New role of platelets in schizophrenia:predicting drug response

Background Elevated platelet count(PLTc)is associated with first-episode schizophrenia and adverse outcomes in individuals with precursory psychosis.However,the impact of antipsychotic medications on PLTc and its association with symptom improvement remain unclear.Aims We aimed to investigate changes in PLTc levels following antipsychotic treatment and assess whether PLTc can predict antipsychotic responses and metabolic changes after accounting for other related variables.Methods A total of 2985 patients with schizophrenia were randomised into seven groups.Each group received one of seven antipsychotic treatments and was assessed at 2,4 and 6 weeks.Clinical symptoms were evaluated using the positive and negative syndrome scale(PANSS).Additionally,we measured blood cell counts and metabolic parameters,such as blood lipids.Repeated measures analysis of variance was used to examine the effect of antipsychotics on PLTc changes,while structural equation modelling was used to assess the predictive value of PLTc on PANSS changes.Results PLTc significantly increased in patients treated with aripiprazole(F=6.00,p=0.003),ziprasidone(F=7.10,p<0.001)and haloperidol(F=3.59,p=0.029).It exhibited a positive association with white blood cell count and metabolic indicators.Higher baseline PLTc was observed in non-responders,particularly in those defined by the PANSS-negative subscale.In the structural equation model,PLTc,white blood cell count and a latent metabolic variable predicted the rate of change in the PANSS-negative subscale scores.Moreover,higher baseline PLTc was observed in individuals with less metabolic change,although this association was no longer significant after accounting for baseline metabolic values.Conclusions Platelet parameters,specifically PLTc,are influenced by antipsychotic treatment and could potentially elevate the risk of venous thromboembolism in patients with schizophrenia.Elevated PLTc levels and associated factors may impede symptom improvement by promoting inflammation.Given PLTc’s easy measurement and clinical relevance,it warrants increased attention from psychiatrists.Trial registration number ChiCTR-TRC-10000934.

Meiotic transcriptional reprogramming mediated by cell-cell communications in humans and mice revealed by scATACseq and scRNA-seq

Meiosis is a highly complex process significantly influenced by transcriptional regulation.However,studies on the mechanisms that govern transcriptomic changes during meiosis,especially in prophase I,are limited.Here,we performed single-cell ATAC-seq of human testis tissues and observed reprogramming during the transition from zygotene to pachytene spermatocytes.This event,conserved in mice,involved the deactivation of genes associated with meiosis after reprogramming and the activation of those related to spermatogenesis before their functional onset.Furthermore,we identified 282 transcriptional regulators(TRs)that underwent activation or deactivation subsequent to this process.Evidence suggested that physical contact signals from Sertoli cells may regulate these TRs in spermatocytes,while secreted ENHO signals may alter metabolic patterns in these cells.Our results further indicated that defective transcriptional reprogramming may be associated with non-obstructive azoospermia(NOA).This study revealed the importance of both physical contact and secreted signals between Sertoli cells and germ cells in meiotic progression.

3D Printing of Tough Hydrogel Scaffolds with Functional Surface Structures for Tissue Regeneration

Hydrogel scaffolds have numerous potential applications in the tissue engineering field.However,tough hydrogel scaffolds implanted in vivo are seldom reported because it is difficult to balance biocompatibility and high mechanical properties.Inspired by Chinese ramen,we propose a universal fabricating method(printing-P,training-T,cross-linking-C,PTC&PCT)for tough hydrogel scaffolds to fill this gap.First,3D printing fabricates a hydrogel scaffold with desired structures(P).Then,the scaffold could have extraordinarily high mechanical properties and functional surface structure by cycle mechanical training with salting-out assistance(T).Finally,the training results are fixed by photo-cross-linking processing(C).The tough gelatin hydrogel scaffolds exhibit excellent tensile strength of 6.66 MPa(622-fold untreated)and have excellent biocompatibility.Furthermore,this scaffold possesses functional surface structures from nanometer to micron to millimeter,which can efficiently induce directional cell growth.Interestingly,this strategy can produce bionic human tissue with mechanical properties of 10 kPa-10 MPa by changing the type of salt,and many hydrogels,such as gelatin and silk,could be improved with PTC or PCT strategies.Animal experiments show that this scaffold can effectively promote the new generation of muscle fibers,blood vessels,and nerves within 4 weeks,prompting the rapid regeneration of large-volume muscle loss injuries.

Epstein-Barr virus positive post-transplant lymphoproliferative disorder with significantly decreased T-cell chimerism early after transplantation:A case report

BACKGROUND Post-transplant lymphoproliferative disorder(PTLD)is a rare but highly fatal complication occurring after allogeneic hematopoietic cell transplantation(allo-HCT)or solid organ transplantation(SOT).Unlike SOT,PTLD after allo-HCT usually originates from the donor and is rarely accompanied by a loss of donor chimerism.CASE SUMMARY We report a case of Epstein-Barr virus positive PTLD manifesting as diffuse large B-cell lymphoma(DLBCL)with significantly decreased T-cell chimerism early after allo-HCT.A 30-year-old patient with acute myeloid leukemia underwent unrelated allo-HCT after first complete remission.Nearly 3 mo after transplantation,the patient developed cervical lymph node enlargement and gastric lesions,both of which were pathologically suggestive of DLBCL.Meanwhile,the patient experienced a significant and persistent decrease in T-cell chimerism.A partial remission was achieved after chemotherapy with single agent rituximab and subsequent R-CHOP combined chemotherapy.CONCLUSION The loss of T-cell chimerism and the concomitant T-cell insufficiency may be the cause of PTLD in this patient.

Chinese version of the Perth Alexithymia Questionnaire:psychometric properties and clinical applications

Background The alexithymia trait is of high clinical interest.The Perth Alexithymia Questionnaire(PAQ)was recently developed to enable detailed facet-level and valence-specific assessments of alexithymia.Aims In this paper,we introduce the first Chinese version of the PAQ and examine its psychometric properties and clinical applications.Methods In Study 1,the PAQ was administered to 990 Chinese participants.We examined its factor structure,internal consistency,test-retest reliability,as well as convergent,concurrent and discriminant validity.In Study 2,four groups,including a major depressive disorder(MDD)group(n=50),a matched healthy control group for MDD(n=50),a subclinical depression group(n=50)and a matched healthy control group for subclinical depression(n=50),were recruited.Group comparisons were conducted to assess the clinical relevance of the PAQ.Results In Study 1,the intended five-factor structure of the PAQ was found to fit the data well.The PAQ showed good internal consistency and test-retest reliability,as well as good convergent,concurrent and discriminant validity.In Study 2,the PAQ was able to successfully distinguish the MDD group and the subclinical depression group from their matched healthy controls.Conclusions The Chinese version of the PAQ is a valid and reliable instrument for comprehensively assessing alexithymia in the general population and adults with clinical/subclinical depression.

OpenNAU:An open-source platform for normalizing,analyzing,and visualizing cancer untargeted metabolomics data

Objective:As an important part of metabolomics analysis,untargeted metabolomics has become a powerful tool in the study of tumor mechanisms and the discovery of metabolic markers with high-throughput spectrometric data which also poses great challenges to data analysis,from the extraction of raw data to the identification of differential metabolites.To date,a large number of analytical tools and processes have been developed and constructed to serve untargeted metabolomics research.The different selection of analytical tools and parameter settings lead to varied results of untargeted metabolomics data.Our goal is to establish an easily operated platform and obtain a repeatable analysis result.Methods:We used the R language basic environment to construct the preprocessing system of the original data and the LAMP(Linux+Apache+MySQL+PHP)architecture to build a cloud mass spectrum data analysis system.Results:An open-source analysis software for untargeted metabolomics data(openNAU)was constructed.It includes the extraction of raw mass data and quality control for the identification of differential metabolic ion peaks.A reference metabolomics database based on public databases was also constructed.Conclusions:A complete analysis system platform for untargeted metabolomics was established.This platform provides a complete template interface for the addition and updating of the analysis process,so we can finish complex analyses of untargeted metabolomics with simple human-computer interactions.The source code can be downloaded from https://github.com/zjuRong/openNAU.

神经胶质细胞与神经突触的相互作用——从星形胶质细胞到小胶质细胞和少突胶质细胞谱系细胞

哺乳动物的大脑是一个由神经元、神经胶质细胞和超过1×1014个突触组成的复杂的器官。神经元是一组异质的电活性细胞,形成大脑复杂电回路的框架。然而,神经胶质细胞约占哺乳动物中枢神经系统(CNS)所有神经细胞的一半,主要分为星形胶质细胞、小胶质细胞、少突胶质细胞(OL)和少突胶质细胞前体细胞(OPC);神经胶质细胞主要为大脑中的神经元提供营养支持。近二十年来,“三联突触”的概念引起了广泛关注,该概念强调星形胶质细胞是突触的组成部分,并在接受神经元信号后以反馈方式调节神经元活动。自此,神经胶质细胞的突触调节得到了广泛的研究和实质性的修改。本综述总结了关于神经胶质细胞(特别是小胶质细胞和OL谱系细胞)如何影响和重塑大脑突触结构和功能的最新重要发现。我们的综述强调了神经元-神经胶质细胞串扰的细胞和分子方面,并提供了有关神经元和神经胶质细胞之间的异常突触通讯如何导致神经病理学的额外信息。

Harvesting the fruits of the first stage of the Primate Genome Project

Primates are highly successful mammals with significant morphological,behavioral,and physiological diversity.Studying the genomes of non-human primates,as the closest relative of humans,can provide insights into human evolution,genetic structure,and potential drug targets relevant to human health,thus making important contributions to medical research.Additionally,primate genome research can support ecological balance and resource conservation and promote sustainable development and human well-being.Despite the existence of more than 500 primate species belonging to 80 genera and 16 families worldwide,with new species still being discovered in recent years(Fan et al.,2017;Khanal et al.,2021;Roos et al.,2020),genome sequencing efforts have been limited to a relatively small number of species from only 22 genera(Ensembl v103).Notably,approximately 72%of primate genera remain unsequenced,leading to significant knowledge gaps in our understanding of their evolutionary history.This situation presents considerable challenges for the development,utilization,and protection of primate genetic resources.It is for these compelling reasons that we initiated the Primate Genome Project(PGP)(Wu et al.,2022).

Single-cell and spatially resolved omics:Advances and limitations

Recent advances in experimental and computational single-cell and spatially resolved omics have opened new avenues for research in biology and medicine.These technologies allow for the study of individual cells in unprecedented detail,providing insights into the heterogeneity within tissues and organs,and how different cells interact with each other.Humans and other eukaryotes are composed of billions of cells,each with vastly heterogeneous cell types and functional cell states determined by intrinsic and extrinsic factors.

Tissue Engineering in Neuroscience: Applications and Perspectives

Neurological disorders have always been a threat to human physical and mental health nowadays,which are closely related to the nonregeneration of neurons in the nervous system(NS).The damage to the NS is currently difficult to repair using conventional therapies,such as surgery and medication.Therefore,repairing the damaged NS has always been a vast challenge in the area of neurology.Tissue engineering(TE),which integrates the cell biology and materials science to reconstruct or repair organs and tissues,has widespread applications in bone,periodontal tissue defects,skin repairs,and corneal transplantation.Recently,tremendous advances have been made in TE regarding neuroscience.In this review,we summarize TE’s recent progress in neuroscience,including pathological mechanisms of various neurological disorders,the concepts and classification of TE,and the most recent development of TE in neuroscience.Lastly,we prospect the future directions and unresolved problems of TE in neuroscience.

Knowledge,attitudes and experiences of genetic testing for autism spectrum disorders among caregivers,patients,and health providers:A systematic review

BACKGROUND Several genetic testing techniques have been recommended as a first-tier diagnostic tool in clinical practice for diagnosing autism spectrum disorder(ASD).However,the actual usage rate varies dramatically.This is due to various reasons,including knowledge and attitudes of caregivers,patients,and health providers toward genetic testing.Several studies have therefore been conducted worldwide to investigate the knowledge,experiences,and attitudes toward genetic testing among caregivers of children with ASD,adolescent and adult ASD patients,and health providers who provide medical services for them.However,no systematic review has been done.AIM To systematically review research on knowledge,experiences,and attitudes towards genetic testing among caregivers of children with ASD,adolescent and adult ASD patients,and health providers.METHODS We followed the Preferred Reporting Items for Systematic Reviews and Metaanalyses guidelines and searched the literature in three English language databases(PubMed,Web of Science,and PsychInfo)and two Chinese databases(CNKI and Wanfang).Searched literature was screened independently by two reviewers and discussed when inconsistency existed.Information on characteristics of the study,characteristics of participants,and main findings regarding knowledge,experience,and attitudes of caregivers of children with ASD,adolescent and adult ASD patients,and health providers concerning ASD genetic testing were extracted from included papers into a charting form for analysis.RESULTS We included 30 studies published between 2012 and 2022 and conducted in 9 countries.Most of the studies(n=29)investigated caregivers of children with ASD,one study also included adolescent and adult patients,and two covered health providers.Most(51.0%-100%)of the caregivers/patients knew there was a genetic cause for ASD and 17.0%to 78.1%were aware of ASD genetic testing.However,they lacked full understanding of genetic testing.They acquired relevant and necessary information from physicians,the internet,ASD organizations,and other caregivers.Between 9.1%to 72.7%of caregivers in different studies were referred for genetic testing,and between 17.4%to 61.7%actually obtained genetic testing.Most caregivers agreed there are potential benefits following genetic testing,including benefits for children,families,and others.However,two studies compared perceived pre-test and post-test benefits with conflicting findings.Caregivers concerns included high costs,unhelpful results,negative influences(e.g.,causing family conflicts,causing stress/risk/pain to children etc.)prevented some caregivers from using genetic testing.Nevertheless,46.7%to 95.0%caregivers without previous genetic testing experience intended to obtain it in the future,and 50.5%to 59.6%of parents previously obtaining genetic testing would recommend it to other parents.In a single study of child and adolescent psychiatrists,54.9%of respondents had ordered ASD genetic testing for their patients in the prior 12 mo,which was associated with greater knowledge of genetic testing.CONCLUSION Most caregivers are willing to learn about and use genetic testing.However,the review showed their current knowledge is limited and usage rates varied widely in different studies.

Combination of CRISPR/Cas9 System and CAR-T Cell Therapy:A New Era for Refractory and Relapsed Hematological Malignancies

Chimeric antigen receptor T(CAR-T)cell therapy is the novel treatment strategy for hematological malignancies such as acute lymphoblastic leukemia(ALL),lymphoma and multiple myeloma.However,treatment-related toxicities such as cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS)have become significant hurdles to CAR-T treatment.Multiple strategies were established to alter the CAR structure on the genomic level to improve efficacy and reduce toxicities.Recently,the innovative gene-editing technology-clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated nuclease9(Cas9)system,which particularly exhibits preponderance in knock-in and knockout at specific sites,is widely utilized to manufacture CAR-T products.The application of CRISPR/Cas9 to CAR-T cell therapy has shown promising clinical results with minimal toxicity.In this review,we summarized the past achievements of CRISPR/Cas9 in CAR-T therapy and focused on the potential CAR-T targets.

受自体材料启发的药物递送系统

随着个性化医疗理念的深入研究,基于自体来源材料的药物递送系统受到越来越多的关注并快速发展.自体来源材料具有保留其体内天然生理学特性和优良的生物相容性等特点,这为其在材料功能化和药物递送方面开辟了广泛的研究空间,也为疾病治疗提供了坚实的基础.借助这些优势,受自体来源材料启发的药物递送系统有望在疾病治疗方面实现减毒增效.本文对基于人源蛋白、细胞材料及细胞外基质支架的药物递送系统的最新研究进行了全面回顾,重点关注了这类药物递送系统的载药策略和应用场景,深入分析了它们在疾病治疗中的优势和限制.此外,本文还探讨了受自体来源材料启发的药物递送系统在临床转化过程中面临的潜在机遇和挑战.

Rationally designed approaches to augment CAR-T therapy for solid tumor treatment

Chimeric antigen receptor T cell denoted as CAR-T therapy has realized incredible therapeutic advancements for B cell malignancy treatment.However,its therapeutic validity has yet to be successfully achieved in solid tumors.Different from hematological cancers,solid tumors are characterized by dysregulated blood vessels,dense extracellular matrix,and filled with immunosuppressive signals,which together result in CAR-T cells’insufficient infiltration and rapid dysfunction.The insufficient recognition of tumor cells and tumor heterogeneity eventually causes cancer reoccurrences.In addition,CAR-T therapy also raises safety concerns,including potential cytokine release storm,on-target/off-tumor toxicities,and neuro-system side effects.Here we comprehensively review various targeting aspects,including CAR-T cell design,tumor modulation,and delivery strategy.We believe it is essential to rationally design a combinatory CAR-T therapy via constructing optimized CAR-T cells,directly manipulating tumor tissue microenvironments,and selecting the most suitable delivery strategy to achieve the optimal outcome in both safety and efficacy.

Alzheimer’s disease early diagnostic and staging biomarkers revealed by large-scale cerebrospinal fluid and serum proteomic profiling

Amyloid-b,tau pathology,and biomarkers of neurodegeneration make up the core diagnostic biomarkers of Alzheimer disease(AD).However,these proteins represent only a fraction of the complex biological processes underlying AD,and individuals with other brain diseases in which AD pathology is a comorbidity also test positive for these diagnostic biomarkers.More ADspecific early diagnostic and disease staging biomarkers are needed.In this study,we performed tandem mass tag proteomic analysis of paired cerebrospinal fluid(CSF)and serum samples in a discovery cohort comprising 98 participants.Candidate biomarkers were validated by parallel reaction monitoring–based targeted proteomic assays in an independent multicenter cohort comprising 288 participants.We quantified 3,238 CSF and 1,702 serum proteins in the discovery cohort,identifying 171 and 860 CSF proteins and 37 and 323 serum proteins as potential early diagnostic and staging biomarkers,respectively.In the validation cohort,58 and 21 CSF proteins,as well as 12 and 18 serum proteins,were verified as early diagnostic and staging biomarkers,respectively.Separate 19-protein CSF and an 8-protein serum biomarker panels were built by machine learning to accurately classify mild cognitive impairment(MCI)due to AD from normal cognition with areas under the curve of 0.984 and 0.881,respectively.The 19-protein CSF biomarker panel also effectively discriminated patients with MCI due to AD from patients with other neurodegenerative diseases.Moreover,we identified 21 CSF and 18 serum stage-associated proteins re-flecting AD stages.Our findings provide a foundation for developing bloodbased tests for AD screening and staging in clinical practice.

Suppressor tRNA in gene therapy

Suppressor tRNAs are engineered or naturally occurring transfer RNA molecules that have shown promise in gene therapy for diseases caused by nonsense mutations,which result in premature termination codons(PTCs)in coding sequence,leading to truncated,often nonfunctional proteins.Suppressor t RNAs can recognize and pair with these PTCs,allowing the ribosome to continue translation and produce a full-length protein.This review introduces the mechanism and development of suppressor t RNAs,compares suppressor tRNAs with other readthrough therapies,discusses their potential for clinical therapy,limitations,and obstacles.We also summarize the applications of suppressor tRNAs in both in vitro and in vivo,offering new insights into the research and treatment of nonsense mutation diseases.

Establishment of a humanized mouse model using steady-state peripheral blood-derived hematopoietic stem and progenitor cells facilitates screening of cancer-targeted T-cell repertoires

Background:Cancer-targeted T-cell receptor T(TCR-T)cells hold promise in treating cancers such as hematological malignancies and breast cancers.However,approaches to obtain cancer-reactive TCR-T cells have been unsuccessful.Methods:Here,we developed a novel strategy to screen for cancer-targeted TCR-T cells using a special humanized mouse model with person-specific immune fingerprints.Rare steady-state circulating hematopoietic stem and progenitor cells were expanded via three-dimensional culture of steady-state peripheral blood mononuclear cells,and then the expanded cells were applied to establish humanized mice.The human immune system was evaluated according to the kinetics of dendritic cells,monocytes,T-cell subsets,and cytokines.To fully stimulate the immune response and to obtain B-cell precursor NAML-6-and triple-negative breast cancer MDA-MB-231-targeted TCR-T cells,we used the inactivated cells above to treat humanized mice twice a day every 7 days.Then,human T cells were processed for TCRβ-chain(TRB)sequencing analysis.After the repertoires had been constructed,features such as the fraction,diversity,and immune signature were investigated.Results:The results demonstrated an increase in diversity and clonality of T cells after treatment.The preferential usage and features of TRBV,TRBJ,and the V–J combination were also changed.The stress also induced highly clonal Science and Technology,Grant/Award Number:2021C03010;Zhejiang Provincial Natural Science Foundation of China,Grant/Award Numbers:LTGY24H080003,LY21H080004 expansion.Tumor burden and survival analysis demonstrated that stress induction could significantly inhibit the growth of subsequently transfused live tumor cells and prolong the survival of the humanized mice.Conclusions:We constructed a personalized humanized mouse model to screen cancer-targeted TCR-T pools.Our platform provides an effective source of cancer-targeted TCR-T cells and allows for the design of patient-specific engineered T cells.It therefore has the potential to greatly benefit cancer treatment.

PRC2 primes bivalent genes for transcription induction independent of histone methyltransferase activity

Dear Editor,Polycomb group proteins,conserved epigenetic transcriptional repressors,are crucial for orchestrating diverse developmental gene expression programs(Schuettengruber et al.,2017).The polycomb repressive complex 2(PRC2)catalyzes H3 lysine-27 trimethylation(H3K27me3)to establish a delicate balance with H3K4me3,forming a bivalent chromatin state at target gene promoters and thereby poising them for subsequent transcription activation(Bernstein et al.,2006).

Microglia Suppresses Breast Cancer Brain Metastasis via a Pro-inflammatory Response

Due to the obstacle of the blood-brain barrier(BBB)for drug delivery[1],breast cancer brain metastasis(BCBM)represents a worldwide health challenge with high mortality.During BCBM formation and progression,brain metastases(BrMs)secret various factors,including cytokines and exosomes,and trigger the infiltration of tumours-associated macrophages(TAMs),which in turn become important components of brain tumour microenvironments(TME).

The non-canonical poly(A)polymerase FAM46C promotes erythropoiesis

The post-transcriptional regulation of mRNA is a crucial component of gene expression.The disruption of this process has detrimental effects on the normal development and gives rise to various diseases.Searching for novel post-transcriptional regulators and exploring their roles are essential for understanding development and disease.Through a multimodal analysis of red blood cell trait genome-wide association studies(GWAS)and transcriptomes of erythropoiesis,we identify FAM46C,a non-canonical RNA poly(A)polymerase,as a necessary factor for proper red blood cell development.FAM46C is highly expressed in the late stages of the erythroid lineage,and its developmental upregulation is controlled by an erythroidspecific enhancer.We demonstrate that FAM46C stabilizes mRNA and regulates erythroid differentiation in a polymerase activity-dependent manner.Furthermore,we identify transcripts of lysosome and mitochondria components as highly confident in vivo targets of FAM46C,which aligns with the need of maturing red blood cells for substantial clearance of organelles and maintenance of cellular redox homeostasis.In conclusion,our study unveils a unique role of FAM46C in positively regulating lysosome and mitochondria components,thereby promoting erythropoiesis.