Nanoscale Reorganization of Glutamate Receptors Underlies Synaptic Plasticity and Pathology

Excitatory synapses serve as the primary sites for information transmission between neurons in the brain.Seminal work over the past decades has identified and revealed multiple compositions and functions of the synaptic proteome in the postsynaptic density(PSD),including receptors,scaffold proteins,and signaling molecules,which work together to ensure stable and effective synaptic transmission.

Structural and dynamic properties of the YTH domain in complex with N^(6)-methyladenosine RNA studied by accelerated molecular dynamics simulations

Background:N^(6)-methyladenosine(m^(6)A)modifications of mRNA and long non-coding RNA(lncRNAs)are known to play a significant role in regulation of gene expression and organismal development.Besides writer and eraser proteins of this dynamic modification,the YT521-B homology(YTH)domain can recognize the modification involved in numerous cellular processes.The function of proteins containing YTH domain and its binding mode with N^(6)-methyladenosine RNA has attracted considerable attention.However,the structural and dynamic characteristics of the YTH domain in complex with m^(6)A RNA is still unknown.Method:This work presents results of accelerated molecular dynamics(aMD)simulations at the timescale of microseconds.Principal component analysis(PCA),molecular mechanics generalized Born surface area(MM/GBSA)calculations,contact analysis and contact-based principal component analysis(conPCA)provide new insights into structure and dynamics of the YTH-RNA complex.Results:The aMD simulations indicate that the recognition loop has a larger movement away from the binding pocket in the YTH-A3 RNA than that in the YTH-m^(6)A3 RNA.In aMD trajectories of the apo YTH,there is a significant close-open transition of the recognition loop,that is to say,the apo YTH can take both the closed and open structure.We have found that the YTH domain binds more favorably to the methylated RNA than the nonmethylated RNA.The per-residue free energy decomposition and conPCA suggest that hydrophobic residues including W380,L383-V385,W431-P434,M437,and M441-L442,may play important roles in favorable binding of the m^(6)A RNA to the YTH domain,which is also supported by aMD simulations of a double mutated system(L383A/M437A).Conclusion:The results are in good agreement with higher structural stability of the YTH-m^(6)A RNA than that of the YTH-A3 RNA.The addition of a methylation group on A3 can enhance its binding to the hydrophobic pocket in the YTH domain.Our simulations support a‘conformational selection’mechanism between the YTH-RNA binding.This work may aid in our understanding of the structural and dynamic characteristics of the YTH protein in complex with the methylated RNA.

Chemical inhibition of Arabidopsis PIN-FORMED auxin transporters by the anti-inflammatory drug naproxen

The phytohormone auxin plays central roles in many growth and developmental processes in plants.Development of chemical tools targeting the auxin pathway is useful for both plant biology and agriculture.Here we reveal that naproxen,a synthetic compound with anti-inflammatory activity in humans,acts as an auxin transport inhibitor targeting PIN-FORMED(PIN)transporters in plants.Physiological experiments indicate that exogenous naproxen treatment affects pleiotropic auxin-regulated developmental processes.Additional cellular and biochemical evidence indicates that naproxen suppresses auxin transport,specifically PIN-mediated auxin efflux.Moreover,biochemical and structural analyses confirm that naproxen binds directly to PIN1 protein via the same binding cavity as the indole-3-acetic acid substrate.Thus,by combining cellular,biochemical,and structural approaches,this study clearly establishes that naproxen is a PIN inhibitor and elucidates the underlying mechanisms.Further use of this compound may advance our understanding of the molecular mechanisms of PIN-mediated auxin transport and expand our toolkit in auxin biology and agriculture.

Computationally predicted pathogenic USP9X mutation identified in infertile men does not affect spermatogenesis in mice

Infertility is a major health issue,affecting approximately 15%of couples of child-bearing age.Although nearly half of idiopathic infertility cases are assumed to have a genetic basis,the underlying causes remain largely unknown in most infertile men.

A novel homozygous frameshift variant in DNAH8 causes multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family

Multiple morphological abnormalities of the sperm flagella(MMAF)is a severe form of asthenozoospermia categorized by immotile spermatozoa with abnormal flagella in ejaculate.Whole-exome sequencing(WES)is used to detect pathogenic variants in patients with MMAF.In this study,a novel homozygous frameshift variant(c.6158_6159insT)in dynein axonemal heavy chain 8(DNAH8)from two infertile brothers with MMAF in a consanguineous Pakistani family was identified by WES.Reverse transcription-polymerase chain reaction(RT-PCR)confirmed DNAH8 mRNA decay in these patients with the DNAH8 mutation.Hematoxylin–eosin staining and transmission electron microscopy revealed highly divergent morphology and ultrastructure of sperm flagella in these patients.Furthermore,an immunofluorescence assay showed the absence of DNAH8 and a reduction in its associated protein DNAH17 in the patients'spermatozoa.Collectively,our study expands the phenotypic spectrum of patients with DNAH8-related MMAF worldwide.

Single-dose AAV-based vaccine induces a high level of neutralizing antibodies against SARS-CoV-2 in rhesus macaques

Dear Editor,Coronavirus disease 2019(COVID-19)is a highly infectious respiratory disease that continues to pose a serious global public health emergency.The disease shows a high infection rate,long incubation period,and rapidly emerging variants,which have led to its rapid spread worldwide(Krammer 2020).Many vaccines have been developed for the control of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the virus responsible for COVID-19,including vaccines based on messenger RNA(mRNA)(Polack et al.2020),viral vectors(Zhu et al.2020),recombinant proteins(Yang et al.2020),and inactivated SARS-CoV-2(Zhang et al.2021).

Polarized condensates confer row identity of hair cell stereocilia

Sound waves are converted into electric signals by hair bundles(also known as stereocilia)in the cochlear hair cells.Stereocilia,a cluster of actin protrusions at the apical surface of hair cells,are organized into rows of graded height(Figure 1).Mechanical force induced by sound waves leads to stereocilia deflection towards the tallest row and subsequent activation of mechanoelectrical transducer channels at the tips of the shorter rows,thus achieving mechanoelectrical transduction(Gillespie and Muller,2009).Such a staircase-like architecture is essential for auditory perception as manifested by severe deafness caused by genetic mutations that disrupt stereocilia morphology(Barr-Gillespie,2015).However,little is known about how this planar asymmetry of stereocilia is achieved.

探究非编码RNA在学习记忆过程中的作用机制

The mechanisms underlying learning and memory have been a longstanding focus of neuroscience research.In recent decades,there has been a substantial increase in the investigation and understanding of the intricate molecular processes involved in learning and memory.Epigenetic mechanisms,which encompass dynamic and reversible modifications at various levels of cellular regulation.

Advances in NK cell production

Immunotherapy based on natural killer(NK)cells is a promising approach for treating a variety of cancers.Unlike T cells,NK cells recognize target cells via a major histocompatibility complex(MHC)-independent mechanism and,without being sensitized,kill the cells directly.Several strategies for obtaining large quantities of NK cells with high purity and high cytotoxicity have been developed.These strategies include the use of cytokine−antibody fusions,feeder cells or membrane particles to stimulate the proliferation of NK cells and enhance their cytotoxicity.Various materials,including peripheral blood mononuclear cells(PBMCs),umbilical cord blood(UCB),induced pluripotent stem cells(iPSCs)and NK cell lines,have been used as sources to generate NK cells for immunotherapy.Moreover,genetic modification technologies to improve the proliferation of NK cells have also been developed to enhance the functions of NK cells.Here,we summarize the recent advances in expansion strategies with or without genetic manipulation of NK cells derived from various cellular sources.We also discuss the closed,automated and GMP-controlled large-scale expansion systems used for NK cells and possible future NK cell-based immunotherapy products.

The SNAPc complex mediates starvation-induced trans-splicing in Caenorhabditis elegans

Dietary restriction usually suppresses biosynthesis but activates catabolic pathways in animals.However,the short-term starvation enhances biosynthetic activities and promotes ribosomal biogenesis in adult Caenorhabditis elegans.The mechanism underlying the processes remains largely unknown.Here,we find that the short-term starvation enhances the SL1 trans-splicing of translation-related genes in adult C.elegans by transcriptome analysis.The small nuclear RNA-activating protein complex(SNAPc)promotes SL RNA production and mediates starvation-induced trans-splicing.TOFU-5,a core factor in the upstream sequence transcription complex(USTC)essential for piRNA production,is also involved in the starvationinduced trans-splicing processes.Knocking down components of the SNAPc complex and tofu-5 extends worm survival under starvation conditions.Taken together,our study highlights the importance of SL transsplicing in the nutrition response and reveals a mechanism of the survival regulation by food deprivation via SNAPc and TOFU-5.