Congestive heart failure(CHF) secondary to chronic coronary artery disease is a major cause of morbidity and mortality world-wide. Its prevalence is increasing despite advances in medical and device therapies. Cell ba...Congestive heart failure(CHF) secondary to chronic coronary artery disease is a major cause of morbidity and mortality world-wide. Its prevalence is increasing despite advances in medical and device therapies. Cell based therapies generating new cardiomyocytes and vessels have emerged as a promising treatment to reverse functional deterioration and prevent the progression to CHF. Functional efficacy of progenitor cells isolated from the bone marrow and the heart have been evaluated in preclinical large animal models. Furthermore, several clinical trials using autologous and allogeneic stem cells and progenitor cells have demonstrated their safety in humans yet their clinical relevance is inconclusive. This review will discuss the clinical therapeutic applications of three specific adult stem cells that have shown particularly promising regenerative effects in preclinical studies, bone marrow derived mesenchymal stem cell, heart derived cardiosphere-derived cell and cardiac stem cell. We will also discuss future therapeutic approaches.展开更多
Objective To develop and validate a preoperative clinical-radiomics model for predicting overall survival(OS)and disease-free survival(DFS)in patients with extrahepatic cholangiocarcinoma(eCCA)undergoing radical resec...Objective To develop and validate a preoperative clinical-radiomics model for predicting overall survival(OS)and disease-free survival(DFS)in patients with extrahepatic cholangiocarcinoma(eCCA)undergoing radical resection.Methods In this retrospective study,consecutive patients with pathologically-confirmed eCCA who underwent radical resection at our institution from 2015 to 2022 were included.The patients were divided into a training cohort and a validation cohort according to the chronological order of their CT examinations.Least absolute shrinkage and selection operator(LASSO)-Cox regression was employed to select predictive radiomic features and clinical variables.The selected features and variables were incorporated into a Cox regression model.Model performance for 1-year OS and DFS prediction was assessed using calibration curves,area under receiver operating characteristic curve(AUC),and concordance index(C-index).Results This study included 123 patients(mean age 64.0±8.4 years,85 males/38 females),with 86 in the training cohort and 37 in the validation cohort.The OS-predicting model included four clinical variables and four radiomic features.It achieved a training cohort AUC of 0.858(C-index=0.800)and a validation cohort AUC of 0.649(C-index=0.605).The DFS-predicting model included four clinical variables and four other radiomic features.It achieved a training cohort AUC of 0.830(C-index=0.760)and a validation cohort AUC of 0.717(C-index=0.616).Conclusion The preoperative clinical-radiomics models show promise as a tool for predicting 1-year OS and DFS in eCCA patients after radical surgery.展开更多
Stroke,particularly ischemic stroke,is the leading cause of long-term disability and mortality worldwide.It occurs due to the occlusion of the cerebral arteries,which significantly reduces the delivery of blood,oxygen...Stroke,particularly ischemic stroke,is the leading cause of long-term disability and mortality worldwide.It occurs due to the occlusion of the cerebral arteries,which significantly reduces the delivery of blood,oxygen,and essential nutrients to brain tissues.This deprivation triggers a cascade of cellular events that ultimately leads to neuronal death.Recent studies have clarified the multifactorial pathogenesis of ischemic stroke,highlighting the roles of energy failure,excitotoxicity,oxidative stress,neuroinflammation,and apoptosis.This review aimed to provide a comprehensive insight into the fundamental mechanisms driving neuronal death triggered by ischemia and to examine the progress of neuroprotective therapeutic approaches designed to mitigate neuronal loss and promote neurological recovery after a stroke.Additionally,we explored widely accepted findings regarding the potential pathways implicated in neuronal death during ischemic stroke,including the interplay of apoptosis,autophagy,pyroptosis,ferroptosis,and necrosis,which collectively influence neuronal fate.We also discussed advancements in neuroprotective therapeutics,encompassing a range of interventions from pharmacological modulation to stem cell-based therapies,aimed at reducing neuronal injury and enhancing functional recovery following ischemic stroke.Despite these advancements,challenges remain in translating mechanistic insights into effective clinical therapies.Although neuroprotective strategies have shown promise in preclinical models,their efficacy in human trials has been inconsistent,often due to the complex pathology of ischemic stroke and the timing of interventions.In conclusion,this review synthesizes mechanistic insights into the intricate interplay of molecular and cellular pathways driving neuronal death post-ischemia.It sheds light on cutting-edge advancements in potential neuroprotective therapeutics,underscores the promise of regenerative medicine,and offers a forward-looking perspective on potential clinical breakthroughs.The ongoing evolution of precision-targeted interventions is expected to significantly enhance preventative strategies and improve clinical outcomes.展开更多
GNAO1-associated disorder is a rare disease and an example of developmental and epileptic encephalopathies.Caused by ca.150 different dominant missense mutations in the gene encoding the major neuronal G protein Gao,i...GNAO1-associated disorder is a rare disease and an example of developmental and epileptic encephalopathies.Caused by ca.150 different dominant missense mutations in the gene encoding the major neuronal G protein Gao,it spans a wide range of neurological clinical manifestations,that may include epileptic seizures,motor dysfunctions,developmental and intellectual delay,and other symptoms(Sáez González et al.,2023).展开更多
Spinal cord injury results in permanent loss of neurological functions due to severance of neural networks.Transplantation of neural stem cells holds promise to repair disrupted connections.Yet,ensuring the survival a...Spinal cord injury results in permanent loss of neurological functions due to severance of neural networks.Transplantation of neural stem cells holds promise to repair disrupted connections.Yet,ensuring the survival and integration of neural stem cells into the host neural circuit remains a formidable challenge.Here,we investigated whether modifying the intrinsic properties of neural stem cells could enhance their integration post-transplantation.We focused on phosphatase and tensin homolog(PTEN),a well-characterized tumor suppressor known to critically regulate neuronal survival and axonal regeneration.By deleting Pten in mouse neural stem cells,we observed increased neurite outgrowth and enhanced resistance to neurotoxic environments in culture.Upon transplantation into injured spinal cords,Pten-deficient neural stem cells exhibited higher survival and more extensive rostrocaudal distribution.To examine the potential influence of partial PTEN suppression,rat neural stem cells were treated with short hairpin RNA targeting PTEN,and the PTEN knockdown resulted in significant improvements in neurite growth,survival,and neurosphere motility in vitro.Transplantation of sh PTEN-treated neural stem cells into the injured spinal cord also led to an increase in graft survival and migration to an extent similar to that of complete deletion.Moreover,PTEN suppression facilitated neurite elongation from NSC-derived neurons migrating from the lesion epicenter.These findings suggest that modifying intrinsic signaling pathways,such as PTEN,within neural stem cells could bolster their therapeutic efficacy,offering potential avenues for future regenerative strategies for spinal cord injury.展开更多
Organoids are three-dimensional culture systems generated from embryonic stem cells,induced pluripotent stem cells,and adult stem cells.They are capable of cell proliferation,differentiation,and self-renewal.Upon stim...Organoids are three-dimensional culture systems generated from embryonic stem cells,induced pluripotent stem cells,and adult stem cells.They are capable of cell proliferation,differentiation,and self-renewal.Upon stimulation by signal factors and/or growth factors,organoids self-assemble to replicate the morphological and structural characteristics of the corresponding organs.They provide an extraordinary platform for investigating organ development and mimicking pathological processes.Organoid biobanks derived from a wide range of carcinomas have been established to represent different lesions or stages of clinical tumors.Importantly,genomic and transcriptomic analyses have confirmed maintenance of intra-and interpatient heterogeneities in organoids.Therefore,this technology has the potential to revolutionize drug screening and personalized medicine.In this review,we summarized the characteristics and applications of organoids in cancer research by the establishment of organoid biobanks directly from tumor organoids or from genetically modified non-cancerous organoids.We also analyzed the current state of organoid applications in drug screening and personalized medicine.展开更多
BACKGROUND Single-nucleotide polymorphisms(SNPs)of the serotonin type 3 receptor subunit(HTR3)genes have been associated with psychosomatic symptoms,but it is not clear whether these associations exist in irritable bo...BACKGROUND Single-nucleotide polymorphisms(SNPs)of the serotonin type 3 receptor subunit(HTR3)genes have been associated with psychosomatic symptoms,but it is not clear whether these associations exist in irritable bowel syndrome(IBS).AIM To assess the association of HTR3 polymorphisms with depressive,anxiety,and somatization symptoms in individuals with IBS.METHODS In this retrospective study,623 participants with IBS were recruited from five specialty centers in Germany,Sweden,the United States,the United Kingdom,and Ireland.Depressive,anxiety,and somatization symptoms and sociodemographic characteristics were collected.Four functional SNPs—HTR3A c.-42C>T,HTR3B c.386A>C,HTR3C c.489C>A,and HTR3E c.*76G>A—were genotyped and analyzed using the dominant and recessive models.We also performed separate analyses for sex and IBS subtypes.SNP scores were calculated as the number of minor alleles of the SNPs above.The impact of HTR3C c.489C>A was tested by radioligand-binding and calcium influx assays.RESULTS Depressive and anxiety symptoms significantly worsened with increasing numbers of minor HTR3C c.489C>A alleles in the dominant model(F_(depressive)=7.475,P_(depressive)=0.006;F_(anxiety)=6.535,P_(anxiety)=0.011).A higher SNP score(range 0-6)was linked to a worsened depressive symptoms score(F=7.710,P-linear trend=0.006)in IBS.The potential relevance of the HTR3C SNP was corroborated,showing changes in the expression level of 5-HT3AC variant receptors.CONCLUSION We have provided the first evidence that HTR3C c.489C>A is involved in depressive and anxiety symptoms in individuals with IBS.The SNP score indicated that an increasing number of minor alleles is linked to the worsening of depressive symptoms in IBS.展开更多
Background:Isotonic crystalloids are recommended as the first choice for fluid therapy in acute pan-creatitis(AP),with normal saline(NS)and lactate Ringer’s(LR)used most often.Evidence based recom-mendations on the t...Background:Isotonic crystalloids are recommended as the first choice for fluid therapy in acute pan-creatitis(AP),with normal saline(NS)and lactate Ringer’s(LR)used most often.Evidence based recom-mendations on the type of fluid are conflicting and generally come from small single-center randomized controlled trials(RCTs).We therefore conducted a systematic review and meta-analysis to compare the effect of balanced solutions(BS)versus NS on patient-centered clinical outcomes in AP.Methods:From four databases searched up to October 2024,we included only RCTs of adult patients with AP that compared the use of BS(including LR,acetate Ringer’s,etc.)with NS.The primary out-come was the disease advances from AP to moderately severe and severe AP(MSAP/SAP).Trial sequential analyses(TSA)were conducted to control for type-I and type-II errors and Grading of Recommendations Assessment,Development,and Evaluation(GRADE)was used to assess the quality of evidence.Results:Six RCTs were identified and included,involving 260 patients treated with BS and 298 patients with NS.Patients who received the BS had less MSAP/SAP[odds ratio(OR)=0.50,95%confidence in-terval(CI):0.29 to 0.85,P=0.01,I^(2)=0%;5 studies,299 patients],reduced the need of ICU admission(OR=0.60,95%CI:0.39 to 0.93,P=0.02,I^(2)=0%;5 studies,507 patients)and shorter length of hospital stay[mean difference(MD)=-0.88,95%CI:-1.48 to-0.28,P=0.004,I^(2)=0%;6 studies,558 patients;confirmed by TSA with high certainty]compared with those who received NS.The evidence for most of the clinical outcomes was rated as moderate to low due to the risk of bias,imprecision and inconsistency.Conclusions:BS,compared with NS,was associated with improved clinical outcomes in patients with AP.However,given the moderate to low quality of evidence for most of the outcomes assessed,further trials are warranted.展开更多
The effective intracellular accumulation of doxorubicin(DOX)is crucial for improving antitumor efficacy,which is severely impeded by limited drug penetration,uncontrollable drug release,and drug resistance.In this stu...The effective intracellular accumulation of doxorubicin(DOX)is crucial for improving antitumor efficacy,which is severely impeded by limited drug penetration,uncontrollable drug release,and drug resistance.In this study,a thermal-deformative polymer embedding ultrasmall ceria(CeO_(2))was rationally designed for deep tumor drug shuttling and hypoxia reversal to improve chemotherapy.Structurally,the CeO_(2)nanozyme was covalently grafted with a polymer of p(NIPAM-co-AM)that could sharply shrink for DOX loading,which was consolidated with polydopamine(PDA)film encapsulation.Thereafter,a tumor penetration guide of apolipoprotein A-I(apoA-I)conjugated iRGD peptide(apoA-I-iRGD)was further decorated onto the PDA shell via Michael addition for preparing CeO_(2)P/DOX@iAPDA.With the aid of apoA-I-iRGD,CeO_(2)P/DOX@iAPDA penetrated both the tumor spheroids(∼78μm)and the tumors of the mouse model deeply.After internalization by tumor cells and triggering by low pH in lysosomes,rapid DOX release was achieved by peeling off the PDA shell and thermosensitive deformation of p(NIPAM-co-AM).CeO_(2)P/DOX@iAPDA provided 66.4%tumor suppression in 4T1-derived tumor spheroids and 63.2%in 4T1-tumorbearing mice,respectively.Preliminary mechanistic research involving western blotting and immunohistochemistry revealed that CeO_(2)P/DOX@iAPDA reversed resistance through the through HIF-1α-P-gp/lipid axis.Collectively,this study intelligently integrated CeO_(2)nanozymes,temperature-sensitive polymers,and imitated biochemical modifications to improve chemotherapy for breast cancer.展开更多
BACKGROUND The liver exerts profound influence on skeletal health,while osseous tissues reciprocally modulate hepatic function.This bidirectional metabolic axis between these two organ systems plays a pivotal role in ...BACKGROUND The liver exerts profound influence on skeletal health,while osseous tissues reciprocally modulate hepatic function.This bidirectional metabolic axis between these two organ systems plays a pivotal role in both physiological homeostasis and pathological states.AIM To investigate and analyze the literatures on liver-bone axis using bibliometrics.METHODS A comprehensive literature search pertaining to the liver-bone axis was conducted using the Science Citation Index Expanded within the Web of Science Core Collection.Subsequently,visualization and bibliometric analyses were performed utilizing VOSviewer(version 1.6.20),Citespace(version 6.2.R4),and the R programming language.RESULTS This comprehensive analysis encompasses 855 publications,comprising 694 articles and 161 reviews,authored by 4988 researchers from 425 institutions across 61 countries.The United States and China emerge as the leading nations in terms of publication volume.The University of California system stands out as the most influential institution in liver-bone axis research.Guanabens N is identified as the most prolific author in this field.The annual increase in publications related to the liver-bone axis underscores its growing prominence as a research focus.The study highlights key areas of investigation,including osteoporosis,bone metabolism,non-alcoholic fatty liver disease,and insulin-like growth factor-1,which represent both current and prospective hot topics within this domain.CONCLUSION This investigation employs bibliometric methodologies to conduct a systematic analysis of liver-bone axis literature spanning from 2001 to 2024.The exponential growth in publications over the past two decades underscores the significance of synthesizing research outcomes in this domain.Through rigorous statistical analyses,we delineate fundamental contributions to the field while providing strategic direction for emerging scholars.Furthermore,we illuminate current research trajectories and identify promising future investigative directions.Investigation of the liver-bone axis enhances our comprehension of inter-organ communication networks.Conceptualizing these organs as an integrated system provides profound insights into pathophysiological mechanisms and disease management strategies.This paradigm not only facilitates the development of sophisticated diagnostic modalities but also catalyzes the discovery of novel therapeutic agents targeting these mechanistic pathways,thereby advancing our capacity to diagnose and treat hepatic and skeletal disorders.展开更多
A binder-free Ru@NiMoS electrode was engineered by in situ growth of twodimensional NiMoS nanosheets on nickel foam.This process effectively promoted the electrostatic-driven aggregation of Ru(bpy)_(3)^(2+),harnessing...A binder-free Ru@NiMoS electrode was engineered by in situ growth of twodimensional NiMoS nanosheets on nickel foam.This process effectively promoted the electrostatic-driven aggregation of Ru(bpy)_(3)^(2+),harnessing the synergistic effect to enhance electrochemiluminescence(ECL)performance.The integration(Ru@NiMoS)achieved an impressive ECL efficiency of 70.1%,marking an impressive 36.9-fold enhancement over conventional Ru.Additionally,its ECL intensity was found to be remarkably 172.2 times greater than that of Ru.Within the Ru(bpy)_(3)^(2+)/TPA system,NiMoS emerged as a pivotal electrochemical catalyst,markedly boosting both the oxygen evolution reaction and the generation of reactive intermediates.Leveraging these distinctive properties,a highly efficient ECL sensor for lidocaine detection was developed.This sensor exhibited a linear response within the concentration range of 1 nM to 1μM and achieved a remarkably low detection limit of 0.22 nM,underlining its substantial potential for practical application.展开更多
The KCNQ potassium channels play a crucial role in modulating neural excitability,and their dysfunction is closely associated with epileptic disorders.While variants in KCNQ2 have been extensively studied,KCNQ3-relate...The KCNQ potassium channels play a crucial role in modulating neural excitability,and their dysfunction is closely associated with epileptic disorders.While variants in KCNQ2 have been extensively studied,KCNQ3-related disorders have rarely been reported.With advances in next-generation sequencing technologies,an increasing number of cases of KCNQ3-related disorders have been identified.However,the correlation between genotype and phenotype remains poorly understood.In this study,we established a variant library consisting of 24 missense mutations in KCNQ3 and introduced these mutations into three different template types:KCNQ3,KCNQ3-A315T(Q3^(*)),and KCNQ3-KCNQ2 tandem(Q3-Q2).We then analyzed the effects of these mutations on the KCNQ3 channel function using patch-clamp recording.The most informative parameter across all three backgrounds was the current density of the mutant channels.The current density patterns in the Q3^(*)and Q3-Q2 backgrounds were similar,with most mutations resulting in an almost complete loss of function(LOF),they were concentrated in the pore-forming domain of KCNQ3.In contrast,mutations in the voltage-sensing domain or C-terminus did not show significant differences from the wild-type channel.Interestingly,these LOF mutations were typically associated with self-limited familial neonatal epilepsy,while neurodevelopmental disorders(NDD)were more closely associated with mutations that did not significantly differ from the wild-type.V1/2,another important parameter of the electrophysiological properties,could not be accurately determined in the majority of KCNQ3 mutations due to its nearly complete LOF in the Q3^(*)and Q3-Q2 backgrounds.Intriguingly,the V1/2 of functional mutations were primarily leftward shifted,indicating a gain-of-function(GOF)effect,which was typically associated with NDD.In addition to previously reported mutations,we identified G553R as a novel GOF mutation.In the co-transfection background,parameters such as V1/2 could be determined,but the dysfunctional effects of these mutations were mitigated by the co-expression of wild-type KCNQ3 and KCNQ2 subunits,resulting in no significant differences between most mutations and the wild-type channel.Furthermore,we applied KCNQ modulators to reverse the electrophysiological abnormalities caused by KCNQ3 variants.The LOF mutations were reversed by the application of Pynegabine(HN37),a KCNQ opener,while the GOF mutation responded well to Amitriptyline(AMI),a KCNQ inhibitor.These findings provide essential insights into the pathogenic mechanisms underlying KCNQ3-related disorders and may inform clinical decision-making.展开更多
Background:Chimeric antigen receptor T(CAR-T)cell therapies have demonstrated significant clinical efficacy in hematological malignancies.However,their application to solid tumors remains substantially limited by mult...Background:Chimeric antigen receptor T(CAR-T)cell therapies have demonstrated significant clinical efficacy in hematological malignancies.However,their application to solid tumors remains substantially limited by multiple challenges,including the risk of off-target effects.Hence,optimizing CAR-T cells for stronger antigen binding is essential.Methods:In this study,we employed a classical anti-human endothelial growth factor receptor 2(HER2)single-chain variable fragment(scFv)derived from trastuzumab,alongside an anti-HER2-13 scFv identified from a combinatorial cellular CAR library,for the construction of a third-generation CAR-T cell.Meanwhile,the phenotypes and both in vitro and in vivo functions of CAR-T cells transduced with the two scFvs via PiggyBac transposon-mediated gene transfer were compared.Results:The optimal ratio between the PiggyBac HER2-CAR-puro transposon and the Super PiggyBac transposase plasmid differed during the construction of the two HER2-targeted CAR-T cell types.The expansion abilities,CD3^(+)CAR^(+)population,CD4^(+)CAR^(+)/CD8^(+)CAR^(+)proportions,and memory and exhaustion markers between the two CAR-T groups were similar after using the optimized proportion of plasmid.Both CAR-T cell types exhibited significant antitumor activity,with the anti-HER2-13 CAR-T cells demonstrating superior target specificity.Therapeutic effects were observed with both CAR-T cells and trastuzumab in theMDA-MB-231HER2+breast tumor xenograft model,with anti-HER2-13 CAR-T cells demonstrating slightly enhanced efficacy and no evident offtarget toxicity.Conclusion:These results highlight the potential of anti-HER2-13 CAR-T cells to serve as a safer and more efficacious alternative in HER2-targeted therapy.展开更多
In this paper,a framework of model predictive optimization and control for quadruped whole-body locomotion is presented,which enables dynamic balance and minimizes the control effort.First,we propose a hierarchical co...In this paper,a framework of model predictive optimization and control for quadruped whole-body locomotion is presented,which enables dynamic balance and minimizes the control effort.First,we propose a hierarchical control scheme consisting of two modules.The first layer is to find an optimal ground reaction force(GRF)by employing inner model predictive control(MPC)along a full motor gait cycle,ensuring the minimal energy consumption of the system.Based on the output GRF of inner layer,the second layer is designed to prioritize tasks for motor execution sequentially using an outer model predictive control.In inner MPC,an objective function about GRF is designed by using a model with relatively long time horizons.Then a neural network solver is used to obtain the optimal GRF by minimizing the objective function.By using a two-layered MPC architecture,we design a hybrid motion/force controller to handle the impedance of leg joints and robotic uncertainties including external perturbation.Finally,we perform extensive experiments with a quadruped robot,including the crawl and trotting gaits,to verify the proposed control framework.展开更多
Background:Poor sleep quality has been associated with changes in brain volume among veterans,particularly those who have experienced mild traumatic brain injury(mTBI)and post-traumatic stress disorder(PTSD).This stud...Background:Poor sleep quality has been associated with changes in brain volume among veterans,particularly those who have experienced mild traumatic brain injury(mTBI)and post-traumatic stress disorder(PTSD).This study sought to investigate:1)whether poor sleep quality is associated with decreased cortical thickness in Iraq and Afghanistan war veterans,and 2)whether these associations differ topographically depending on the presence or absence of mTBI and PTSD.Methods:A sample of 440 post-9/11 era U.S.veterans enrolled in the Translational Research Center for Traumatic Brain Injury and Stress Disorders study at VA Boston,MA from 2010 to 2022 was included in the study.We examined the relationship between sleep quality,as measured by the Pittsburgh Sleep Quality Index(PSQI),and cortical thickness in veterans with mTBI(n=57),PTSD(n=110),comorbid mTBI and PTSD(n=129),and neither PTSD nor mTBI(n=144).To determine the topographical relationship between subjective sleep quality and cortical thickness in each diagnostic group,we employed a General Linear Model(GLM)at each vertex on the cortical mantle.The extent of topographical overlap between the resulting statistical maps was assessed using Dice coefficients.Results:There were no significant associations between PSQI and cortical thickness in the group without PTSD or mTBI(n=144)or in the PTSD-only group(n=110).In the mTBI-only group(n=57),lower sleep quality was significantly associated with reduced thickness bilaterally in frontal,cingulate,and precuneus regions,as well as in the right parietal and temporal regions(β=-0.0137,P<0.0005).In the comorbid mTBI and PTSD group(n=129),significant associations were observed bilaterally in frontal,precentral,and precuneus regions,in the left cingulate and the right parietal regions(β=-0.0094,P<0.0005).Interaction analysis revealed that there was a stronger relationship between poor sleep quality and decreased cortical thickness in individuals with mTBI(n=186)compared with those without mTBI(n=254)specifically in the frontal and cingulate regions(β=-0.0077,P<0.0005).Conclusions:This study demonstrates a significant relationship between poor sleep quality and lower cortical thickness primarily within frontal regions among individuals with both isolated mTBI or comorbid diagnoses of mTBI and PTSD.Thus,if directionality is established in longitudinal and interventional studies,it may be crucial to consider addressing sleep in the treatment of veterans who have sustained mTBI.展开更多
BACKGROUND Abdominal postoperative patients are susceptible to postoperative depression resulting from pain and stress,which can hinder their rehabilitation.Acupuncture has shown potential to relieve this condition.AI...BACKGROUND Abdominal postoperative patients are susceptible to postoperative depression resulting from pain and stress,which can hinder their rehabilitation.Acupuncture has shown potential to relieve this condition.AIM To analyze the mechanism by which acupuncture relieves postoperative depression in patients post-abdominal surgery.METHODS Abdominal postoperative patients with depression between January 2015 and December 2023 at the First Affiliated Hospital of Heilongjiang University of Chinese Medicine were enrolled.Patients were divided into two groups using the random throwing method:Observation(250 cases,fluoxetine hydrochloride+acupuncture treatment)and control(250 cases,fluoxetine hydrochloride treatment).Changes in negative emotions Hamilton Depression Scale 24,serum inflammatory factors[tumor necrosis factorα,interleukin(IL)-1β,IL-6],miR-155 expression levels,and BDNF levels were assessed.RESULTS Significant improvements were observed in the observation group compared to the control group in all assessed parameters after six weeks(P<0.05).This suggests that the combination of fluoxetine hydrochloride and acupuncture may be more effective in managing postoperative depression than medication alone.CONCLUSION Acupuncture complies with the principle of traditional Chinese medicine syndrome differentiation and ensures the pertinence and effectiveness of treatment.In addition,it not only actively improves depressive symptoms but also effectively regulates the serum level of inflammatory factors.展开更多
AIM:To compare refractive error and angle of deviation in patients with basic esotropia and basic exotropia.METHODS:A retrospective review was conducted on the medical records of patients with basic-type strabismus.De...AIM:To compare refractive error and angle of deviation in patients with basic esotropia and basic exotropia.METHODS:A retrospective review was conducted on the medical records of patients with basic-type strabismus.Demographic data,refractive error,best-corrected distance visual acuity(BCVA),and the horizontal and vertical angle of deviation between basic esotropia and exotropia patients were compared.RESULTS:Among the 7129 patients(mean age 22.98±14.81y)evaluated,44.7%(3185 cases,54.9%male)exhibited basic-type esotropia,while 55.3%(3944 cases,53.9%male)presented with basic-type exotropia.Basic esotropia cases exhibited more hyperopic spherical equivalent measurements in both eyes(right:0.53±3.07 vs left:0.56±2.98 D)than those with basic exotropia(right eye:-0.33±2.84 vs left eye:-0.24±2.68 D,P<0.001 for both eyes).Patients with basic esotropia had significantly greater horizontal deviation angles(near:36.08±18.87 PD and far:35.56±18.75 PD)compared to those with basic exotropia(near:33.75±16.11 PD and far:33.26±15.90 PD,P<0.001).Conversely,patients with basic exotropia had slightly higher vertical deviation angles(near:1.67±5.80 PD and far:1.72±5.89 PD)compared to those with basic esotropia(near:1.12±4.57 PD and far:1.12±4.58 PD,P<0.001).Patients with basic esotropia underwent surgical intervention at younger ages compared to basic exotropia individuals(19.68±15.99 vs 25.66±13.20,P<0.001).CONCLUSION:Basic esotropia patients present more hyperopic refractive errors,better visual acuity,larger horizontal yet smaller vertical ocular misalignments,and tend to undergo strabismus surgery at younger ages relative to basic exotropia cases.展开更多
AIM:To compare objective dry retinoscopy and subjective refraction measurements in patients with mild keratoconus(KCN)and quantify any differences.METHODS:This cross-sectional study was done on 68 eyes of 68 patients ...AIM:To compare objective dry retinoscopy and subjective refraction measurements in patients with mild keratoconus(KCN)and quantify any differences.METHODS:This cross-sectional study was done on 68 eyes of 68 patients diagnosed with mild KCN.Objective dry retinoscopy using autorefractometer and subjective refraction measurements were performed.Sphere,cylinder,J0,J45,and spherical equivalent values were compared between the two techniques.RESULTS:The mean age of 68 patients with mild KCN was 21.32±5.03y(12–35y).There were 37(54.4%)males.Objective refraction yielded significantly more myopic sphere(-1.44 D vs-0.57 D),higher cylinder magnitude(-2.24 D vs-1.48 D),and more myopic spherical equivalent(-2.56 D vs-1.31 D)compared to subjective refraction(all P<0.05).The mean differences were-0.87 D for sphere,-0.76 D for cylinder,and-1.25 D for spherical equivalent.No significant differences were found for J0 and J45 values,indicating agreement in astigmatism axis(P>0.05).CONCLUSION:In patients with mild KCN,objective dry retinoscopy overestimates the degree of myopia and astigmatism compared to subjective refraction.The irregular cornea in KCN likely impacts objective measurements.Subjective refraction allows compensation for irregularity,providing a more accurate correction.When determining refractive targets,the tendency of objective methods to overcorrect should be considered.展开更多
Surgical incision infection is the most common postoperative complication that poses a serious threat to human health.In this work,the iron gallate(GA-Fe)modified hyaluronic acid microspheres(GFe@HAMSs)multifunctional...Surgical incision infection is the most common postoperative complication that poses a serious threat to human health.In this work,the iron gallate(GA-Fe)modified hyaluronic acid microspheres(GFe@HAMSs)multifunctional dressings with antibacterial activity,biodegradability,and the ability to promote tissue re-generation for infectious wound healing are prepared via the bonding engineering between bioactive iron ions and ligands from both polyphenol(i.e.gallic acid,GA)and HAMSs matrix.In our strategy,the Fe-HAMS interaction is first constructed,leading to the shrinkage of iron-doped HAMSs(Fe@HAMSs).Then,the addition of GA further tunes the metal-matrix bonding by introducing the competitive equilibrium between Fe-HAMS and Fe-GA chelation,leading to the volume expansion of GFe@HAMSs.The introduc-tion of iron ions can effectively shorten the inflammatory response and reverse the iron-deficient mi-croenvironment,thereby transforming the wound microenvironment into one conducive to tissue regen-eration.Benefitting from these bioactive effects of iron ions and the photothermal antibacterial activity of GA-Fe,the GFe@HAMSs significantly accelerate the wound healing process for rat skin-infected wounds by inhibiting the inflammatory response and macrophage polarization and promoting angiogenesis and tissue remodeling.The GFe@HAMSs proposed in this work not only provide a biomaterial for infectious wound healing but also offer a new strategy for designing multifunctional dressing.展开更多
AIM:To explore the prevalence of pterygium and pinguecula and their risk factors.METHODS:This population-based cross-sectional study was conducted on geriatric population aged 60 and over in Tehran,Iran from Jan 2019 ...AIM:To explore the prevalence of pterygium and pinguecula and their risk factors.METHODS:This population-based cross-sectional study was conducted on geriatric population aged 60 and over in Tehran,Iran from Jan 2019 to Jan 2020.Selected subjects were interviewed and subjected to optometric and ophthalmic examinations.RESULTS:The age and sex standardized prevalence of pterygium and pinguecula was 3.64%[95%confidence interval(CI):2.94%–4.49%]and 55.57%(95%CI:52.89%–58.22%),respectively.The prevalence of pterygium was 4.52%(95%CI:3.5%–5.81%)in men and 2.79%(95%CI:1.97%–3.94%)in women and the prevalence of pinguecula was 64.56%(95%CI:60.92%–68.03%)in men and 46.72%(95%CI:43.74%–49.72%)in women.According to the results of multiple logistic regression,pinguecula had a significant correlation with male sex[odds ratio(OR):2.21,95%CI:1.63–2.99]and education level(OR:0.52,95%CI:0.35-0.77)and pterygium had a significant relationship with male sex(OR:2.2,95%CI:1.38–3.52),socioeconomic status(SES,OR:0.5,95%CI:0.26–0.97),education level(OR:0.22,95%CI:0.08–0.61).CONCLUSION:The prevalence of pinguecula and pterygium in this study are lower than other studies.Sex,SES,and education level are the risk factors of the prevalence of pinguecula and pterygium.展开更多
基金Supported by New York State NYSTEM foundation,No.N08G-433
文摘Congestive heart failure(CHF) secondary to chronic coronary artery disease is a major cause of morbidity and mortality world-wide. Its prevalence is increasing despite advances in medical and device therapies. Cell based therapies generating new cardiomyocytes and vessels have emerged as a promising treatment to reverse functional deterioration and prevent the progression to CHF. Functional efficacy of progenitor cells isolated from the bone marrow and the heart have been evaluated in preclinical large animal models. Furthermore, several clinical trials using autologous and allogeneic stem cells and progenitor cells have demonstrated their safety in humans yet their clinical relevance is inconclusive. This review will discuss the clinical therapeutic applications of three specific adult stem cells that have shown particularly promising regenerative effects in preclinical studies, bone marrow derived mesenchymal stem cell, heart derived cardiosphere-derived cell and cardiac stem cell. We will also discuss future therapeutic approaches.
文摘Objective To develop and validate a preoperative clinical-radiomics model for predicting overall survival(OS)and disease-free survival(DFS)in patients with extrahepatic cholangiocarcinoma(eCCA)undergoing radical resection.Methods In this retrospective study,consecutive patients with pathologically-confirmed eCCA who underwent radical resection at our institution from 2015 to 2022 were included.The patients were divided into a training cohort and a validation cohort according to the chronological order of their CT examinations.Least absolute shrinkage and selection operator(LASSO)-Cox regression was employed to select predictive radiomic features and clinical variables.The selected features and variables were incorporated into a Cox regression model.Model performance for 1-year OS and DFS prediction was assessed using calibration curves,area under receiver operating characteristic curve(AUC),and concordance index(C-index).Results This study included 123 patients(mean age 64.0±8.4 years,85 males/38 females),with 86 in the training cohort and 37 in the validation cohort.The OS-predicting model included four clinical variables and four radiomic features.It achieved a training cohort AUC of 0.858(C-index=0.800)and a validation cohort AUC of 0.649(C-index=0.605).The DFS-predicting model included four clinical variables and four other radiomic features.It achieved a training cohort AUC of 0.830(C-index=0.760)and a validation cohort AUC of 0.717(C-index=0.616).Conclusion The preoperative clinical-radiomics models show promise as a tool for predicting 1-year OS and DFS in eCCA patients after radical surgery.
基金supported by the National Natural Science Foundation of China,Nos.82171387 and 31830111(both to SL).
文摘Stroke,particularly ischemic stroke,is the leading cause of long-term disability and mortality worldwide.It occurs due to the occlusion of the cerebral arteries,which significantly reduces the delivery of blood,oxygen,and essential nutrients to brain tissues.This deprivation triggers a cascade of cellular events that ultimately leads to neuronal death.Recent studies have clarified the multifactorial pathogenesis of ischemic stroke,highlighting the roles of energy failure,excitotoxicity,oxidative stress,neuroinflammation,and apoptosis.This review aimed to provide a comprehensive insight into the fundamental mechanisms driving neuronal death triggered by ischemia and to examine the progress of neuroprotective therapeutic approaches designed to mitigate neuronal loss and promote neurological recovery after a stroke.Additionally,we explored widely accepted findings regarding the potential pathways implicated in neuronal death during ischemic stroke,including the interplay of apoptosis,autophagy,pyroptosis,ferroptosis,and necrosis,which collectively influence neuronal fate.We also discussed advancements in neuroprotective therapeutics,encompassing a range of interventions from pharmacological modulation to stem cell-based therapies,aimed at reducing neuronal injury and enhancing functional recovery following ischemic stroke.Despite these advancements,challenges remain in translating mechanistic insights into effective clinical therapies.Although neuroprotective strategies have shown promise in preclinical models,their efficacy in human trials has been inconsistent,often due to the complex pathology of ischemic stroke and the timing of interventions.In conclusion,this review synthesizes mechanistic insights into the intricate interplay of molecular and cellular pathways driving neuronal death post-ischemia.It sheds light on cutting-edge advancements in potential neuroprotective therapeutics,underscores the promise of regenerative medicine,and offers a forward-looking perspective on potential clinical breakthroughs.The ongoing evolution of precision-targeted interventions is expected to significantly enhance preventative strategies and improve clinical outcomes.
文摘GNAO1-associated disorder is a rare disease and an example of developmental and epileptic encephalopathies.Caused by ca.150 different dominant missense mutations in the gene encoding the major neuronal G protein Gao,it spans a wide range of neurological clinical manifestations,that may include epileptic seizures,motor dysfunctions,developmental and intellectual delay,and other symptoms(Sáez González et al.,2023).
基金supported by the National Research Foundation of Korea,Nos.2021R1A2C2006110,2021M3E5D9021364,2019R1A5A2026045(to BGK)the Korea Initiative for Fostering University of Research and Innovation(KIURI)Program of the NRF funded by the MSIT(to HK),No.NRF2021M3H1A104892211(to HSK)。
文摘Spinal cord injury results in permanent loss of neurological functions due to severance of neural networks.Transplantation of neural stem cells holds promise to repair disrupted connections.Yet,ensuring the survival and integration of neural stem cells into the host neural circuit remains a formidable challenge.Here,we investigated whether modifying the intrinsic properties of neural stem cells could enhance their integration post-transplantation.We focused on phosphatase and tensin homolog(PTEN),a well-characterized tumor suppressor known to critically regulate neuronal survival and axonal regeneration.By deleting Pten in mouse neural stem cells,we observed increased neurite outgrowth and enhanced resistance to neurotoxic environments in culture.Upon transplantation into injured spinal cords,Pten-deficient neural stem cells exhibited higher survival and more extensive rostrocaudal distribution.To examine the potential influence of partial PTEN suppression,rat neural stem cells were treated with short hairpin RNA targeting PTEN,and the PTEN knockdown resulted in significant improvements in neurite growth,survival,and neurosphere motility in vitro.Transplantation of sh PTEN-treated neural stem cells into the injured spinal cord also led to an increase in graft survival and migration to an extent similar to that of complete deletion.Moreover,PTEN suppression facilitated neurite elongation from NSC-derived neurons migrating from the lesion epicenter.These findings suggest that modifying intrinsic signaling pathways,such as PTEN,within neural stem cells could bolster their therapeutic efficacy,offering potential avenues for future regenerative strategies for spinal cord injury.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.31671421,82030079,and 82003187).
文摘Organoids are three-dimensional culture systems generated from embryonic stem cells,induced pluripotent stem cells,and adult stem cells.They are capable of cell proliferation,differentiation,and self-renewal.Upon stimulation by signal factors and/or growth factors,organoids self-assemble to replicate the morphological and structural characteristics of the corresponding organs.They provide an extraordinary platform for investigating organ development and mimicking pathological processes.Organoid biobanks derived from a wide range of carcinomas have been established to represent different lesions or stages of clinical tumors.Importantly,genomic and transcriptomic analyses have confirmed maintenance of intra-and interpatient heterogeneities in organoids.Therefore,this technology has the potential to revolutionize drug screening and personalized medicine.In this review,we summarized the characteristics and applications of organoids in cancer research by the establishment of organoid biobanks directly from tumor organoids or from genetically modified non-cancerous organoids.We also analyzed the current state of organoid applications in drug screening and personalized medicine.
基金results in part from collaboration and network activities promoted under the frame of the international network GENIEUR (Genes in Irritable Bowel Syndrome Research Network Europe),which has been funded by the COST program (BM1106, www.GENIEUR.eu)currently supported by the European Society of Neurogastroenterology and Motility (ESNM, www.ESNM.eu)
文摘BACKGROUND Single-nucleotide polymorphisms(SNPs)of the serotonin type 3 receptor subunit(HTR3)genes have been associated with psychosomatic symptoms,but it is not clear whether these associations exist in irritable bowel syndrome(IBS).AIM To assess the association of HTR3 polymorphisms with depressive,anxiety,and somatization symptoms in individuals with IBS.METHODS In this retrospective study,623 participants with IBS were recruited from five specialty centers in Germany,Sweden,the United States,the United Kingdom,and Ireland.Depressive,anxiety,and somatization symptoms and sociodemographic characteristics were collected.Four functional SNPs—HTR3A c.-42C>T,HTR3B c.386A>C,HTR3C c.489C>A,and HTR3E c.*76G>A—were genotyped and analyzed using the dominant and recessive models.We also performed separate analyses for sex and IBS subtypes.SNP scores were calculated as the number of minor alleles of the SNPs above.The impact of HTR3C c.489C>A was tested by radioligand-binding and calcium influx assays.RESULTS Depressive and anxiety symptoms significantly worsened with increasing numbers of minor HTR3C c.489C>A alleles in the dominant model(F_(depressive)=7.475,P_(depressive)=0.006;F_(anxiety)=6.535,P_(anxiety)=0.011).A higher SNP score(range 0-6)was linked to a worsened depressive symptoms score(F=7.710,P-linear trend=0.006)in IBS.The potential relevance of the HTR3C SNP was corroborated,showing changes in the expression level of 5-HT3AC variant receptors.CONCLUSION We have provided the first evidence that HTR3C c.489C>A is involved in depressive and anxiety symptoms in individuals with IBS.The SNP score indicated that an increasing number of minor alleles is linked to the worsening of depressive symptoms in IBS.
文摘Background:Isotonic crystalloids are recommended as the first choice for fluid therapy in acute pan-creatitis(AP),with normal saline(NS)and lactate Ringer’s(LR)used most often.Evidence based recom-mendations on the type of fluid are conflicting and generally come from small single-center randomized controlled trials(RCTs).We therefore conducted a systematic review and meta-analysis to compare the effect of balanced solutions(BS)versus NS on patient-centered clinical outcomes in AP.Methods:From four databases searched up to October 2024,we included only RCTs of adult patients with AP that compared the use of BS(including LR,acetate Ringer’s,etc.)with NS.The primary out-come was the disease advances from AP to moderately severe and severe AP(MSAP/SAP).Trial sequential analyses(TSA)were conducted to control for type-I and type-II errors and Grading of Recommendations Assessment,Development,and Evaluation(GRADE)was used to assess the quality of evidence.Results:Six RCTs were identified and included,involving 260 patients treated with BS and 298 patients with NS.Patients who received the BS had less MSAP/SAP[odds ratio(OR)=0.50,95%confidence in-terval(CI):0.29 to 0.85,P=0.01,I^(2)=0%;5 studies,299 patients],reduced the need of ICU admission(OR=0.60,95%CI:0.39 to 0.93,P=0.02,I^(2)=0%;5 studies,507 patients)and shorter length of hospital stay[mean difference(MD)=-0.88,95%CI:-1.48 to-0.28,P=0.004,I^(2)=0%;6 studies,558 patients;confirmed by TSA with high certainty]compared with those who received NS.The evidence for most of the clinical outcomes was rated as moderate to low due to the risk of bias,imprecision and inconsistency.Conclusions:BS,compared with NS,was associated with improved clinical outcomes in patients with AP.However,given the moderate to low quality of evidence for most of the outcomes assessed,further trials are warranted.
基金supported by National Natural Science Foundation of China(Nos.82473949 and 82273955)Scientific research project of Jiangsu Provincial Health Commission(No.M2022080)+1 种基金Jiangsu Province Capability Improvement Project through Science,Technology and Education(ZDXK202234)Jiangsu Provincial Research Hospital(YJXYY202204),China.
文摘The effective intracellular accumulation of doxorubicin(DOX)is crucial for improving antitumor efficacy,which is severely impeded by limited drug penetration,uncontrollable drug release,and drug resistance.In this study,a thermal-deformative polymer embedding ultrasmall ceria(CeO_(2))was rationally designed for deep tumor drug shuttling and hypoxia reversal to improve chemotherapy.Structurally,the CeO_(2)nanozyme was covalently grafted with a polymer of p(NIPAM-co-AM)that could sharply shrink for DOX loading,which was consolidated with polydopamine(PDA)film encapsulation.Thereafter,a tumor penetration guide of apolipoprotein A-I(apoA-I)conjugated iRGD peptide(apoA-I-iRGD)was further decorated onto the PDA shell via Michael addition for preparing CeO_(2)P/DOX@iAPDA.With the aid of apoA-I-iRGD,CeO_(2)P/DOX@iAPDA penetrated both the tumor spheroids(∼78μm)and the tumors of the mouse model deeply.After internalization by tumor cells and triggering by low pH in lysosomes,rapid DOX release was achieved by peeling off the PDA shell and thermosensitive deformation of p(NIPAM-co-AM).CeO_(2)P/DOX@iAPDA provided 66.4%tumor suppression in 4T1-derived tumor spheroids and 63.2%in 4T1-tumorbearing mice,respectively.Preliminary mechanistic research involving western blotting and immunohistochemistry revealed that CeO_(2)P/DOX@iAPDA reversed resistance through the through HIF-1α-P-gp/lipid axis.Collectively,this study intelligently integrated CeO_(2)nanozymes,temperature-sensitive polymers,and imitated biochemical modifications to improve chemotherapy for breast cancer.
基金Supported by the National Natural Science Foundation of China,No.82172516 and No.82372434.
文摘BACKGROUND The liver exerts profound influence on skeletal health,while osseous tissues reciprocally modulate hepatic function.This bidirectional metabolic axis between these two organ systems plays a pivotal role in both physiological homeostasis and pathological states.AIM To investigate and analyze the literatures on liver-bone axis using bibliometrics.METHODS A comprehensive literature search pertaining to the liver-bone axis was conducted using the Science Citation Index Expanded within the Web of Science Core Collection.Subsequently,visualization and bibliometric analyses were performed utilizing VOSviewer(version 1.6.20),Citespace(version 6.2.R4),and the R programming language.RESULTS This comprehensive analysis encompasses 855 publications,comprising 694 articles and 161 reviews,authored by 4988 researchers from 425 institutions across 61 countries.The United States and China emerge as the leading nations in terms of publication volume.The University of California system stands out as the most influential institution in liver-bone axis research.Guanabens N is identified as the most prolific author in this field.The annual increase in publications related to the liver-bone axis underscores its growing prominence as a research focus.The study highlights key areas of investigation,including osteoporosis,bone metabolism,non-alcoholic fatty liver disease,and insulin-like growth factor-1,which represent both current and prospective hot topics within this domain.CONCLUSION This investigation employs bibliometric methodologies to conduct a systematic analysis of liver-bone axis literature spanning from 2001 to 2024.The exponential growth in publications over the past two decades underscores the significance of synthesizing research outcomes in this domain.Through rigorous statistical analyses,we delineate fundamental contributions to the field while providing strategic direction for emerging scholars.Furthermore,we illuminate current research trajectories and identify promising future investigative directions.Investigation of the liver-bone axis enhances our comprehension of inter-organ communication networks.Conceptualizing these organs as an integrated system provides profound insights into pathophysiological mechanisms and disease management strategies.This paradigm not only facilitates the development of sophisticated diagnostic modalities but also catalyzes the discovery of novel therapeutic agents targeting these mechanistic pathways,thereby advancing our capacity to diagnose and treat hepatic and skeletal disorders.
基金supported by the Natural Science Foun-dation of Jilin Province(20200201238JC)the Science and Technology Development Program of Jilin Province(20200404147YY)+2 种基金Shenzhen Key Laboratory of Func-tional Aggregate Materials(ZDSYS20211021111400001)the Science Technology Innovation Commission of Shenzhen Municipality(KQTD20210811090142053,JCYJ20220818103007014)Tianjin Key Medical Disci-pline(Specialty)Construction Project.Thanks to the AIE Institute(www.aietech.org.cn)for providing some tech-nical assistance.
文摘A binder-free Ru@NiMoS electrode was engineered by in situ growth of twodimensional NiMoS nanosheets on nickel foam.This process effectively promoted the electrostatic-driven aggregation of Ru(bpy)_(3)^(2+),harnessing the synergistic effect to enhance electrochemiluminescence(ECL)performance.The integration(Ru@NiMoS)achieved an impressive ECL efficiency of 70.1%,marking an impressive 36.9-fold enhancement over conventional Ru.Additionally,its ECL intensity was found to be remarkably 172.2 times greater than that of Ru.Within the Ru(bpy)_(3)^(2+)/TPA system,NiMoS emerged as a pivotal electrochemical catalyst,markedly boosting both the oxygen evolution reaction and the generation of reactive intermediates.Leveraging these distinctive properties,a highly efficient ECL sensor for lidocaine detection was developed.This sensor exhibited a linear response within the concentration range of 1 nM to 1μM and achieved a remarkably low detection limit of 0.22 nM,underlining its substantial potential for practical application.
文摘The KCNQ potassium channels play a crucial role in modulating neural excitability,and their dysfunction is closely associated with epileptic disorders.While variants in KCNQ2 have been extensively studied,KCNQ3-related disorders have rarely been reported.With advances in next-generation sequencing technologies,an increasing number of cases of KCNQ3-related disorders have been identified.However,the correlation between genotype and phenotype remains poorly understood.In this study,we established a variant library consisting of 24 missense mutations in KCNQ3 and introduced these mutations into three different template types:KCNQ3,KCNQ3-A315T(Q3^(*)),and KCNQ3-KCNQ2 tandem(Q3-Q2).We then analyzed the effects of these mutations on the KCNQ3 channel function using patch-clamp recording.The most informative parameter across all three backgrounds was the current density of the mutant channels.The current density patterns in the Q3^(*)and Q3-Q2 backgrounds were similar,with most mutations resulting in an almost complete loss of function(LOF),they were concentrated in the pore-forming domain of KCNQ3.In contrast,mutations in the voltage-sensing domain or C-terminus did not show significant differences from the wild-type channel.Interestingly,these LOF mutations were typically associated with self-limited familial neonatal epilepsy,while neurodevelopmental disorders(NDD)were more closely associated with mutations that did not significantly differ from the wild-type.V1/2,another important parameter of the electrophysiological properties,could not be accurately determined in the majority of KCNQ3 mutations due to its nearly complete LOF in the Q3^(*)and Q3-Q2 backgrounds.Intriguingly,the V1/2 of functional mutations were primarily leftward shifted,indicating a gain-of-function(GOF)effect,which was typically associated with NDD.In addition to previously reported mutations,we identified G553R as a novel GOF mutation.In the co-transfection background,parameters such as V1/2 could be determined,but the dysfunctional effects of these mutations were mitigated by the co-expression of wild-type KCNQ3 and KCNQ2 subunits,resulting in no significant differences between most mutations and the wild-type channel.Furthermore,we applied KCNQ modulators to reverse the electrophysiological abnormalities caused by KCNQ3 variants.The LOF mutations were reversed by the application of Pynegabine(HN37),a KCNQ opener,while the GOF mutation responded well to Amitriptyline(AMI),a KCNQ inhibitor.These findings provide essential insights into the pathogenic mechanisms underlying KCNQ3-related disorders and may inform clinical decision-making.
基金supported by the Yunnan Fundamental Research Projects,China(Grant No.202201AS070068)Central Funds Guiding the Local Science and Technology Development,China(202207AB110017)+1 种基金The Science and Technology Fund of Kunming City,China(No.2019-1-N-25318000002027)The Scientific and Technological Innovation Team in Kunming Medical University,China(CXTD202215).
文摘Background:Chimeric antigen receptor T(CAR-T)cell therapies have demonstrated significant clinical efficacy in hematological malignancies.However,their application to solid tumors remains substantially limited by multiple challenges,including the risk of off-target effects.Hence,optimizing CAR-T cells for stronger antigen binding is essential.Methods:In this study,we employed a classical anti-human endothelial growth factor receptor 2(HER2)single-chain variable fragment(scFv)derived from trastuzumab,alongside an anti-HER2-13 scFv identified from a combinatorial cellular CAR library,for the construction of a third-generation CAR-T cell.Meanwhile,the phenotypes and both in vitro and in vivo functions of CAR-T cells transduced with the two scFvs via PiggyBac transposon-mediated gene transfer were compared.Results:The optimal ratio between the PiggyBac HER2-CAR-puro transposon and the Super PiggyBac transposase plasmid differed during the construction of the two HER2-targeted CAR-T cell types.The expansion abilities,CD3^(+)CAR^(+)population,CD4^(+)CAR^(+)/CD8^(+)CAR^(+)proportions,and memory and exhaustion markers between the two CAR-T groups were similar after using the optimized proportion of plasmid.Both CAR-T cell types exhibited significant antitumor activity,with the anti-HER2-13 CAR-T cells demonstrating superior target specificity.Therapeutic effects were observed with both CAR-T cells and trastuzumab in theMDA-MB-231HER2+breast tumor xenograft model,with anti-HER2-13 CAR-T cells demonstrating slightly enhanced efficacy and no evident offtarget toxicity.Conclusion:These results highlight the potential of anti-HER2-13 CAR-T cells to serve as a safer and more efficacious alternative in HER2-targeted therapy.
基金supported in part by the National Natural Science Foundation of China(62133013,U22A2060)Dreams Foundation of Jianghuai Advance Technology Center(2023-ZM01Z024)。
文摘In this paper,a framework of model predictive optimization and control for quadruped whole-body locomotion is presented,which enables dynamic balance and minimizes the control effort.First,we propose a hierarchical control scheme consisting of two modules.The first layer is to find an optimal ground reaction force(GRF)by employing inner model predictive control(MPC)along a full motor gait cycle,ensuring the minimal energy consumption of the system.Based on the output GRF of inner layer,the second layer is designed to prioritize tasks for motor execution sequentially using an outer model predictive control.In inner MPC,an objective function about GRF is designed by using a model with relatively long time horizons.Then a neural network solver is used to obtain the optimal GRF by minimizing the objective function.By using a two-layered MPC architecture,we design a hybrid motion/force controller to handle the impedance of leg joints and robotic uncertainties including external perturbation.Finally,we perform extensive experiments with a quadruped robot,including the crawl and trotting gaits,to verify the proposed control framework.
基金supported by the U.S.Department of Veterans Affairs through the Translational Research Center for TBI and Stress Disorders(TRACTS B3001-C),a VA Rehabilitation Research and Development Traumatic Brain Injury National Network Research Center,and the Boston University Chobanian&Avedisian School of Medicine’s Medical Student Summer Research Program,with funding from the Gabriel Family Foundation CTE Research Fund(MA).
文摘Background:Poor sleep quality has been associated with changes in brain volume among veterans,particularly those who have experienced mild traumatic brain injury(mTBI)and post-traumatic stress disorder(PTSD).This study sought to investigate:1)whether poor sleep quality is associated with decreased cortical thickness in Iraq and Afghanistan war veterans,and 2)whether these associations differ topographically depending on the presence or absence of mTBI and PTSD.Methods:A sample of 440 post-9/11 era U.S.veterans enrolled in the Translational Research Center for Traumatic Brain Injury and Stress Disorders study at VA Boston,MA from 2010 to 2022 was included in the study.We examined the relationship between sleep quality,as measured by the Pittsburgh Sleep Quality Index(PSQI),and cortical thickness in veterans with mTBI(n=57),PTSD(n=110),comorbid mTBI and PTSD(n=129),and neither PTSD nor mTBI(n=144).To determine the topographical relationship between subjective sleep quality and cortical thickness in each diagnostic group,we employed a General Linear Model(GLM)at each vertex on the cortical mantle.The extent of topographical overlap between the resulting statistical maps was assessed using Dice coefficients.Results:There were no significant associations between PSQI and cortical thickness in the group without PTSD or mTBI(n=144)or in the PTSD-only group(n=110).In the mTBI-only group(n=57),lower sleep quality was significantly associated with reduced thickness bilaterally in frontal,cingulate,and precuneus regions,as well as in the right parietal and temporal regions(β=-0.0137,P<0.0005).In the comorbid mTBI and PTSD group(n=129),significant associations were observed bilaterally in frontal,precentral,and precuneus regions,in the left cingulate and the right parietal regions(β=-0.0094,P<0.0005).Interaction analysis revealed that there was a stronger relationship between poor sleep quality and decreased cortical thickness in individuals with mTBI(n=186)compared with those without mTBI(n=254)specifically in the frontal and cingulate regions(β=-0.0077,P<0.0005).Conclusions:This study demonstrates a significant relationship between poor sleep quality and lower cortical thickness primarily within frontal regions among individuals with both isolated mTBI or comorbid diagnoses of mTBI and PTSD.Thus,if directionality is established in longitudinal and interventional studies,it may be crucial to consider addressing sleep in the treatment of veterans who have sustained mTBI.
文摘BACKGROUND Abdominal postoperative patients are susceptible to postoperative depression resulting from pain and stress,which can hinder their rehabilitation.Acupuncture has shown potential to relieve this condition.AIM To analyze the mechanism by which acupuncture relieves postoperative depression in patients post-abdominal surgery.METHODS Abdominal postoperative patients with depression between January 2015 and December 2023 at the First Affiliated Hospital of Heilongjiang University of Chinese Medicine were enrolled.Patients were divided into two groups using the random throwing method:Observation(250 cases,fluoxetine hydrochloride+acupuncture treatment)and control(250 cases,fluoxetine hydrochloride treatment).Changes in negative emotions Hamilton Depression Scale 24,serum inflammatory factors[tumor necrosis factorα,interleukin(IL)-1β,IL-6],miR-155 expression levels,and BDNF levels were assessed.RESULTS Significant improvements were observed in the observation group compared to the control group in all assessed parameters after six weeks(P<0.05).This suggests that the combination of fluoxetine hydrochloride and acupuncture may be more effective in managing postoperative depression than medication alone.CONCLUSION Acupuncture complies with the principle of traditional Chinese medicine syndrome differentiation and ensures the pertinence and effectiveness of treatment.In addition,it not only actively improves depressive symptoms but also effectively regulates the serum level of inflammatory factors.
文摘AIM:To compare refractive error and angle of deviation in patients with basic esotropia and basic exotropia.METHODS:A retrospective review was conducted on the medical records of patients with basic-type strabismus.Demographic data,refractive error,best-corrected distance visual acuity(BCVA),and the horizontal and vertical angle of deviation between basic esotropia and exotropia patients were compared.RESULTS:Among the 7129 patients(mean age 22.98±14.81y)evaluated,44.7%(3185 cases,54.9%male)exhibited basic-type esotropia,while 55.3%(3944 cases,53.9%male)presented with basic-type exotropia.Basic esotropia cases exhibited more hyperopic spherical equivalent measurements in both eyes(right:0.53±3.07 vs left:0.56±2.98 D)than those with basic exotropia(right eye:-0.33±2.84 vs left eye:-0.24±2.68 D,P<0.001 for both eyes).Patients with basic esotropia had significantly greater horizontal deviation angles(near:36.08±18.87 PD and far:35.56±18.75 PD)compared to those with basic exotropia(near:33.75±16.11 PD and far:33.26±15.90 PD,P<0.001).Conversely,patients with basic exotropia had slightly higher vertical deviation angles(near:1.67±5.80 PD and far:1.72±5.89 PD)compared to those with basic esotropia(near:1.12±4.57 PD and far:1.12±4.58 PD,P<0.001).Patients with basic esotropia underwent surgical intervention at younger ages compared to basic exotropia individuals(19.68±15.99 vs 25.66±13.20,P<0.001).CONCLUSION:Basic esotropia patients present more hyperopic refractive errors,better visual acuity,larger horizontal yet smaller vertical ocular misalignments,and tend to undergo strabismus surgery at younger ages relative to basic exotropia cases.
文摘AIM:To compare objective dry retinoscopy and subjective refraction measurements in patients with mild keratoconus(KCN)and quantify any differences.METHODS:This cross-sectional study was done on 68 eyes of 68 patients diagnosed with mild KCN.Objective dry retinoscopy using autorefractometer and subjective refraction measurements were performed.Sphere,cylinder,J0,J45,and spherical equivalent values were compared between the two techniques.RESULTS:The mean age of 68 patients with mild KCN was 21.32±5.03y(12–35y).There were 37(54.4%)males.Objective refraction yielded significantly more myopic sphere(-1.44 D vs-0.57 D),higher cylinder magnitude(-2.24 D vs-1.48 D),and more myopic spherical equivalent(-2.56 D vs-1.31 D)compared to subjective refraction(all P<0.05).The mean differences were-0.87 D for sphere,-0.76 D for cylinder,and-1.25 D for spherical equivalent.No significant differences were found for J0 and J45 values,indicating agreement in astigmatism axis(P>0.05).CONCLUSION:In patients with mild KCN,objective dry retinoscopy overestimates the degree of myopia and astigmatism compared to subjective refraction.The irregular cornea in KCN likely impacts objective measurements.Subjective refraction allows compensation for irregularity,providing a more accurate correction.When determining refractive targets,the tendency of objective methods to overcorrect should be considered.
基金the National Key R&D Program of China(No.2022YFE0123500)the National Natural Science Foundation of China(Nos.32201102,31771081),the Science and Technology Bureau of Suzhou City(No.SZKJXM202318)+1 种基金the Science and Technology Commission of Shanghai Municipality(No.22S31903300)the Shanghai Pujiang Program(No.22PJD055).
文摘Surgical incision infection is the most common postoperative complication that poses a serious threat to human health.In this work,the iron gallate(GA-Fe)modified hyaluronic acid microspheres(GFe@HAMSs)multifunctional dressings with antibacterial activity,biodegradability,and the ability to promote tissue re-generation for infectious wound healing are prepared via the bonding engineering between bioactive iron ions and ligands from both polyphenol(i.e.gallic acid,GA)and HAMSs matrix.In our strategy,the Fe-HAMS interaction is first constructed,leading to the shrinkage of iron-doped HAMSs(Fe@HAMSs).Then,the addition of GA further tunes the metal-matrix bonding by introducing the competitive equilibrium between Fe-HAMS and Fe-GA chelation,leading to the volume expansion of GFe@HAMSs.The introduc-tion of iron ions can effectively shorten the inflammatory response and reverse the iron-deficient mi-croenvironment,thereby transforming the wound microenvironment into one conducive to tissue regen-eration.Benefitting from these bioactive effects of iron ions and the photothermal antibacterial activity of GA-Fe,the GFe@HAMSs significantly accelerate the wound healing process for rat skin-infected wounds by inhibiting the inflammatory response and macrophage polarization and promoting angiogenesis and tissue remodeling.The GFe@HAMSs proposed in this work not only provide a biomaterial for infectious wound healing but also offer a new strategy for designing multifunctional dressing.
基金Supported by National Institute for Medical Research Development(NIMAD)affiliated with the Iranian Ministry of Health and Medical Education(No.963660).
文摘AIM:To explore the prevalence of pterygium and pinguecula and their risk factors.METHODS:This population-based cross-sectional study was conducted on geriatric population aged 60 and over in Tehran,Iran from Jan 2019 to Jan 2020.Selected subjects were interviewed and subjected to optometric and ophthalmic examinations.RESULTS:The age and sex standardized prevalence of pterygium and pinguecula was 3.64%[95%confidence interval(CI):2.94%–4.49%]and 55.57%(95%CI:52.89%–58.22%),respectively.The prevalence of pterygium was 4.52%(95%CI:3.5%–5.81%)in men and 2.79%(95%CI:1.97%–3.94%)in women and the prevalence of pinguecula was 64.56%(95%CI:60.92%–68.03%)in men and 46.72%(95%CI:43.74%–49.72%)in women.According to the results of multiple logistic regression,pinguecula had a significant correlation with male sex[odds ratio(OR):2.21,95%CI:1.63–2.99]and education level(OR:0.52,95%CI:0.35-0.77)and pterygium had a significant relationship with male sex(OR:2.2,95%CI:1.38–3.52),socioeconomic status(SES,OR:0.5,95%CI:0.26–0.97),education level(OR:0.22,95%CI:0.08–0.61).CONCLUSION:The prevalence of pinguecula and pterygium in this study are lower than other studies.Sex,SES,and education level are the risk factors of the prevalence of pinguecula and pterygium.
