We present a numerical framework for simulating viscous compressible flows in the presence of solid particles with large size ratios.The volume-filtered Navier-Stokes equations are discretized using a class of high-or...We present a numerical framework for simulating viscous compressible flows in the presence of solid particles with large size ratios.The volume-filtered Navier-Stokes equations are discretized using a class of high-order low-dissipative finite difference operators with energy-preserving properties.No-slip,adiabatic boundary conditions are enforced at the surface of large particles(with diameters significantly larger than the local grid spacing)using a ghost-point immersed boundary method.Two-way coupling between the gas phase and small particles(with diameters proportional to the grid spacing)is accounted for through volumetric source terms for interphase momentum and energy exchange.A simple and efficient approach for collision detection between small and large particles is proposed.The framework is applied to simulations of planar shocks interacting with bidisperse distributions of particles with size ratios of approximately thirty.Particle dispersion and size segregation are reported and a simple analytical model for size segregation is proposed.展开更多
All-solid-state batteries(ASSBs)represent a next-generation energy storage technology,offering enhanced safety,higher energy density,and improved cycling stability compared to conventional liquid-electrolyte-based lit...All-solid-state batteries(ASSBs)represent a next-generation energy storage technology,offering enhanced safety,higher energy density,and improved cycling stability compared to conventional liquid-electrolyte-based lithium-ion batteries.Understanding and optimizing the complex chemistries and interfaces that underpin ASSB performance present significant challenges from both experimental and modeling perspectives.In particular,atomistic simulations face difficulties in capturing the complex structure,disorder,and dynamic evolution of materials and interfaces under practically relevant conditions.While established methods such as density functional theory and classical force fields have provided valuable insights,some questions remain difficult to address,particularly those involving large system sizes or long timescales.Recently,machine learning interatomic potentials(MLIPs)have emerged as a transformative tool,enabling atomistic simulations at length and time scales that were previously challenging to access with conventional approaches.By delivering near first-principles accuracy with much greater efficiency,MLIPs open new avenues for large-scale,long-timescale,and high-throughput simulations of solid-state battery materials.In this review,we present a comparative overview of density functional theory,classical force fields,and MLIPs,highlighting their respective strengths and limitations in ASSB research.We then discuss how MLIPs enable simulations that reach longer timescales,larger system sizes,and support high-throughput calculations,providing unique insights into ion transport and interfacial evolution in ASSBs.Finally,we conclude with a summary and outlook on current challenges and future opportunities for expanding MLIP capabilities and accelerating their impact in solid-state battery research.展开更多
Healthy behavior has long been linked to mental health outcomes.However,the role of artificial intelligence(AI)literacy in shaping healthy behaviors and its potential impact on mental health remains underexplored.This...Healthy behavior has long been linked to mental health outcomes.However,the role of artificial intelligence(AI)literacy in shaping healthy behaviors and its potential impact on mental health remains underexplored.This paper presents a scoping review offering a novel perspective on the intersection of healthy behaviors,mental health,and AI literacy.By examining how individuals’understanding of AI influences their choices regarding nutrition and their susceptibility to mental health issues,the current study explores emerging trends in health behavior decision-making.This emphasizes the need for integrating AI literacy into mental health and health behaviors education,as well as the development of AI-driven tools to support healthier behavior choices.It highlights that individuals with low AI literacy may misinterpret or overly depend on AI guidance,resulting in maladaptive health choices,while those with high AI literacy may be more likely to engage reflectively and sustain positive behaviors.The paper outlines the importance of inclusive education,user-centered design,and community-based support systems to enhance AI literacy for digitally marginalized groups.AI literacy may be positioned as a key determinant of health equity,better allowing for interdisciplinary strategies that empower individuals to make informed,autonomous decisions that promote both physical and mental health.展开更多
As a large family of RNA helicases,DEAD-box(DDX)RNA helicases play crucial roles in almost all cellular RNA processing activities.However,the role of the DDX gene family in cold tolerance of mei(Prunus mume)remains un...As a large family of RNA helicases,DEAD-box(DDX)RNA helicases play crucial roles in almost all cellular RNA processing activities.However,the role of the DDX gene family in cold tolerance of mei(Prunus mume)remains unclear.In this study,we identified 45 DDX genes through whole-genome analysis unevenly distributed across eight chromosomes and scaffolds of mei.Based on the phylogenetic tree and gene structure analysis,the DDX genes were classified into nine subfamilies based on their motif compositions and intron-exon structures.The results of synteny analysis showed that segmental duplication was considered a major factor contributing to the amplification of the PmDDX family.RNA-Seq and qRT-PCR results revealed differential expression of PmDDX genes under cold stress.Among these,PmDDX39 was significantly up-regulated under cold stress,suggesting its positive role in modulating mei cold tolerance.We found that silenced PmDDX39 under cold stress led to greater damage than the wild seedlings via virus-induced gene silencing(VIGS).Conversely,overexpression of PmDDX39 in Arabidopsis enhanced cold stress tolerance.Moreover,dual luciferase and yeast one-hybrid(Y1H)demonstrated that PmDDX39 directly activates the expression of the C-repeat binding factor(PmCBFf)by binding to its promoters.This study provides new insights into the structure,evolution,and functional role of the PmDDX gene family in mei responses to cold stress.展开更多
O3-types layered cathode materials in sodium-ion batteries(SIBs)suffer from the obvious lattice distortion induced by the complex phase transitions during Na^(+)intercalation/deintercalation process,leading to severe ...O3-types layered cathode materials in sodium-ion batteries(SIBs)suffer from the obvious lattice distortion induced by the complex phase transitions during Na^(+)intercalation/deintercalation process,leading to severe structural collapse and performance degradation.Herein,a series of high valence tantalum(Ta^(5+))doped Na(Ni_(0.4)Fe_(0.2)Mn_(0.4))_(1−x)Ta_(x)O_(2)(x=0/0.0025/0.005/0.01)secondary spherical particles are firstly developed,where Ta^(5+)doping enables the refined primary grain with a tightly stacked rod-like morphology.Comprehensive structural analysis via Neutron powder diffraction(NPD)and Synchrotron radiation X-ray diffraction(SXRD)reveals an expanded NaO_(2)slab and a reduction in Na site vacancy.The potential charge compensation mechanism is further illustrated by X-ray absorption spectroscopy(XAS)and X-ray photoelectron spectroscopy(XPS),unveiling a partial reduction from Ni^(3+)to Ni^(2+)with Ta^(5+)doping.In situ X-ray diffraction(in situ XRD)suggests that the decorated sample undergoes a volume change as low as 0.8%,in contrast with the pristine one(1.5%).Thus,the optimized sample with x=0.005 retains an enhanced capacity retention up to 70.4%at 1 C after 300 cycles in half-cell and delivers a high energy density of 251 Wh kg^(-1)(0.1 C)and with a good capacity retention of 81.0%at 1 C after 200 cycles in full-cell.Our findings provide new insights into the mechanism of high valence Ta^(5+)doping in stabilizing layered oxides cathode materials for SIBs.展开更多
While oceanic and coastal acidification has gained increased attention,long-term pH trends and their drivers in large freshwater systems remain poorly understood.The Laurentian Great Lakes are the world’s largest fre...While oceanic and coastal acidification has gained increased attention,long-term pH trends and their drivers in large freshwater systems remain poorly understood.The Laurentian Great Lakes are the world’s largest freshwater system,and in many ways resemble marine ecosystems.However,unlike the open ocean and coastal waters where pH has declined due to rising atmospheric CO_(2),no significant pH trends have been observed in the Laurentian Great Lakes,despite significant ecosystem changes driven partly by the invasion of dreissenid mussels.This study examined 41 years of field observations from Lake Michigan to investigate the long-term carbonate chemistry dynamics.Observational results revealed substantial declines in both total alkalinity(TA)and dissolved inorganic carbon(DIC)over the four decades.Mussel shell calcification emerged as the primary mechanism behind these declines,accounting for 97%and 47%of the observed changes in TA and DIC,respectively,lowering water column pH by 0.24 units.Elevated carbon accumulation in soft mussel tissues,coupled with long-term changes in the air-water pCO_(2)gradient during summer,significantly contributed to long-term DIC variations,explaining 18%and 28%of the lake-wide DIC loss.These two mechanisms also resulted in an overall pH increase of 0.09 and 0.12 units,largely offsetting the calcification-driven pH decrease.These findings bridge a gap in acidification research for large freshwater systems and provide valuable insights for comprehensive lake-wide management strategies.展开更多
Tilted metasurface nanostructures,with excellent physical properties and enormous application potential,pose an urgent need for manufacturing methods.Here,electric-field-driven generative-nanoimprinting technique is p...Tilted metasurface nanostructures,with excellent physical properties and enormous application potential,pose an urgent need for manufacturing methods.Here,electric-field-driven generative-nanoimprinting technique is proposed.The electric field applied between the template and the substrate drives the contact,tilting,filling,and holding processes.By accurately controlling the introduced included angle between the flexible template and the substrate,tilted nanostructures with a controllable angle are imprinted onto the substrate,although they are vertical on the template.By flexibly adjusting the electric field intensity and the included angle,large-area uniform-tilted,gradient-tilted,and high-angle-tilted nanostructures are fabricated.In contrast to traditional replication,the morphology of the nanoimprinting structure is extended to customized control.This work provides a cost-effective,efficient,and versatile technology for the fabrication of various large-area tilted metasurface structures.As an illustration,a tilted nanograting with a high coupling efficiency is fabricated and integrated into augmented reality displays,demonstrating superior imaging quality.展开更多
Covert timing channels(CTC)exploit network resources to establish hidden communication pathways,posing signi cant risks to data security and policy compliance.erefore,detecting such hidden and dangerous threats remain...Covert timing channels(CTC)exploit network resources to establish hidden communication pathways,posing signi cant risks to data security and policy compliance.erefore,detecting such hidden and dangerous threats remains one of the security challenges. is paper proposes LinguTimeX,a new framework that combines natural language processing with arti cial intelligence,along with explainable Arti cial Intelligence(AI)not only to detect CTC but also to provide insights into the decision process.LinguTimeX performs multidimensional feature extraction by fusing linguistic attributes with temporal network patterns to identify covert channels precisely.LinguTimeX demonstrates strong e ectiveness in detecting CTC across multiple languages;namely English,Arabic,and Chinese.Speci cally,the LSTM and RNN models achieved F1 scores of 90%on the English dataset,89%on the Arabic dataset,and 88%on the Chinese dataset,showcasing their superior performance and ability to generalize across multiple languages. is highlights their robustness in detecting CTCs within security systems,regardless of the language or cultural context of the data.In contrast,the DeepForest model produced F1-scores ranging from 86%to 87%across the same datasets,further con rming its e ectiveness in CTC detection.Although other algorithms also showed reasonable accuracy,the LSTM and RNN models consistently outperformed them in multilingual settings,suggesting that deep learning models might be better suited for this particular problem.展开更多
Interferon-related genes are involved in antiviral responses,inflammation,and immunity,which are closely related to sepsis-associated acute respiratory distress syndrome(ARDS).We analyzed 1972 participants with genoty...Interferon-related genes are involved in antiviral responses,inflammation,and immunity,which are closely related to sepsis-associated acute respiratory distress syndrome(ARDS).We analyzed 1972 participants with genotype data and 681 participants with gene expression data from the Molecular Epidemiology of ARDS(MEARDS),the Molecular Epidemiology of Sepsis in the ICU(MESSI),and the Molecular Diagnosis and Risk Stratification of Sepsis(MARS)cohorts in a three-step study focusing on sepsis-associated ARDS and sepsis-only controls.First,we identified and validated interferon-related genes associated with sepsis-associated ARDS risk using genetically regulated gene expression(GReX).Second,we examined the association of the confirmed gene(interferon regulatory factor 1,IRF1)with ARDS risk and survival and conducted a mediation analysis.Through discovery and validation,we found that the GReX of IRF1 was associated with ARDS risk(odds ratio[OR_(MEARDS)]=0.84,P=0.008;OR_(MESSI)=0.83,P=0.034).Furthermore,individual-level measured IRF1 expression was associated with reduced ARDS risk(OR=0.58,P=8.67×10^(-4)),and improved overall survival in ARDS patients(hazard ratio[HR_(28-day)]=0.49,P=0.009)and sepsis patients(HR_(28-day)=0.76,P=0.008).Mediation analysis revealed that IRF1 may enhance immune function by regulating the major histocompatibility complex,including HLA-F,which mediated more than 70%of protective effects of IRF1 on ARDS.The findings were validated by in vitro biological experiments including time-series infection dynamics,overexpression,knockout,and chromatin immunoprecipitation sequencing.Early prophylactic interventions to activate IRF1 in sepsis patients,thereby regulating HLA-F,may reduce the risk of ARDS and mortality,especially in severely ill patients.展开更多
Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)iso...Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic CEC-sEVs.In the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector.Small EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a control.Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs.An array of behavior assays was used to measure neurological function.Compared with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological outcomes.In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth.Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone.Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs.Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes.Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.展开更多
Understanding the neural underpinning of human gait and balance is one of the most pertinent challenges for 21st-century translational neuroscience due to the profound impact that falls and mobility disturbances have ...Understanding the neural underpinning of human gait and balance is one of the most pertinent challenges for 21st-century translational neuroscience due to the profound impact that falls and mobility disturbances have on our aging population.Posture and gait control does not happen automatically,as previously believed,but rather requires continuous involvement of central nervous mechanisms.To effectively exert control over the body,the brain must integrate multiple streams of sensory information,including visual,vestibular,and somatosensory signals.The mechanisms which underpin the integration of these multisensory signals are the principal topic of the present work.Existing multisensory integration theories focus on how failure of cognitive processes thought to be involved in multisensory integration leads to falls in older adults.Insufficient emphasis,however,has been placed on specific contributions of individual sensory modalities to multisensory integration processes and cross-modal interactions that occur between the sensory modalities in relation to gait and balance.In the present work,we review the contributions of somatosensory,visual,and vestibular modalities,along with their multisensory intersections to gait and balance in older adults and patients with Parkinson’s disease.We also review evidence of vestibular contributions to multisensory temporal binding windows,previously shown to be highly pertinent to fall risk in older adults.Lastly,we relate multisensory vestibular mechanisms to potential neural substrates,both at the level of neurobiology(concerning positron emission tomography imaging)and at the level of electrophysiology(concerning electroencephalography).We hope that this integrative review,drawing influence across multiple subdisciplines of neuroscience,paves the way for novel research directions and therapeutic neuromodulatory approaches,to improve the lives of older adults and patients with neurodegenerative diseases.展开更多
This study shows that sulfide solid-state electrolytes,β-Li_(3)PS_(4)and Li_(6)PS_(5)Cl,are flammable solids.Both solid-state electrolytes release sulfur vapor in a dry,oxidizing environment at elevated temperature&l...This study shows that sulfide solid-state electrolytes,β-Li_(3)PS_(4)and Li_(6)PS_(5)Cl,are flammable solids.Both solid-state electrolytes release sulfur vapor in a dry,oxidizing environment at elevated temperature<300℃.Sulfur vapor is a highly flammable gas,which then auto-ignites to produce a flame.This behavior suggests that an O_(2)-S gas-gas reaction mechanism may contribute to all-solid-state battery thermal runaway.To improve all-solid-state battery safety,current work focuses on eliminating the O_(2)source by changing the cathode active material.The conclusion of this study suggests that all-solidstate battery safety can also be realized by the development of solid-state electrolytes with less susceptibility to sulfur volatilization.展开更多
Transformer models have emerged as pivotal tools within the realm of drug discovery,distinguished by their unique architectural features and exceptional performance in managing intricate data landscapes.Leveraging the...Transformer models have emerged as pivotal tools within the realm of drug discovery,distinguished by their unique architectural features and exceptional performance in managing intricate data landscapes.Leveraging the innate capabilities of transformer architectures to comprehend intricate hierarchical dependencies inherent in sequential data,these models showcase remarkable efficacy across various tasks,including new drug design and drug target identification.The adaptability of pre-trained trans-former-based models renders them indispensable assets for driving data-centric advancements in drug discovery,chemistry,and biology,furnishing a robust framework that expedites innovation and dis-covery within these domains.Beyond their technical prowess,the success of transformer-based models in drug discovery,chemistry,and biology extends to their interdisciplinary potential,seamlessly combining biological,physical,chemical,and pharmacological insights to bridge gaps across diverse disciplines.This integrative approach not only enhances the depth and breadth of research endeavors but also fosters synergistic collaborations and exchange of ideas among disparate fields.In our review,we elucidate the myriad applications of transformers in drug discovery,as well as chemistry and biology,spanning from protein design and protein engineering,to molecular dynamics(MD),drug target iden-tification,transformer-enabled drug virtual screening(VS),drug lead optimization,drug addiction,small data set challenges,chemical and biological image analysis,chemical language understanding,and single cell data.Finally,we conclude the survey by deliberating on promising trends in transformer models within the context of drug discovery and other sciences.展开更多
The cranial base synchondroses,comprised of opposite-facing bidirectional chondrocyte layers,drive anteroposterior cranial base growth.In humans,RUNX2 haploinsufficiency causes cleidocranial dysplasia associated with ...The cranial base synchondroses,comprised of opposite-facing bidirectional chondrocyte layers,drive anteroposterior cranial base growth.In humans,RUNX2 haploinsufficiency causes cleidocranial dysplasia associated with deficient midfacial growth.However,how RUNX2 regulates chondrocytes in the cranial base synchondroses remains unknown.To address this,we inactivated Runx2 in postnatal synchondrosis chondrocytes using a tamoxifen-inducible Fgfr3-creER(Fgfr3-Runx2cKO)mouse model.Fgfr3-Runx2cKO mice displayed skeletal dwarfism and reduced anteroposterior cranial base growth associated with premature synchondrosis ossification due to impaired chondrocyte proliferation,accelerated hypertrophy,apoptosis,and osteoclast-mediated cartilage resorption.Lineage tracing reveals that Runx2-deficient Fgfr3+cells failed to differentiate into osteoblasts.Notably,Runx2-deficient chondrocytes showed an elevated level of FGFR3 and its downstream signaling components,pERK1/2 and SOX9,suggesting that RUNX2 downregulates FGFR3 in the synchondrosis.This study unveils a new role of Runx2 in cranial base chondrocytes,identifying a possible RUNX2-FGFR3-MAPK-SOX9 signaling axis that may control cranial base growth.展开更多
CD47 is a ubiquitous and pleiotropic cell-surface receptor.Disrupting CD47 enhances injury repair in various tissues but the role of CD47 has not been studied in bone injuries.In a murine closed-fracture model,CD47-nu...CD47 is a ubiquitous and pleiotropic cell-surface receptor.Disrupting CD47 enhances injury repair in various tissues but the role of CD47 has not been studied in bone injuries.In a murine closed-fracture model,CD47-null mice showed decreased callus bone formation as assessed by microcomputed tomography 10 days post-fracture and increased fibrous volume as determined by histology.To understand the cellular basis for this phenotype,mesenchymal progenitors(MSC)were harvested from bone marrow.CD47-null MSC showed decreased large fibroblast colony formation(CFU-F),significantly less proliferation,and fewer cells in Sphase,although osteoblast differentiation was unaffected.However,consistent with prior research,CD47-null endothelial cells showed increased proliferation relative to WT cells.Similarly,in a murine ischemic fracture model,CD47-null mice showed reduced fracture callus size due to a reduction in bone relative to WT 15 days-post fracture.Consistent with our in vitro results,in vivo EdU labeling showed decreased cell proliferation in the callus of CD47-null mice,while staining for CD31 and endomucin demonstrated increased endothelial cell density.Finally,WT mice with ischemic fracture that were administered a CD47 morpholino,which blocks CD47 protein production,showed a callus phenotype similar to that of ischemic fractures in CD47-null mice,suggesting the phenotype was not due to developmental changes in the knockout mice.Thus,inhibition of CD47 during bone healing reduces both non-ischemic and ischemic fracture healing,in part,by decreasing MSC proliferation.Furthermore,the increase in endothelial cell proliferation and early blood vessel density caused by CD47 disruption is not sufficient to overcome MSC dysfunction.展开更多
Although the benefits of physical activity are established across all age groups,researchers have recently noted that there is uncertainty as to which correlates and determinants of physical activity contribute to wel...Although the benefits of physical activity are established across all age groups,researchers have recently noted that there is uncertainty as to which correlates and determinants of physical activity contribute to well-informed interventions and policies,particularly for the time frame of early childhood.The following narrative review highlights salient factors related to physical activity during early childhood,particularly in the United States,with respect to a socioecological framework.Discussion of factors at the individual(demographic,genetic),interpersonal(family support and perceptions of competence),organizational(e.g.,preschool attended,preschool quality,teacher characteristics),community(availability,use,and perceptions of play spaces),and policy levels is included.While researchers often work within a public health framework that focuses on moderate-to-vigorous physical activity,or total(light-to-vigorous)physical activity,this may not fully align with how young children move.The importance of structured and unstructured play,risky play,and nature-based play are highlighted.Implications for basic and applied scientists,clinicians,and practitioners are addressed.Suggestions for future work include consideration of the context of physical activity,associations with other health behaviors,and further examination of the interpersonal and community level factors.展开更多
Bone morphogenetic proteins are essential for bone regeneration/fracture healing but can also induce heterotopic ossification(HO).Understanding accessory factors modulating BMP signaling would provide both a means of ...Bone morphogenetic proteins are essential for bone regeneration/fracture healing but can also induce heterotopic ossification(HO).Understanding accessory factors modulating BMP signaling would provide both a means of enhancing BMP-dependent regeneration while preventing HO.This study focuses on the ability of the collagen receptor,discoidin domain receptor 2(DDR2),to regulate BMP activity.As will be shown,induction of bone formation by subcutaneous BMP2 implants is severely compromised in Ddr2-deficient mice.In addition,Ddr2 deficiency attenuates HO in mice expressing the ACVR1 mutation associated with human fibrodysplasia ossificans progressiva.In cells migrating into BMP2 implants,DDR2 is co-expressed with GLI1,a skeletal stem cell marker,and DDR2/GLI1-positive cells participate in BMP2-induced bone formation where they contribute to chondrogenic and osteogenic lineages.Consistent with this distribution,conditional knockout of Ddr2 in Gli1-expressing cells inhibited bone formation to the same extent seen in globally Ddr2-deficient animals.This response was explained by selective inhibition of Gli1+cell proliferation without changes in apoptosis.The basis for this DDR2 requirement was explored further using bone marrow stromal cells.Although Ddr2 deficiency inhibited BMP2-dependent chondrocyte and osteoblast differentiation and in vivo,bone formation,early BMP responses including SMAD phosphorylation remained largely intact.Instead,Ddr2 deficiency reduced the nuclear/cytoplasmic ratio of the Hippo pathway intermediates,YAP and TAZ.This suggests that DDR2 regulates Hippo pathway-mediated responses to the collagen matrix,which subsequently affect BMP responsiveness.In summary,DDR2 is an important modulator of BMP signaling and a potential therapeutic target both for enhancing regeneration and treating HO.展开更多
This review focuses on the diagnostic algorithm for nonobstructive azoospermia(NOA),a significant male factor contributing to infertility.NOA,characterized by the absence of sperm in the ejaculate,requires a systemati...This review focuses on the diagnostic algorithm for nonobstructive azoospermia(NOA),a significant male factor contributing to infertility.NOA,characterized by the absence of sperm in the ejaculate,requires a systematic diagnostic approach to identify reversible conditions,genetic factors,and prognosis for achieving pregnancy.The diagnostic pathway involves semen analysis and a comprehensive evaluation for hormonal deficiencies,anatomical abnormalities,and genetic factors.The importance of medical history,physical examination,endocrine evaluation,imaging,and genetic testing is emphasized.This review highlights the significance of differentiating NOA from obstructive azoospermia(OA)and outlines key considerations for effective management,including surgical sperm retrieval and assisted reproductive techniques.Testicular biopsy is discussed as a definitive method to distinguish obstructive cases from nonobstructive cases,providing valuable prognostic information.Overall,a thorough and systematic diagnostic approach is essential for the effective management of men suspected with NOA,offering insights into potential treatment options and reproductive outcomes.展开更多
Conducting predictability studies is essential for tracing the source of forecast errors,which not only leads to the improvement of observation and forecasting systems,but also enhances the understanding of weather an...Conducting predictability studies is essential for tracing the source of forecast errors,which not only leads to the improvement of observation and forecasting systems,but also enhances the understanding of weather and climate phenomena.In the past few decades,dynamical numerical models have been the primary tools for predictability studies,achieving significant progress.Nowadays,with the advances in artificial intelligence(AI)techniques and accumulations of vast meteorological data,modeling weather and climate events using modern data-driven approaches is becoming trendy,where FourCastNet,Pangu-Weather,and GraphCast are successful pioneers.In this perspective article,we suggest AI models should not be limited to forecasting but be expanded to predictability studies,leveraging AI's advantages of high efficiency and self-contained optimization modules.To this end,we first remark that AI models should possess high simulation capability with fine spatiotemporal resolution for two kinds of predictability studies.AI models with high simulation capabilities comparable to numerical models can be considered to provide solutions to partial differential equations in a data-driven way.Then,we highlight several specific predictability issues with well-determined nonlinear optimization formulizations,which can be well-studied using AI models,holding significant scientific value.In addition,we advocate for the incorporation of AI models into the synergistic cycle of the cognition–observation–model paradigm.Comprehensive predictability studies have the potential to transform“big data”to“big and better data”and shift the focus from“AI for forecasts”to“AI for science”,ultimately advancing the development of the atmospheric and oceanic sciences.展开更多
基金This work used Expanse systems at UCSD through an allocation[PHY240089]from the Advanced Cyberinfrastructure Coordination Ecosystem:Services&Support(ACCESS)programsupported by U.S.National Science Foundation(Grant Nos.2138259,2138286,2138307,2137603 and 2138296).
文摘We present a numerical framework for simulating viscous compressible flows in the presence of solid particles with large size ratios.The volume-filtered Navier-Stokes equations are discretized using a class of high-order low-dissipative finite difference operators with energy-preserving properties.No-slip,adiabatic boundary conditions are enforced at the surface of large particles(with diameters significantly larger than the local grid spacing)using a ghost-point immersed boundary method.Two-way coupling between the gas phase and small particles(with diameters proportional to the grid spacing)is accounted for through volumetric source terms for interphase momentum and energy exchange.A simple and efficient approach for collision detection between small and large particles is proposed.The framework is applied to simulations of planar shocks interacting with bidisperse distributions of particles with size ratios of approximately thirty.Particle dispersion and size segregation are reported and a simple analytical model for size segregation is proposed.
文摘All-solid-state batteries(ASSBs)represent a next-generation energy storage technology,offering enhanced safety,higher energy density,and improved cycling stability compared to conventional liquid-electrolyte-based lithium-ion batteries.Understanding and optimizing the complex chemistries and interfaces that underpin ASSB performance present significant challenges from both experimental and modeling perspectives.In particular,atomistic simulations face difficulties in capturing the complex structure,disorder,and dynamic evolution of materials and interfaces under practically relevant conditions.While established methods such as density functional theory and classical force fields have provided valuable insights,some questions remain difficult to address,particularly those involving large system sizes or long timescales.Recently,machine learning interatomic potentials(MLIPs)have emerged as a transformative tool,enabling atomistic simulations at length and time scales that were previously challenging to access with conventional approaches.By delivering near first-principles accuracy with much greater efficiency,MLIPs open new avenues for large-scale,long-timescale,and high-throughput simulations of solid-state battery materials.In this review,we present a comparative overview of density functional theory,classical force fields,and MLIPs,highlighting their respective strengths and limitations in ASSB research.We then discuss how MLIPs enable simulations that reach longer timescales,larger system sizes,and support high-throughput calculations,providing unique insights into ion transport and interfacial evolution in ASSBs.Finally,we conclude with a summary and outlook on current challenges and future opportunities for expanding MLIP capabilities and accelerating their impact in solid-state battery research.
文摘Healthy behavior has long been linked to mental health outcomes.However,the role of artificial intelligence(AI)literacy in shaping healthy behaviors and its potential impact on mental health remains underexplored.This paper presents a scoping review offering a novel perspective on the intersection of healthy behaviors,mental health,and AI literacy.By examining how individuals’understanding of AI influences their choices regarding nutrition and their susceptibility to mental health issues,the current study explores emerging trends in health behavior decision-making.This emphasizes the need for integrating AI literacy into mental health and health behaviors education,as well as the development of AI-driven tools to support healthier behavior choices.It highlights that individuals with low AI literacy may misinterpret or overly depend on AI guidance,resulting in maladaptive health choices,while those with high AI literacy may be more likely to engage reflectively and sustain positive behaviors.The paper outlines the importance of inclusive education,user-centered design,and community-based support systems to enhance AI literacy for digitally marginalized groups.AI literacy may be positioned as a key determinant of health equity,better allowing for interdisciplinary strategies that empower individuals to make informed,autonomous decisions that promote both physical and mental health.
基金supported by the Fundamental Research Funds for the Central Universities(Grant No.QNTD202503)Forestry and Grassland Science and Technology Innovation Youth Top Talent Project of China(Grant No.2020132608)Beijing High-Precision Discipline Project,Discipline of Ecological Environment of Urban and Rural Human Settlements.
文摘As a large family of RNA helicases,DEAD-box(DDX)RNA helicases play crucial roles in almost all cellular RNA processing activities.However,the role of the DDX gene family in cold tolerance of mei(Prunus mume)remains unclear.In this study,we identified 45 DDX genes through whole-genome analysis unevenly distributed across eight chromosomes and scaffolds of mei.Based on the phylogenetic tree and gene structure analysis,the DDX genes were classified into nine subfamilies based on their motif compositions and intron-exon structures.The results of synteny analysis showed that segmental duplication was considered a major factor contributing to the amplification of the PmDDX family.RNA-Seq and qRT-PCR results revealed differential expression of PmDDX genes under cold stress.Among these,PmDDX39 was significantly up-regulated under cold stress,suggesting its positive role in modulating mei cold tolerance.We found that silenced PmDDX39 under cold stress led to greater damage than the wild seedlings via virus-induced gene silencing(VIGS).Conversely,overexpression of PmDDX39 in Arabidopsis enhanced cold stress tolerance.Moreover,dual luciferase and yeast one-hybrid(Y1H)demonstrated that PmDDX39 directly activates the expression of the C-repeat binding factor(PmCBFf)by binding to its promoters.This study provides new insights into the structure,evolution,and functional role of the PmDDX gene family in mei responses to cold stress.
基金supported by the National Natural Science Foundation of China (52402298, 52172224, 52202228, 22479112)the Science and Technology Correspondent Project of Tianjin(24YDTPJC00240)+3 种基金Science Research Project of Hebei Education Department (BJK2022011)Central Funds Guiding the Local Science and Technology Development of Hebei Province (236Z4404G)the Beijing Tianjin Hebei Basic Research Cooperation Special Project(E2024202273)Tianjin Sci.&Tech. Program (22YFYSHZ00220)
文摘O3-types layered cathode materials in sodium-ion batteries(SIBs)suffer from the obvious lattice distortion induced by the complex phase transitions during Na^(+)intercalation/deintercalation process,leading to severe structural collapse and performance degradation.Herein,a series of high valence tantalum(Ta^(5+))doped Na(Ni_(0.4)Fe_(0.2)Mn_(0.4))_(1−x)Ta_(x)O_(2)(x=0/0.0025/0.005/0.01)secondary spherical particles are firstly developed,where Ta^(5+)doping enables the refined primary grain with a tightly stacked rod-like morphology.Comprehensive structural analysis via Neutron powder diffraction(NPD)and Synchrotron radiation X-ray diffraction(SXRD)reveals an expanded NaO_(2)slab and a reduction in Na site vacancy.The potential charge compensation mechanism is further illustrated by X-ray absorption spectroscopy(XAS)and X-ray photoelectron spectroscopy(XPS),unveiling a partial reduction from Ni^(3+)to Ni^(2+)with Ta^(5+)doping.In situ X-ray diffraction(in situ XRD)suggests that the decorated sample undergoes a volume change as low as 0.8%,in contrast with the pristine one(1.5%).Thus,the optimized sample with x=0.005 retains an enhanced capacity retention up to 70.4%at 1 C after 300 cycles in half-cell and delivers a high energy density of 251 Wh kg^(-1)(0.1 C)and with a good capacity retention of 81.0%at 1 C after 200 cycles in full-cell.Our findings provide new insights into the mechanism of high valence Ta^(5+)doping in stabilizing layered oxides cathode materials for SIBs.
基金Supported by the National Natural Science Foundation of China(No.43277051)the Key Laboratory of Integrated Regulation and Resources Development of Shallow Lakes of Ministry of Education(No.B230203006).
文摘While oceanic and coastal acidification has gained increased attention,long-term pH trends and their drivers in large freshwater systems remain poorly understood.The Laurentian Great Lakes are the world’s largest freshwater system,and in many ways resemble marine ecosystems.However,unlike the open ocean and coastal waters where pH has declined due to rising atmospheric CO_(2),no significant pH trends have been observed in the Laurentian Great Lakes,despite significant ecosystem changes driven partly by the invasion of dreissenid mussels.This study examined 41 years of field observations from Lake Michigan to investigate the long-term carbonate chemistry dynamics.Observational results revealed substantial declines in both total alkalinity(TA)and dissolved inorganic carbon(DIC)over the four decades.Mussel shell calcification emerged as the primary mechanism behind these declines,accounting for 97%and 47%of the observed changes in TA and DIC,respectively,lowering water column pH by 0.24 units.Elevated carbon accumulation in soft mussel tissues,coupled with long-term changes in the air-water pCO_(2)gradient during summer,significantly contributed to long-term DIC variations,explaining 18%and 28%of the lake-wide DIC loss.These two mechanisms also resulted in an overall pH increase of 0.09 and 0.12 units,largely offsetting the calcification-driven pH decrease.These findings bridge a gap in acidification research for large freshwater systems and provide valuable insights for comprehensive lake-wide management strategies.
基金supported by National Natural Science Foundation of China(No.52025055 and 52275571)Basic Research Operation Fund of China(No.xzy012024024).
文摘Tilted metasurface nanostructures,with excellent physical properties and enormous application potential,pose an urgent need for manufacturing methods.Here,electric-field-driven generative-nanoimprinting technique is proposed.The electric field applied between the template and the substrate drives the contact,tilting,filling,and holding processes.By accurately controlling the introduced included angle between the flexible template and the substrate,tilted nanostructures with a controllable angle are imprinted onto the substrate,although they are vertical on the template.By flexibly adjusting the electric field intensity and the included angle,large-area uniform-tilted,gradient-tilted,and high-angle-tilted nanostructures are fabricated.In contrast to traditional replication,the morphology of the nanoimprinting structure is extended to customized control.This work provides a cost-effective,efficient,and versatile technology for the fabrication of various large-area tilted metasurface structures.As an illustration,a tilted nanograting with a high coupling efficiency is fabricated and integrated into augmented reality displays,demonstrating superior imaging quality.
基金This study is financed by the European Union-NextGenerationEU,through the National Recovery and Resilience Plan of the Republic of Bulgaria,Project No.BG-RRP-2.013-0001.
文摘Covert timing channels(CTC)exploit network resources to establish hidden communication pathways,posing signi cant risks to data security and policy compliance.erefore,detecting such hidden and dangerous threats remains one of the security challenges. is paper proposes LinguTimeX,a new framework that combines natural language processing with arti cial intelligence,along with explainable Arti cial Intelligence(AI)not only to detect CTC but also to provide insights into the decision process.LinguTimeX performs multidimensional feature extraction by fusing linguistic attributes with temporal network patterns to identify covert channels precisely.LinguTimeX demonstrates strong e ectiveness in detecting CTC across multiple languages;namely English,Arabic,and Chinese.Speci cally,the LSTM and RNN models achieved F1 scores of 90%on the English dataset,89%on the Arabic dataset,and 88%on the Chinese dataset,showcasing their superior performance and ability to generalize across multiple languages. is highlights their robustness in detecting CTCs within security systems,regardless of the language or cultural context of the data.In contrast,the DeepForest model produced F1-scores ranging from 86%to 87%across the same datasets,further con rming its e ectiveness in CTC detection.Although other algorithms also showed reasonable accuracy,the LSTM and RNN models consistently outperformed them in multilingual settings,suggesting that deep learning models might be better suited for this particular problem.
基金supported by the National Natural Science Foundation of China(Grant No.82220108002 to F.C.and Grant No.82273737 to R.Z.)the U.S.National Institutes of Health(Grant Nos.CA209414,HL060710,and ES000002 to D.C.C.,Grant Nos.CA209414 and CA249096 to Y.L.)+1 种基金the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)supported by the Qing Lan Project of the Higher Education Institutions of Jiangsu Province and the Outstanding Young Level Academic Leadership Training Program of Nanjing Medical University.
文摘Interferon-related genes are involved in antiviral responses,inflammation,and immunity,which are closely related to sepsis-associated acute respiratory distress syndrome(ARDS).We analyzed 1972 participants with genotype data and 681 participants with gene expression data from the Molecular Epidemiology of ARDS(MEARDS),the Molecular Epidemiology of Sepsis in the ICU(MESSI),and the Molecular Diagnosis and Risk Stratification of Sepsis(MARS)cohorts in a three-step study focusing on sepsis-associated ARDS and sepsis-only controls.First,we identified and validated interferon-related genes associated with sepsis-associated ARDS risk using genetically regulated gene expression(GReX).Second,we examined the association of the confirmed gene(interferon regulatory factor 1,IRF1)with ARDS risk and survival and conducted a mediation analysis.Through discovery and validation,we found that the GReX of IRF1 was associated with ARDS risk(odds ratio[OR_(MEARDS)]=0.84,P=0.008;OR_(MESSI)=0.83,P=0.034).Furthermore,individual-level measured IRF1 expression was associated with reduced ARDS risk(OR=0.58,P=8.67×10^(-4)),and improved overall survival in ARDS patients(hazard ratio[HR_(28-day)]=0.49,P=0.009)and sepsis patients(HR_(28-day)=0.76,P=0.008).Mediation analysis revealed that IRF1 may enhance immune function by regulating the major histocompatibility complex,including HLA-F,which mediated more than 70%of protective effects of IRF1 on ARDS.The findings were validated by in vitro biological experiments including time-series infection dynamics,overexpression,knockout,and chromatin immunoprecipitation sequencing.Early prophylactic interventions to activate IRF1 in sepsis patients,thereby regulating HLA-F,may reduce the risk of ARDS and mortality,especially in severely ill patients.
基金supported by the NIH grants,R01 NS111801(to ZGZ)American Heart Association 16SDG29860003(to YZ)。
文摘Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic CEC-sEVs.In the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector.Small EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a control.Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs.An array of behavior assays was used to measure neurological function.Compared with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological outcomes.In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth.Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone.Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs.Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes.Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.
文摘Understanding the neural underpinning of human gait and balance is one of the most pertinent challenges for 21st-century translational neuroscience due to the profound impact that falls and mobility disturbances have on our aging population.Posture and gait control does not happen automatically,as previously believed,but rather requires continuous involvement of central nervous mechanisms.To effectively exert control over the body,the brain must integrate multiple streams of sensory information,including visual,vestibular,and somatosensory signals.The mechanisms which underpin the integration of these multisensory signals are the principal topic of the present work.Existing multisensory integration theories focus on how failure of cognitive processes thought to be involved in multisensory integration leads to falls in older adults.Insufficient emphasis,however,has been placed on specific contributions of individual sensory modalities to multisensory integration processes and cross-modal interactions that occur between the sensory modalities in relation to gait and balance.In the present work,we review the contributions of somatosensory,visual,and vestibular modalities,along with their multisensory intersections to gait and balance in older adults and patients with Parkinson’s disease.We also review evidence of vestibular contributions to multisensory temporal binding windows,previously shown to be highly pertinent to fall risk in older adults.Lastly,we relate multisensory vestibular mechanisms to potential neural substrates,both at the level of neurobiology(concerning positron emission tomography imaging)and at the level of electrophysiology(concerning electroencephalography).We hope that this integrative review,drawing influence across multiple subdisciplines of neuroscience,paves the way for novel research directions and therapeutic neuromodulatory approaches,to improve the lives of older adults and patients with neurodegenerative diseases.
文摘This study shows that sulfide solid-state electrolytes,β-Li_(3)PS_(4)and Li_(6)PS_(5)Cl,are flammable solids.Both solid-state electrolytes release sulfur vapor in a dry,oxidizing environment at elevated temperature<300℃.Sulfur vapor is a highly flammable gas,which then auto-ignites to produce a flame.This behavior suggests that an O_(2)-S gas-gas reaction mechanism may contribute to all-solid-state battery thermal runaway.To improve all-solid-state battery safety,current work focuses on eliminating the O_(2)source by changing the cathode active material.The conclusion of this study suggests that all-solidstate battery safety can also be realized by the development of solid-state electrolytes with less susceptibility to sulfur volatilization.
基金supported in part by National Institute of Health(NIH),USA(Grant Nos.:R01GM126189,R01AI164266,and R35GM148196)the National Science Foundation,USA(Grant Nos.DMS2052983,DMS-1761320,and IIS-1900473)+3 种基金National Aero-nautics and Space Administration(NASA),USA(Grant No.:80NSSC21M0023)Michigan State University(MSU)Foundation,USA,Bristol-Myers Squibb(Grant No.:65109)USA,and Pfizer,USAsupported by the National Natural Science Foundation of China(Grant Nos.:11971367,12271416,and 11972266).
文摘Transformer models have emerged as pivotal tools within the realm of drug discovery,distinguished by their unique architectural features and exceptional performance in managing intricate data landscapes.Leveraging the innate capabilities of transformer architectures to comprehend intricate hierarchical dependencies inherent in sequential data,these models showcase remarkable efficacy across various tasks,including new drug design and drug target identification.The adaptability of pre-trained trans-former-based models renders them indispensable assets for driving data-centric advancements in drug discovery,chemistry,and biology,furnishing a robust framework that expedites innovation and dis-covery within these domains.Beyond their technical prowess,the success of transformer-based models in drug discovery,chemistry,and biology extends to their interdisciplinary potential,seamlessly combining biological,physical,chemical,and pharmacological insights to bridge gaps across diverse disciplines.This integrative approach not only enhances the depth and breadth of research endeavors but also fosters synergistic collaborations and exchange of ideas among disparate fields.In our review,we elucidate the myriad applications of transformers in drug discovery,as well as chemistry and biology,spanning from protein design and protein engineering,to molecular dynamics(MD),drug target iden-tification,transformer-enabled drug virtual screening(VS),drug lead optimization,drug addiction,small data set challenges,chemical and biological image analysis,chemical language understanding,and single cell data.Finally,we conclude the survey by deliberating on promising trends in transformer models within the context of drug discovery and other sciences.
基金National Institutes of Health grant F30DE030675(S.A.H.)National Institutes of Health grant T32DE007057(S.A.H.)+7 种基金University of Michigan Rackham Graduate School Pre-Candidate Research Grant(S.A.H.)University of Michigan Rackham Graduate School Candidate Research Grant(S.A.H.)National Institutes of Health grant R35DE034348(N.O.)National Institutes of Health grant R01DE026666(N.O.)National Institutes of Health grant R01DE030630(N.O.)National Institutes of Health grant R01DE029465(R.T.F.)Department of Defense grant W81XWH2010571(R.T.F.)National Institutes of Health grant P30 AR069620(The Michigan Integrative Musculoskeletal.Health Core Center).
文摘The cranial base synchondroses,comprised of opposite-facing bidirectional chondrocyte layers,drive anteroposterior cranial base growth.In humans,RUNX2 haploinsufficiency causes cleidocranial dysplasia associated with deficient midfacial growth.However,how RUNX2 regulates chondrocytes in the cranial base synchondroses remains unknown.To address this,we inactivated Runx2 in postnatal synchondrosis chondrocytes using a tamoxifen-inducible Fgfr3-creER(Fgfr3-Runx2cKO)mouse model.Fgfr3-Runx2cKO mice displayed skeletal dwarfism and reduced anteroposterior cranial base growth associated with premature synchondrosis ossification due to impaired chondrocyte proliferation,accelerated hypertrophy,apoptosis,and osteoclast-mediated cartilage resorption.Lineage tracing reveals that Runx2-deficient Fgfr3+cells failed to differentiate into osteoblasts.Notably,Runx2-deficient chondrocytes showed an elevated level of FGFR3 and its downstream signaling components,pERK1/2 and SOX9,suggesting that RUNX2 downregulates FGFR3 in the synchondrosis.This study unveils a new role of Runx2 in cranial base chondrocytes,identifying a possible RUNX2-FGFR3-MAPK-SOX9 signaling axis that may control cranial base growth.
基金supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases(NIAMS)of the National Institutes of Health(NIH)under award numbers F30AR071201(R.L.Z.)and R01 AR066028(K.D.H.)Additional research support is provided by the NIH under a training award T32TR004371(C.A.C.).
文摘CD47 is a ubiquitous and pleiotropic cell-surface receptor.Disrupting CD47 enhances injury repair in various tissues but the role of CD47 has not been studied in bone injuries.In a murine closed-fracture model,CD47-null mice showed decreased callus bone formation as assessed by microcomputed tomography 10 days post-fracture and increased fibrous volume as determined by histology.To understand the cellular basis for this phenotype,mesenchymal progenitors(MSC)were harvested from bone marrow.CD47-null MSC showed decreased large fibroblast colony formation(CFU-F),significantly less proliferation,and fewer cells in Sphase,although osteoblast differentiation was unaffected.However,consistent with prior research,CD47-null endothelial cells showed increased proliferation relative to WT cells.Similarly,in a murine ischemic fracture model,CD47-null mice showed reduced fracture callus size due to a reduction in bone relative to WT 15 days-post fracture.Consistent with our in vitro results,in vivo EdU labeling showed decreased cell proliferation in the callus of CD47-null mice,while staining for CD31 and endomucin demonstrated increased endothelial cell density.Finally,WT mice with ischemic fracture that were administered a CD47 morpholino,which blocks CD47 protein production,showed a callus phenotype similar to that of ischemic fractures in CD47-null mice,suggesting the phenotype was not due to developmental changes in the knockout mice.Thus,inhibition of CD47 during bone healing reduces both non-ischemic and ischemic fracture healing,in part,by decreasing MSC proliferation.Furthermore,the increase in endothelial cell proliferation and early blood vessel density caused by CD47 disruption is not sufficient to overcome MSC dysfunction.
文摘Although the benefits of physical activity are established across all age groups,researchers have recently noted that there is uncertainty as to which correlates and determinants of physical activity contribute to well-informed interventions and policies,particularly for the time frame of early childhood.The following narrative review highlights salient factors related to physical activity during early childhood,particularly in the United States,with respect to a socioecological framework.Discussion of factors at the individual(demographic,genetic),interpersonal(family support and perceptions of competence),organizational(e.g.,preschool attended,preschool quality,teacher characteristics),community(availability,use,and perceptions of play spaces),and policy levels is included.While researchers often work within a public health framework that focuses on moderate-to-vigorous physical activity,or total(light-to-vigorous)physical activity,this may not fully align with how young children move.The importance of structured and unstructured play,risky play,and nature-based play are highlighted.Implications for basic and applied scientists,clinicians,and practitioners are addressed.Suggestions for future work include consideration of the context of physical activity,associations with other health behaviors,and further examination of the interpersonal and community level factors.
基金Scientific Research Training Program for Young Talents of Union Hospital,Tongji Medical College,Huazhong University of Science and Technology(F.W.),NIH/NIDCR grants DE029012 and DE029465Department of Defense Grant PR190899(R.T.F.)Michigan Musculoskeletal Health Core Center(NIH/NIAMS P30 AR069620)。
文摘Bone morphogenetic proteins are essential for bone regeneration/fracture healing but can also induce heterotopic ossification(HO).Understanding accessory factors modulating BMP signaling would provide both a means of enhancing BMP-dependent regeneration while preventing HO.This study focuses on the ability of the collagen receptor,discoidin domain receptor 2(DDR2),to regulate BMP activity.As will be shown,induction of bone formation by subcutaneous BMP2 implants is severely compromised in Ddr2-deficient mice.In addition,Ddr2 deficiency attenuates HO in mice expressing the ACVR1 mutation associated with human fibrodysplasia ossificans progressiva.In cells migrating into BMP2 implants,DDR2 is co-expressed with GLI1,a skeletal stem cell marker,and DDR2/GLI1-positive cells participate in BMP2-induced bone formation where they contribute to chondrogenic and osteogenic lineages.Consistent with this distribution,conditional knockout of Ddr2 in Gli1-expressing cells inhibited bone formation to the same extent seen in globally Ddr2-deficient animals.This response was explained by selective inhibition of Gli1+cell proliferation without changes in apoptosis.The basis for this DDR2 requirement was explored further using bone marrow stromal cells.Although Ddr2 deficiency inhibited BMP2-dependent chondrocyte and osteoblast differentiation and in vivo,bone formation,early BMP responses including SMAD phosphorylation remained largely intact.Instead,Ddr2 deficiency reduced the nuclear/cytoplasmic ratio of the Hippo pathway intermediates,YAP and TAZ.This suggests that DDR2 regulates Hippo pathway-mediated responses to the collagen matrix,which subsequently affect BMP responsiveness.In summary,DDR2 is an important modulator of BMP signaling and a potential therapeutic target both for enhancing regeneration and treating HO.
文摘This review focuses on the diagnostic algorithm for nonobstructive azoospermia(NOA),a significant male factor contributing to infertility.NOA,characterized by the absence of sperm in the ejaculate,requires a systematic diagnostic approach to identify reversible conditions,genetic factors,and prognosis for achieving pregnancy.The diagnostic pathway involves semen analysis and a comprehensive evaluation for hormonal deficiencies,anatomical abnormalities,and genetic factors.The importance of medical history,physical examination,endocrine evaluation,imaging,and genetic testing is emphasized.This review highlights the significance of differentiating NOA from obstructive azoospermia(OA)and outlines key considerations for effective management,including surgical sperm retrieval and assisted reproductive techniques.Testicular biopsy is discussed as a definitive method to distinguish obstructive cases from nonobstructive cases,providing valuable prognostic information.Overall,a thorough and systematic diagnostic approach is essential for the effective management of men suspected with NOA,offering insights into potential treatment options and reproductive outcomes.
基金in part supported by the National Natural Science Foundation of China(Grant Nos.42288101,42405147 and 42475054)in part by the China National Postdoctoral Program for Innovative Talents(Grant No.BX20230071)。
文摘Conducting predictability studies is essential for tracing the source of forecast errors,which not only leads to the improvement of observation and forecasting systems,but also enhances the understanding of weather and climate phenomena.In the past few decades,dynamical numerical models have been the primary tools for predictability studies,achieving significant progress.Nowadays,with the advances in artificial intelligence(AI)techniques and accumulations of vast meteorological data,modeling weather and climate events using modern data-driven approaches is becoming trendy,where FourCastNet,Pangu-Weather,and GraphCast are successful pioneers.In this perspective article,we suggest AI models should not be limited to forecasting but be expanded to predictability studies,leveraging AI's advantages of high efficiency and self-contained optimization modules.To this end,we first remark that AI models should possess high simulation capability with fine spatiotemporal resolution for two kinds of predictability studies.AI models with high simulation capabilities comparable to numerical models can be considered to provide solutions to partial differential equations in a data-driven way.Then,we highlight several specific predictability issues with well-determined nonlinear optimization formulizations,which can be well-studied using AI models,holding significant scientific value.In addition,we advocate for the incorporation of AI models into the synergistic cycle of the cognition–observation–model paradigm.Comprehensive predictability studies have the potential to transform“big data”to“big and better data”and shift the focus from“AI for forecasts”to“AI for science”,ultimately advancing the development of the atmospheric and oceanic sciences.
