Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rode...Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s disease.However,the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly understood.Recently,regulator of G protein signaling 6(RGS6)was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in mice.Here,we generated novel RGS6fl/fl;APP_(SWE) mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse model.We found that voluntary running in APP_(SWE) mice restored their hippocampal cognitive impairments to that of control mice.This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells,which also abolished running-mediated increases in adult hippocampal neurogenesis.Adult hippocampal neurogenesis was reduced in sedentary APP_(SWE) mice versus control mice,with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells.RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing neurons.Thus,RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP_(SWE) mice,identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.展开更多
The epidermal growth factor receptor(EGFR)is a transmembrane glycoprotein that plays a crucial role in signal transduction and cellular responses.This review explores the function of EGFR in kidney physiology and its ...The epidermal growth factor receptor(EGFR)is a transmembrane glycoprotein that plays a crucial role in signal transduction and cellular responses.This review explores the function of EGFR in kidney physiology and its implications for various kidney diseases.EGFR signaling is essential for kidney function and repair mechanisms,and its dysregulation significantly impacts both acute and chronic kidney conditions.The review discusses the normal distribution of EGFR in kidney tubular segments,the mechanism of its activation and inhibition,and the therapeutic potential of EGFR-targeting antagonists and ligands.Additionally,it explores the pathophysiological characteristics observed in rodent models of kidney diseases through pharmacological and genetic inhibition of EGFR,highlighting therapeutic challenges and limitations such as species differences,variability in disease models,and potential adverse effects.Overall,the findings underscore the multifaceted role of EGFR in kidney diseases,influencing inflammation,fibrosis,and tissue injury.This complex involvement suggests that targeting EGFR may be a beneficial therapeutic strategy for managing these conditions,potentially mitigating inflammation and fibrosis while promoting tissue repair.展开更多
Alginate-based magnetic micro/millirobots have demonstrated significant potential for biomedical applications due to their flexible structures and capacity to carry various types of cargo,such as cells,enabling target...Alginate-based magnetic micro/millirobots have demonstrated significant potential for biomedical applications due to their flexible structures and capacity to carry various types of cargo,such as cells,enabling targeted therapy to specific diseased regions within the body.Their active therapy is typically achieved through magnetic actuation and magnetic heating,while monitored by medical imaging methods like CT which pose additional risks due to radiation exposure.In the last decades,a novel imaging method for superparamagnetic materials,known as magnetic particle imaging(MPI),has been under active development,offering not only positional tracking but also the ability to measure concentration and temperature.Here,we report the world's first MPI-traceable magnetic hydrogel robots,which employ a combination of iron oxide nanoflowers,NdFeB powder,and calcium alginate.Unlike previous magnetic alginate robots composed of a single magnetic material,the synergistic combination of NdFeB and nanoflowers enables these robots to exhibit triple magnetic functionalities:magnetic heating,locomotion at low magnetic fields,and tracking,all of which can be controlled using a single all-in-one electromagnetic coil system.The effects of various magnetization fields,as well as different concentrations of NdFeB and nanoflowers on the robots'magnetic properties were analyzed.This led to the development of three types of triple-function robots(spiral,droplet,and hybrid),with experimental results demonstrating biocompatibility,a magnetic heating temperature increase of over 10℃in plasma fluid under a magnetic field of 13 kA·m^(-1)at 200 kHz,locomotion speeds of up to 25 mm·s^(-1)in fields below 2 mT,and an MPI tracking error of 2.8 mm with a selection field of 0.4 mT·mm^(-1).Additionally,the robots'capacity for localized thermal therapy and selectively targeted cell delivery,as well as their locomotion within a medical phantom against a maximum flow of 50 mm·s^(-1)were demonstrated.展开更多
Southern corn rust is one of destructive diseases in maize caused by Puccinia polysora Undrew. A mapping population of tropical sweet corn recombinant inbred lines (RILs) derived from a cross between hA9104 and hA9035...Southern corn rust is one of destructive diseases in maize caused by Puccinia polysora Undrew. A mapping population of tropical sweet corn recombinant inbred lines (RILs) derived from a cross between hA9104 and hA9035 inbred lines were set up to detect quantitative trait loci (QTLs) involved in partial resistance to southern corn rust. Eighty nine RILs were used to evaluate resistance levels using nine-point relative scale (1-9) at Sweet Seeds, Suwan Farm, Thailand include combined analysis. A genetic linkage map was constructed with 157 SSR markers, with a total length of 2123.1 cM, covering 10 chromosomes. Broad-sense heritability of individual location ranged from 0.76 and 0.82 and combined across locations was 0.87. Multiple QTL mapping (MQM) was applied for the identification of the QTLs. Fifteen QTLs were detected on chromosome 1, 2, 5, 6, 9 and 10 in both locations and combined across locations. QTLs on chromosome 1, 5 and 6 were contributed by alleles of resistant parent hA9104 while others were contributed by alleles from the susceptible parent, hA9035. Phenotypic variance of each QTL explained ranged from 6.1% to 41.8% with a total of 69.8% - 81.9%. QTL on chromosome 1, 6 and 10 were stable QTLs detected in both locations.展开更多
Transition metal dichalcogenides(TMDs)and perovskites are among the most attractive and widely investigated semiconductors in the recent decade.They are promising materials for various applications,such as photodetect...Transition metal dichalcogenides(TMDs)and perovskites are among the most attractive and widely investigated semiconductors in the recent decade.They are promising materials for various applications,such as photodetection,solar energy harvesting,light emission,and many others.Combining these materials to form heterostructures can enrich the already fascinating properties and bring up new phenomena and opportunities.Work in this field is growing rapidly in both fundamental studies and device applications.Here,we review the recent findings in the perovskite-TMD heterostructures and give our perspectives on the future development of this promising field.The fundamental properties of the perovskites,TMDs,and their heterostructures are discussed first,followed by a summary of the synthesis methods of the perovskites and TMDs and the approaches to obtain high-quality interfaces.Particular attention is paid to the TMD-perovskite heterostructures that have been applied in solar cells and photodetectors with notable performance improvement.Finally through our analysis,we propose an outline on further fundamental studies and the promising applications of perovskite-TMD heterostructures.展开更多
Acquired neurological injuries initiate a pathological cascade of secondary injury processes,including inflammation,which continue for days to weeks following injury.Injury-induced neuroinflammation acts as a host def...Acquired neurological injuries initiate a pathological cascade of secondary injury processes,including inflammation,which continue for days to weeks following injury.Injury-induced neuroinflammation acts as a host defense mechanism contributing to the neutralization of the insult（removing offending factors）and restoring structure and function of the brain（establish homeostasis）.The timing of these protective functions of the immune response is vital,since chronic inflammation展开更多
This paper proposes an additive nanomanufacturing approach to fabricate a personalized lab-on-a-chip fluorescent peptide nanoparticles （f-PNPs） array for simultaneous multi-biomarker detection that can be used in Al...This paper proposes an additive nanomanufacturing approach to fabricate a personalized lab-on-a-chip fluorescent peptide nanoparticles （f-PNPs） array for simultaneous multi-biomarker detection that can be used in Alzheimer＇s disease （AD） diagnosis. We will discuss optimization techniques for the additive nanomanufacturing process in terms of reliability, yield and manufacturing efficiency. One contribution of this paper lies in utilization of additive nanomanufacturing techniques to fabricate a patient-specific customize-designed lab-on-a-chip device for personalized AD diagnosis, which remains a major challenge for biomedical engineering. Through the integrated bio-design and bio-manufacturing process, doctor＇s check- up and computer-aided customized design are integrated into the lab-on-a-chip array for patient-specific AD diagnosis. In addition, f-PNPs with targeting moieties for personalized AD biomarkers will be self-assembled onto the customized lab-on-a- chip through the additive nanomanufacturing process, which has not been done before. Another contribution of this research is the personalized lab-on-a-chip f-PNPs array for AD diagnosis utilizing limited human blood. Blood-based AD assessment has been described as ＂the holy grail＂ of early AD detection. This research created the computer-aided design, fabrication through additive nanomanufacturing, and validation of the f-PNPs array for AD diagnosis. This is a highly interdisciplinary research contributing to nanotechnology, biomaterials, and biomedical engineering for neurodegenerative disease. The conceptual work is preliminary with intent to introduce novel techniques to the application. Large-scale manufacturing based on the proposed framework requires extensive validation and optimization.展开更多
A model based on Watson’s power law for the species-area relationship predicts that full global warming, projected up to the year 2050, could provoke the disappearance of roughly one-quarter of existing species. Here...A model based on Watson’s power law for the species-area relationship predicts that full global warming, projected up to the year 2050, could provoke the disappearance of roughly one-quarter of existing species. Here, an alternative approach is worked out, based on the combination of two ecology laws: Taylor and Watson’s power laws, where the former relates species variability with their mean abundance. Just how severely global warming would affect not only the number but the diversity of the surviving species is addressed by this approach, while at the same time giving indications for the post-disaster fate of the remaining species (extinction or recovery).展开更多
The endoplasmic reticulum(ER)is a cellular organelle responsible for protein synthesis and folding.When its protein folding capacity is exceeded,unfolded or misfolded proteins accumulate,causing ER stress and triggeri...The endoplasmic reticulum(ER)is a cellular organelle responsible for protein synthesis and folding.When its protein folding capacity is exceeded,unfolded or misfolded proteins accumulate,causing ER stress and triggering the unfolded protein response(UPR)to restore ER proteostasis.Although UPR gene expression in plants follows a diel cycle,the mechanisms by which the circadian clock regulates these genes remain unclear.Here,we demonstrate that sensitivity to ER stress in root growth exhibits time-of-day phases and that the circadian clock regulates UPR target gene expression during ER stress.Notably,mutations in the core morning clock component CIRCADIAN CLOCK ASSOCIATED 1(CCA1)impair ER stress recovery.CCA1 forms a complex with the UPR modulator basic leucine zipper 28(bZIP28)and acts as an upstream regulator of ER stress recovery.Upon ER stress,CCA1 is stabilized and associates with bZIP28 at the ER stress response element within the BiP3 promoter,enhancing the ER stress response.Thus,CCA1 and bZIP28 coordinate a time-dependent adaptive response to ER stress to maintain ER proteostasis.Our re-sults suggest that the circadian clock primes the timing and levels of ER chaperone expression to enhance ER stress tolerance.展开更多
Exhausted CD8^(+)T(Tex)cells are dysfunctional due to persistent antigen exposure in chronic viral infection and tumor contexts.A stem cell-like Tex(Tex-stem)subset can self-renew and differentiate into terminally exh...Exhausted CD8^(+)T(Tex)cells are dysfunctional due to persistent antigen exposure in chronic viral infection and tumor contexts.A stem cell-like Tex(Tex-stem)subset can self-renew and differentiate into terminally exhausted(Tex-term)cells.Here,we show that ectopic Tcf1 expression potently promoted the generation of Tex-stem cells in both a chronic viral infection and preclinical tumor models.Tcf1 overexpression diminished coinhibitory receptor expression and enhanced polycytokine-producing capacity while retaining a heightened responses to checkpoint blockade,leading to enhanced viral and tumor control.Mechanistically,ectopically expressed Tcf1 exploited existing and novel chromatin accessible sites as transcriptional enhancers or repressors and modulated the transcriptome by enforcing pre-existing expression patterns in Tex-stem cells,such as enhanced suppression of Blimp1 and Bim and acquisition of new downstream genes,including Mx1,Tox2,and Runx3.These findings reveal a pronounced impact of ectopic Tcf1 expression on Tex functional restoration and highlight the therapeutic potential of harnessing Tcf1-enforced transcriptional programs.展开更多
Background:Binge drinking(BD)has been associated with elevated liver enzymes,but the joint association of BD and adiposity with liver enzymes is understudied.We aimed to examine the combined association of BD and obes...Background:Binge drinking(BD)has been associated with elevated liver enzymes,but the joint association of BD and adiposity with liver enzymes is understudied.We aimed to examine the combined association of BD and obesity with elevated liver enzymes.Methods:Data were obtained from 285,600 patients in the Korean National Health check-up program during 2009-2015.Level I BD(BD I)was defined as alcohol consumption of>60g(men)or>40g(women)on one occasion in the previous year.High-intensity BD(HIBD)corresponded to at least two times the BD I levels.General and abdominal obesity were defined by body mass index and waist circumference.Logistic regression was used to examine the independent and joint associations of BD and obesity with elevated alanine aminotransferase(ALT),aspartate aminotransferase(AST),and gamma-glutamyl transferase(GGT)levels.Relative excess risk(RERI),attributable proportion(AP),and synergy index(SI)were calculated to estimate the additive interaction effects.Results:The mean age was 42.1±0.03years and 50.2%were women.Elevated ALT[odds ratio(OR)1.09,95%confidence interval(CI)1.02-1.16],AST(OR 1.16,95%CI 1.11-1.23),and GGT(OR 1.84,95%CI 1.05-1.94)were associated with HIBD.Higher odds of elevated ALT(OR 3.57,95%CI 3.43-3.71),AST(OR 3.47,95%CI 3.37-3.58),and GGT(OR 2.10,95%CI 1.98-2.12)were observed in individuals with general obesity.A similar trend was observed for abdominal obesity.The RERI,AP,and SI for the interaction effect of BD and general obesity were 23%,7%,and 13%for elevated AST levels,and 67%,24%,and 58%for elevated GGT levels,respectively.Similar effects were observed for the interaction between BD and abdominal obesity.Conclusions:Obesity aggravated the odds of elevated liver AST and GGT levels in HIBD.展开更多
We previously demonstrated that endogenous phosphatidic acid(PA)promotes liver regeneration after acetaminophen(APAP)hepatotoxicity.Here,we hypothesized that exogenous PA is also beneficial.To test that,we treated mic...We previously demonstrated that endogenous phosphatidic acid(PA)promotes liver regeneration after acetaminophen(APAP)hepatotoxicity.Here,we hypothesized that exogenous PA is also beneficial.To test that,we treated mice with a toxic APAP dose at 0 h,followed by PA or vehicle(Veh)posttreatment.We then collected blood and liver at 6,24,and 52 h.Post-treatment with PA 2 h after APAP protected against liver injury at 6 h,and the combination of PA and N-acetyl-L-cysteine(NAC)reduced injury more than NAC alone.Interestingly,PA did not affect canonical mechanisms of APAP toxicity.Instead,transcriptomics revealed that PA activated interleukin-6(IL-6)signaling in the liver.Consistent with that,serum IL-6 and hepatic signal transducer and activator of transcription 3(Stat3)phosphorylation increased in PA-treated mice.Furthermore,PA failed to protect against APAP in IL-6-deficient animals.Interestingly,IL-6 expression increased 18-fold in adipose tissue after PA,indicating that adipose is a source of PA-induced circulating IL-6.Surprisingly,however,exogenous PA did not alter regeneration,despite the importance of endogenous PA in liver repair,possibly due to its short half-life.These data demonstrate that exogenous PA is also beneficial in APAP toxicity and reinforce the protective effects of IL-6 in this model.展开更多
Hearing loss is the most common neurosensory deficit.It results froma variety of heritable and acquired causes and is linked to multiple deleterious effects on a child’s development that can be ameliorated by prompt ...Hearing loss is the most common neurosensory deficit.It results froma variety of heritable and acquired causes and is linked to multiple deleterious effects on a child’s development that can be ameliorated by prompt identification and individualized therapies.Diagnosing hearing loss in newborns is challenging,especially in mild or progressive cases,and its management requires a multidisciplinary team of healthcare providers comprising audiologists,pediatricians,otolaryngologists,and genetic counselors.While physiologic newborn hearing screening has resulted in earlier diagnosis of hearing loss than ever before,a growing body of knowledge supports the concurrent implementation of genetic and cytomegalovirus testing to offset the limitations inherent to a singular screening modality.In this review,we discuss the contemporary role of screening for hearing loss in newborns as well as future directions in its diagnosis and treatment.展开更多
Flowering is the primary stage of the plant developmental transition and is tightly regulated by environmental factors such as light and temperature.However,the mechanisms by which temperature signals are integrated i...Flowering is the primary stage of the plant developmental transition and is tightly regulated by environmental factors such as light and temperature.However,the mechanisms by which temperature signals are integrated into the photoperiodic flowering pathway are still poorly understood.Here,we demonstrate that HOS15,which is known as a GI transcriptional repressor in the photoperiodic flowering pathway,controls flowering time in response to low ambient temperature.At 16℃,the hos15 mutant exhibits an early flowering phenotype,and HOS15 acts upstream of photoperiodic flowering genes(GI,CO,and FT).GI protein abundance is increased in the hos15 mutant and is insensitive to the proteasome inhibitor MG132.Furthermore,the hos15 mutant has a defect in low ambient temperature-mediated GI degradation,and HOS15 interacts with COP1,an E3 ubiquitin ligase for GI degradation.Phenotypic analyses of the hos15 cop1 double mutant revealed that repression of flowering by HOS15 is dependent on COP1 at 16℃.However,the HOS15-COP1 interaction was attenuated at 16℃,and GI protein abundance was additively increased in the hos15 cop1 double mutant,indicating that HOS15 acts independently of COP1 in GI turnover at low ambient temperature.This study proposes that HOS15 controls GI abundance through multiple modes as an E3 ubiquitin ligase and transcriptional repressor to coordinate appropriate flowering time in response to ambient environmental conditions such as temperature and day length.展开更多
Cancer is the second leading cause of death in the US.Current major treatments for cancer management include surgery,cytotoxic chemotherapy,targeted therapy,radiation therapy,endocrine therapy and immunotherapy.Despit...Cancer is the second leading cause of death in the US.Current major treatments for cancer management include surgery,cytotoxic chemotherapy,targeted therapy,radiation therapy,endocrine therapy and immunotherapy.Despite the endeavors and achievements made in treating cancers during the past decades,resistance to classical chemotherapeutic agents and/or novel targeted drugs continues to be a major problem in cancer therapies.Drug resistance,either existing before treatment(intrinsic)or generated after therapy(acquired),is responsible for most relapses of cancer,one of the major causes of death of the disease.Heterogeneity among patients and tumors,and the versatility of cancer to circumvent therapies make drug resistance more challenging to deal with.Better understanding the mechanisms of drug resistance is required to provide guidance to future cancer treatment and achieve better outcomes.In this review,intrinsic and acquired resistance will be discussed.In addition,new discoveries in mechanisms of drug resistance will be reviewed.Particularly,we will highlight roles of ATP in drug resistance by discussing recent findings of exceptionally high levels of intratumoral extracellular ATP as well as intracellular ATP internalized from extracellular environment.The complexity of drug resistance development suggests that combinational and personalized therapies,which should take ATP into consideration,might provide better strategies and improved efficacy for fighting drug resistance in cancer.展开更多
With small thickness,commercial polyolefin separators own low porosity to ensure sufficient thermomechanical properties,resulting in tortuous and enlarged Li+diffusion pathways that induce large overpotentials and det...With small thickness,commercial polyolefin separators own low porosity to ensure sufficient thermomechanical properties,resulting in tortuous and enlarged Li+diffusion pathways that induce large overpotentials and detrimental dendrite growth.As a dilemma,the exploration of highly porous separators has been challenged by their large thickness,impairing the applicability of such pursuits.Herein,an ultraporous architecture is designed to shorten Li+transfer pathways by impregnating electrolyteaffinitive poly(vinylidene fluoride-co-hexafluoropropylene)into ultralight~3μm 3D-polytetrafluoroethylene scaffold(abbreviated as UP3D).The UP3D separator with a porosity of 74%gives rise to 70%enhancement in Li+transference and 77%reduction in Li+transfer resistance(2.67 mΩmm^(−1))and thus enables an ultrahigh Li+flux of 22.7 mA cm^(−2),effectively alleviating Li+concentration gradient across the separator.With the separator,the LiFePO4 half cell delivers a capacity of 118 mAh g^(−1) with an unparalleled capacity retention of 90%after 1000 cycles at 2 C,and a graphite||LiNi_(0.6)Co_(0.2)Mn_(0.2)O_(2)pouch full cell delivers an areal energy density of 6.8 mWh cm^(−2)at 8.848 mA(1.4 mA cm^(−2))with a high cathode loading of 134.9 mg.Such results,together with the scalable production of the separator,reflect its promising potential in high-flux battery applications of separators that require both ultrahigh porosity and reliability.展开更多
Background and aim:Acetaminophen(APAP)overdose is a major cause of acute liver injury,but the role of macrophages in the propagation of the hepatotoxicity is controversial.Early research revealed that macrophage inhib...Background and aim:Acetaminophen(APAP)overdose is a major cause of acute liver injury,but the role of macrophages in the propagation of the hepatotoxicity is controversial.Early research revealed that macrophage inhibitors protect against APAP injury.However,later work demonstrated that macrophage ablation by acute pre-treatment with liposomal clodronate(LC)exacerbates the toxicity.To our surprise,during other studies,we observed that pre-treatment twice with LC seemed to protect against APAP hepatotoxicity,in contrast to acute pre-treatment.The aim of this study was to confirm that observation and to explore the mechanisms.Methods:We treated mice with empty liposomes(LE)or LC twice per week for 1 week before APAP overdose and collected blood and liver tissue at 0,2,and 6 h post-APAP.We then measured liver injury(serum alanine aminotransferase activity,histology),APAP bioactivation(total glutathione,APAP-protein adducts),oxidative stress(oxidized glutathione(GSSG)),glutamate-cysteine ligase subunit c(Gclc)mRNA,and nuclear factor erythroid 2-related factor(Nrf2)immunofluorescence.We also confirmed the ablation of macrophages by F4/80 immunohistochemistry.Results:Pre-treatment twice with LC dramatically reduced F4/80 staining,protected against liver injury,and reduced oxidative stress at 6 h post-APAP,without affecting APAP bioactivation.Importantly,Gclc mRNA was higher in the LC group at 0 h and total glutathione was higher at 2 h,indicating accelerated glutathione re-synthesis after APAP overdose due to greater basal glutamate-cysteine ligase.Oxidative stress was lower in the LC groups at both time points.Finally,total Nrf2 immunofluorescence was higher in the LC group.Conclusions:We conclude that multiple pre-treatments with LC protect against APAP by accelerating glutathione re-synthesis through glutamate-cysteine ligase.Investigators using twice or possibly more LC pre-treatments to deplete macrophages,including peritoneal macrophages,should be aware of this possible confounder.展开更多
The cancer stem cell(CSC)state and epithelial-mesenchymal transition(EMT)activation are tightly interconnected.Cancer cells that acquire the EMT/CSC phenotype are equipped with adaptive metabolic changes to maintain l...The cancer stem cell(CSC)state and epithelial-mesenchymal transition(EMT)activation are tightly interconnected.Cancer cells that acquire the EMT/CSC phenotype are equipped with adaptive metabolic changes to maintain low reactive oxygen species levels and stemness,enhanced drug transporters,anti-apoptotic machinery and DNA repair system.Factors present in the tumor microenvironment such as hypoxia and the communication with non-cancer stromal cells also promote cancer cells to enter the EMT/CSC state and display related resistance.ATP,particularly the high levels of intratumoral extracellular ATP functioning through both signaling pathways and ATP internalization,induces and regulates EMT and CSC.The three of them work together to enhance drug resistance.New findings in each of these factors will help us explore deeper into mechanisms of drug resistance and suggest new resistance-associated markers and therapeutic targets.展开更多
There has been a surge of diagnosis of autism spectrum disorders （ASD） over the past decade. While large, high powered genome screening studies of children with ASD have identified numerous genetic risk factors, res...There has been a surge of diagnosis of autism spectrum disorders （ASD） over the past decade. While large, high powered genome screening studies of children with ASD have identified numerous genetic risk factors, research efforts to understanding how each of these risk factors contributes to the development autism has met with limited success. Revealing the mechanisms by which these genetic risk factors affect brain development and predispose a child to autism requires mechanistic understanding of the neurobiological changes underlying this devastating group of developmental disorders at multifaceted molecular, cellular and system levels. It has been increasingly clear that the normal trajectory of neurodevelopment is compromised in autism, in multiple domains as much as aberrant neuronal production, growth, functional maturation, patterned connectivity, and balanced excitation and inhibition of brain networks. Many autism risk factors identified in humans have been now reconstituted in experimental mouse models to allow mechanistic interrogation of the biological role of the risk gene. Studies utilizing these mouse models have revealed that underlying the enormous heterogeneity of perturbed cellular events, mechanisms directing synaptic and circuit assembly may provide a unifying explanation for the pathophysiological changes and behavioral endophenotypes seen in autism, although synaptic perturbations are far from being the only alterations relevant for ASD. In this review, we discuss synaptic and circuit abnormalities obtained from several prevalent mouse models, particularly those reflecting syndromic forms of ASD that are caused by single gene perturbations. These compiled results reveal that ASD risk genes contribute to proper signaling of the developing gene networks that maintain synaptic and circuit homeostasis, which is fundamental to normal brain development.展开更多
Transcription factors and DNA/histone modification enzymes work in concert to establish and maintain cell identity. CD4^＋ and CD8^＋ T cells are key players in cellular immunity with distinct functions. Recent studie...Transcription factors and DNA/histone modification enzymes work in concert to establish and maintain cell identity. CD4^＋ and CD8^＋ T cells are key players in cellular immunity with distinct functions. Recent studies offer novel insights into how their identities are established in the thymus and maintained in the periphery during immune responses. During thymic maturation, Thpok, HDAC1 and HDAC2 guard CD4^＋ T cells from activation of CD8^＋ cytotoxic genes, and Tcfl and Left utilize their intrinsic HDAC activity to shut down CD4^＋ lineage-associated genes in CD8^＋ T cells. In activated CD4＋ T cells, Tcfl and Left act upstream of the Bc16-Blimpl axis to direct differentiation of follicular helper T （Tfh） cells, and prevent diversion of Tfh to IL-17-producing cells. In parallel, T-bet, together with Eomes or Blimpl, ensures proper induction of the cytotoxic program in CD8^＋ effectors elicited by acute infection, and prevents generation of pathogenic, IL-17-producing CD8^＋ effector T cells. Antigen persistence due to chronic viral infection leads to CD8^＋ T cell exhaustion. A portion of exhausted CD8^＋ T cells has the capacity to activate the Tfh program in a Tcfl-dependent manner. Those Tfh-like CD8^＋ T cells exhibit enhanced proliferative capacity in response to PD-1 blockage therapy and are more effective in curtailing viral replication. Thus, dissecting the molecular aspects of T cell identity, during development and immune responses, may lead to new therapies for treating autoimmunity, tumors, and persistent infections.展开更多
基金supported by the National Institutes of Health,Nos.AA025919,AA025919-03S1,and AA025919-05S1(all to RAF).
文摘Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s disease.However,the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly understood.Recently,regulator of G protein signaling 6(RGS6)was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in mice.Here,we generated novel RGS6fl/fl;APP_(SWE) mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse model.We found that voluntary running in APP_(SWE) mice restored their hippocampal cognitive impairments to that of control mice.This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells,which also abolished running-mediated increases in adult hippocampal neurogenesis.Adult hippocampal neurogenesis was reduced in sedentary APP_(SWE) mice versus control mice,with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells.RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing neurons.Thus,RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP_(SWE) mice,identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.
基金supported by the Basic Science Research Program through the National Research Foundation of Korea(NRF)and funded by the Ministry of Education(2021R1I1A3056002,to Jinu Kim,RS-2023-00274853,to Daeun MOON).
文摘The epidermal growth factor receptor(EGFR)is a transmembrane glycoprotein that plays a crucial role in signal transduction and cellular responses.This review explores the function of EGFR in kidney physiology and its implications for various kidney diseases.EGFR signaling is essential for kidney function and repair mechanisms,and its dysregulation significantly impacts both acute and chronic kidney conditions.The review discusses the normal distribution of EGFR in kidney tubular segments,the mechanism of its activation and inhibition,and the therapeutic potential of EGFR-targeting antagonists and ligands.Additionally,it explores the pathophysiological characteristics observed in rodent models of kidney diseases through pharmacological and genetic inhibition of EGFR,highlighting therapeutic challenges and limitations such as species differences,variability in disease models,and potential adverse effects.Overall,the findings underscore the multifaceted role of EGFR in kidney diseases,influencing inflammation,fibrosis,and tissue injury.This complex involvement suggests that targeting EGFR may be a beneficial therapeutic strategy for managing these conditions,potentially mitigating inflammation and fibrosis while promoting tissue repair.
基金supported by a Korea University Grantby the National Research Foundation of Korea(NRF)funded by the Korean government(MSIT)with Grant Number 2022R1A2C1003381。
文摘Alginate-based magnetic micro/millirobots have demonstrated significant potential for biomedical applications due to their flexible structures and capacity to carry various types of cargo,such as cells,enabling targeted therapy to specific diseased regions within the body.Their active therapy is typically achieved through magnetic actuation and magnetic heating,while monitored by medical imaging methods like CT which pose additional risks due to radiation exposure.In the last decades,a novel imaging method for superparamagnetic materials,known as magnetic particle imaging(MPI),has been under active development,offering not only positional tracking but also the ability to measure concentration and temperature.Here,we report the world's first MPI-traceable magnetic hydrogel robots,which employ a combination of iron oxide nanoflowers,NdFeB powder,and calcium alginate.Unlike previous magnetic alginate robots composed of a single magnetic material,the synergistic combination of NdFeB and nanoflowers enables these robots to exhibit triple magnetic functionalities:magnetic heating,locomotion at low magnetic fields,and tracking,all of which can be controlled using a single all-in-one electromagnetic coil system.The effects of various magnetization fields,as well as different concentrations of NdFeB and nanoflowers on the robots'magnetic properties were analyzed.This led to the development of three types of triple-function robots(spiral,droplet,and hybrid),with experimental results demonstrating biocompatibility,a magnetic heating temperature increase of over 10℃in plasma fluid under a magnetic field of 13 kA·m^(-1)at 200 kHz,locomotion speeds of up to 25 mm·s^(-1)in fields below 2 mT,and an MPI tracking error of 2.8 mm with a selection field of 0.4 mT·mm^(-1).Additionally,the robots'capacity for localized thermal therapy and selectively targeted cell delivery,as well as their locomotion within a medical phantom against a maximum flow of 50 mm·s^(-1)were demonstrated.
文摘Southern corn rust is one of destructive diseases in maize caused by Puccinia polysora Undrew. A mapping population of tropical sweet corn recombinant inbred lines (RILs) derived from a cross between hA9104 and hA9035 inbred lines were set up to detect quantitative trait loci (QTLs) involved in partial resistance to southern corn rust. Eighty nine RILs were used to evaluate resistance levels using nine-point relative scale (1-9) at Sweet Seeds, Suwan Farm, Thailand include combined analysis. A genetic linkage map was constructed with 157 SSR markers, with a total length of 2123.1 cM, covering 10 chromosomes. Broad-sense heritability of individual location ranged from 0.76 and 0.82 and combined across locations was 0.87. Multiple QTL mapping (MQM) was applied for the identification of the QTLs. Fifteen QTLs were detected on chromosome 1, 2, 5, 6, 9 and 10 in both locations and combined across locations. QTLs on chromosome 1, 5 and 6 were contributed by alleles of resistant parent hA9104 while others were contributed by alleles from the susceptible parent, hA9035. Phenotypic variance of each QTL explained ranged from 6.1% to 41.8% with a total of 69.8% - 81.9%. QTL on chromosome 1, 6 and 10 were stable QTLs detected in both locations.
基金J.H.Teng acknowledges A*STAR for funding support in Grants A20E5c0084,A2083c0058 and CRF SC25/21-110318.
文摘Transition metal dichalcogenides(TMDs)and perovskites are among the most attractive and widely investigated semiconductors in the recent decade.They are promising materials for various applications,such as photodetection,solar energy harvesting,light emission,and many others.Combining these materials to form heterostructures can enrich the already fascinating properties and bring up new phenomena and opportunities.Work in this field is growing rapidly in both fundamental studies and device applications.Here,we review the recent findings in the perovskite-TMD heterostructures and give our perspectives on the future development of this promising field.The fundamental properties of the perovskites,TMDs,and their heterostructures are discussed first,followed by a summary of the synthesis methods of the perovskites and TMDs and the approaches to obtain high-quality interfaces.Particular attention is paid to the TMD-perovskite heterostructures that have been applied in solar cells and photodetectors with notable performance improvement.Finally through our analysis,we propose an outline on further fundamental studies and the promising applications of perovskite-TMD heterostructures.
文摘Acquired neurological injuries initiate a pathological cascade of secondary injury processes,including inflammation,which continue for days to weeks following injury.Injury-induced neuroinflammation acts as a host defense mechanism contributing to the neutralization of the insult（removing offending factors）and restoring structure and function of the brain（establish homeostasis）.The timing of these protective functions of the immune response is vital,since chronic inflammation
文摘This paper proposes an additive nanomanufacturing approach to fabricate a personalized lab-on-a-chip fluorescent peptide nanoparticles （f-PNPs） array for simultaneous multi-biomarker detection that can be used in Alzheimer＇s disease （AD） diagnosis. We will discuss optimization techniques for the additive nanomanufacturing process in terms of reliability, yield and manufacturing efficiency. One contribution of this paper lies in utilization of additive nanomanufacturing techniques to fabricate a patient-specific customize-designed lab-on-a-chip device for personalized AD diagnosis, which remains a major challenge for biomedical engineering. Through the integrated bio-design and bio-manufacturing process, doctor＇s check- up and computer-aided customized design are integrated into the lab-on-a-chip array for patient-specific AD diagnosis. In addition, f-PNPs with targeting moieties for personalized AD biomarkers will be self-assembled onto the customized lab-on-a- chip through the additive nanomanufacturing process, which has not been done before. Another contribution of this research is the personalized lab-on-a-chip f-PNPs array for AD diagnosis utilizing limited human blood. Blood-based AD assessment has been described as ＂the holy grail＂ of early AD detection. This research created the computer-aided design, fabrication through additive nanomanufacturing, and validation of the f-PNPs array for AD diagnosis. This is a highly interdisciplinary research contributing to nanotechnology, biomaterials, and biomedical engineering for neurodegenerative disease. The conceptual work is preliminary with intent to introduce novel techniques to the application. Large-scale manufacturing based on the proposed framework requires extensive validation and optimization.
基金supported by grants from FAPESP,CNEN and CNPq,Brazilian funding agencies for the promotion of science.
文摘A model based on Watson’s power law for the species-area relationship predicts that full global warming, projected up to the year 2050, could provoke the disappearance of roughly one-quarter of existing species. Here, an alternative approach is worked out, based on the combination of two ecology laws: Taylor and Watson’s power laws, where the former relates species variability with their mean abundance. Just how severely global warming would affect not only the number but the diversity of the surviving species is addressed by this approach, while at the same time giving indications for the post-disaster fate of the remaining species (extinction or recovery).
基金supported by National Research Foundation of Korea(NRF)grants funded by the Korean government(RS-2020-NR049332 and RS-2022-NR070837 to W.-Y.K.and RS-2024-00358746 to G.A.).
文摘The endoplasmic reticulum(ER)is a cellular organelle responsible for protein synthesis and folding.When its protein folding capacity is exceeded,unfolded or misfolded proteins accumulate,causing ER stress and triggering the unfolded protein response(UPR)to restore ER proteostasis.Although UPR gene expression in plants follows a diel cycle,the mechanisms by which the circadian clock regulates these genes remain unclear.Here,we demonstrate that sensitivity to ER stress in root growth exhibits time-of-day phases and that the circadian clock regulates UPR target gene expression during ER stress.Notably,mutations in the core morning clock component CIRCADIAN CLOCK ASSOCIATED 1(CCA1)impair ER stress recovery.CCA1 forms a complex with the UPR modulator basic leucine zipper 28(bZIP28)and acts as an upstream regulator of ER stress recovery.Upon ER stress,CCA1 is stabilized and associates with bZIP28 at the ER stress response element within the BiP3 promoter,enhancing the ER stress response.Thus,CCA1 and bZIP28 coordinate a time-dependent adaptive response to ER stress to maintain ER proteostasis.Our re-sults suggest that the circadian clock primes the timing and levels of ER chaperone expression to enhance ER stress tolerance.
基金supported by grants from the NIH(AI112579,AI121080 and AI139874 to H.-H.X.,GM133712 to C.Z.,and GM113961,AI147064 and AI114543 to V.P.B.)the Veteran Affairs BLR&D Merit Review Program(BX002903)to H.-H.X.
文摘Exhausted CD8^(+)T(Tex)cells are dysfunctional due to persistent antigen exposure in chronic viral infection and tumor contexts.A stem cell-like Tex(Tex-stem)subset can self-renew and differentiate into terminally exhausted(Tex-term)cells.Here,we show that ectopic Tcf1 expression potently promoted the generation of Tex-stem cells in both a chronic viral infection and preclinical tumor models.Tcf1 overexpression diminished coinhibitory receptor expression and enhanced polycytokine-producing capacity while retaining a heightened responses to checkpoint blockade,leading to enhanced viral and tumor control.Mechanistically,ectopically expressed Tcf1 exploited existing and novel chromatin accessible sites as transcriptional enhancers or repressors and modulated the transcriptome by enforcing pre-existing expression patterns in Tex-stem cells,such as enhanced suppression of Blimp1 and Bim and acquisition of new downstream genes,including Mx1,Tox2,and Runx3.These findings reveal a pronounced impact of ectopic Tcf1 expression on Tex functional restoration and highlight the therapeutic potential of harnessing Tcf1-enforced transcriptional programs.
基金supported by the Regional Innovation Strategy through the National Research Foundation of Korea(NRF)funded by the Ministry of Education(MOE)(2022RIS-005).
文摘Background:Binge drinking(BD)has been associated with elevated liver enzymes,but the joint association of BD and adiposity with liver enzymes is understudied.We aimed to examine the combined association of BD and obesity with elevated liver enzymes.Methods:Data were obtained from 285,600 patients in the Korean National Health check-up program during 2009-2015.Level I BD(BD I)was defined as alcohol consumption of>60g(men)or>40g(women)on one occasion in the previous year.High-intensity BD(HIBD)corresponded to at least two times the BD I levels.General and abdominal obesity were defined by body mass index and waist circumference.Logistic regression was used to examine the independent and joint associations of BD and obesity with elevated alanine aminotransferase(ALT),aspartate aminotransferase(AST),and gamma-glutamyl transferase(GGT)levels.Relative excess risk(RERI),attributable proportion(AP),and synergy index(SI)were calculated to estimate the additive interaction effects.Results:The mean age was 42.1±0.03years and 50.2%were women.Elevated ALT[odds ratio(OR)1.09,95%confidence interval(CI)1.02-1.16],AST(OR 1.16,95%CI 1.11-1.23),and GGT(OR 1.84,95%CI 1.05-1.94)were associated with HIBD.Higher odds of elevated ALT(OR 3.57,95%CI 3.43-3.71),AST(OR 3.47,95%CI 3.37-3.58),and GGT(OR 2.10,95%CI 1.98-2.12)were observed in individuals with general obesity.A similar trend was observed for abdominal obesity.The RERI,AP,and SI for the interaction effect of BD and general obesity were 23%,7%,and 13%for elevated AST levels,and 67%,24%,and 58%for elevated GGT levels,respectively.Similar effects were observed for the interaction between BD and abdominal obesity.Conclusions:Obesity aggravated the odds of elevated liver AST and GGT levels in HIBD.
基金funded in part by a 2018 Pinnacle Research Award from the AASLD Foundation,USA(Mitchell R.McGill)the Arkansas Biosciences Institute(Mitchell R.McGill),which is the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000,USAthe National Institutes of Health grants(USA)T32 GM106999(Mitchell R.Mc Gill and Joel H.Vazquez),R01 DK104735(Brian N.Finck),R01 DK117657(Brian N.Finck),R42 DK121652(Brian N.Finck),R56 DK111735(Brian N.Finck),R42 DK079387(Laura P.James),UL1 TR003107(Laura P.James and Stefanie Kennon-Mc Gill),and TR003108(Laura P.James and Stefanie Kennon-McGill)。
文摘We previously demonstrated that endogenous phosphatidic acid(PA)promotes liver regeneration after acetaminophen(APAP)hepatotoxicity.Here,we hypothesized that exogenous PA is also beneficial.To test that,we treated mice with a toxic APAP dose at 0 h,followed by PA or vehicle(Veh)posttreatment.We then collected blood and liver at 6,24,and 52 h.Post-treatment with PA 2 h after APAP protected against liver injury at 6 h,and the combination of PA and N-acetyl-L-cysteine(NAC)reduced injury more than NAC alone.Interestingly,PA did not affect canonical mechanisms of APAP toxicity.Instead,transcriptomics revealed that PA activated interleukin-6(IL-6)signaling in the liver.Consistent with that,serum IL-6 and hepatic signal transducer and activator of transcription 3(Stat3)phosphorylation increased in PA-treated mice.Furthermore,PA failed to protect against APAP in IL-6-deficient animals.Interestingly,IL-6 expression increased 18-fold in adipose tissue after PA,indicating that adipose is a source of PA-induced circulating IL-6.Surprisingly,however,exogenous PA did not alter regeneration,despite the importance of endogenous PA in liver repair,possibly due to its short half-life.These data demonstrate that exogenous PA is also beneficial in APAP toxicity and reinforce the protective effects of IL-6 in this model.
基金This project was supported by NIH-NIDCD(Grants No.R01 DC002842,DC012049,and DC017955)(RJHS)NIH-NIDCD(Grant No.5T32DC000040)(RKT).
文摘Hearing loss is the most common neurosensory deficit.It results froma variety of heritable and acquired causes and is linked to multiple deleterious effects on a child’s development that can be ameliorated by prompt identification and individualized therapies.Diagnosing hearing loss in newborns is challenging,especially in mild or progressive cases,and its management requires a multidisciplinary team of healthcare providers comprising audiologists,pediatricians,otolaryngologists,and genetic counselors.While physiologic newborn hearing screening has resulted in earlier diagnosis of hearing loss than ever before,a growing body of knowledge supports the concurrent implementation of genetic and cytomegalovirus testing to offset the limitations inherent to a singular screening modality.In this review,we discuss the contemporary role of screening for hearing loss in newborns as well as future directions in its diagnosis and treatment.
基金This research was supported by National Research Foundation of Korea(NRF)grants funded by the Korean Government(MSIT-2022R1A5A1031361 and MSIT-2020R1A2C3014814 to W.-Y.K.)the Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education(NRF-2021R1I1A1A01059532 to G.A.and NRF-2019R1I1A1A01041422 to H.J.P.)。
文摘Flowering is the primary stage of the plant developmental transition and is tightly regulated by environmental factors such as light and temperature.However,the mechanisms by which temperature signals are integrated into the photoperiodic flowering pathway are still poorly understood.Here,we demonstrate that HOS15,which is known as a GI transcriptional repressor in the photoperiodic flowering pathway,controls flowering time in response to low ambient temperature.At 16℃,the hos15 mutant exhibits an early flowering phenotype,and HOS15 acts upstream of photoperiodic flowering genes(GI,CO,and FT).GI protein abundance is increased in the hos15 mutant and is insensitive to the proteasome inhibitor MG132.Furthermore,the hos15 mutant has a defect in low ambient temperature-mediated GI degradation,and HOS15 interacts with COP1,an E3 ubiquitin ligase for GI degradation.Phenotypic analyses of the hos15 cop1 double mutant revealed that repression of flowering by HOS15 is dependent on COP1 at 16℃.However,the HOS15-COP1 interaction was attenuated at 16℃,and GI protein abundance was additively increased in the hos15 cop1 double mutant,indicating that HOS15 acts independently of COP1 in GI turnover at low ambient temperature.This study proposes that HOS15 controls GI abundance through multiple modes as an E3 ubiquitin ligase and transcriptional repressor to coordinate appropriate flowering time in response to ambient environmental conditions such as temperature and day length.
文摘Cancer is the second leading cause of death in the US.Current major treatments for cancer management include surgery,cytotoxic chemotherapy,targeted therapy,radiation therapy,endocrine therapy and immunotherapy.Despite the endeavors and achievements made in treating cancers during the past decades,resistance to classical chemotherapeutic agents and/or novel targeted drugs continues to be a major problem in cancer therapies.Drug resistance,either existing before treatment(intrinsic)or generated after therapy(acquired),is responsible for most relapses of cancer,one of the major causes of death of the disease.Heterogeneity among patients and tumors,and the versatility of cancer to circumvent therapies make drug resistance more challenging to deal with.Better understanding the mechanisms of drug resistance is required to provide guidance to future cancer treatment and achieve better outcomes.In this review,intrinsic and acquired resistance will be discussed.In addition,new discoveries in mechanisms of drug resistance will be reviewed.Particularly,we will highlight roles of ATP in drug resistance by discussing recent findings of exceptionally high levels of intratumoral extracellular ATP as well as intracellular ATP internalized from extracellular environment.The complexity of drug resistance development suggests that combinational and personalized therapies,which should take ATP into consideration,might provide better strategies and improved efficacy for fighting drug resistance in cancer.
基金National Natural Science Foundation of China,Grant/Award Number:12002109Science Foundation of National Key Laboratory of Science and Technology on Advanced Composites in Special EnvironmentsNatural Science Foundation of Chongqing,China,Grant/Award Numbers:CSTB2022NSCQ-MSX1533,CSTC2021jcyj-msxmX10305,CSTB2022NSCQ-MSX1583,CSTB2022NSCQ-MSX1365,CSTB2022NSCQ-MSX1572,CSTB2022NSCQ-MSX0246,CSTB2022NSCQ-MSX0242,CSTB2022NSCQ-MSX0441,CSTB2022NSCQ-MSX0487,CSTB2022TFII-OFX0034。
文摘With small thickness,commercial polyolefin separators own low porosity to ensure sufficient thermomechanical properties,resulting in tortuous and enlarged Li+diffusion pathways that induce large overpotentials and detrimental dendrite growth.As a dilemma,the exploration of highly porous separators has been challenged by their large thickness,impairing the applicability of such pursuits.Herein,an ultraporous architecture is designed to shorten Li+transfer pathways by impregnating electrolyteaffinitive poly(vinylidene fluoride-co-hexafluoropropylene)into ultralight~3μm 3D-polytetrafluoroethylene scaffold(abbreviated as UP3D).The UP3D separator with a porosity of 74%gives rise to 70%enhancement in Li+transference and 77%reduction in Li+transfer resistance(2.67 mΩmm^(−1))and thus enables an ultrahigh Li+flux of 22.7 mA cm^(−2),effectively alleviating Li+concentration gradient across the separator.With the separator,the LiFePO4 half cell delivers a capacity of 118 mAh g^(−1) with an unparalleled capacity retention of 90%after 1000 cycles at 2 C,and a graphite||LiNi_(0.6)Co_(0.2)Mn_(0.2)O_(2)pouch full cell delivers an areal energy density of 6.8 mWh cm^(−2)at 8.848 mA(1.4 mA cm^(−2))with a high cathode loading of 134.9 mg.Such results,together with the scalable production of the separator,reflect its promising potential in high-flux battery applications of separators that require both ultrahigh porosity and reliability.
基金This work was supported by the American Association for the Study of Liver Diseases Foundation,Alexandria,VA,USA(2018 Pinnacle Research Award)by the United States National Institutes of Health(grant numbers T32 GM106999,UL1 TR003107,R42 DK079387 and KL2 TR003108).
文摘Background and aim:Acetaminophen(APAP)overdose is a major cause of acute liver injury,but the role of macrophages in the propagation of the hepatotoxicity is controversial.Early research revealed that macrophage inhibitors protect against APAP injury.However,later work demonstrated that macrophage ablation by acute pre-treatment with liposomal clodronate(LC)exacerbates the toxicity.To our surprise,during other studies,we observed that pre-treatment twice with LC seemed to protect against APAP hepatotoxicity,in contrast to acute pre-treatment.The aim of this study was to confirm that observation and to explore the mechanisms.Methods:We treated mice with empty liposomes(LE)or LC twice per week for 1 week before APAP overdose and collected blood and liver tissue at 0,2,and 6 h post-APAP.We then measured liver injury(serum alanine aminotransferase activity,histology),APAP bioactivation(total glutathione,APAP-protein adducts),oxidative stress(oxidized glutathione(GSSG)),glutamate-cysteine ligase subunit c(Gclc)mRNA,and nuclear factor erythroid 2-related factor(Nrf2)immunofluorescence.We also confirmed the ablation of macrophages by F4/80 immunohistochemistry.Results:Pre-treatment twice with LC dramatically reduced F4/80 staining,protected against liver injury,and reduced oxidative stress at 6 h post-APAP,without affecting APAP bioactivation.Importantly,Gclc mRNA was higher in the LC group at 0 h and total glutathione was higher at 2 h,indicating accelerated glutathione re-synthesis after APAP overdose due to greater basal glutamate-cysteine ligase.Oxidative stress was lower in the LC groups at both time points.Finally,total Nrf2 immunofluorescence was higher in the LC group.Conclusions:We conclude that multiple pre-treatments with LC protect against APAP by accelerating glutathione re-synthesis through glutamate-cysteine ligase.Investigators using twice or possibly more LC pre-treatments to deplete macrophages,including peritoneal macrophages,should be aware of this possible confounder.
基金This work was supported in part by a NIH grant R15 CA242177-01 to Chen X.
文摘The cancer stem cell(CSC)state and epithelial-mesenchymal transition(EMT)activation are tightly interconnected.Cancer cells that acquire the EMT/CSC phenotype are equipped with adaptive metabolic changes to maintain low reactive oxygen species levels and stemness,enhanced drug transporters,anti-apoptotic machinery and DNA repair system.Factors present in the tumor microenvironment such as hypoxia and the communication with non-cancer stromal cells also promote cancer cells to enter the EMT/CSC state and display related resistance.ATP,particularly the high levels of intratumoral extracellular ATP functioning through both signaling pathways and ATP internalization,induces and regulates EMT and CSC.The three of them work together to enhance drug resistance.New findings in each of these factors will help us explore deeper into mechanisms of drug resistance and suggest new resistance-associated markers and therapeutic targets.
文摘There has been a surge of diagnosis of autism spectrum disorders （ASD） over the past decade. While large, high powered genome screening studies of children with ASD have identified numerous genetic risk factors, research efforts to understanding how each of these risk factors contributes to the development autism has met with limited success. Revealing the mechanisms by which these genetic risk factors affect brain development and predispose a child to autism requires mechanistic understanding of the neurobiological changes underlying this devastating group of developmental disorders at multifaceted molecular, cellular and system levels. It has been increasingly clear that the normal trajectory of neurodevelopment is compromised in autism, in multiple domains as much as aberrant neuronal production, growth, functional maturation, patterned connectivity, and balanced excitation and inhibition of brain networks. Many autism risk factors identified in humans have been now reconstituted in experimental mouse models to allow mechanistic interrogation of the biological role of the risk gene. Studies utilizing these mouse models have revealed that underlying the enormous heterogeneity of perturbed cellular events, mechanisms directing synaptic and circuit assembly may provide a unifying explanation for the pathophysiological changes and behavioral endophenotypes seen in autism, although synaptic perturbations are far from being the only alterations relevant for ASD. In this review, we discuss synaptic and circuit abnormalities obtained from several prevalent mouse models, particularly those reflecting syndromic forms of ASD that are caused by single gene perturbations. These compiled results reveal that ASD risk genes contribute to proper signaling of the developing gene networks that maintain synaptic and circuit homeostasis, which is fundamental to normal brain development.
文摘Transcription factors and DNA/histone modification enzymes work in concert to establish and maintain cell identity. CD4^＋ and CD8^＋ T cells are key players in cellular immunity with distinct functions. Recent studies offer novel insights into how their identities are established in the thymus and maintained in the periphery during immune responses. During thymic maturation, Thpok, HDAC1 and HDAC2 guard CD4^＋ T cells from activation of CD8^＋ cytotoxic genes, and Tcfl and Left utilize their intrinsic HDAC activity to shut down CD4^＋ lineage-associated genes in CD8^＋ T cells. In activated CD4＋ T cells, Tcfl and Left act upstream of the Bc16-Blimpl axis to direct differentiation of follicular helper T （Tfh） cells, and prevent diversion of Tfh to IL-17-producing cells. In parallel, T-bet, together with Eomes or Blimpl, ensures proper induction of the cytotoxic program in CD8^＋ effectors elicited by acute infection, and prevents generation of pathogenic, IL-17-producing CD8^＋ effector T cells. Antigen persistence due to chronic viral infection leads to CD8^＋ T cell exhaustion. A portion of exhausted CD8^＋ T cells has the capacity to activate the Tfh program in a Tcfl-dependent manner. Those Tfh-like CD8^＋ T cells exhibit enhanced proliferative capacity in response to PD-1 blockage therapy and are more effective in curtailing viral replication. Thus, dissecting the molecular aspects of T cell identity, during development and immune responses, may lead to new therapies for treating autoimmunity, tumors, and persistent infections.
