BACKGROUND Human epidermal growth factor receptor 2(HER2)-positive gastric cancer(GC)represents a distinct molecular cancer subtype that is often associated with a poor prognosis.While perioperative chemotherapy regim...BACKGROUND Human epidermal growth factor receptor 2(HER2)-positive gastric cancer(GC)represents a distinct molecular cancer subtype that is often associated with a poor prognosis.While perioperative chemotherapy regimens are currently the primary recommendation for locally advanced HER2-positive GC,combination therapies incorporating immune checkpoint inhibitors are under active investigation.CASE SUMMARY The present case describes a patient with locally advanced HER2-positive GC who underwent perioperative treatment with chemotherapy combined with trastuzumab.Although significant tumor shrinkage was observed,surgical pathology results did not confirm the achievement of a pathological complete response.The current treatment strategies for advanced GC were also reviewed.Relevant case reports,retrospective studies,and prospective clinical trials were retrieved for analysis after searching the PubMed/MEDLINE,EMBASE,Cochrane Library,Web of Science,and American Society of Clinical Oncology/European Society for Medical Oncology conference abstracts between 2014 and 2024.CONCLUSION Large-scale phase Ⅲ clinical trials are needed to verify the efficacy of combined neoadjuvant treatment application for GC.展开更多
BACKGROUND Although targeted therapy provides survival benefits for patients with metastatic colorectal cancer,some patients develop resistance to these treatments.Human epidermal growth factor receptor 2(HER2)is over...BACKGROUND Although targeted therapy provides survival benefits for patients with metastatic colorectal cancer,some patients develop resistance to these treatments.Human epidermal growth factor receptor 2(HER2)is overexpressed in a subset of pa-tients with colorectal cancer and has been established as a therapeutic target.CASE SUMMARY This case report describes a Chinese patient with HER2-amplified advanced rectal cancer who showed no response to chemotherapy and targeted therapies against epidermal growth factor receptor and vascular endothelial growth factor but achieved a remarkable response following treatment with immune checkpoint inhibitors(ICIs)in combination with pyrotinib.The combination of oxaliplatin and ICIs with pyrotinib demonstrates synergistic effects after late-stage disease progression.CONCLUSION ICIs and pyrotinib may be effective in treating HER2-amplified advanced rectal cancer.Chemotherapy following disease progression could enhance efficacy synergistically.展开更多
BACKGROUND Human epidermal growth factor receptor 2(HER2)plays pivotal roles in cellular proliferation,survival,and differentiation of several malignancies.Upper tract urothelial carcinoma(UTUC)is a relatively rare ma...BACKGROUND Human epidermal growth factor receptor 2(HER2)plays pivotal roles in cellular proliferation,survival,and differentiation of several malignancies.Upper tract urothelial carcinoma(UTUC)is a relatively rare malignancy.The clinical and molecular significance of HER2 expression level in UTUC remains poorly characterized vs bladder cancer.AIM To comprehensively evaluate HER2 expression patterns and their association with UTUC patients’clinicopathological features.METHODS Data were retrospectively collected from patients diagnosed with UTUC at The First Affiliated Hospital of Guangxi Medical University between January 2023 and December 2024.HER2 status was evaluated by immunohistochemistry in 145 UTUC patients who met the inclusion criteria.Its associations with tumor grade,tumor stage,and other clinicopathological parameters were assessed.Theχ2 test or Fisher’s exact test,along with univariate and multivariate logistic regression analyses,were performed to determine the influences of clinicopathological factors on HER2 expression.RESULTS HER2 positivity was significantly associated with high tumor grade(P=0.003),while other variables,including sex,anatomical tumor location,pathological T stage,Ki-67 proliferation index,nodal metastasis status,lymphovascular invasion,and tumor laterality failed to demonstrate statistically significant correlations.These findings were further substantiated through univariate logistic regression modeling,yielding an odds ratio of 3.56[95%confidence interval(CI):1.30-9.75;P=0.013]for the association between high tumor grade and HER2 positivity.Importantly,this relationship remained robust(hazard ratio=3.42,95%CI:1.22-9.60;P=0.019)even after implementing multivariate logistic regression analysis.With a median follow-up time of 8 months(interquartile range,4-14)months,14 patients experienced intravesical recurrence after radical nephroureterectomy.Certain patient characteristics,such as HER2-negative,male sex,high-grade tumors,and luminal phenotype,were associated with a higher risk of intravesical recurrence.CONCLUSION In UTUC,HER2 overexpression is closely associated with tumor dedifferentiation(high grade),while it does not correlate with conventional indicators of disease progression,indicating that HER2 may serve a distinct biological function in this cancer type.展开更多
BACKGROUND Gastric cancer is one of the most common malignant tumors worldwide,with its incidence and mortality rates ranking among the highest in gastrointestinal cancers.The overexpression or gene amplification of h...BACKGROUND Gastric cancer is one of the most common malignant tumors worldwide,with its incidence and mortality rates ranking among the highest in gastrointestinal cancers.The overexpression or gene amplification of human epidermal growth factor receptor 2(HER-2)occurs in approximately 15%-20%of gastric cancers and serves as a critical molecular target influencing prognosis and treatment out-comes.For patients with HER-2-positive gastric cancer,trastuzumab combined with platinum-based chemotherapy has been established as the standard first-line treatment.However,despite the demonstrated clinical benefits in prolonging survival,the overall efficacy remains limited.In recent years,with the successful application of immune checkpoint inhibitors(ICIs)in various malignant tumors,combining ICIs with existing standard treatment regimens has emerged as a promising approach to enhance the therapeutic efficacy of HER-2-positive gastric cancer.Nevertheless,the efficacy and prognostic factors of ICIs combined with trastuzumab and chemotherapy in HER-2-positive gastric cancer remain unclear.AIM To analyze the efficacy of ICIs combined with standard treatment regimens and the prognostic factors in patients with advanced HER-2-positive gastric cancer.METHODS Clinical data from 104 patients with advanced HER-2-positive gastric cancer who were treated at our hospital between March 2021 and May 2023 were retrospectively analyzed.Patients were divided into a control group(n=54,treated with trastuzumab combined with platinum-based chemotherapy as the standard regimen)and an observation group(n=50,treated with ICIs in addition to the standard regimen).The therapeutic efficacy,survival outcomes,and adverse reactions were compared between the two groups.Univariate and Cox multivariate analyses were performed to identify factors influencing patient prognosis.RESULTS With a median follow-up time of 14.6 months,there were no significant differences between the two groups in terms of objective response rate or disease control rate(P>0.05).The median progression-free survival(mPFS)and mPFS for patients with immunohistochemistry 3+in the observation group were significantly higher than those in the control group(P<0.05).Among patients in the observation group,those with positive programmed death-ligand 1(PD-L1)expression had a significantly higher mPFS than those with negative PD-L1 expression(P<0.05).Regarding adverse events,significant differences were observed between the two groups in hypothyroidism and neutropenia(P<0.05).Cox multivariate analysis showed that Eastern Cooperative Oncology Group(ECOG)performance status,peritoneal metastasis,positive programmed death-1 expression,and treatment regimen were independent factors influencing PFS(hazard ratio>1,P<0.05).CONCLUSION ICIs combined with standard treatment regimens for patients with advanced HER-2-positive gastric cancer demonstrate favorable clinical efficacy,significantly prolonging PFS with manageable safety.ECOG performance status,peritoneal metastasis,positive PD-L1 expression,and treatment regimen are independent factors influ-encing PFS,warranting increased clinical attention to patients exhibiting these factors.展开更多
BACKGROUND Gastric signet ring cell carcinoma(SRCC)is a rare,aggressive subtype of gastric cancer characterized by poor prognosis and distinctive biological behavior.Despite advances in gastric cancer treatment,SRCC r...BACKGROUND Gastric signet ring cell carcinoma(SRCC)is a rare,aggressive subtype of gastric cancer characterized by poor prognosis and distinctive biological behavior.Despite advances in gastric cancer treatment,SRCC remains difficult to diagnose early and manage effectively due to its infiltrative pattern and molecular variability.Reliable prognostic markers are critical to guide clinical management.AIM To investigate the prognostic factors,including human epidermal growth factor receptor 2(HER2)expression,associated with survival outcomes in patients with gastric SRCC.METHODS A retrospective analysis of 100 cases diagnosed between 2015 and 2019 was conducted,assessing demographic,clinical,and pathological data.HER2 expression was analyzed using immunohistochemistry,and survival outcomes,including overall survival and disease-free survival,were examined.RESULTS With a median follow-up of 43 months,the median patient age was 50 years,and males exhibited a higher mortality rate(P=0.0107).Elevated serum carbohydrate antigen 19-9 and carcinoembryonic antigen levels were significantly associated with increased mortality(P=0.00149 and P=0.00163,respectively).Advanced tumornode-metastasis stage and lymphovascular invasion were strong predictors of poor outcomes(P<0.001 and P=0.019).HER2 positivity correlated with higher mortality(P=0.00882)but was not significantly linked to recurrence(P=0.53).Surgical treatment significantly improved survival compared with non-surgical approaches(P=0.0226).CONCLUSION These findings highlight the aggressive nature of SRCC with advanced disease stage,elevated tumor markers,and lymphovascular invasion contributing to poor outcomes.HER2 expression,though infrequent,may indicate worse prognosis,reinforcing the role of surgical intervention in survival improvement.展开更多
Neutrophils,macrophages,CD3^(+),CD4^(+),and CD8^(+)T lymphocytes expressμ-,δ-,andκ-opioid receptors(ORs)with varying affinities for opioids.Mast cells express the atypical OR Mas-related G-protein-coupled receptor ...Neutrophils,macrophages,CD3^(+),CD4^(+),and CD8^(+)T lymphocytes expressμ-,δ-,andκ-opioid receptors(ORs)with varying affinities for opioids.Mast cells express the atypical OR Mas-related G-protein-coupled receptor X2(MRGPRX2),which has a low affinity for morphine.Neutrophils and macrophages can synthesize and release endogenous opioid peptides.Activation of ORs enhances the synthesis of proinflammatory cytokines and the production of reactive oxygen species(ROS)in unstimulated leukocytes.Conversely,OR activation reduces proinflammatory cytokine synthesis in stimulated neutrophils and macrophages.Morphine inhibits Toll-like receptor 4(TLR4)expression in macrophages,thereby attenuating inflammation,whereas methadone induces ROS production in mast cells through TLR4 activation.Stimulation of TLR4 triggersβ-endorphin synthesis in macrophages.The production of proinflammatory cytokines and ROS contributes to cardiac reperfusion injury.Importantly,activation ofκ1-andμ-ORs suppresses proinflammatory cytokine production by leukocytes,thereby mitigating inflammatory injury to the heart and other organs.展开更多
Accumulating evidence has highlighted the functional role of the endogenous nociceptin/orphanin FQ peptide(N/OFQ)and its nociceptin opioid receptor(NOP)in alcohol and cocaine reward.However,the effects of NOP agonists...Accumulating evidence has highlighted the functional role of the endogenous nociceptin/orphanin FQ peptide(N/OFQ)and its nociceptin opioid receptor(NOP)in alcohol and cocaine reward.However,the effects of NOP agonists on methamphetamine(MAP)reinforcement,motivation,and relapse remain uncertain.In this study,we evaluated the effects of Ro 64-6198,a selective NOP agonist,on MAP reinforcement,motivation,and relapse in rats.Rats underwent a fixed-ratio 1(FR1)training to establish stable MAP intravenous self-administration(0.05 mg/kg/infusion)for 12 days,and the motivation for MAP was quantified using a progressive-ratio(PR)schedule,while the relapse was assessed through cue-and MAP-primed reinstatement after abstinence.Western blot analysis was employed to measure the relative expression of phosphorylated CREB,ERK,and Akt in the nucleus accumbens(NAc)following drug priming.Acute treatment of Ro 64-6198(1 mg/kg)significantly reduced the motivated behavior for MAP under PR testing(P<0.05 vs.vehicle).Ro 64-6198 at doses of 0.3 and 1 mg/kg could suppress the drug-seeking behavior induced by extinction or cues,respectively(P<0.05),whereas only the higher dose(1 mg/kg)could attenuate MAP primed drug-seeking(P<0.05).These behavioral effects were related to the upregulated phosphorylation of CREB and Akt in the NAc.Our results provide preclinical evidence that NOP activation disrupts multiple addiction-relevant behaviors,positioning Ro 64-6198 as a potential therapeutic candidate for treating MAP use disorders.展开更多
Activation of neutrophil membrane receptors initiates intracellular signal transduction cascades that orchestrate the cell's effector functions,including phagocytosis,production of reactive oxygen and halogen spec...Activation of neutrophil membrane receptors initiates intracellular signal transduction cascades that orchestrate the cell's effector functions,including phagocytosis,production of reactive oxygen and halogen species,degranulation,and NETosis(formation of neutrophil extracellular traps[NETs]).NETs,which contain antimicrobial compounds such as myeloperoxidase(MPO),represent a strategy to combat infection.However,excessive production of NETs promotes thrombosis,diabetes mellitus,and other diseases.Therefore,investigations into the mechanisms of NETosis and the identification of modulators of this process are critical for developing strategies to address NETosis-related disorders.Here,we identified a novel NETosis inducer,human serum albumin(HSA)modified by the MPO product hypochlorous acid(HSAHOCl),whose accumulation in vivo was correlated with inflammatory processes.Using human blood neutrophils,we investigated HSAHOCl-induced NETosis and detected NET formation by flow cytometry.The results showed that the mechanism of HSAHOClinduced NETosis involved MPO,NADPH oxidase,and phosphatidylinositol 3-kinases(PI3Ks),and that HSAHOCl activated a reactive oxygen species-dependent suicidal type of NETosis.Moreover,HSAHOCl-induced NETosis was inhibited by an anti-HSAHOCl monoclonal antibody.Thus,our findings may facilitate the development of strategies to modulate NETosis in inflammation associated with elevated MPO activity.展开更多
Food Science and Human Wellness (FSHW ISSN:2213-4530, CN 10-1750/TS) publishes original research papers demonstrating the latest advancement of multidisciplinary subjects related to food science and human health.Topic...Food Science and Human Wellness (FSHW ISSN:2213-4530, CN 10-1750/TS) publishes original research papers demonstrating the latest advancement of multidisciplinary subjects related to food science and human health.Topics may include but not limited to: nutriology, biochemistry, microbiology, immunology and toxicology.展开更多
Food Science and Human Wellness(FSHW ISSN:2213-4530,CN 10-1750/TS)publishes original research papers demonstrating the latest advancement of multidisci plinary subjects related to food science and human health Topics ...Food Science and Human Wellness(FSHW ISSN:2213-4530,CN 10-1750/TS)publishes original research papers demonstrating the latest advancement of multidisci plinary subjects related to food science and human health Topics may include but not limited to:nutriology,bio.chemistry,microbiology,immunology and toxicology.展开更多
Lip synchronization serves as a core technology for enabling natural interactions in digital virtual humans.However,it faces challenges such as insufficient dynamic correspondence between speech and lip movements and ...Lip synchronization serves as a core technology for enabling natural interactions in digital virtual humans.However,it faces challenges such as insufficient dynamic correspondence between speech and lip movements and inadequate modeling of image details.To address these limitations,a comprehensively optimized lip synchronization framework extending the Wav2Lip architecture was proposed in this study.Firstly,based on the Wav2Lip model,a facial region extraction strategy using facial keypoints was designed,which effectively enhances the robustness of facial alignment during lip synchronization for digital virtual humans.Then,a cross-modal attention fusion module between visual and speech features was introduced to improve cross-modal information fusion,and a dynamic receptive field convolution module was developed in the generation branch to enhance the modeling performance of the lip region.Finally,experiments were conducted on the VFHQ dataset.The proposed method was compared with Wav2Lip,VideoRetalking,and DI-Net models,and its performance was evaluated using three metrics:LSE-C,CSIM,and FID.Experimental results showed that the proposed method achieves significant improvements in synchronization accuracy and image fidelity,providing an efficient and feasible solution for lip-synthesis tasks of digital virtual humans.展开更多
G protein-coupled receptor 37(GPR37)is an orphan receptor predominantly expressed in the brain,particularly in oligodendrocytes and certain types of neurons.Notably,it has been shown that the N-terminal domain of GPR3...G protein-coupled receptor 37(GPR37)is an orphan receptor predominantly expressed in the brain,particularly in oligodendrocytes and certain types of neurons.Notably,it has been shown that the N-terminal domain of GPR37 undergoes proteolysis under normal physiological conditions,resulting in the formation of cleaved receptor forms and the release of its ectodomain(ecto-GPR37)into the extracellular milieu(Mattila et al.,2021).Importantly,ecto-GPR37 density is increased in cerebrospinal fluid(CSF)of patients suffering from sporadic Parkinson’s disease(PD),together with an abnormal GPR37 processing in post-mortem PD substantia nigra(Moratóet al.,2021;Figure 1A).展开更多
With the growing advancement of wireless communication technologies,WiFi-based human sensing has gained increasing attention as a non-intrusive and device-free solution.Among the available signal types,Channel State I...With the growing advancement of wireless communication technologies,WiFi-based human sensing has gained increasing attention as a non-intrusive and device-free solution.Among the available signal types,Channel State Information(CSI)offers fine-grained temporal,frequency,and spatial insights into multipath propagation,making it a crucial data source for human-centric sensing.Recently,the integration of deep learning has significantly improved the robustness and automation of feature extraction from CSI in complex environments.This paper provides a comprehensive review of deep learning-enhanced human sensing based on CSI.We first outline mainstream CSI acquisition tools and their hardware specifications,then provide a detailed discussion of preprocessing methods such as denoising,time–frequency transformation,data segmentation,and augmentation.Subsequently,we categorize deep learning approaches according to sensing tasks—namely detection,localization,and recognition—and highlight representative models across application scenarios.Finally,we examine key challenges including domain generalization,multi-user interference,and limited data availability,and we propose future research directions involving lightweight model deployment,multimodal data fusion,and semantic-level sensing.展开更多
Glutamate receptors and schizophrenia:Schizophrenia is a chronic mental disorder affecting approximately 1%of the global population,with 70%-80%heritability.It has a multifactorial etiology involving both environmenta...Glutamate receptors and schizophrenia:Schizophrenia is a chronic mental disorder affecting approximately 1%of the global population,with 70%-80%heritability.It has a multifactorial etiology involving both environmental factors and a complex polygenic genetic architecture.Over the last two decades,large-scale genome-wide approaches revealed contributions of common variants with individually small effect sizes and of rare copy number variants with a large effect size.N-methy l-D-a spar tat e receptor(NMDAR)hypofunction has been implicated as a central mechanism in the pathophysiology of schizophrenia(Coyle et al.,2020).展开更多
The temporal pole(TP),one of the most expanded cortical regions in humans relative to other primates,plays a crucial role in human language processing.It is also one of the most structurally and functionally asymmetri...The temporal pole(TP),one of the most expanded cortical regions in humans relative to other primates,plays a crucial role in human language processing.It is also one of the most structurally and functionally asymmetric regions.However,whether the functional architecture of the TP is shared by humans and macaques is an open question.We used spectral clustering algorithms to define a cross-species fine-grained TP atlas with different anatomical connectivity patterns.We identified three similar subregions,two ventral and one dorsal,within the TP in both humans and macaques.The parcellation scheme for the TP was validated using functional gradient mapping,anatomical connectivity and resting-state functional connectivity pattern analysis,and functional characterization.Furthermore,in conjunction with the Allen Human Brain Atlas,we revealed the molecular basis for the functional connectivity patterns of each human TP subregion.In addition,we compared the hemispheric asymmetry in mean gray matter volume,anatomical connectivity fingerprints,and whole brain functional connectivity patterns to reveal the evolutionary differences in the TP and found different asymmetric patterns between humans and macaques.In conclusion,our findings reveal that the asymmetry in structure and connectivity may underpin the hemispheric functional specialization of the brain and provide a novel insight into understanding the evolutionary origin of the TP.展开更多
Brassinosteroids(BRs)are essential phytohormones that broadly regulate plant growth,development,and adaptation to biotic and abiotic stresses.In Arabidopsis,apoplastic BR molecules are perceived by a plasma membrane-l...Brassinosteroids(BRs)are essential phytohormones that broadly regulate plant growth,development,and adaptation to biotic and abiotic stresses.In Arabidopsis,apoplastic BR molecules are perceived by a plasma membrane-localized receptor complex comprising the ligand-binding receptor BRI1 and the co-receptor BAK1.While negative regulators of the BR receptor complex,such as BKI1,BIR3,and PUB12/13,have been well characterized,how BRI1 and BAK1 are positively modulated in the BR pathway remains largely unknown.In this study,a genetic screen involving overexpression of RLP genes in the bak1-3 bkk1-1 double mutant reveals that enhanced RLP51 expression partially suppresses the BR-deficient phenotypes of bak1-3 bkk1-1.RLP51 overexpression also partially rescues the weak bri1 mutant allele,bri1-301.Although the rlp51 single mutant exhibits wild-type-like phenotypes,it enhances BR-defective phenotypes in bri1-301 and bak1 serk1 mutants.RLP51 is next found to interact with both BRI1 and BAK1 without affecting BRI1–BAK1 interaction.Critically,co-expression of RLP51 with BRI1 or BAK1 significantly increases BRI1 and BAK1 protein abundances.RLP51 appears to promote protein synthesis rather than stabilize BRI1 and BAK1 proteins.Thus,our study identifies RLP51 as a positive regulator of BR signaling that enhances the protein levels of BRI1 and BAK1.展开更多
The brain is the most complex human organ,and commonly used models,such as two-dimensional-cell cultures and animal brains,often lack the sophistication needed to accurately use in research.In this context,human cereb...The brain is the most complex human organ,and commonly used models,such as two-dimensional-cell cultures and animal brains,often lack the sophistication needed to accurately use in research.In this context,human cerebral organoids have emerged as valuable tools offering a more complex,versatile,and human-relevant system than traditional animal models,which are often unable to replicate the intricate architecture and functionality of the human brain.Since human cerebral organoids are a state-of-the-art model for the study of neurodevelopment and different pathologies affecting the brain,this field is currently under constant development,and work in this area is abundant.In this review,we give a complete overview of human cerebral organoids technology,starting from the different types of protocols that exist to generate different human cerebral organoids.We continue with the use of brain organoids for the study of brain pathologies,highlighting neurodevelopmental,psychiatric,neurodegenerative,brain tumor,and infectious diseases.Because of the potential value of human cerebral organoids,we describe their use in transplantation,drug screening,and toxicology assays.We also discuss the technologies available to study cell diversity and physiological characteristics of organoids.Finally,we summarize the limitations that currently exist in the field,such as the development of vasculature and microglia,and highlight some of the novel approaches being pursued through bioengineering.展开更多
In the human spinal cord,astrocytes are the major glial cells.In vitro studies of human astrocytes are relatively simple.However,the straightforward nature of the in vitro environment and complex nature of the in vivo...In the human spinal cord,astrocytes are the major glial cells.In vitro studies of human astrocytes are relatively simple.However,the straightforward nature of the in vitro environment and complex nature of the in vivo environment limit comprehensive investigations into the structure and function of human astrocytes.Additionally,in vivo studies of human astrocytes are further limited by ethical issues.This means there is an urgent need to develop effective in vivo models to study the structure and function of human astrocytes.Here,we first directed human embryonic stem cells to differentiate into human spinal cord dorsal neural stem/progenitor cells in vitro,before transplanting these cells into the gray matter of the cervical spinal cord(C5-T2 segments)of naïve nude rats to create a chimeric human astrocytic rat spinal cord model.The transplanted human spinal cord dorsal neural stem/progenitor cells survived for at least 20 months in the spinal cord environment of the rats,with over 90%differentiating into human astrocytes.These human astrocytes were able to migrate caudally for long distances along the white matter towards the spinal cord.They expressed astrocytic cytoskeletal proteins and functionally-related proteins,suggesting their maturation and structural integration into the rat spinal cord.Thus,this humanized astrocyte chimeric rat spinal cord model provides a valuable tool for studying the role of human spinal cord astrocytes in various spinal diseases.展开更多
Background:Humanized mouse models are essential for studying the human immune response and antibody development.However,conventional models show limited B cell maturation and antigen-specific humoral responses.To over...Background:Humanized mouse models are essential for studying the human immune response and antibody development.However,conventional models show limited B cell maturation and antigen-specific humoral responses.To overcome these limitations,we used the NOG-EXL mice expressing human interleukin 3(IL-3)and granulocyte-macrophage colony-stimulating factor(GM-CSF)to enhance myeloid and B-cell lineage differentiation.Methods:Human CD34^(+)hematopoietic stem cells(HSC)were transplanted into NOG-EXL mice to produce humanized immune systems.After immune cell reconstitution was confirmed across 12 weeks,the mice were immunized twice with inactivated severe fever with thrombocytopenia syndrome virus(SFTSV)antigens.Peripheral blood mononuclear cells and splenocytes were analyzed using multicolor flow cytometry to assess human immune cell subsets.Antigen-specific immunoglobulin G(IgG)production was quantified using enzyme-linked immunosorbent assay(ELISA),and virus-specific B cells were isolated using antigen-labeled recombinant protein probes.Results:Twelve weeks after transplantation of HSCs into NOG-EXL mice,they exhibited robust engraftment of human leukocytes,including T,B,and dendritic cells,compared to NOG mice.Unlike NOG mice,humanized NOG-EXL mice exhibited an increase in human IgG levels,indicating the production of human antibody responses to antigens.Humanized NOG-EXL mice were immunized twice every 2 weeks with inactivated SFTSV,and antigen-specific human antibodies against the virus were detected in the mouse sera by ELISA.Sera from SFTSV-immunized humanized mice demonstrated neutralizing activity against SFTSV,confirming the induction of functional virus-specific neutralizing antibodies.Antigen-binding IgG-positive human B cells were isolated from mouse splenocytes using recombinant protein probes.Conclusion:This model provides a valuable platform for evaluating humoral immunity and isolating B cells using high-affinity human monoclonal antibodies without genetic engineering.展开更多
Brain insulin resistance(BIR)is a prevalent detrimental feature of Alzheimer’s disease(AD)and all-cause dementia.Therapies designed to activate insulin signaling and enhance insulin receptor sensitivity have proven b...Brain insulin resistance(BIR)is a prevalent detrimental feature of Alzheimer’s disease(AD)and all-cause dementia.Therapies designed to activate insulin signaling and enhance insulin receptor sensitivity have proven beneficial for cognitive enhancement in pre-clinical models,non-human primates,and humans.BIR encompasses dysregulated brain insulin signaling,which is either due to insulin receptor resistance,reduced insulin receptor levels,or reduced levels of insulin in the brain,affecting processes involved in AD development and progression.展开更多
基金Supported by CAMS Innovation Fund for Medical Sciences CIFMS,No.2023-I2M-3-012.
文摘BACKGROUND Human epidermal growth factor receptor 2(HER2)-positive gastric cancer(GC)represents a distinct molecular cancer subtype that is often associated with a poor prognosis.While perioperative chemotherapy regimens are currently the primary recommendation for locally advanced HER2-positive GC,combination therapies incorporating immune checkpoint inhibitors are under active investigation.CASE SUMMARY The present case describes a patient with locally advanced HER2-positive GC who underwent perioperative treatment with chemotherapy combined with trastuzumab.Although significant tumor shrinkage was observed,surgical pathology results did not confirm the achievement of a pathological complete response.The current treatment strategies for advanced GC were also reviewed.Relevant case reports,retrospective studies,and prospective clinical trials were retrieved for analysis after searching the PubMed/MEDLINE,EMBASE,Cochrane Library,Web of Science,and American Society of Clinical Oncology/European Society for Medical Oncology conference abstracts between 2014 and 2024.CONCLUSION Large-scale phase Ⅲ clinical trials are needed to verify the efficacy of combined neoadjuvant treatment application for GC.
基金Supported by the Jiangsu Provincial Health and Family Planning Commission Personnel Talent Project,No.R2017005.
文摘BACKGROUND Although targeted therapy provides survival benefits for patients with metastatic colorectal cancer,some patients develop resistance to these treatments.Human epidermal growth factor receptor 2(HER2)is overexpressed in a subset of pa-tients with colorectal cancer and has been established as a therapeutic target.CASE SUMMARY This case report describes a Chinese patient with HER2-amplified advanced rectal cancer who showed no response to chemotherapy and targeted therapies against epidermal growth factor receptor and vascular endothelial growth factor but achieved a remarkable response following treatment with immune checkpoint inhibitors(ICIs)in combination with pyrotinib.The combination of oxaliplatin and ICIs with pyrotinib demonstrates synergistic effects after late-stage disease progression.CONCLUSION ICIs and pyrotinib may be effective in treating HER2-amplified advanced rectal cancer.Chemotherapy following disease progression could enhance efficacy synergistically.
基金Supported by Scientific Research Project of Health Commission of Guangxi Zhuang Autonomous Region,No.Z-A20240546Undergraduate Education and Teaching Reform Project of Guangxi Medical University,No.2025XJGYC38and Key Textbook Construction Project of Guangxi Medical University,No.Gxmuzdjc2417。
文摘BACKGROUND Human epidermal growth factor receptor 2(HER2)plays pivotal roles in cellular proliferation,survival,and differentiation of several malignancies.Upper tract urothelial carcinoma(UTUC)is a relatively rare malignancy.The clinical and molecular significance of HER2 expression level in UTUC remains poorly characterized vs bladder cancer.AIM To comprehensively evaluate HER2 expression patterns and their association with UTUC patients’clinicopathological features.METHODS Data were retrospectively collected from patients diagnosed with UTUC at The First Affiliated Hospital of Guangxi Medical University between January 2023 and December 2024.HER2 status was evaluated by immunohistochemistry in 145 UTUC patients who met the inclusion criteria.Its associations with tumor grade,tumor stage,and other clinicopathological parameters were assessed.Theχ2 test or Fisher’s exact test,along with univariate and multivariate logistic regression analyses,were performed to determine the influences of clinicopathological factors on HER2 expression.RESULTS HER2 positivity was significantly associated with high tumor grade(P=0.003),while other variables,including sex,anatomical tumor location,pathological T stage,Ki-67 proliferation index,nodal metastasis status,lymphovascular invasion,and tumor laterality failed to demonstrate statistically significant correlations.These findings were further substantiated through univariate logistic regression modeling,yielding an odds ratio of 3.56[95%confidence interval(CI):1.30-9.75;P=0.013]for the association between high tumor grade and HER2 positivity.Importantly,this relationship remained robust(hazard ratio=3.42,95%CI:1.22-9.60;P=0.019)even after implementing multivariate logistic regression analysis.With a median follow-up time of 8 months(interquartile range,4-14)months,14 patients experienced intravesical recurrence after radical nephroureterectomy.Certain patient characteristics,such as HER2-negative,male sex,high-grade tumors,and luminal phenotype,were associated with a higher risk of intravesical recurrence.CONCLUSION In UTUC,HER2 overexpression is closely associated with tumor dedifferentiation(high grade),while it does not correlate with conventional indicators of disease progression,indicating that HER2 may serve a distinct biological function in this cancer type.
基金This study was approved by the ethics committee of the First People’s Hospital of Fuzhou City(No.FZ202103).
文摘BACKGROUND Gastric cancer is one of the most common malignant tumors worldwide,with its incidence and mortality rates ranking among the highest in gastrointestinal cancers.The overexpression or gene amplification of human epidermal growth factor receptor 2(HER-2)occurs in approximately 15%-20%of gastric cancers and serves as a critical molecular target influencing prognosis and treatment out-comes.For patients with HER-2-positive gastric cancer,trastuzumab combined with platinum-based chemotherapy has been established as the standard first-line treatment.However,despite the demonstrated clinical benefits in prolonging survival,the overall efficacy remains limited.In recent years,with the successful application of immune checkpoint inhibitors(ICIs)in various malignant tumors,combining ICIs with existing standard treatment regimens has emerged as a promising approach to enhance the therapeutic efficacy of HER-2-positive gastric cancer.Nevertheless,the efficacy and prognostic factors of ICIs combined with trastuzumab and chemotherapy in HER-2-positive gastric cancer remain unclear.AIM To analyze the efficacy of ICIs combined with standard treatment regimens and the prognostic factors in patients with advanced HER-2-positive gastric cancer.METHODS Clinical data from 104 patients with advanced HER-2-positive gastric cancer who were treated at our hospital between March 2021 and May 2023 were retrospectively analyzed.Patients were divided into a control group(n=54,treated with trastuzumab combined with platinum-based chemotherapy as the standard regimen)and an observation group(n=50,treated with ICIs in addition to the standard regimen).The therapeutic efficacy,survival outcomes,and adverse reactions were compared between the two groups.Univariate and Cox multivariate analyses were performed to identify factors influencing patient prognosis.RESULTS With a median follow-up time of 14.6 months,there were no significant differences between the two groups in terms of objective response rate or disease control rate(P>0.05).The median progression-free survival(mPFS)and mPFS for patients with immunohistochemistry 3+in the observation group were significantly higher than those in the control group(P<0.05).Among patients in the observation group,those with positive programmed death-ligand 1(PD-L1)expression had a significantly higher mPFS than those with negative PD-L1 expression(P<0.05).Regarding adverse events,significant differences were observed between the two groups in hypothyroidism and neutropenia(P<0.05).Cox multivariate analysis showed that Eastern Cooperative Oncology Group(ECOG)performance status,peritoneal metastasis,positive programmed death-1 expression,and treatment regimen were independent factors influencing PFS(hazard ratio>1,P<0.05).CONCLUSION ICIs combined with standard treatment regimens for patients with advanced HER-2-positive gastric cancer demonstrate favorable clinical efficacy,significantly prolonging PFS with manageable safety.ECOG performance status,peritoneal metastasis,positive PD-L1 expression,and treatment regimen are independent factors influ-encing PFS,warranting increased clinical attention to patients exhibiting these factors.
文摘BACKGROUND Gastric signet ring cell carcinoma(SRCC)is a rare,aggressive subtype of gastric cancer characterized by poor prognosis and distinctive biological behavior.Despite advances in gastric cancer treatment,SRCC remains difficult to diagnose early and manage effectively due to its infiltrative pattern and molecular variability.Reliable prognostic markers are critical to guide clinical management.AIM To investigate the prognostic factors,including human epidermal growth factor receptor 2(HER2)expression,associated with survival outcomes in patients with gastric SRCC.METHODS A retrospective analysis of 100 cases diagnosed between 2015 and 2019 was conducted,assessing demographic,clinical,and pathological data.HER2 expression was analyzed using immunohistochemistry,and survival outcomes,including overall survival and disease-free survival,were examined.RESULTS With a median follow-up of 43 months,the median patient age was 50 years,and males exhibited a higher mortality rate(P=0.0107).Elevated serum carbohydrate antigen 19-9 and carcinoembryonic antigen levels were significantly associated with increased mortality(P=0.00149 and P=0.00163,respectively).Advanced tumornode-metastasis stage and lymphovascular invasion were strong predictors of poor outcomes(P<0.001 and P=0.019).HER2 positivity correlated with higher mortality(P=0.00882)but was not significantly linked to recurrence(P=0.53).Surgical treatment significantly improved survival compared with non-surgical approaches(P=0.0226).CONCLUSION These findings highlight the aggressive nature of SRCC with advanced disease stage,elevated tumor markers,and lymphovascular invasion contributing to poor outcomes.HER2 expression,though infrequent,may indicate worse prognosis,reinforcing the role of surgical intervention in survival improvement.
基金supported by the Russian Science Foundation(Grant No.23-65-10017 to B.K.K.and M.K.)The Ministry of Science and Higher Education of the Russian Federation(Grant No.122020300042-4 to L.N.M.)supported the preparation of the minichapter titled"Opioids reduce inflammatory injury of the heart".
文摘Neutrophils,macrophages,CD3^(+),CD4^(+),and CD8^(+)T lymphocytes expressμ-,δ-,andκ-opioid receptors(ORs)with varying affinities for opioids.Mast cells express the atypical OR Mas-related G-protein-coupled receptor X2(MRGPRX2),which has a low affinity for morphine.Neutrophils and macrophages can synthesize and release endogenous opioid peptides.Activation of ORs enhances the synthesis of proinflammatory cytokines and the production of reactive oxygen species(ROS)in unstimulated leukocytes.Conversely,OR activation reduces proinflammatory cytokine synthesis in stimulated neutrophils and macrophages.Morphine inhibits Toll-like receptor 4(TLR4)expression in macrophages,thereby attenuating inflammation,whereas methadone induces ROS production in mast cells through TLR4 activation.Stimulation of TLR4 triggersβ-endorphin synthesis in macrophages.The production of proinflammatory cytokines and ROS contributes to cardiac reperfusion injury.Importantly,activation ofκ1-andμ-ORs suppresses proinflammatory cytokine production by leukocytes,thereby mitigating inflammatory injury to the heart and other organs.
基金supported by Ningbo Top Medical and Health Research Program(No.2022030410)National Key Research and Development Program of China(No.2022YFC3300905,2023YFC3304202).
文摘Accumulating evidence has highlighted the functional role of the endogenous nociceptin/orphanin FQ peptide(N/OFQ)and its nociceptin opioid receptor(NOP)in alcohol and cocaine reward.However,the effects of NOP agonists on methamphetamine(MAP)reinforcement,motivation,and relapse remain uncertain.In this study,we evaluated the effects of Ro 64-6198,a selective NOP agonist,on MAP reinforcement,motivation,and relapse in rats.Rats underwent a fixed-ratio 1(FR1)training to establish stable MAP intravenous self-administration(0.05 mg/kg/infusion)for 12 days,and the motivation for MAP was quantified using a progressive-ratio(PR)schedule,while the relapse was assessed through cue-and MAP-primed reinstatement after abstinence.Western blot analysis was employed to measure the relative expression of phosphorylated CREB,ERK,and Akt in the nucleus accumbens(NAc)following drug priming.Acute treatment of Ro 64-6198(1 mg/kg)significantly reduced the motivated behavior for MAP under PR testing(P<0.05 vs.vehicle).Ro 64-6198 at doses of 0.3 and 1 mg/kg could suppress the drug-seeking behavior induced by extinction or cues,respectively(P<0.05),whereas only the higher dose(1 mg/kg)could attenuate MAP primed drug-seeking(P<0.05).These behavioral effects were related to the upregulated phosphorylation of CREB and Akt in the NAc.Our results provide preclinical evidence that NOP activation disrupts multiple addiction-relevant behaviors,positioning Ro 64-6198 as a potential therapeutic candidate for treating MAP use disorders.
文摘Activation of neutrophil membrane receptors initiates intracellular signal transduction cascades that orchestrate the cell's effector functions,including phagocytosis,production of reactive oxygen and halogen species,degranulation,and NETosis(formation of neutrophil extracellular traps[NETs]).NETs,which contain antimicrobial compounds such as myeloperoxidase(MPO),represent a strategy to combat infection.However,excessive production of NETs promotes thrombosis,diabetes mellitus,and other diseases.Therefore,investigations into the mechanisms of NETosis and the identification of modulators of this process are critical for developing strategies to address NETosis-related disorders.Here,we identified a novel NETosis inducer,human serum albumin(HSA)modified by the MPO product hypochlorous acid(HSAHOCl),whose accumulation in vivo was correlated with inflammatory processes.Using human blood neutrophils,we investigated HSAHOCl-induced NETosis and detected NET formation by flow cytometry.The results showed that the mechanism of HSAHOClinduced NETosis involved MPO,NADPH oxidase,and phosphatidylinositol 3-kinases(PI3Ks),and that HSAHOCl activated a reactive oxygen species-dependent suicidal type of NETosis.Moreover,HSAHOCl-induced NETosis was inhibited by an anti-HSAHOCl monoclonal antibody.Thus,our findings may facilitate the development of strategies to modulate NETosis in inflammation associated with elevated MPO activity.
文摘Food Science and Human Wellness (FSHW ISSN:2213-4530, CN 10-1750/TS) publishes original research papers demonstrating the latest advancement of multidisciplinary subjects related to food science and human health.Topics may include but not limited to: nutriology, biochemistry, microbiology, immunology and toxicology.
文摘Food Science and Human Wellness(FSHW ISSN:2213-4530,CN 10-1750/TS)publishes original research papers demonstrating the latest advancement of multidisci plinary subjects related to food science and human health Topics may include but not limited to:nutriology,bio.chemistry,microbiology,immunology and toxicology.
文摘Lip synchronization serves as a core technology for enabling natural interactions in digital virtual humans.However,it faces challenges such as insufficient dynamic correspondence between speech and lip movements and inadequate modeling of image details.To address these limitations,a comprehensively optimized lip synchronization framework extending the Wav2Lip architecture was proposed in this study.Firstly,based on the Wav2Lip model,a facial region extraction strategy using facial keypoints was designed,which effectively enhances the robustness of facial alignment during lip synchronization for digital virtual humans.Then,a cross-modal attention fusion module between visual and speech features was introduced to improve cross-modal information fusion,and a dynamic receptive field convolution module was developed in the generation branch to enhance the modeling performance of the lip region.Finally,experiments were conducted on the VFHQ dataset.The proposed method was compared with Wav2Lip,VideoRetalking,and DI-Net models,and its performance was evaluated using three metrics:LSE-C,CSIM,and FID.Experimental results showed that the proposed method achieves significant improvements in synchronization accuracy and image fidelity,providing an efficient and feasible solution for lip-synthesis tasks of digital virtual humans.
基金FEDER/Ministerio de Ciencia,Innovacióny Universidades-Agencia Estatal de Investigación(PID2023-147425OB-I00 to FC)Agència de Gestiód’Ajuts Universitaris i de Recerca(AGAUR)-Generalitat de Catalunya(2021 SGR 00698 to FC).
文摘G protein-coupled receptor 37(GPR37)is an orphan receptor predominantly expressed in the brain,particularly in oligodendrocytes and certain types of neurons.Notably,it has been shown that the N-terminal domain of GPR37 undergoes proteolysis under normal physiological conditions,resulting in the formation of cleaved receptor forms and the release of its ectodomain(ecto-GPR37)into the extracellular milieu(Mattila et al.,2021).Importantly,ecto-GPR37 density is increased in cerebrospinal fluid(CSF)of patients suffering from sporadic Parkinson’s disease(PD),together with an abnormal GPR37 processing in post-mortem PD substantia nigra(Moratóet al.,2021;Figure 1A).
基金supported by National Natural Science Foundation of China(NSFC)under grant U23A20310.
文摘With the growing advancement of wireless communication technologies,WiFi-based human sensing has gained increasing attention as a non-intrusive and device-free solution.Among the available signal types,Channel State Information(CSI)offers fine-grained temporal,frequency,and spatial insights into multipath propagation,making it a crucial data source for human-centric sensing.Recently,the integration of deep learning has significantly improved the robustness and automation of feature extraction from CSI in complex environments.This paper provides a comprehensive review of deep learning-enhanced human sensing based on CSI.We first outline mainstream CSI acquisition tools and their hardware specifications,then provide a detailed discussion of preprocessing methods such as denoising,time–frequency transformation,data segmentation,and augmentation.Subsequently,we categorize deep learning approaches according to sensing tasks—namely detection,localization,and recognition—and highlight representative models across application scenarios.Finally,we examine key challenges including domain generalization,multi-user interference,and limited data availability,and we propose future research directions involving lightweight model deployment,multimodal data fusion,and semantic-level sensing.
文摘Glutamate receptors and schizophrenia:Schizophrenia is a chronic mental disorder affecting approximately 1%of the global population,with 70%-80%heritability.It has a multifactorial etiology involving both environmental factors and a complex polygenic genetic architecture.Over the last two decades,large-scale genome-wide approaches revealed contributions of common variants with individually small effect sizes and of rare copy number variants with a large effect size.N-methy l-D-a spar tat e receptor(NMDAR)hypofunction has been implicated as a central mechanism in the pathophysiology of schizophrenia(Coyle et al.,2020).
基金supported by the Yunnan Fundamental Research Projects(202501AV070005 and 202201BE070001-004).
文摘The temporal pole(TP),one of the most expanded cortical regions in humans relative to other primates,plays a crucial role in human language processing.It is also one of the most structurally and functionally asymmetric regions.However,whether the functional architecture of the TP is shared by humans and macaques is an open question.We used spectral clustering algorithms to define a cross-species fine-grained TP atlas with different anatomical connectivity patterns.We identified three similar subregions,two ventral and one dorsal,within the TP in both humans and macaques.The parcellation scheme for the TP was validated using functional gradient mapping,anatomical connectivity and resting-state functional connectivity pattern analysis,and functional characterization.Furthermore,in conjunction with the Allen Human Brain Atlas,we revealed the molecular basis for the functional connectivity patterns of each human TP subregion.In addition,we compared the hemispheric asymmetry in mean gray matter volume,anatomical connectivity fingerprints,and whole brain functional connectivity patterns to reveal the evolutionary differences in the TP and found different asymmetric patterns between humans and macaques.In conclusion,our findings reveal that the asymmetry in structure and connectivity may underpin the hemispheric functional specialization of the brain and provide a novel insight into understanding the evolutionary origin of the TP.
基金supported by the National Natural Science Foundation of China(32370295 and 32170280 to K.H.)Foundation of Science and Technology of Gansu Province(22ZD6NA049)+3 种基金the Fundamental Research Funds for the Central Universities(lzujbky-2021-kb05 to Y.F.and lzujbky-2023-kb05 to P.L.)the Science and Technology Department of Gansu Province(24JRRA392 to K.H.and 23JRRA1132 to C.X.)China Postdoctoral Science Foundation(2024M751259 and GZB20240285 to B.L.)Science and Technology Program of Gansu Province(25JRRA718 to B.L.).
文摘Brassinosteroids(BRs)are essential phytohormones that broadly regulate plant growth,development,and adaptation to biotic and abiotic stresses.In Arabidopsis,apoplastic BR molecules are perceived by a plasma membrane-localized receptor complex comprising the ligand-binding receptor BRI1 and the co-receptor BAK1.While negative regulators of the BR receptor complex,such as BKI1,BIR3,and PUB12/13,have been well characterized,how BRI1 and BAK1 are positively modulated in the BR pathway remains largely unknown.In this study,a genetic screen involving overexpression of RLP genes in the bak1-3 bkk1-1 double mutant reveals that enhanced RLP51 expression partially suppresses the BR-deficient phenotypes of bak1-3 bkk1-1.RLP51 overexpression also partially rescues the weak bri1 mutant allele,bri1-301.Although the rlp51 single mutant exhibits wild-type-like phenotypes,it enhances BR-defective phenotypes in bri1-301 and bak1 serk1 mutants.RLP51 is next found to interact with both BRI1 and BAK1 without affecting BRI1–BAK1 interaction.Critically,co-expression of RLP51 with BRI1 or BAK1 significantly increases BRI1 and BAK1 protein abundances.RLP51 appears to promote protein synthesis rather than stabilize BRI1 and BAK1 proteins.Thus,our study identifies RLP51 as a positive regulator of BR signaling that enhances the protein levels of BRI1 and BAK1.
基金supported by the Grant PID2021-126715OB-IOO financed by MCIN/AEI/10.13039/501100011033 and"ERDFA way of making Europe"by the Grant PI22CⅢ/00055 funded by Instituto de Salud CarlosⅢ(ISCⅢ)+6 种基金the UFIECPY 398/19(PEJ2018-004965) grant to RGS funded by AEI(Spain)the UFIECPY-396/19(PEJ2018-004961)grant financed by MCIN (Spain)FI23CⅢ/00003 grant funded by ISCⅢ-PFIS Spain) to PMMthe UFIECPY 328/22 (PEJ-2021-TL/BMD-21001) grant to LM financed by CAM (Spain)the grant by CAPES (Coordination for the Improvement of Higher Education Personnel)through the PDSE program (Programa de Doutorado Sanduiche no Exterior)to VSCG financed by MEC (Brazil)
文摘The brain is the most complex human organ,and commonly used models,such as two-dimensional-cell cultures and animal brains,often lack the sophistication needed to accurately use in research.In this context,human cerebral organoids have emerged as valuable tools offering a more complex,versatile,and human-relevant system than traditional animal models,which are often unable to replicate the intricate architecture and functionality of the human brain.Since human cerebral organoids are a state-of-the-art model for the study of neurodevelopment and different pathologies affecting the brain,this field is currently under constant development,and work in this area is abundant.In this review,we give a complete overview of human cerebral organoids technology,starting from the different types of protocols that exist to generate different human cerebral organoids.We continue with the use of brain organoids for the study of brain pathologies,highlighting neurodevelopmental,psychiatric,neurodegenerative,brain tumor,and infectious diseases.Because of the potential value of human cerebral organoids,we describe their use in transplantation,drug screening,and toxicology assays.We also discuss the technologies available to study cell diversity and physiological characteristics of organoids.Finally,we summarize the limitations that currently exist in the field,such as the development of vasculature and microglia,and highlight some of the novel approaches being pursued through bioengineering.
基金Ministry of Science and Technology of China(STI2030-Major Projects),No.2022ZD0204700(to WW)the National Natural Science Foundation of China,No.82301572(to XZ)China Postdoctoral Science Foundation,No.2023M731202(to XZ).
文摘In the human spinal cord,astrocytes are the major glial cells.In vitro studies of human astrocytes are relatively simple.However,the straightforward nature of the in vitro environment and complex nature of the in vivo environment limit comprehensive investigations into the structure and function of human astrocytes.Additionally,in vivo studies of human astrocytes are further limited by ethical issues.This means there is an urgent need to develop effective in vivo models to study the structure and function of human astrocytes.Here,we first directed human embryonic stem cells to differentiate into human spinal cord dorsal neural stem/progenitor cells in vitro,before transplanting these cells into the gray matter of the cervical spinal cord(C5-T2 segments)of naïve nude rats to create a chimeric human astrocytic rat spinal cord model.The transplanted human spinal cord dorsal neural stem/progenitor cells survived for at least 20 months in the spinal cord environment of the rats,with over 90%differentiating into human astrocytes.These human astrocytes were able to migrate caudally for long distances along the white matter towards the spinal cord.They expressed astrocytic cytoskeletal proteins and functionally-related proteins,suggesting their maturation and structural integration into the rat spinal cord.Thus,this humanized astrocyte chimeric rat spinal cord model provides a valuable tool for studying the role of human spinal cord astrocytes in various spinal diseases.
基金The Korea Centers for Disease Control and Prevention,Grant/Award Number:2022-ER1701-00,2022-NI-041-02,2024-ER1702-00 and 2025-NI-014-00。
文摘Background:Humanized mouse models are essential for studying the human immune response and antibody development.However,conventional models show limited B cell maturation and antigen-specific humoral responses.To overcome these limitations,we used the NOG-EXL mice expressing human interleukin 3(IL-3)and granulocyte-macrophage colony-stimulating factor(GM-CSF)to enhance myeloid and B-cell lineage differentiation.Methods:Human CD34^(+)hematopoietic stem cells(HSC)were transplanted into NOG-EXL mice to produce humanized immune systems.After immune cell reconstitution was confirmed across 12 weeks,the mice were immunized twice with inactivated severe fever with thrombocytopenia syndrome virus(SFTSV)antigens.Peripheral blood mononuclear cells and splenocytes were analyzed using multicolor flow cytometry to assess human immune cell subsets.Antigen-specific immunoglobulin G(IgG)production was quantified using enzyme-linked immunosorbent assay(ELISA),and virus-specific B cells were isolated using antigen-labeled recombinant protein probes.Results:Twelve weeks after transplantation of HSCs into NOG-EXL mice,they exhibited robust engraftment of human leukocytes,including T,B,and dendritic cells,compared to NOG mice.Unlike NOG mice,humanized NOG-EXL mice exhibited an increase in human IgG levels,indicating the production of human antibody responses to antigens.Humanized NOG-EXL mice were immunized twice every 2 weeks with inactivated SFTSV,and antigen-specific human antibodies against the virus were detected in the mouse sera by ELISA.Sera from SFTSV-immunized humanized mice demonstrated neutralizing activity against SFTSV,confirming the induction of functional virus-specific neutralizing antibodies.Antigen-binding IgG-positive human B cells were isolated from mouse splenocytes using recombinant protein probes.Conclusion:This model provides a valuable platform for evaluating humoral immunity and isolating B cells using high-affinity human monoclonal antibodies without genetic engineering.
文摘Brain insulin resistance(BIR)is a prevalent detrimental feature of Alzheimer’s disease(AD)and all-cause dementia.Therapies designed to activate insulin signaling and enhance insulin receptor sensitivity have proven beneficial for cognitive enhancement in pre-clinical models,non-human primates,and humans.BIR encompasses dysregulated brain insulin signaling,which is either due to insulin receptor resistance,reduced insulin receptor levels,or reduced levels of insulin in the brain,affecting processes involved in AD development and progression.
