our study reveals that TE improvement is critical for constructing a functional embryo using stem cells in vitro.

Single-cell RNA Sequencing Reveals Sexually Dimorphic Transcriptome and Type 2 Diabetes Genes in Mouse Islet β Cells

Type 2 diabetes(T2D)is characterized by the malfunction of pancreaticβcells.Susceptibility and pathogenesis of T2D can be affected by multiple factors,including sex differences.However,the mechanisms underlying sex differences in T2D susceptibility and pathogenesis remain unclear.Using single-cell RNA sequencing(scRNA-seq),we demonstrate the presence of sexually dimorphic transcriptomes in mouseβcells.Using a high-fat diet-induced T2D mouse model,we identified sex-dependent T2D altered genes,suggesting sex-based differences in the pathological mechanisms of T2D.Furthermore,based on islet transplantation experiments,we found that compared to mice with sexmatched islet transplants,sex-mismatched islet transplants in healthy mice showed down-regulation of genes involved in the longevity regulating pathway ofβcells.Moreover,the diabetic mice with sex-mismatched islet transplants showed impaired glucose tolerance.These data suggest sexual dimorphism in T2D pathogenicity,indicating that sex should be considered when treating T2D.We hope that our findings could provide new insights for the development of precision medicine in T2D.

DrSim: Similarity Learning for Transcriptional Phenotypic Drug Discovery

Transcriptional phenotypic drug discovery has achieved great success,and various compound perturbation-based data resources,such as connectivity map(CMap)and library of integrated network-based cellular signatures(LINCS),have been presented.Computational strategies fully mining these resources for phenotypic drug discovery have been proposed.Among them,the fundamental issue is to define the proper similarity between transcriptional profiles.Traditionally,such similarity has been defined in an unsupervised way.However,due to the high dimensionality and the existence of high noise in high-throughput data,similarity defined in the traditional way lacks robustness and has limited performance.To this end,we present Dr Sim,which is a learning-based framework that automatically infers similarity rather than defining it.We evaluated Dr Sim on publicly available in vitro and in vivo datasets in drug annotation and repositioning.The results indicated that Dr Sim outperforms the existing methods.In conclusion,by learning transcriptional similarity,Dr Sim facilitates the broad utility of high-throughput transcriptional perturbation data for phenotypic drug discovery.The source code and manual of Dr Sim are available at https://github.com/bm2-lab/Dr Sim/.

Single-cell transcriptomics of cardiac progenitors reveals functional subpopulations and their cooperative crosstalk in cardiac repair

Dear Editor,Myocardial infarction is one of the leading causes of morbidity and mortality.Stem/progenitor cells therapy has emerged as a promising strategy for the cardiac repair,especially those derived from cardiac tissue,have attracted worldwide attention(Tompkins et al.,2018).However,challenges and controversies remain in characterizing functional progenitors and explaining their mechanisms of action.

The excessive response： a preparation for harder conditions

Reactive oxygen species （ROS） are kinds of reactive chemicals mainly formed in mitochondria as byproduct of normal metabolism of oxygen （Balaban et al., 2005）. Because of the high reactiveness they usually react with proteins, lipid, and nuclear acids （Labuschagne and Brenkman, 2013; Landolfo et al., 2008）, and in theory may participate in every aspects of cellular metabolism.

HPC-Atlas:Computationally Constructing A Comprehensive Atlas of Human Protein Complexes

A fundamental principle of biology is that proteins tend to form complexes to play important roles in the core functions of cells.For a complete understanding of human cellular functions,it is crucial to have a comprehensive atlas of human protein complexes.Unfortunately,we still lack such a comprehensive atlas of experimentally validated protein complexes,which prevents us from gaining a complete understanding of the compositions and functions of human protein complexes,as well as the underlying biological mechanisms.To fill this gap,we built Human Protein Complexes Atlas(HPC-Atlas),as far as we know,the most accurate and comprehensive atlas of human protein complexes available to date.We integrated two latest protein interaction networks,and developed a novel computational method to identify nearly 9000 protein complexes,including many previously uncharacterized complexes.Compared with the existing methods,our method achieved outstanding performance on both testing and independent datasets.Furthermore,with HPC-Atlas we identified 751 severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)-affected human protein complexes,and 456 multifunctional proteins that contain many potential moonlighting proteins.These results suggest that HPC-Atlas can serve as not only a computing framework to effectively identify biologically meaningful protein complexes by integrating multiple protein data sources,but also a valuable resource for exploring new biological findings.The HPCAtlas webserver is freely available at http://www.yulpan.top/HPC-Atlas.

Activation of the Melanocortin-4 receptor signaling byα-MSH stimulates nervedependent mouse digit regeneration

Background:Expression of Mc4r in peripheral organs indicates it has broader roles in organ homeostasis and regeneration.However,the expression and function of Mc4r in the mouse limb and digit has not been fully investigated.Our previous work showed that Mc4r−/−mice fail to regenerate the digit,but whether activation of MC4R signaling could rescue digit regeneration,or stimulate proximal digit regeneration is not clear.Results:We analyzed the expression dynamics of Mc4r in the embryonic and postnatal mouse limb and digit using the Mc4r-gfp mice.We found that Mc4r-GFP is mainly expressed in the limb nerves,and in the limb muscles that are undergoing secondary myogenesis.Expression of Mc4r-GFP in the adult mouse digit is restricted to the nail matrix.We also examined the effect ofα-MSH on mouse digit regeneration.We found that administration ofα-MSH in the Mc4r+/−mice rescue the delayed regeneration of distal digit tip.α-MSH could rescue distal digit regeneration in denervated hindlimbs.In addition,α-MSH could stimulate regeneration of the proximally amputated digit,which is non-regenerative.Conclusions:Mc4r expression in the mouse limb and digit is closely related to nerve tissues,andα-MSH/MC4R signaling has a neurotrophic role in mouse digit tip regeneration.

基于分子机制的CRISPR-Cas9靶向效应预测

The CRISPR-Cas9 system,serving as a powerful genome-editing technology,has revolutionized the life sciences.However,it exhibits off-target activities that may present severe problems in clinical applications.Although a great number of in silico models have been developed to predict CRISPR targeting efficiency and specificity,they are running into a bottleneck with the lack of a mechanistic understanding of the on-and off-target activities of Cas9.

β-Catenin Deletion in Regional Neural Progenitors Leads to Congenital Hydrocephalus in Mice

Congenital hydrocephalus is a major neurological disorder with high rates of morbidity and mortality;however,the underlying cellular and molecular mechanisms remain largely unknown.Reproducible animal models mirroring both embryonic and postnatal hydrocephalus are also limited.Here,we describe a new mouse model of congenital hydrocephalus through knockout ofβ-catenin in Nkx2.1-expressing regional neural progenitors.Progressive ventriculomegaly and an enlarged brain were consistently observed in knockout mice from embryonic day 12.5 through to adulthood.Transcriptome profiling revealed severe dysfunctions in progenitor maintenance in the ventricular zone and therefore in cilium biogenesis afterβ-catenin knockout.Histological analyses also revealed an aberrant neuronal layout in both the ventral and dorsal telencephalon in hydrocephalic mice at both embryonic and postnatal stages.Thus,knockout ofβ-catenin in regional neural progenitors leads to congenital hydrocephalus and provides a reproducible animal model for studying pathological changes and developing therapeutic interventions for this devastating disease.

BMAL1 functions as a cAMP-responsive coactivator of HDAC5 to regulate hepatic gluconeogenesis

Dear Editor, Gluconeogenesis is one of the major mechanisms to main- tain hepatic glucose homeostasis and dysregulation of hepatic gluconeogenesis contributes to hyperglycemia in type 2 diabetes. Under fasted conditions, increases in cir- culating glucagon promote hepatic glucose production through activation of gluconeogenic pathway by HDAC5 and CREB coactivator CRTC2 （Lv et al., 2016; Lv et al., 2017; Qiu et al., 2017）. The circadian clock coordinates behavior and metabolism into rhythms not only in the central hypothalamus but also in peripheral tissues （Marcheva et al., 2010; Vollmers et al., 2009）. Transcription factor BMAL1 heterodimerizes with CLOCK to activate the expression of Per and Cry, which in turn suppress CLOCK/BMAL1 activity （Reppert ＆ Weaver, 2002）. Although BMAL1 knockout mice show fasting hypoglycemia （Rudic et al., 2004）, the detailed mechanism of BMAL1 regulation on hepatic gluco- neogenesis has not been thoroughly understood.

Synthetic Analogues of Betulinic Acid as Potent Inhibitors of PS1/BACE1 Interaction to Reduce Aβ Generation

The lupane-type triterpenoids are endowed with a wide range of biological activities such as antiviral, anti-inflammatory and anticancer activity. We describe here its potential application in Alzheimer＇s disease （AD） treatment as an inhibitor of PS1/BACE1 interaction. 3-a-Akebonoic acid, which emanated from a high throughput screening （HTS）, was discovered to interfere with P S 1/BACE 1 interaction and reduce amyloid β-protein （Aβ） production. In view of the limited source, we instead used naturally rich betulinic acid （compound 2） as starting material for lead optimization and a focused library of its derivatives was constructed to gain a better understanding of the structure activity relationship （SAR） of triterpenoid-type inhibitor of PS1/BACE1 interaction. Compound 22 was finally chosen as the most potent PS 1/BACE 1 interaction inhibitor, which reduced Aβgeneration effectively.

X-MOL:多样化药物小分子设计的大规模预训练模型

In silico modeling and analysis of small molecules substantially accelerates the process of drug development. Representing and understanding molecules is the fundamental step for various in silico molecular analysis tasks. Traditionally, these molecular analysis tasks have been investigated individually and separately.

CRISPR-mediated gene editing to rescue haploinsufficient obesity syndrome

CRISPR and adeno-associated virus are becoming powerful tools to remedy genetic disorders in somatic cells of adulthood.A recent study published in Science(Matharu et al.,2019)safely targeted the non-coding genomic region of Sim1 and MC4R with rAAV packed with CRISPRa,and successfully rescued the obesity syndrome caused by hap?loinsufficiency in a murine model,which shed light on their potential therapeutic applications in the future(Matharu et al.,2019).