Schizophrenia is a complex psychiatric disorder marked by positive and negative symptoms,leading to mood disturbances,cognitive impairments,and social withdrawal.While anti-psychotic medications remain the cornerstone...Schizophrenia is a complex psychiatric disorder marked by positive and negative symptoms,leading to mood disturbances,cognitive impairments,and social withdrawal.While anti-psychotic medications remain the cornerstone of treatment,they often fail to fully address certain symptoms.Additionally,treatment-resistant schizophrenia,affecting 30%-40%of patients,remains a substantial clinical challenge.Positive,negative symptoms and cognitive impairments have been linked to disruptions in the glutamatergic,serotonin,GABAergic,and muscarinic pathways in the brain.Recent advances using genome-wide association study and other approaches have uncovered a significant number of new schizophrenia risk genes that uncovered new,and reinforced prior,concepts on the genetic and neurological underpinnings of schizophrenia,including abnormalities in synaptic function,immune processes,and lipid metabolism.Concurrently,new therapeutics targeting different modalities,which are expected to address some of the limitations of anti-psychotic drugs currently being offered to patients,are currently being evaluated.Collectively,these efforts provide new momentum for the next phase of schizophrenia research and treatment.展开更多
The human skeleton is a multifunctional organ made up of multiple cell types working in concert to maintain bone and mineral homeostasis and to perform critical mechanical and endocrine functions.From the beginning st...The human skeleton is a multifunctional organ made up of multiple cell types working in concert to maintain bone and mineral homeostasis and to perform critical mechanical and endocrine functions.From the beginning steps of chondrogenesis that prefigures most of the skeleton,to the rapid bone accrual during skeletal growth,followed by bone remodeling of the mature skeleton,cell differentiation is integral to skeletal health.展开更多
Current scientific endeavours in the field of geroscience have begun to reveal how factors such as exercise could modulate the brain aging process.In this review,we ask how exercise could potentially modulate aging,an...Current scientific endeavours in the field of geroscience have begun to reveal how factors such as exercise could modulate the brain aging process.In this review,we ask how exercise could potentially modulate aging,and by extension,the development of Alzheimer’s Disease(AD).Furthermore,we discuss how exercise could mitigate the cascade of debilitating manifestations in AD.Mechanistically,we discuss how biomolecules such as brain-derived neurotrophic factor(BDNF)and its cognate receptor,tropomyosin receptor kinase B(TrkB)could change during the life course and how its signalling pathways could be altered with exercise(acute sessions or chronic training).Tackling these questions could help the scientific and medical community mitigate age-related decline in terms of neurological functions.展开更多
1.Introduction Cancer continues to be a major cause of global mortality rates,with conventional treatments such as chemotherapy and radiotherapy exhibiting inconsistent efficacy,high costs,and considerable side effect...1.Introduction Cancer continues to be a major cause of global mortality rates,with conventional treatments such as chemotherapy and radiotherapy exhibiting inconsistent efficacy,high costs,and considerable side effects.Over the past decade,a promising alternative has emerged:cancer immunotherapy,which leverages the body's immune system to identify and eradicate cancer cells[1].展开更多
Aging and regeneration represent complex biological phenomena that have long captivated the scientific community.To fully comprehend these processes,it is essential to investigate molecular dynamics through a lens tha...Aging and regeneration represent complex biological phenomena that have long captivated the scientific community.To fully comprehend these processes,it is essential to investigate molecular dynamics through a lens that encompasses both spatial and temporal dimensions.Conventional omics methodologies,such as genomics and transcriptomics,have been instrumental in identifying critical molecular facets of aging and regeneration.However,these methods are somewhat limited,constrained by their spatial resolution and their lack of capacity to dynamically represent tissue alterations.The advent of emerging spatiotemporal multi-omics approaches,encompassing transcriptomics,proteomics,metabolomics,and epigenomics,furnishes comprehensive insights into these intricate molecular dynamics.These sophisticated techniques facilitate accurate delineation of molecular patterns across an array of cells,tissues,and organs,thereby offering an in-depth understanding of the fundamental mechanisms at play.This review meticulously examines the significance of spatiotemporal multi-omics in the realms of aging and regeneration research.It underscores how these methodologies augment our comprehension of molecular dynamics,cellular interactions,and signaling pathways.Initially,the review delineates the foundational principles underpinning these methods,followed by an evaluation of their recent applications within the field.The review ultimately concludes by addressing the prevailing challenges and projecting future advancements in the field.Indubitably,spatiotemporal multi-omics are instrumental in deciphering the complexities inherent in aging and regeneration,thus charting a course toward potential therapeutic innovations.展开更多
There remain unmet clinical needs for safe and effective bone anabolic therapies to treat aging-related osteoporosis and to improve fracture healing in cases of nonunion or delayed union. Wnt signaling has emerged as ...There remain unmet clinical needs for safe and effective bone anabolic therapies to treat aging-related osteoporosis and to improve fracture healing in cases of nonunion or delayed union. Wnt signaling has emerged as a promising target pathway for developing novel bone anabolic drugs. Although neutralizing antibodies against the Wnt antagonist sclerostin have been tested,Wnt ligands themselves have not been fully explored as a potential therapy. Previous work has demonstrated Wnt7b as an endogenous ligand upregulated during osteoblast differentiation, and that Wnt7b overexpression potently stimulates bone accrual in the mouse. The earlier studies however did not address whether Wnt7b could promote bone formation when specifically applied to aged or fractured bones. Here we have developed a doxycycline-inducible strategy where Wnt7b is temporally induced in the bones of aged mice or during fracture healing. We report that forced expression of Wnt7b for 1 month starting at 15 months of age greatly stimulated trabecular and endosteal bone formation, resulting in a marked increase in bone mass. We further tested the effect of Wnt7b on bone healing in a murine closed femur fracture model. Induced expression of Wnt7b at the onset of fracture did not affect the initial cartilage formation but promoted mineralization of the subsequent bone callus. Thus, targeted delivery of Wnt7b to aged bones or fracture sites may be explored as a potential therapy.展开更多
To identify which blood and mucosal lymphocyte populations are specifically depleted by thiopurine use in vivo.METHODSThe thiopurines azathioprine and 6-mercaptopurine have been a mainstay of inflammatory bowel diseas...To identify which blood and mucosal lymphocyte populations are specifically depleted by thiopurine use in vivo.METHODSThe thiopurines azathioprine and 6-mercaptopurine have been a mainstay of inflammatory bowel disease (IBD) therapy for decades, but their mechanism of action in vivo remains obscure. Although thiopurines are lymphotoxic at high doses, and have been reported to cause T cell apoptosis in vitro, their ability to control IBD at lower doses suggests that they may selectively deplete particular lymphocyte populations. Blood cells from 19 IBD patients on a thiopurine, 19 IBD patients not on a thiopurine, and 38 matched healthy control subjects were analyzed by multiple multi-color flow cytometry panels to quantify the immune cell subsets contained therein, both as a percent of cells, and as an absolute cell count. Similar analyses were performed on colon biopsies from 17 IBD patients on a thiopurine, 17 IBD patients not on a thiopurine, and 49 healthy screening colonoscopy recipients.RESULTSComplete blood counts revealed lower lymphocyte, but not monocyte or granulocyte, counts in IBD patients who were taking thiopurines at the time of sampling. This reduction was restricted to CD3-negative lymphocytes, wherein both natural killer (NK) and B cells were significantly reduced among thiopurine recipients. Among CD19+ B cells, the transitional B cells were particularly depleted, being nearly absent in both blood and colon biopsies of thiopurine recipients. No differences were associated with thiopurine use in CD8+ T cells, mucosa-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells, gamma/delta T cells, Th1, Th17, regulatory T cells (Tregs) or naïve CD4+ T cells. However, patients with IBD had significantly more circulating FOXP3+, Helios+ Tregs and fewer iNKT and MAIT cells than healthy controls.CONCLUSIONThiopurine use is associated with reduced B and NK cell, but not T cell, subpopulations in the blood of IBD patients.展开更多
Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is a newly identified member of the coronavirus family that has caused the coronavirus disease 2019 (COVID-19) pandemic. This rapidly evolving and unrelenting...Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is a newly identified member of the coronavirus family that has caused the coronavirus disease 2019 (COVID-19) pandemic. This rapidly evolving and unrelenting SARS-CoV-2has disrupted the lives and livelihoods of millions worldwide. As of 23 August 2021, a total of 211,373,303 COVID-19cases have been confirmed globally with a death toll of 4,424,341. A strong understanding of the infection pathway of SARS-CoV-2, and how our immune system responds to the virus is highly pertinent for guiding the development and improvement of effective treatments. In this review, we discuss the current understanding of neutralising antibodies(NAbs) and their implications in clinical practice. The aspects include the pathophysiology of the immune response,particularly humoral adaptive immunity and the roles of NAbs from B cells in infection clearance. We summarise the onset and persistence of IgA, IgM and IgG antibodies, and we explore their roles in neutralising SARS-CoV-2, their persistence in convalescent individuals, and in reinfection. Furthermore, we also review the applications of neutralising antibodies in the clinical setting—from predictors of disease severity to serological testing to vaccinations, and finally in therapeutics such as convalescent plasma infusion.展开更多
The human brain contains an estimated 100 billion neurons that must be systematically organized into functional neural circuits for it to function properly.These circuits range from short-range local signaling network...The human brain contains an estimated 100 billion neurons that must be systematically organized into functional neural circuits for it to function properly.These circuits range from short-range local signaling networks between neighboring neurons to long-range networks formed between various brain regions.Compelling converging evidence indicates that alterations in neural circuits arising from abnormalities during early neuronal development or neurodegeneration contribute significantly to the etiology of neurological disorders.Supporting this notion,efforts to identify genetic causes of these disorders have uncovered an over-representation of genes encoding proteins involved in the processes of neuronal differentiation,maturation,synaptogenesis and synaptic function.Fasciculation and elongation protein zeta-1,a Kinesin-1 adapter,has emerged as a key central player involved in many of these processes.Fasciculation and elongation protein zeta-1-dependent transport of synaptic cargoes and mitochondria is essential for neuronal development and synapse establishment.Furthermore,it acts downstream of guidance cue pathways to regulate axo-dendritic development.Significantly,perturbing its function causes abnormalities in neuronal development and synapse formation both in the brain as well as the peripheral nervous system.Mutations and deletions of the fasciculation and elongation protein zeta-1 gene are linked to neurodevelopmental disorders.Moreover,altered phosphorylation of the protein contributes to neurodegenerative disorders.Together,these findings strongly implicate the importance of fasciculation and elongation protein zeta-1 in the establishment of neuronal circuits and its maintenance.展开更多
The highly condensed chromatin of mammalian spermatozoa is usually considered to be biologically inert before fertilization. However, we have demonstrated that even in this compacted state, sperm chromatin is subject ...The highly condensed chromatin of mammalian spermatozoa is usually considered to be biologically inert before fertilization. However, we have demonstrated that even in this compacted state, sperm chromatin is subject to degradation at open configurations associated with the nuclear matrix through a process we have termed sperm chromatin fragmentation （SCF）. ＂[his suggests that a mechanism exists to monitor the health of spermatozoa during transit through the male reproductive tract and to destroy the genome of defective sperm cells. The site of DNA damage in SCF, the matrix attachment sites, are the same that we hypothesize initiate DNA synthesis in the zygote. When sperm that have damaged DNA are injected into the oocyte, the newly created zygote responds by delaying DNA synthesis in the male pronudeus and, if the damage is severe enough, arresting the embryo＇s development. Here we present a model for paternal DNA regulation by the nuclear matrix that begins during sperm maturation and continues through early embryonic development.展开更多
Background: Neuroblastoma exhibits a high incidence of chromosomal translocations, the most common being the gain of a portion of the long arm of chromosome 17. This region includes the gene BIRC5/survivin, which is h...Background: Neuroblastoma exhibits a high incidence of chromosomal translocations, the most common being the gain of a portion of the long arm of chromosome 17. This region includes the gene BIRC5/survivin, which is highly upregulated in neuroblastoma and correlates with poor prognosis. Survivin is a member of the inhibitor of apoptosis family of proteins and is involved in tumor cell survival and migration. YM155 is a small molecule inhibitor of survivin transcription and has shown efficacy in several cancer model systems both?in vitro?and?in vivo. Procedure: Cells were treated with YM155 and effects on migration, invasion, and apoptosis signaling were investigated?in vitro. Tumor burden was assessed in xenografted mice by measuring tumor volume and liver metastases. Results: Treatment with YM155 caused a dose-dependent decrease in survivin expression and induction of apoptosis. Lower concentrations of YM155 reduced cell migration and invasion by 15% - 50% which varied by cell line. In a xenograft model, YM155 treatment inhibited tumor growth by 25% - 70%, reduced metastatic burden in the liver by 50%, and prolonged animal survival. Conclusion: The data suggest YM155 as a possible therapeutic agent for metastatic neuroblastoma.展开更多
In the ever-evolving landscape of cancer research and treatment,the quest for novel and non-invasive imaging techniques has become crucial for accurate diagnosis and effective therapy.This study[1]successfully develop...In the ever-evolving landscape of cancer research and treatment,the quest for novel and non-invasive imaging techniques has become crucial for accurate diagnosis and effective therapy.This study[1]successfully developed a good manufacturing practices(GMP)grade ^(89)Zr-labeled anti-Claudin18.2(CLDN18.2)recombinant humanized antibody TST001.^(89)Zr-DFO-TST001 exhibited high radiochemical purity(>99%)and specific activity(24.15±1.34 GBq/mmol).It demonstrated good specificity and rapid tumor accumulation in vivo and in vivo.Through immuno-PET imaging,it enables non-invasive visualization and quantification of CLDN18.2 expression level in CLDN18.2-positive gastrointestinal tumor models.展开更多
In the current issue of the Journal of Sport and Health Science,Wang et al.^(1)describe their prospective study,where they analyzed whether or not multiple pregnancies would influence glycemia and the glycemic respons...In the current issue of the Journal of Sport and Health Science,Wang et al.^(1)describe their prospective study,where they analyzed whether or not multiple pregnancies would influence glycemia and the glycemic response to physical exercise in gestational diabetes mellitus(GDM).2 Multiparous women are known to be at a higher risk for GDM than primiparas.GDM carries an increased risk for adverse perinatal outcomes,not only for the mothers but also for the newborn babies.Due to a contemporary environment that is conducive to a sedentary lifestyle and obesity,the incidence of GDM among pregnant women is increasing.展开更多
Background: Neuroblastoma is the most common extracranial solid tumor in children, and treatment options for recurrent neuroblastoma are limited. Using molecular profiling to target the molecular vulnerabilities of ne...Background: Neuroblastoma is the most common extracranial solid tumor in children, and treatment options for recurrent neuroblastoma are limited. Using molecular profiling to target the molecular vulnerabilities of neuroblastoma with existing therapeutic agents may result in a rational, data-driven approach with potential to improve clinical outcomes. Methods: The primary objective of this pilot study was to evaluate the feasibility of supporting real-time treatment decisions through predictive modeling of genome-wide mRNA gene expression data from neuroblastoma tumor biopsies. Feasibility was defined as completion of tumor biopsy, histopathological evaluation, RNA extraction and quality control, gene expression profiling within a CLIA-certified laboratory, bioinformatic analysis, generation of a drug predicttion report, molecular tumor board review yielding a formulated treatment plan, and independent medical monitor review within a 2-week period. Results: Five patients with multiply relapsed or refractory neuroblastoma were enrolled between April and June 2010. All biopsies passed histopathology and RNA quality control. Generation of gene expression data and its analysis (3-7 days), reports which linked this data into medically actionable drug candidates (1-5 days), molecular tumor board (1-3 days) and independent medical monitor review (1 day) were all completed in real-time. The average time was 10.5 days for all patients. Conclusion: This study shows that it is feasible to create therapeutic treatment plans based on genomic profiling in less than 12 days. This warrants further testing in a Phase I study to determine safety of predicted treatments and evaluate whether the information obtained in these analyses would result in patient benefit.展开更多
Head and neck cancer is a significant threat to human health and is charac-terized by high 5-year morbidity and mortality rates.Addressing this challenge requires the application of precision medicine,but the inherent...Head and neck cancer is a significant threat to human health and is charac-terized by high 5-year morbidity and mortality rates.Addressing this challenge requires the application of precision medicine,but the inherent heterogeneity of head and neck cancer complicates its treatment.Radiogenomics,an inter-disciplinary field at the intersection of genomics and radiology,may represent a solution.Radiogenomics offers the potential to revolutionize the diagnosis and treatment of this complex and diverse disease.By comprehensively analyzing the genetic information and radiological features of tumors,clini-cians can gain a profound understanding of patients'conditions.Gaining such in-depth insight facilitates early detection and implementation of personalized treatment strategies,both of which are integral components of precision medicine.Tailored treatments,including surgical interventions and targeted therapies,provide improved outcomes and reduced side effects.Radio-genomics represents a groundbreaking advancement that has the potential to significantly enhance the quality of care and outcomes of patients with head and neck cancer.To shed light on this transformative approach,we performed a comprehensive overview of radiomics and radiogenomics-based diagnostic methods tailored to the unique characteristics of head and neck cancer.展开更多
Radiopharmaceuticals are reshaping the landscape of cancer therapy,offering a unique theranostic advantage that is becoming increasingly central to precision medicine.By labeling the same molecular scaffold with diffe...Radiopharmaceuticals are reshaping the landscape of cancer therapy,offering a unique theranostic advantage that is becoming increasingly central to precision medicine.By labeling the same molecular scaffold with different radionuclides,these agents enable seamless integration of diagnostic imaging and targeted therapy.Clinical breakthroughs with somatostatin receptor subtype 2(SSTR2)-and prostate-specificmembrane antigen(PSMA)-targeted radiopharmaceuticals have significantly enhanced both tumor visualization and therapeutic efficacy,establishing new benchmarks in oncology.Ongoing research is exploring novel molecular targets such as cholecystokinin-2 receptor(CCK2R),fibroblast activation protein(FAP),and C-X-C chemokine receptor type 4(CXCR4).In parallel,there is growing interest in utilizing alternative radionuclides,including alpha-particle emitters and Auger electron emitters,beyond the commonly used beta-emitters,to improve therapeutic outcomes.Simultaneously,advances in ligand and linker design are being leveraged to optimize in vivo pharmacokinetics and tissue distribution.Among the emerging targets,CCK2R has attracted notable attention due to its overexpression in multiple malignancies.Research efforts have focused on improving ligand stability,receptor-binding affinity,and tumor retention,while also exploring strategies to enhance CCK2R expression on cancer cells.This review offers a comprehensive overview of the current landscape in cancer radiotheranostics,exploring the role of CCK2R in cancer biology and summarizing the latest advancements in the development of CCK2R-targeted radiopharmaceuticals.Using these advancements as a case study,we systematically examine key aspects of next-generation radiopharmaceutical design,from target selection and ligand engineering to pharmacokinetic optimization and clinical translation,providing a multidimensional framework for future innovation in cancer radiotheranostics.展开更多
Interleukin 27(IL-27),a heterodimeric cytokine composed of Epstein-Barr virus-induced 3 and p28,is a pleiotropic cytokine with both pro-and anti-inflammatory properties.However,the precise role of IL-27 in acute graft...Interleukin 27(IL-27),a heterodimeric cytokine composed of Epstein-Barr virus-induced 3 and p28,is a pleiotropic cytokine with both pro-and anti-inflammatory properties.However,the precise role of IL-27 in acute graft-versus-host disease is not yet fully understood.In this study,utilizing mice with IL-27 p28 deficiency in dendritic cells(DCs),we demonstrated that IL-27 p28 deficiency resulted in impaired Treg cell function and enhanced effector T cell responses,corresponding to aggravated aGVHD in mice.In addition,using single-cell RNA sequencing,we found that loss of IL-27 p28 impaired Treg cell generation and promoted IL1R2^(+)TIGIT^(+)pathogenic CD4+T cells in the thymus at a steady state.Mechanistically,IL-27 p28 deficiency promoted STAT1 phosphorylation and Th1 cell responses,leading to the inhibition of Treg cell differentiation and function.Finally,patients with high levels of IL-27 p28 in serum showed a substantially decreased occurrence of grade II-IV aGVHD and more favorable overall survival than those with low levels of IL-27 p28.Thus,our results suggest a protective role of DC-derived IL-27 p28 in the pathogenesis of aGVHD through modulation of the Treg/Teff cell balance during thymic development.IL-27 p28 may be a valuable marker for predicting aGVHD development after transplantation in humans.展开更多
INTRODUCTION With the expansion of the ageing population,cognitive decline has become an increas-ingly pressing challenge.1 As life expectancy increases,its socioeconomic burden is also increasing,highlighting the urg...INTRODUCTION With the expansion of the ageing population,cognitive decline has become an increas-ingly pressing challenge.1 As life expectancy increases,its socioeconomic burden is also increasing,highlighting the urgent need for effective interventions.Numerous studies suggest that specific dietary patterns and nutritional interventions may help mitigate cognitive decline associated with ageing.展开更多
Objective Impaired hepatic expression of protein tyrosine phosphatase delta(PTPRD)is associated with increased STAT3 transcriptional activity and reduced survival from hepatocellular carcinoma in patients with chronic...Objective Impaired hepatic expression of protein tyrosine phosphatase delta(PTPRD)is associated with increased STAT3 transcriptional activity and reduced survival from hepatocellular carcinoma in patients with chronic hepatitis C virus infection.However,the PTPRD-expressing hepatic cell types,signalling pathways responsive to PTPRD and their role in non-viral liver disease are largely unknown.Methods We studied PTPRD expression in single-cell and bulk liver transcriptomic data from mice and humans,and established a Ptprd-deficient mouse model for metabolic dysfunction-associated steatohepatitis(MASH).Identified pathways were validated by perturbation studies in human hepatocytes and PTPRD substrates by pull-down assays.The clinical relevance was further explored in a cohort with metabolic disease by ranking patients according to PTPRD expression and analysing its association with metabolic disease markers.Results The analysis of individuals ranked according to PTPRD expression and Ptprd-deficient mice,showed that PTPRD levels were associated with hepatic glucose/lipid signalling and peroxisome function.Hepatic PTPRD expression is impaired in aetiologies of chronic liver diseases that are associated with metabolic disease.We further validated PTPRD as a STAT3 phosphatase in the liver,acting as a regulator of peroxisomal fatty acid metabolism.During MASH,low PTPRD led to increased liver steatosis in Ptprd+/−mice and a pronounced unfolded protein response,which impacts insulin signalling.Accordingly,silencing of PTPRD blunted insulin-induced AKT phosphorylation.Patients with obesity and low hepatic PTPRD expression exhibit increased levels of metabolic risk factors.Conclusion Our data revealed an important regulatory role of the hepatic PTPRD-STAT3 axis in maintaining glucose/lipid homeostasis,which is recapitulated in clinical manifestations of metabolic liver disease.展开更多
The variety and functionality of current clinical vaccine adjuvants remain limited.Conventional aluminum-based adjuvants predominantly induce Th2-biased humoral immunity but exhibit a limited capacity to elicit Th1-me...The variety and functionality of current clinical vaccine adjuvants remain limited.Conventional aluminum-based adjuvants predominantly induce Th2-biased humoral immunity but exhibit a limited capacity to elicit Th1-mediated cellular immune responses,particularly tumor antigen-specific cytotoxic CD8+T lymphocytes(CTLs),which are essential for effective cancer vaccine performance.Inspired by natural biomolecular condensates,we developed a versatile noncovalent protein self-assembly strategy distinct from traditional approaches requiring structural domain modifications or bifunctional crosslinkers.Our methodology employs amphiphilic molecules(sodium myristate/SMA and sodium dodecyl thiolate/SDT)as molecular bridges to mediate protein-protein interactions through hydrophobic forces and disulfide bond formation.This process generates nanoscale protein condensate(PCD)vaccines with exceptional stability.As a novel adjuvant system,these synthetic condensates significantly enhance antigen cross-presentation by optimizing key parameters:antigen loading capacity,lymph node targeting,cytosolic delivery,and lysosomal escape.Consequently,they induce robust antigen-specific CTL responses and humoral immunity,demonstrating potent antitumor efficacy.Importantly,we found that the synthetic protein condensate(PCD)alone can act as a nanoadjuvant.By increasing mitochondrial membrane permeability,PCD induces mitochondrial DNA leakage into the cytosol,activating the cGAS-STING pathway and promoting DC maturation.This safe and scalable platform eliminates the need for complex covalent modifications or genetic engineering,and it facilitates the design of diverse modular antigens,including neoantigens and viral antigens.Given its straightforward manufacturing process and superior immunogenicity,this synthetic PCD vaccine adjuvant has significant potential for clinical application and translation.展开更多
基金supported by the Ministry of Health National Medical Research Council (to JL)the National University of Singapore (to JJEC)
文摘Schizophrenia is a complex psychiatric disorder marked by positive and negative symptoms,leading to mood disturbances,cognitive impairments,and social withdrawal.While anti-psychotic medications remain the cornerstone of treatment,they often fail to fully address certain symptoms.Additionally,treatment-resistant schizophrenia,affecting 30%-40%of patients,remains a substantial clinical challenge.Positive,negative symptoms and cognitive impairments have been linked to disruptions in the glutamatergic,serotonin,GABAergic,and muscarinic pathways in the brain.Recent advances using genome-wide association study and other approaches have uncovered a significant number of new schizophrenia risk genes that uncovered new,and reinforced prior,concepts on the genetic and neurological underpinnings of schizophrenia,including abnormalities in synaptic function,immune processes,and lipid metabolism.Concurrently,new therapeutics targeting different modalities,which are expected to address some of the limitations of anti-psychotic drugs currently being offered to patients,are currently being evaluated.Collectively,these efforts provide new momentum for the next phase of schizophrenia research and treatment.
文摘The human skeleton is a multifunctional organ made up of multiple cell types working in concert to maintain bone and mineral homeostasis and to perform critical mechanical and endocrine functions.From the beginning steps of chondrogenesis that prefigures most of the skeleton,to the rapid bone accrual during skeletal growth,followed by bone remodeling of the mature skeleton,cell differentiation is integral to skeletal health.
文摘Current scientific endeavours in the field of geroscience have begun to reveal how factors such as exercise could modulate the brain aging process.In this review,we ask how exercise could potentially modulate aging,and by extension,the development of Alzheimer’s Disease(AD).Furthermore,we discuss how exercise could mitigate the cascade of debilitating manifestations in AD.Mechanistically,we discuss how biomolecules such as brain-derived neurotrophic factor(BDNF)and its cognate receptor,tropomyosin receptor kinase B(TrkB)could change during the life course and how its signalling pathways could be altered with exercise(acute sessions or chronic training).Tackling these questions could help the scientific and medical community mitigate age-related decline in terms of neurological functions.
基金supported by Australian Centre for AI in Medical Innovation(ACAMI)funded by the Victoria State Government,National University of Singapore(NUHSRO/2020/133/Startup/08,NUHSRO/2023/008/NUSMed/TCE/LOA,NUHSRO/2021/034/TRP/09/Nanomedicine,NUHSRO/2021/044/Kickstart/09/LOA,and 230173-A0001)National Medical Research Council(MOH-001388-00,CG21APR1005,MOH-001500-00,and MOH-001609-00)+1 种基金Singapore Ministry of Education(MOE-000387-00 and MOET32023-0005)National Research Foundation(NRF-000352-00)。
文摘1.Introduction Cancer continues to be a major cause of global mortality rates,with conventional treatments such as chemotherapy and radiotherapy exhibiting inconsistent efficacy,high costs,and considerable side effects.Over the past decade,a promising alternative has emerged:cancer immunotherapy,which leverages the body's immune system to identify and eradicate cancer cells[1].
基金supported by the Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang(2023R01002)the National Natural Science Foundation of China(82271629,82301790)。
文摘Aging and regeneration represent complex biological phenomena that have long captivated the scientific community.To fully comprehend these processes,it is essential to investigate molecular dynamics through a lens that encompasses both spatial and temporal dimensions.Conventional omics methodologies,such as genomics and transcriptomics,have been instrumental in identifying critical molecular facets of aging and regeneration.However,these methods are somewhat limited,constrained by their spatial resolution and their lack of capacity to dynamically represent tissue alterations.The advent of emerging spatiotemporal multi-omics approaches,encompassing transcriptomics,proteomics,metabolomics,and epigenomics,furnishes comprehensive insights into these intricate molecular dynamics.These sophisticated techniques facilitate accurate delineation of molecular patterns across an array of cells,tissues,and organs,thereby offering an in-depth understanding of the fundamental mechanisms at play.This review meticulously examines the significance of spatiotemporal multi-omics in the realms of aging and regeneration research.It underscores how these methodologies augment our comprehension of molecular dynamics,cellular interactions,and signaling pathways.Initially,the review delineates the foundational principles underpinning these methods,followed by an evaluation of their recent applications within the field.The review ultimately concludes by addressing the prevailing challenges and projecting future advancements in the field.Indubitably,spatiotemporal multi-omics are instrumental in deciphering the complexities inherent in aging and regeneration,thus charting a course toward potential therapeutic innovations.
基金supported by AR060456 (F.L.), AR047867 (M.J.S.)the Washington University Musculoskeletal Research Center (NIH P30 AR057235)
文摘There remain unmet clinical needs for safe and effective bone anabolic therapies to treat aging-related osteoporosis and to improve fracture healing in cases of nonunion or delayed union. Wnt signaling has emerged as a promising target pathway for developing novel bone anabolic drugs. Although neutralizing antibodies against the Wnt antagonist sclerostin have been tested,Wnt ligands themselves have not been fully explored as a potential therapy. Previous work has demonstrated Wnt7b as an endogenous ligand upregulated during osteoblast differentiation, and that Wnt7b overexpression potently stimulates bone accrual in the mouse. The earlier studies however did not address whether Wnt7b could promote bone formation when specifically applied to aged or fractured bones. Here we have developed a doxycycline-inducible strategy where Wnt7b is temporally induced in the bones of aged mice or during fracture healing. We report that forced expression of Wnt7b for 1 month starting at 15 months of age greatly stimulated trabecular and endosteal bone formation, resulting in a marked increase in bone mass. We further tested the effect of Wnt7b on bone healing in a murine closed femur fracture model. Induced expression of Wnt7b at the onset of fracture did not affect the initial cartilage formation but promoted mineralization of the subsequent bone callus. Thus, targeted delivery of Wnt7b to aged bones or fracture sites may be explored as a potential therapy.
基金Supported by Virginia Mason Medical Center,Digestive Disease Institute Research Grant Award,No.0506812-2011
文摘To identify which blood and mucosal lymphocyte populations are specifically depleted by thiopurine use in vivo.METHODSThe thiopurines azathioprine and 6-mercaptopurine have been a mainstay of inflammatory bowel disease (IBD) therapy for decades, but their mechanism of action in vivo remains obscure. Although thiopurines are lymphotoxic at high doses, and have been reported to cause T cell apoptosis in vitro, their ability to control IBD at lower doses suggests that they may selectively deplete particular lymphocyte populations. Blood cells from 19 IBD patients on a thiopurine, 19 IBD patients not on a thiopurine, and 38 matched healthy control subjects were analyzed by multiple multi-color flow cytometry panels to quantify the immune cell subsets contained therein, both as a percent of cells, and as an absolute cell count. Similar analyses were performed on colon biopsies from 17 IBD patients on a thiopurine, 17 IBD patients not on a thiopurine, and 49 healthy screening colonoscopy recipients.RESULTSComplete blood counts revealed lower lymphocyte, but not monocyte or granulocyte, counts in IBD patients who were taking thiopurines at the time of sampling. This reduction was restricted to CD3-negative lymphocytes, wherein both natural killer (NK) and B cells were significantly reduced among thiopurine recipients. Among CD19+ B cells, the transitional B cells were particularly depleted, being nearly absent in both blood and colon biopsies of thiopurine recipients. No differences were associated with thiopurine use in CD8+ T cells, mucosa-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells, gamma/delta T cells, Th1, Th17, regulatory T cells (Tregs) or naïve CD4+ T cells. However, patients with IBD had significantly more circulating FOXP3+, Helios+ Tregs and fewer iNKT and MAIT cells than healthy controls.CONCLUSIONThiopurine use is associated with reduced B and NK cell, but not T cell, subpopulations in the blood of IBD patients.
基金supported by the National Medical Research Council,Singapore (NMRC COVID19RF2-0002)。
文摘Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is a newly identified member of the coronavirus family that has caused the coronavirus disease 2019 (COVID-19) pandemic. This rapidly evolving and unrelenting SARS-CoV-2has disrupted the lives and livelihoods of millions worldwide. As of 23 August 2021, a total of 211,373,303 COVID-19cases have been confirmed globally with a death toll of 4,424,341. A strong understanding of the infection pathway of SARS-CoV-2, and how our immune system responds to the virus is highly pertinent for guiding the development and improvement of effective treatments. In this review, we discuss the current understanding of neutralising antibodies(NAbs) and their implications in clinical practice. The aspects include the pathophysiology of the immune response,particularly humoral adaptive immunity and the roles of NAbs from B cells in infection clearance. We summarise the onset and persistence of IgA, IgM and IgG antibodies, and we explore their roles in neutralising SARS-CoV-2, their persistence in convalescent individuals, and in reinfection. Furthermore, we also review the applications of neutralising antibodies in the clinical setting—from predictors of disease severity to serological testing to vaccinations, and finally in therapeutics such as convalescent plasma infusion.
基金the Singapore Ministry of Education(T1-2015 Apr-03)the National University of SingaporeInstitute for Health Innovation and Technology to JJEC.
文摘The human brain contains an estimated 100 billion neurons that must be systematically organized into functional neural circuits for it to function properly.These circuits range from short-range local signaling networks between neighboring neurons to long-range networks formed between various brain regions.Compelling converging evidence indicates that alterations in neural circuits arising from abnormalities during early neuronal development or neurodegeneration contribute significantly to the etiology of neurological disorders.Supporting this notion,efforts to identify genetic causes of these disorders have uncovered an over-representation of genes encoding proteins involved in the processes of neuronal differentiation,maturation,synaptogenesis and synaptic function.Fasciculation and elongation protein zeta-1,a Kinesin-1 adapter,has emerged as a key central player involved in many of these processes.Fasciculation and elongation protein zeta-1-dependent transport of synaptic cargoes and mitochondria is essential for neuronal development and synapse establishment.Furthermore,it acts downstream of guidance cue pathways to regulate axo-dendritic development.Significantly,perturbing its function causes abnormalities in neuronal development and synapse formation both in the brain as well as the peripheral nervous system.Mutations and deletions of the fasciculation and elongation protein zeta-1 gene are linked to neurodevelopmental disorders.Moreover,altered phosphorylation of the protein contributes to neurodegenerative disorders.Together,these findings strongly implicate the importance of fasciculation and elongation protein zeta-1 in the establishment of neuronal circuits and its maintenance.
文摘The highly condensed chromatin of mammalian spermatozoa is usually considered to be biologically inert before fertilization. However, we have demonstrated that even in this compacted state, sperm chromatin is subject to degradation at open configurations associated with the nuclear matrix through a process we have termed sperm chromatin fragmentation （SCF）. ＂[his suggests that a mechanism exists to monitor the health of spermatozoa during transit through the male reproductive tract and to destroy the genome of defective sperm cells. The site of DNA damage in SCF, the matrix attachment sites, are the same that we hypothesize initiate DNA synthesis in the zygote. When sperm that have damaged DNA are injected into the oocyte, the newly created zygote responds by delaying DNA synthesis in the male pronudeus and, if the damage is severe enough, arresting the embryo＇s development. Here we present a model for paternal DNA regulation by the nuclear matrix that begins during sperm maturation and continues through early embryonic development.
文摘Background: Neuroblastoma exhibits a high incidence of chromosomal translocations, the most common being the gain of a portion of the long arm of chromosome 17. This region includes the gene BIRC5/survivin, which is highly upregulated in neuroblastoma and correlates with poor prognosis. Survivin is a member of the inhibitor of apoptosis family of proteins and is involved in tumor cell survival and migration. YM155 is a small molecule inhibitor of survivin transcription and has shown efficacy in several cancer model systems both?in vitro?and?in vivo. Procedure: Cells were treated with YM155 and effects on migration, invasion, and apoptosis signaling were investigated?in vitro. Tumor burden was assessed in xenografted mice by measuring tumor volume and liver metastases. Results: Treatment with YM155 caused a dose-dependent decrease in survivin expression and induction of apoptosis. Lower concentrations of YM155 reduced cell migration and invasion by 15% - 50% which varied by cell line. In a xenograft model, YM155 treatment inhibited tumor growth by 25% - 70%, reduced metastatic burden in the liver by 50%, and prolonged animal survival. Conclusion: The data suggest YM155 as a possible therapeutic agent for metastatic neuroblastoma.
基金supported by the National University of Singapore(Grant Nos.:NUHSRO/2021/097/Startup/13,NUHSRO/2020/133/Startup/08,NUHSRO/2023/008/NUSMed/TCE/LOA,NUHSRO/2021/034/TRP/09/Nanomedicine,and NUHSRO/2021/044/Kickstart/09/LOA)National Medical Research Council(Grant Nos.:OFYIRG23jan-0025,OFYIRG23jan-0017,MOH-001254-01,and CG21APR1005)+2 种基金Singapore Ministry of Education Academic Research Fund(Grant Nos.:NUHSRO/2022/093/T1/Seed-Sep/06 and MOE-000387-01)National Research Foundation(Grant No.:CRP28-2022RS-0001),National Natural Science Foundation of China(Grant No.:82202206)Beijing Natural Science Foundation(Grant No.:7224365).
文摘In the ever-evolving landscape of cancer research and treatment,the quest for novel and non-invasive imaging techniques has become crucial for accurate diagnosis and effective therapy.This study[1]successfully developed a good manufacturing practices(GMP)grade ^(89)Zr-labeled anti-Claudin18.2(CLDN18.2)recombinant humanized antibody TST001.^(89)Zr-DFO-TST001 exhibited high radiochemical purity(>99%)and specific activity(24.15±1.34 GBq/mmol).It demonstrated good specificity and rapid tumor accumulation in vivo and in vivo.Through immuno-PET imaging,it enables non-invasive visualization and quantification of CLDN18.2 expression level in CLDN18.2-positive gastrointestinal tumor models.
文摘In the current issue of the Journal of Sport and Health Science,Wang et al.^(1)describe their prospective study,where they analyzed whether or not multiple pregnancies would influence glycemia and the glycemic response to physical exercise in gestational diabetes mellitus(GDM).2 Multiparous women are known to be at a higher risk for GDM than primiparas.GDM carries an increased risk for adverse perinatal outcomes,not only for the mothers but also for the newborn babies.Due to a contemporary environment that is conducive to a sedentary lifestyle and obesity,the incidence of GDM among pregnant women is increasing.
文摘Background: Neuroblastoma is the most common extracranial solid tumor in children, and treatment options for recurrent neuroblastoma are limited. Using molecular profiling to target the molecular vulnerabilities of neuroblastoma with existing therapeutic agents may result in a rational, data-driven approach with potential to improve clinical outcomes. Methods: The primary objective of this pilot study was to evaluate the feasibility of supporting real-time treatment decisions through predictive modeling of genome-wide mRNA gene expression data from neuroblastoma tumor biopsies. Feasibility was defined as completion of tumor biopsy, histopathological evaluation, RNA extraction and quality control, gene expression profiling within a CLIA-certified laboratory, bioinformatic analysis, generation of a drug predicttion report, molecular tumor board review yielding a formulated treatment plan, and independent medical monitor review within a 2-week period. Results: Five patients with multiply relapsed or refractory neuroblastoma were enrolled between April and June 2010. All biopsies passed histopathology and RNA quality control. Generation of gene expression data and its analysis (3-7 days), reports which linked this data into medically actionable drug candidates (1-5 days), molecular tumor board (1-3 days) and independent medical monitor review (1 day) were all completed in real-time. The average time was 10.5 days for all patients. Conclusion: This study shows that it is feasible to create therapeutic treatment plans based on genomic profiling in less than 12 days. This warrants further testing in a Phase I study to determine safety of predicted treatments and evaluate whether the information obtained in these analyses would result in patient benefit.
基金National University of Singapore,Grant/Award Number:NUHSRO/2022/005/Startup/02NSFC,Grant/Award Number:82202231。
文摘Head and neck cancer is a significant threat to human health and is charac-terized by high 5-year morbidity and mortality rates.Addressing this challenge requires the application of precision medicine,but the inherent heterogeneity of head and neck cancer complicates its treatment.Radiogenomics,an inter-disciplinary field at the intersection of genomics and radiology,may represent a solution.Radiogenomics offers the potential to revolutionize the diagnosis and treatment of this complex and diverse disease.By comprehensively analyzing the genetic information and radiological features of tumors,clini-cians can gain a profound understanding of patients'conditions.Gaining such in-depth insight facilitates early detection and implementation of personalized treatment strategies,both of which are integral components of precision medicine.Tailored treatments,including surgical interventions and targeted therapies,provide improved outcomes and reduced side effects.Radio-genomics represents a groundbreaking advancement that has the potential to significantly enhance the quality of care and outcomes of patients with head and neck cancer.To shed light on this transformative approach,we performed a comprehensive overview of radiomics and radiogenomics-based diagnostic methods tailored to the unique characteristics of head and neck cancer.
基金National University of Singapore,Grant/Award Numbers:NUHSRO/2021/097/Startup/13,NUHSRO/2020/133/Startup/08,NUHSRO/2023/008/NUS Med/TCE/LOANational Medical Research Council,Grant/Award Numbers:MOH-001483-00,MOH-001334-00,MOH-001388-00,MOH-001254-01,CG21APR1005+1 种基金Singapore Ministry of Education,Grant/Award Number:(FY2022)-Tier1-NUHSRO/2022/093/T1/Seed-Sep/06NUS School of Medicine Nanomedicine Translational Research Programme,Grant/Award Number:NUHSRO/2021/034/TRP/09/Nanomedicine。
文摘Radiopharmaceuticals are reshaping the landscape of cancer therapy,offering a unique theranostic advantage that is becoming increasingly central to precision medicine.By labeling the same molecular scaffold with different radionuclides,these agents enable seamless integration of diagnostic imaging and targeted therapy.Clinical breakthroughs with somatostatin receptor subtype 2(SSTR2)-and prostate-specificmembrane antigen(PSMA)-targeted radiopharmaceuticals have significantly enhanced both tumor visualization and therapeutic efficacy,establishing new benchmarks in oncology.Ongoing research is exploring novel molecular targets such as cholecystokinin-2 receptor(CCK2R),fibroblast activation protein(FAP),and C-X-C chemokine receptor type 4(CXCR4).In parallel,there is growing interest in utilizing alternative radionuclides,including alpha-particle emitters and Auger electron emitters,beyond the commonly used beta-emitters,to improve therapeutic outcomes.Simultaneously,advances in ligand and linker design are being leveraged to optimize in vivo pharmacokinetics and tissue distribution.Among the emerging targets,CCK2R has attracted notable attention due to its overexpression in multiple malignancies.Research efforts have focused on improving ligand stability,receptor-binding affinity,and tumor retention,while also exploring strategies to enhance CCK2R expression on cancer cells.This review offers a comprehensive overview of the current landscape in cancer radiotheranostics,exploring the role of CCK2R in cancer biology and summarizing the latest advancements in the development of CCK2R-targeted radiopharmaceuticals.Using these advancements as a case study,we systematically examine key aspects of next-generation radiopharmaceutical design,from target selection and ligand engineering to pharmacokinetic optimization and clinical translation,providing a multidimensional framework for future innovation in cancer radiotheranostics.
基金supported by the National Natural Science Foundation of China(No.81730003,81700173,81974001,82170222,and 81900180)National Science and Technology Major Project(2017ZX09304021)+9 种基金National Key R&D Program of China(2019YFC0840604 and 2017YFA0104502)Key R&D Program of Jiangsu Province(BE2019798)Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD),Jiangsu Medical Outstanding Talents Project(JCRCA2016002)Jiangsu Provincial Key Medical Center(YXZXA2016002)the Jiangsu“333”Talent Project(BRA2015497)the Jiangsu Social Development Program(BE2018651)the Jiangsu Summit Six Top Talent Person project,Jiangsu Medical Junior Talent Person award(QNRC2016707)Natural Science Foundation of Jiangsu Province(BK20220246),Suzhou Science and Technology Program Project(SLT201911)the Natural Science Foundation of Jiangsu Higher Education Institutions of China(20KJD320001)Natural Science Basic Research Program of Shaanxi(2022JQ-800).
文摘Interleukin 27(IL-27),a heterodimeric cytokine composed of Epstein-Barr virus-induced 3 and p28,is a pleiotropic cytokine with both pro-and anti-inflammatory properties.However,the precise role of IL-27 in acute graft-versus-host disease is not yet fully understood.In this study,utilizing mice with IL-27 p28 deficiency in dendritic cells(DCs),we demonstrated that IL-27 p28 deficiency resulted in impaired Treg cell function and enhanced effector T cell responses,corresponding to aggravated aGVHD in mice.In addition,using single-cell RNA sequencing,we found that loss of IL-27 p28 impaired Treg cell generation and promoted IL1R2^(+)TIGIT^(+)pathogenic CD4+T cells in the thymus at a steady state.Mechanistically,IL-27 p28 deficiency promoted STAT1 phosphorylation and Th1 cell responses,leading to the inhibition of Treg cell differentiation and function.Finally,patients with high levels of IL-27 p28 in serum showed a substantially decreased occurrence of grade II-IV aGVHD and more favorable overall survival than those with low levels of IL-27 p28.Thus,our results suggest a protective role of DC-derived IL-27 p28 in the pathogenesis of aGVHD through modulation of the Treg/Teff cell balance during thymic development.IL-27 p28 may be a valuable marker for predicting aGVHD development after transplantation in humans.
基金supported by the Shandong Second Medical University Overseas Visiting Scholar Program,and the National Medical Research Council of Singapore(grant numbers NMRC/TA/0053/2016 and NMRC/CSA/INV/0009/2022).
文摘INTRODUCTION With the expansion of the ageing population,cognitive decline has become an increas-ingly pressing challenge.1 As life expectancy increases,its socioeconomic burden is also increasing,highlighting the urgent need for effective interventions.Numerous studies suggest that specific dietary patterns and nutritional interventions may help mitigate cognitive decline associated with ageing.
基金supported by the European Union(ERC-AdG-2014 HEPCIR ERC POC PRELICAN 755460,ERC POC HEPCAN 862551 to TFB,EU H2020 HEPCAR 667273 to TFB and JL,HORIZON-HLTH-2021-DISEASE-04-07 D-SOLVE#101057917 to TFB and JL,IP-cure-B project#847939 to FZ,ERC-AdG-2020-101021417 to YH)the French Cancer Agency(TheraHCC2.0 IHU201901299 to TFB)+9 种基金the Agence Nationale de la Recherche(ANR-21-RHUS-001 to TFB)the ANRS Maladies infectieusesémergentes(ANRS-MIE)(ECTZ103701,ECTZ131760,ECTZ160436,ECTZ171594 to JL,ECTZ104017 and ECTZ75178 to TFB,ECTZ4446 and ECTZ206376 to AARS)the Fondation de l’Universitéde Strasbourg(HEPKIN)(TBA-DON-0002),SATT Conectus,University of Strasbourg(CANCLAU)(TFB)the Inserm Plan Cancer 2019-2023the US National Institutes of Health(CA233794,CA255621,CA282178,CA288375 and CA283935 to YH)the Cancer Prevention and Research Institute of Texas(RR180016,RP200554 to YH)The AEPIC animal facility platform is financially supported by the CoRTecS network of the University of StrasbourgThis work of the Interdisciplinary Thematic Institute IMCBio,as part of the ITI 2021-2028 programme of the University of Strasbourg,CNRS and Inserm,was supported by IdEx Unistra(ANR-10-IDEX-0002)SFRI-STRAT’US project(ANR 20-SFRI-0012)EUR IMCBio(ANR-17-EURE-0023)under the framework of the French Investments for the Future Programme,as well as state funds managed within the France 2030 programme(reference ANR-21-RHUS-0001).
文摘Objective Impaired hepatic expression of protein tyrosine phosphatase delta(PTPRD)is associated with increased STAT3 transcriptional activity and reduced survival from hepatocellular carcinoma in patients with chronic hepatitis C virus infection.However,the PTPRD-expressing hepatic cell types,signalling pathways responsive to PTPRD and their role in non-viral liver disease are largely unknown.Methods We studied PTPRD expression in single-cell and bulk liver transcriptomic data from mice and humans,and established a Ptprd-deficient mouse model for metabolic dysfunction-associated steatohepatitis(MASH).Identified pathways were validated by perturbation studies in human hepatocytes and PTPRD substrates by pull-down assays.The clinical relevance was further explored in a cohort with metabolic disease by ranking patients according to PTPRD expression and analysing its association with metabolic disease markers.Results The analysis of individuals ranked according to PTPRD expression and Ptprd-deficient mice,showed that PTPRD levels were associated with hepatic glucose/lipid signalling and peroxisome function.Hepatic PTPRD expression is impaired in aetiologies of chronic liver diseases that are associated with metabolic disease.We further validated PTPRD as a STAT3 phosphatase in the liver,acting as a regulator of peroxisomal fatty acid metabolism.During MASH,low PTPRD led to increased liver steatosis in Ptprd+/−mice and a pronounced unfolded protein response,which impacts insulin signalling.Accordingly,silencing of PTPRD blunted insulin-induced AKT phosphorylation.Patients with obesity and low hepatic PTPRD expression exhibit increased levels of metabolic risk factors.Conclusion Our data revealed an important regulatory role of the hepatic PTPRD-STAT3 axis in maintaining glucose/lipid homeostasis,which is recapitulated in clinical manifestations of metabolic liver disease.
基金supported by the Guangdong Basic and Applied Basic Research Foundation(2023A1515012356,P.Z.)the National Natural Science Foundation of China(Grant No.82003158,Y.Z.)+5 种基金the National Natural Science Foundation of China(32371518 and 32101209,P.Z.)X.C.acknowledges financial support from the National University of Singapore(NUHSRO/2020/133/Startup/08,NUHSRO/2023/008/NUSMed/TCE/LOA,NUHSRO/2021/034/TRP/09/Nanomedicine,23-0173-A0001)National Medical Research Council(MOH-001388-00,CG21APR1005,MOH001500-00,MOH-001609-00,MOH-001740-01)Singapore Ministry of Education(MOE-000387-00,MOE-MOET32023-004)National Research Foundation(NRF000352-00)jointly supported by the National University of Singapore and Nanjing University through the NUS-Nanjing University Research Collaboration Fund 2025 Award.
文摘The variety and functionality of current clinical vaccine adjuvants remain limited.Conventional aluminum-based adjuvants predominantly induce Th2-biased humoral immunity but exhibit a limited capacity to elicit Th1-mediated cellular immune responses,particularly tumor antigen-specific cytotoxic CD8+T lymphocytes(CTLs),which are essential for effective cancer vaccine performance.Inspired by natural biomolecular condensates,we developed a versatile noncovalent protein self-assembly strategy distinct from traditional approaches requiring structural domain modifications or bifunctional crosslinkers.Our methodology employs amphiphilic molecules(sodium myristate/SMA and sodium dodecyl thiolate/SDT)as molecular bridges to mediate protein-protein interactions through hydrophobic forces and disulfide bond formation.This process generates nanoscale protein condensate(PCD)vaccines with exceptional stability.As a novel adjuvant system,these synthetic condensates significantly enhance antigen cross-presentation by optimizing key parameters:antigen loading capacity,lymph node targeting,cytosolic delivery,and lysosomal escape.Consequently,they induce robust antigen-specific CTL responses and humoral immunity,demonstrating potent antitumor efficacy.Importantly,we found that the synthetic protein condensate(PCD)alone can act as a nanoadjuvant.By increasing mitochondrial membrane permeability,PCD induces mitochondrial DNA leakage into the cytosol,activating the cGAS-STING pathway and promoting DC maturation.This safe and scalable platform eliminates the need for complex covalent modifications or genetic engineering,and it facilitates the design of diverse modular antigens,including neoantigens and viral antigens.Given its straightforward manufacturing process and superior immunogenicity,this synthetic PCD vaccine adjuvant has significant potential for clinical application and translation.
