唯一极值拟共形映射的Reich序列的显示示例

拟共形映射的极值理论主要研究给定边界对应的拟共形映射族中极值映射的存在性、唯一性、以及极值映射的性质、特征的刻画等问题。本文中,我们基于极值拟共形映射,研究了在唯一性与非唯一性交界的情况下的正规Reich序列,给出了在唯一性和非唯一性之间的边界情况下唯一极值拟共形映射的Reich序列的示例。

Ablation of Mea6/cTAGE5 in oligodendrocytes significantly impairs white matter structure and lipid content

Lipid-rich myelin is a special structure formed by oligodendrocytes wrapping neuronal axons.Abnormal myelin sheath is associated with many neurological diseases.Meningioma-expressed antigen 6(Mea6)/cutaneous T cell lymphoma-associated antigen 5C(cTAGE5C)plays an important role in vesicle trafficking from the endoplasmic reticulum(ER)to Golgi,and conditional knockout(cKO)of Mea6 in the brain significantly affects neural development and brain function.However,whether the impaired brain function involves the development of oligodendrocytes and white matter beyond neurons remains unclear.In this study,by using different models of diffusion magnetic resonance imaging,we showed that cKO of Mea6 in oligodendrocytes leads to significant impairment of the gross and microstructure of the white matter,as well as a significant decrease of cholesterol and triglycerides in brains.Our lipidomic analysis of purified myelin sheath for the first time showed that Mea6 elimination in oligodendrocytes significantly altered the lipid composition in myelin lipidome,especially the proportion of very long chain fatty acids(VLCFAs).In particular,the levels of most VLCFA-containing phosphatidylcholines were substantially lower in the myelin sheath of the cKO mice.The reduction of VLCFAs is likely due to the downregulated expression of elongation of very long chain fatty acids(ELOVLs).Our study of an animal model with white matter malformation and the comprehensive lipid profiling would provide clues for future studies of the formation of myelin sheath,myelin lipids,and the pathogenesis of white matter diseases.

WDR62-deficiency Causes Autism-like Behaviors Independent of Microcephaly in Mice

Brain size abnormality is correlated with an increased frequency of autism spectrum disorder(ASD)in offspring.Genetic analysis indicates that heterozygous mutations of the WD repeat domain 62(WDR62)are associated with ASD.However,biological evidence is still lacking.Our study showed that Wdr62 knockout(KO)led to reduced brain size with impaired learning and memory,as well as ASD-like behaviors in mice.Interestingly,Wdr62 Nex-cKO mice(depletion of WDR62 in differentiated neurons)had a largely normal brain size but with aberrant social interactions and repetitive behaviors.WDR62 regulated dendritic spinogenesis and excitatory synaptic transmission in cortical pyramidal neurons.Finally,we revealed that retinoic acid gavages significantly alleviated ASD-like behaviors in mice with WDR62 haploinsufficiency,probably by complementing the expression of ASD and synapse-related genes.Our findings provide a new perspective on the relationship between the microcephaly gene WDR62 and ASD etiology that will benefit clinical diagnosis and intervention of ASD.

SARS-CoV-2 induced intestinal responses with a biomimetic human gut-on-chip

Coronavirus disease 2019(COVID-19), caused by severe acute respiratory syndrome coronavirus 2(SARSCo V-2), has become a global pandemic. Clinical evidence suggests that the intestine is another high-risk organ for SARS-Co V-2 infection besides the lungs. However, a model that can accurately reflect the response of the human intestine to the virus is still lacking. Here, we created an intestinal infection model on a chip that allows the recapitulation of human relevant intestinal pathophysiology induced by SARSCo V-2 at organ level. This microengineered gut-on-chip reconstitutes the key features of the intestinal epithelium-vascular endothelium barrier through the three-dimensional(3 D) co-culture of human intestinal epithelial, mucin-secreting, and vascular endothelial cells under physiological fluid flow. The intestinal epithelium showed permissiveness for viral infection and obvious morphological changes with injury of intestinal villi, dispersed distribution of mucus-secreting cells, and reduced expression of tight junction(E-cadherin), indicating the destruction of the intestinal barrier integrity caused by virus.Moreover, the vascular endothelium exhibited abnormal cell morphology, with disrupted adherent junctions. Transcriptional analysis revealed abnormal RNA and protein metabolism, as well as activated immune responses in both epithelial and endothelial cells after viral infection(e.g., upregulated cytokine genes), which may contribute to the injury of the intestinal barrier associated with gastrointestinal symptoms. This human organ system can partially mirror intestinal barrier injury and the human response to viral infection, which is not possible in existing in vitro culture models. It provides a unique and rapid platform to accelerate COVID-19 research and develop novel therapies.

A critical role of foxp3a-positive regulatory T cells in maintaining immune homeostasis in zebrafish testis development

Suppressive regulatory T cells(Treg cells)play a vital role in preventing autoimmunity and restraining excessive immune response to both self-and non-self-antigens.Studies on humans and mice show that the Forkhead box p3(Foxp3)is a key regulatory gene for the development and function of Treg cells.In zebrafish,Treg cells have been identified by using foxp3a as a reliable marker.However,little is known about the function of foxp3a and Treg cells in gonadal development and sex differentiation.Here,we show that foxp3a is essential for maintaining immune homeostasis in zebrafish testis development.We found that foxp3a was specifically expressed in a subset of T cells in zebrafish testis,while knockout of foxp3a led to deficiency of foxp3a-positive Treg cells in the testis.More than 80%of foxp3a^(-/-)mutants developed as subfertile males,and the rest of the mutants developed as fertile females with decreased ovulation.Further study revealed that foxp3a^(-/-)mutants had a delayed juvenile ovary-to-testis transition in definite males and sex reversal in about half of the definite females,which led to a dominance of later male development.Owing to the absence of foxp3a-positive Treg cells in the differentiating testis of foxp3a^(-/-)mutants,abundant T cells and macrophages expand to disrupt an immunosuppressive milieu,resulting in defective development of germ cells and gonadal somatic cells and leading to development of infertile males.Therefore,our study reveals that foxp3a-positive Treg cells play an essential role in the orchestration of gonadal development and sex differentiation in zebrafish.

Corrigendum to“SARS-CoV-2 induced intestinal responses with a biomimetic human gut-on-chip”[Sci.Bull.(2021)66(8)783-793]

The authors would like to correct Fig.2g.An annotation error was introduced in the preparation of this figure for publication.The authors declare that this correction does not change the results or conclusions of this paper.The authors sincerely apologize for having this error in the article,and apologize for any inconvenience caused.

Neurodevelopmental impairment induced by prenatal valproic acid exposure shown with the human cortical organoid-on-a-chip model

Prenatal exposure to environmental insults can increase the risk of developing neurodevelopmental disorders.Administration of the antiepileptic drug valproic acid(VPA)during pregnancy is tightly associated with a high risk of neurological disorders in offspring.However,the lack of an ideal human model hinders our comprehensive understanding of the impact of VPA exposure on fetal brain development,especially in early gestation.Herein,we present the first report indicating the effects of VPA on brain development at early stages using engineered cortical organoids from human induced pluripotent stem cells(hiPSCs).Cortical organoids were generated on micropillar arrays in a controlled manner,recapitulating the critical features of human brain development during early gestation.With VPA exposure,cortical organoids exhibited neurodevelopmental dysfunction characterized by increased neuron progenitors,inhibited neuronal differentiation and altered forebrain regionalization.Transcriptome analysis showed new markedly altered genes(e.g.,KLHL1,LHX9,and MGARP)and a large number of differential expression genes(DEGs),some of which are related to autism.In particular,comparison of transcriptome data via GSEA and correlation analysis revealed the high similarity between VPA-exposed organoids with the postmortem ASD brain and autism patient-derived organoids,implying the high risk of autism with prenatal VPA exposure,even in early gestation.These new findings facilitate a better understanding of the cellular and molecular mechanisms underlying postnatal brain disorders(such as autism)with prenatal VPA exposure.This established cortical organoid-on-a-chip platform is valuable for probing neurodevelopmental disorders under environmental exposure and can be extended to applications in the study of diseases and drug testing.

Molecular mechanisms underlying cTAGE5/MEA6-mediated cargo transport and biological functions

Coat protein complex Ⅱ(COPⅡ)-coated vesicles are responsible for transporting the cargoes from the endoplasmic reticulum(ER) to different destinations. c TAGE5/MEA6 is essential for the development and function of different organs. It regulates the assembly of COPⅡ carrier and cargo trafficking through direct or indirect interaction with COPII components. c TAGE5/MEA6 mainly coordinates with another scaffold protein, TANGO1, to play essential roles in the trafficking and secretion of both large and small cargoes in multiple organs. In this viewpoint, we would like to discuss the molecular mechanisms underlying c TAGE5/MEA6-mediated cargo transport and biological functions.

Brain organoid-on-chip system to study the effects of breast cancer derived exosomes on the neurodevelopment of brain

Early human brain development can be affected by multiple prenatal factors that involve chemical exposures in utero,maternal health characteristics such as psychiatric disorders,and cancer.Breast cancer is one of the most common cancers worldwide arising pregnancy.However,it is not clear whether the breast cancer might influence the brain development of fetus.Exosomes secreted by breast cancer cells play a critical role in mediating intercellular communication and interplay between different organs.In this work,we engineered human induced pluripotent stem cells(hiPSCs)-derived brain organoids in an array of micropillar chip and probed the influences of breast cancer cell(MCF-7)derived-exosomes on the early neurodevelopment of brain.The formed brain organoids can recapitulate essential features of embryonic human brain at early stages,in terms of neurogenesis,forebrain regionalization,and cortical organization.Treatment with breast cancer cell derived-exosomes,brain organoids exhibited enhanced expression of stemness-related marker OCT4 and forebrain marker PAX6.RNA-seq analysis reflected several activated signaling pathways associated with breast cancer,medulloblastoma and neurogenesis in brain organoids induced by tumor-derived exosomes.These results suggested that breast cancer cell-derived exosomes might lead to the impaired neurodevelopment in the brain organoids and the carcinogenesis of brain organoids.It potentially implies the fetus of pregnant women with breast cancer has the risk of impaired neurodevelopmental disorder after birth.

A landscape of differentiated biological processes involved in the initiation of sex differentiation in zebrafish

Zebrafish(Danio rerio)has been used as a promising animal model to study gonadal development and gametogenesis.Although previous studies have identified critical molecules participating in zebrafish gonad differentiation,a landscape view of the biological processes involved in this process is still lacking.Here we isolated intact zebrafish differentiating gonads,at 25 days post-fertilization(dpf)and 30 dpf and conducted RNA-seq analyses on the juvenile gonads that tended to develop into ovaries or testes.Our study demonstrates that the juvenile ovary and testis at 25 dpf and 30 dpf are different at the biological process level.During ovary differentiation,the biological processes related to metabolic activities in the production of energy and maternal substances,RNA degradation,and DNA repair were enriched.During testis differentiation,the biological processes related to cell proliferation,differentiation,and morphogenesis were enriched,with a total of 15 signaling pathways.Notably,we reveal that the immune-related processes are extensively involved in the regulation of testis development.Overall,this study provides a landscape of differentiated biological processes and novel insights into the initiation of sex differentiation in zebrafish.

Regulation of the protein stability of POSH and MLK family

Sequential activation of the JNK pathway components,including Rac1/Cdc42,MLKs(mixed-lineage kinases),MKK4/7 and JNKs,plays a required role in many cell death paradigms.Those components are organized by a scaffold protein,POSH(Plenty of SH3’s),to ensure the effective activation of the JNK pathway and cell death upon apoptotic stimuli.We have shown recently that the expression of POSH and MLK family proteins are regulated through protein stability.By generating a variety of mutants,we provide evidence here that the Nterminal half of POSH is accountable for its stability regulation and its over-expression-induced cell death.In addition,POSH’s ability to induce apoptosis is correlated with its stability as well as its MLK binding ability.MLK family’s stability,like that of POSH,requires activation of JNKs.However,we were surprised to find out that the widely used dominant negative(d/n)form of c-Jun could down-regulate MLK’s stability,indicating that peptide from d/n c-Jun can be potentially developed into a therapeutical drug.