Dengue is an arboviral disease caused by the dengue virus,with 390 million infections reported annually worldwide.It is classified into two categories:dengue without or with warning signs and severe dengue.[1]Given th...Dengue is an arboviral disease caused by the dengue virus,with 390 million infections reported annually worldwide.It is classified into two categories:dengue without or with warning signs and severe dengue.[1]Given the moderate efficacy of the dengue vaccine,[2]there is an urgent necessity to design host-directed therapeutic strategies,such as the repurposing of FDA-approved drugs,to combat dengue virus infection.展开更多
BACKGROUND Acute pancreatitis(AP)is an emergency gastrointestinal disease that requires immediate diagnosis and urgent clinical treatment.An accurate assessment and precise staging of severity are essential in initial...BACKGROUND Acute pancreatitis(AP)is an emergency gastrointestinal disease that requires immediate diagnosis and urgent clinical treatment.An accurate assessment and precise staging of severity are essential in initial intensive therapy.AIM To explore the prognostic value of inflammatory markers and several scoring systems[Acute Physiology and Chronic Health Evaluation II,the bedside index of severity in AP(BISAP),Ranson’s score,the computed tomography severity index(CTSI)and sequential organ failure assessment]in severity stratification of earlyphase AP.METHODS A total of 463 patients with AP admitted to our hospital between 1 January 2021 and 30 June 2024 were retrospectively enrolled in this study.Inflammation marker and scoring system levels were calculated and compared between different severity groups.Relationships between severity and several predictors were evaluated using univariate and multivariate logistic regression models.Predictive ability was estimated using receiver operating characteristic curves.RESULTS Of the 463 patients,50(10.80%)were classified as having severe AP(SAP).The results revealed that the white cell count significantly increased,whereas the prognostic nutritional index measured within 48 hours(PNI48)and calcium(Ca^(2+))were decreased as the severity of AP increased(P<0.001).According to multivariate logistic regression,C-reactive protein measured within 48 hours(CRP_(48)),Ca^(2+)levels,and PNI48 were independent risk factors for predicting SAP.The area under the curve(AUC)values for the CRP_(48),Ca^(2+),PNI48,Acute Physiology and Chronic Health Evaluation II,sequential organ failure assessment,BISAP,CTSI,and Ranson scores for the prediction of SAP were 0.802,0.736,0.871,0.799,0.783,0.895,0.931 and 0.914,respectively.The AUC for the combined CRP_(48)+Ca^(2+)+PNI48 model was 0.892.The combination of PNI48 and Ranson achieved an AUC of 0.936.CONCLUSION Independent risk factors for developing SAP include CRP_(48),Ca^(2+),and PNI48.CTSI,BISAP,and the combination of PNI48 and the Ranson score can act as reliable predictors of SAP.展开更多
Objective:To investigate the expression level of interleukin-17D(IL-17D)in the serum of patients with severe pneumonia and its correlation with disease severity.Methods:This study included 50 patients with severe pneu...Objective:To investigate the expression level of interleukin-17D(IL-17D)in the serum of patients with severe pneumonia and its correlation with disease severity.Methods:This study included 50 patients with severe pneumonia who were diagnosed and treated in the hospital from May 2024 to May 2025.The expression level of IL-17D in the serum of all patients was recorded.Patients were divided into severe and mild groups based on their disease severity.Gender,age,disease duration,presence of fever,atelectasis,pneumothorax,interleukin-2(IL-2),interleukin-4(IL-4),interleukin-6(IL-6),and interleukin-17D were selected as independent variables.Statistical software SPSS 22.00 was used for univariate analysis,and variables with statistical significance in the univariate analysis were included in a multivariate logistic regression analysis to determine the correlation between IL-17D and the severity of severe pneumonia.Results:The results of this study showed that the level of IL-17D in patients with severe pneumonia was significantly higher than the normal threshold.Univariate analysis indicated that atelectasis,IL-2,IL-6,and IL-17D were statistically significant(P<0.05)and could be considered as influencing factors for the severity of severe pneumonia.Multivariate logistic regression analysis revealed that atelectasis(OR=2.141,95%CI:1.684–2.391),IL-2(OR=2.884,95%CI:2.240–3.614),IL-6(OR=2.571,95%CI:2.190–2.943),and IL-17D(OR=2.416,95%CI:2.093–2.735)were positively correlated with the severity of severe pneumonia.Conclusion:The expression level of IL-17D in the serum of patients with severe pneumonia is higher than the normal threshold and is positively correlated with disease severity.展开更多
The clinical treatment of severe trauma withsternoclavicular joint injury is challenging,primarilydue to the irregular shape of the bones surrounding thesternoclavicular joint,as well as the posterior clavicle beingcl...The clinical treatment of severe trauma withsternoclavicular joint injury is challenging,primarilydue to the irregular shape of the bones surrounding thesternoclavicular joint,as well as the posterior clavicle beingclose to the aorta and mediastinal organs.^([1])These patientsnot only suffer direct injuries to the sternoclavicularjoint,but also frequently experience severe injuries toother body parts.The systemic physiological disordersand multi-organ dysfunction caused by severe traumaincrease the surgery di?culty and mortality risk.^([2])展开更多
Acute pancreatitis(AP)is a prevalent gastrointestinal disease necessitating hospitalization globally,with an annual incidence ranging from 13 to 45 per 100,000 individuals[1]and a mortality rate of 5%-10%.[2]While mos...Acute pancreatitis(AP)is a prevalent gastrointestinal disease necessitating hospitalization globally,with an annual incidence ranging from 13 to 45 per 100,000 individuals[1]and a mortality rate of 5%-10%.[2]While most cases follow a self-limiting course,approximately 20%-30%of cases progress to severe acute pancreatitis(SAP),characterized by pancreatic necrosis and multiorgan failure,with the mortality rate increasing to 36%-50%.展开更多
BACKGROUND The imbalance of hormone levels in the body is closely related to the occurrence and progression of schizophrenia,especially thyroid hormones.AIM To study the relationship between triiodothyronine(T3),thyro...BACKGROUND The imbalance of hormone levels in the body is closely related to the occurrence and progression of schizophrenia,especially thyroid hormones.AIM To study the relationship between triiodothyronine(T3),thyroxine(T4),free T3(FT3),free T4(FT4),thyroid stimulating hormone(TSH)and schizophrenia.METHODS In this study,100 schizophrenia patients were selected from our hospital between April 2022 and April 2024.Their clinical data were analyzed retrospectively.Based on the Positive and Negative Syndrome Scale(PANSS)score,patients were divided into mild(1-3 points,n=39),moderate(4 points,n=45),and severe groups(5-7 points,n=16).Additionally,55 healthy individuals served as a control group.Venous blood samples were collected to measure T3,T4,FT3,FT4,TSH,and cortisol concentrations,analyzing their relationship with PANSS scores.RESULTS The serum levels of T3,FT3,FT4,TSH and cortisol in the schizophrenia group were lower than those in the control group(P<0.05).With the increase of the severity of the disease,the concentrations of T3 and T4 decreased,while the con-centrations of TSH and cortisol increased(P<0.05).The concentrations of TSH and cortisol were positively correlated with the PANSS score,while T3 and T4 were negatively correlated with the PANSS score(P<0.05).The receiver ope-rating characteristic curve results showed that T3,T4,TSH,and cortisol had good efficacy in the diagnosis of schizophrenia.Logistic results showed that decreased T3 level,decreased T4 level,decreased TSH level and increased cortisol level may be independent risk factors for schizophrenia.CONCLUSION Thyroid hormone levels are associated with the severity of schizophrenia symptoms,which can provide new solutions for the diagnosis and treatment of schizophrenia.展开更多
BACKGROUND:The lack of a stable,easy-to-operate animal model for severe trauma has hindered the research progress.The aim of this study is to develop a mouse model that replicates the pathophysiological conditions of ...BACKGROUND:The lack of a stable,easy-to-operate animal model for severe trauma has hindered the research progress.The aim of this study is to develop a mouse model that replicates the pathophysiological conditions of severe trauma,providing a reliable research tool.METHODS:Male C57BL/6J mice(aged 8-10 weeks and weighting approximately 20 g)were used to establish the severe trauma model.Under anesthesia,a midshaft femoral fracture was created and packed with sterile cotton.A midline incision was made from the inguinal region to the sternum,exposing the abdominal organs for 30 min.The right femoral artery was cannulated to induce controlled blood loss at 30%,35%,40%,and 50%of the total blood volume.Survival rates were monitored for 24 h post-induction.In the mice that experienced 30%blood loss,the mean arterial pressure,body temperature,blood gas parameters,peripheral blood inflammatory markers,and major organ pathological changes were assessed.RESULTS:Mice with femoral fractures,soft tissue injuries,abdominal organ exposure,and 30%blood loss exhibited stable survival rates.Increased blood loss significantly reduced survival rates.Mean arterial pressure decreased initially,recovering within 0-15 min and returning to baseline by 50 min.Similarly,the body temperature decreased initially and gradually recovered to baseline within 50 min.Levels of peripheral blood inflammatory markers remained elevated for 12 h post-injury.Distant organs,including intestines,lungs,liver,spleen and kidneys,displayed varying degrees of injury.CONCLUSION:The established mouse model replicates the pathophysiological responses to severe trauma,indicating stability and reproducibility,which could be an useful tool for further trauma research.展开更多
Severe fever with thrombocytopenia syndrome(SFTS)is a novel emerging acute infectious disease caused by severe fever with thrombocytopenia syndrome virus(SFTSV),characterized by high fever and thrombocytopenia.It has ...Severe fever with thrombocytopenia syndrome(SFTS)is a novel emerging acute infectious disease caused by severe fever with thrombocytopenia syndrome virus(SFTSV),characterized by high fever and thrombocytopenia.It has been proved that traditional Chinese medicine(TCM)has displayed definite therapeutic effects on viral hemorrhagic fever,indicating its potential to treat SFTS.In this study,SFTS-relative key targets were predicted via gene ontology(GO)analysis and kyoto encyclopedia of genes and genomes(KEGG)enrichment analysis.Molecular docking was then used to select stable binders.Molecules matched TCMs were identified,and a new prescription,Qingqi Guxue decoction(QQGX),was formulated to clear heat and nourish blood,with a resulting drug composition network.We explored the optimal drug proportion for QQGX.Through an in-depth study of molecular mechanisms,we found that QQGX induces S phase arrest by promoting the degradation of cyclin A2(CCNA2)and cyclin-dependent kinase 2(CDK2),thereby inhibiting SFTSV replication.Finally,we verified the effectiveness and safety of QQGX based on the mouse liver bile duct organoid model infected with SFTSV.In summary,our study prepared a TCM decoction using the method of network pharmacology.This decoction has a significant inhibitory effect on the replication of SFTSV and provides a new treatment strategy for hemorrhagic fever with TCM.展开更多
BACKGROUND Coronavirus disease 2019(COVID-19)is strongly associated with an increased risk of thrombotic events,including severe outcomes such as pulmonary embolism.Elevated D-dimer levels are a critical biomarker for...BACKGROUND Coronavirus disease 2019(COVID-19)is strongly associated with an increased risk of thrombotic events,including severe outcomes such as pulmonary embolism.Elevated D-dimer levels are a critical biomarker for assessing this risk.In Gabon,early implementation of anticoagulation therapy and D-dimer testing has been crucial in managing COVID-19.This study hypothesizes that elevated Ddimer levels are linked to increased COVID-19 severity.AIM To determine the impact of D-dimer levels on COVID-19 severity and their role in guiding clinical decisions.METHODS This retrospective study analyzed COVID-19 patients admitted to two hospitals in Gabon between March 2020 and December 2023.The study included patients with confirmed COVID-19 diagnoses and available D-dimer measurements at admission.Data on demographics,clinical outcomes,D-dimer levels,and healthcare costs were collected.COVID-19 severity was classified as non-severe(outpatients)or severe(inpatients).A multivariable logistic regression model was used to assess the relationship between D-dimer levels and disease severity,with adjusted odds ratios(OR)and 95%CI.RESULTS A total of 3004 patients were included,with a mean age of 50.17 years,and the majority were female(53.43%).Elevated D-dimer levels were found in 65.81%of patients,and 57.21%of these experienced severe COVID-19.Univariate analysis showed that patients with elevated D-dimer levels had 3.33 times higher odds of severe COVID-19(OR=3.33,95%CI:2.84-3.92,P<0.001),and this association remained significant in the multivariable analysis,adjusted for age,sex,and year of collection.The financial analysis revealed a substantial burden,particularly for uninsured patients.CONCLUSION D-dimer predicts COVID-19 severity and guides treatment,but the high cost of anticoagulant therapy highlights the need for policies ensuring affordable access in resource-limited settings like Gabon.展开更多
Background: Severe acute malnutrition (SAM) is one of the major public health problems associated with increased mortality in under-five children. In low-income countries, renal dysfunction (RD) contributes to about 3...Background: Severe acute malnutrition (SAM) is one of the major public health problems associated with increased mortality in under-five children. In low-income countries, renal dysfunction (RD) contributes to about 34% mortality in under-five children with severe acute malnutrition. This study aimed to determine the impacts of severe acute malnutrition on the kidney among the admitted under-five children. Methods: In this prospective longitudinal observational study, a total of 190 children aged 6 to 59 months were enrolled from Iringa and Dodoma tertiary hospitals. Socio-demographic, clinical and laboratory data were collected using a structured questionnaire. Estimated Glomerular Filtration Rate (eGFR) and urine albumin creatinine ratio (uACR) were used to determine RD. Data analysis was done using SPSS version 26 and statistical significance was assumed for factors with p-value Results: Out of 190 children with severe acute malnutrition, 36 (19%) had renal dysfunction. Factors associated with RD in malnourished children were the history of local herbs used within one week (AOR = 5.85, 95% CI [1.41, 24.319], p = 0.0152), Acute watery diarrhea with severe dehydration (AOR = 2.15, 95% CI [1.033, 4.711], p = 0.0166), and positive urine leukocytes (AOR = 19.91, 95% CI [4.09, 96.989], p = 0.0002). At three months of follow up, out of 36 children with RD, 20 (55.56%) attained full recovery, while 4 (11.11%) developed chronic kidney disease (CKD). Children with RD had prolonged hospital stays for more than 14 days with a mean 12.25 ± 5.00 days compared to those with no RD with a mean 6.29 ± 1.68 days (p Conclusion: Renal dysfunction is common among children with severe acute malnutrition. It is associated with prolonged hospital stays and increased mortality. Further studies which can determine the burden of RD in children with severe acute malnutrition as compared to those with no severe acute malnutrition are needed.展开更多
This study aimed to introduce a modified Byars staged procedure and investigate its application value in patients with severe hypospadias.We retrospectively analyzed the clinical data of patients with severe hypospadi...This study aimed to introduce a modified Byars staged procedure and investigate its application value in patients with severe hypospadias.We retrospectively analyzed the clinical data of patients with severe hypospadias admitted to the First Affiliated Hospital of Sun Yat-sen University(Guangzhou,China)between October 2012 and October 2022.In total,31 patients underwent the conventional Byars procedure(conventional group),and 45 patients underwent the modified Byars staged procedure(modified group).Our modified strategy was built upon the standard Byars procedure by incorporating glansplasty during the first stage and employing a Y-shaped flap in conjunction with a glandular tunnel for urethroplasty during the second stage.Notably,there were no statistically significant differences in the preoperative baseline characteristics,duration of surgery,amount of blood loss,or occurrence of postoperative complications,including urethral fistula,stricture and diverticulum,or penile curvature,between the conventional and modified groups.However,there was a significantly lower incidence of coronal sulcus fistula(0 vs 16.1%,P=0.02)and glans dehiscence(0 vs 12.9%,P=0.02)in the surgical group than that in the conventional group.In addition,the modified group exhibited a notably greater rate of normotopic urethral opening(100.0%vs 83.9%,P=0.01)and a higher mean score on the Hypospadias Objective Penile Evaluation(HOPE;mean±standard error of mean:8.6±0.2 vs 7.9±0.3,P=0.02)than did the conventional group.In conclusion,the modified Byars staged procedure significantly reduced the risks of glans dehiscence and coronal sulcus fistula.Consequently,it offers a promising approach for achieving favorable penile esthetics,thereby providing a reliable therapeutic option for severe hypospadias.展开更多
Objective:To assess whether there is a correlation between CT scan severity score and pulmonary function in Interstitial Lung Disease,and provide a more reliable basis for clinical diagnosis and treatment.Materials an...Objective:To assess whether there is a correlation between CT scan severity score and pulmonary function in Interstitial Lung Disease,and provide a more reliable basis for clinical diagnosis and treatment.Materials and Methods:Sixty patients with clinical diagnosis of Interstitial Lung Disease(ILD)were collected,and chest CT and pulmonary function tests were performed at the same time.Here DLCO%and FEV1%were used as the pulmonary function indexes.The severity of the patients was assessed by CT scores as mild(range,1~10),moderate(range 11~20),and severe(range 21~30).Correlation analysis was carried out between CT score and pulmonary function index,and the lung function parameters of patients at three grades were compared between groups and pairwise among the means.Results:As per the CT severity classification,there were 13 mild cases,31 moderate cases,and 16 severe cases.CT score was negatively correlated with DLCO%and FEV1%.R value was-0.814 and-0.797,respectively;The comparison of the mean value of DLCO%and FEV1%among the three groups and the pairings of the mean value of DLCO%and FEV1%were statistically significant.Conclusion:There was good correlation between CT score of ILD and the pulmonary function index.The pulmonary function index of patients with different CT severity grading was statistically significant,which can provide a new basis for the clinical evaluation and diagnosis of the disease.展开更多
A recent single-center retrospective study proposed novel combinations of hematological parameters and scoring systems for predicting severe acute pancre-atitis.While these combinations showed promising predictive per...A recent single-center retrospective study proposed novel combinations of hematological parameters and scoring systems for predicting severe acute pancre-atitis.While these combinations showed promising predictive performance,several limitations warrant consideration,including the lack of calibration,the absence of key inflammatory markers such as procalcitonin,and practical challenges in integrating these models into routine clinical workflows.To improve predictive accuracy and clinical applicability,prospective validation and the inclusion of additional variables are recommended.展开更多
Acute pancreatitis(AP)is a complex and potentially life-threatening inflammatory condition with a highly variable clinical course,ranging from mild,selflimiting episodes to severe necrotizing forms.Among its common co...Acute pancreatitis(AP)is a complex and potentially life-threatening inflammatory condition with a highly variable clinical course,ranging from mild,selflimiting episodes to severe necrotizing forms.Among its common complications ascites has traditionally been viewed as a passive byproduct of peritoneal inflammation and enzymatic leakage with limited diagnostic or prognostic utility.However,growing evidence challenges this perspective,suggesting that ascitic fluid in AP represents a dynamic and clinically meaningful component of disease progression.In this editorial we reflected on the findings presented by Rao et al,who highlighted the diagnostic,prognostic,and therapeutic significance of ascitic fluid in AP.Easily accessible markers such as lactate dehydrogenase may provide early prognostic insight while emerging molecular biomarkers and cytokine pro-files offer promise for more precise risk stratification and individualized therapy.We argue that the systematic evaluation of ascitic fluid should be integrated into the clinical management of moderate to severe AP.Incorporating ascites analysis into standard diagnostic protocols may enhance early risk assessment,inform therapeutic decisions,and ultimately improve patient outcomes.Ascitic fluid should be recognized as a clinically valuable marker and an important source of information in the evolving landscape of AP care.展开更多
This study examines the interaction between emotional states(anxiety and depression)and tinnitus severity in individuals undergoing a four-month sound therapy intervention.43 participants(28 males and 15 females)of a ...This study examines the interaction between emotional states(anxiety and depression)and tinnitus severity in individuals undergoing a four-month sound therapy intervention.43 participants(28 males and 15 females)of a study on four-month sound therapy of tinnitus were recruited and their tinnitus severity(Tinnitus Handicap Inventory,THI,and Tinnitus Functional Index,TFI)and emotional state(Hospitalary Anxiety and Depression Scale,HADS)were assessed before and after finishing the treatment.The participants,predominantly with moderate tinnitus,showed a significant reduction in tinnitus-related distress,with a mean reduction of approximately 30 points on both the THI and the TFI.Analysis revealed significant gender differences,with women experiencing higher baseline tinnitus distress but higher response to sound therapy.Emotional state assessments revealed moderate levels of anxiety and depression at baseline,which decreased significantly after therapy,particularly in women.Correlational analyses revealed a strong relationship between changes in emotional state and tinnitus severity,with reductions in anxiety and depression associated with improved tinnitus outcomes.The results highlight the complex relationship between emotional well-being and tinnitus severity and underline the potential of sound therapy to alleviate both emotional distress and tinnitus symptoms.展开更多
BACKGROUND Boerhaave syndrome,or spontaneous esophageal rupture,is a rare and lifethreatening emergency,typically caused by a sudden increase in esophageal pressure due to violent coughing or vomiting.Early diagnosis ...BACKGROUND Boerhaave syndrome,or spontaneous esophageal rupture,is a rare and lifethreatening emergency,typically caused by a sudden increase in esophageal pressure due to violent coughing or vomiting.Early diagnosis is challenging as its symptoms often resemble those of other diseases.Understanding its pathological features and treatment strategies is therefore critical for clinical practice.CASE SUMMARY This report describes a case of spontaneous esophageal rupture triggered by violent coughing in a 55-year-old male with a history of smoking and hypertension.Following severe coughing,the patient developed chest pain,vomiting,and respiratory distress.Initial clinical evaluation was inconclusive,with a suspected diagnosis of cardiovascular or gastrointestinal conditions.After further examination,the diagnosis of spontaneous esophageal rupture was confirmed.Chest X-ray,computed tomography,and endoscopy revealed a rupture in the lower esophagus,along with mediastinal abscess and pleural effusion.Laboratory tests showed mild infection markers.The patient underwent surgical repair of the esophageal rupture(approximately 3 cm in length)with mediastinal drainage.Postoperatively,the patient’s temperature normalized within 3 days,respiratory function improved,and pleural effusion significantly decreased.After two weeks of treatment,the patient was discharged without complications and had a favorable prognosis.The study suggests that while violent coughing is a rare trigger,it can lead to severe damage,and imaging techniques play a crucial role in diagnosis.CONCLUSION Spontaneous esophageal rupture presents significant diagnostic and therapeutic challenges.Early recognition and timely intervention are crucial for improving prognosis.This case highlights the importance of imaging and surgical treatment,offering new insights for managing similar cases and providing valuable clinical guidance.展开更多
Taking short-duration heavy rainfall and convective wind gusts as examples, the present study examined the characteristics of radar reflectivity and several convective parameters. We analyzed nowcasting techniques by ...Taking short-duration heavy rainfall and convective wind gusts as examples, the present study examined the characteristics of radar reflectivity and several convective parameters. We analyzed nowcasting techniques by integrating a high-resolution numerical weather prediction model with these convective parameters. Based on the CMA-GD 1-km model and its assimilation system, we conducted repeated tests on radar reflectivity data assimilation and analyzed their impact on nowcasting accuracy. Based on these analyses, we proposed a method to improve model forecasts using the useful indicative information provided by high-frequency radar reflectivity data and convective parameters. The improved method was applied to the CMA-GD 1-km model for nowcasting tests. Evaluations from batch tests and case analysis show that the proposed method significantly reduced the model's false alarm rates and improved its nowcasting performance.展开更多
Post-translational modification of spastin enables precise spatiotemporal control of its microtubule severing activity.However,the detailed mechanism by which spastin turnover is regulated in the context of neurite ou...Post-translational modification of spastin enables precise spatiotemporal control of its microtubule severing activity.However,the detailed mechanism by which spastin turnover is regulated in the context of neurite outgrowth remains unknown.Here,we found that spastin interacted with ubiquitin and was significantly degraded by K48-mediated poly-ubiquitination.Cullin3 facilitated spastin degradation and ubiquitination.RING-box protein 1,but not RING-box protein 2,acted synergistically with Cullin3 protein to regulate spastin degradation.Overexpression of Culin3 or BRX1 markedly suppressed spastin expression,and inhibited spastin-mediated microtubule severing and promotion of neurite outgrowth.Moreover,USP14 interacted directly with spastin to mediate its deubiquitination.USP14 overexpression significantly increased spastin expression and suppressed its ubiquitination and degradation.Although co-expression of spastin and USP14 did not enhance microtubule severing,it did increase neurite length in hippocampal neurons.Taken together,these findings elucidate the intricate regulatory mechanisms of spastin turnover,highlighting the roles of the Cullin-3–Ring E3 ubiquitin ligase complex and USP14 in orchestrating its ubiquitination and degradation.The dynamic interplay between these factors governs spastin stability and function,ultimately influencing microtubule dynamics and neuronal morphology.These insights shed light on potential therapeutic targets for neurodegenerative disorders associated with spastin defects.展开更多
Fibrotic remodeling of nucleus pulposus(NP)leads to structural and mechanical anomalies of intervertebral discs that prone to degeneration,leading to low back pain incidence and disability.Emergence of fibroblastic ce...Fibrotic remodeling of nucleus pulposus(NP)leads to structural and mechanical anomalies of intervertebral discs that prone to degeneration,leading to low back pain incidence and disability.Emergence of fibroblastic cells in disc degeneration has been reported,yet their nature and origin remain elusive.In this study,we performed an integrative analysis of multiple single-cell RNA sequencing datasets to interrogate the cellular heterogeneity and fibroblast-like entities in degenerative human NP specimens.We found that disc degeneration severity is associated with an enrichment of fibrocyte phenotype,characterized by CD45 and collagen I dual positivity,and expression of myofibroblast markerα-smooth muscle actin.Refined clustering and classification distinguished the fibrocyte-like populations as subtypes in the NP cells-and immunocytes-clusters,expressing disc degeneration markers HTRA1 and ANGPTL4 and genes related to response to TGF-β.In injury-induced mouse disc degeneration model,fibrocytes were found recruited into the NP undergoing fibrosis and adopted a myofibroblast phenotype.Depleting the fibrocytes in CD11b-DTR mice in which myeloid-derived lineages were ablated by diphtheria toxin could markedly attenuate fibrous modeling and myofibroblast formation in the NP of the degenerative discs,and prevent disc height loss and histomorphological abnormalities.Marker analysis supports that disc degeneration progression is dependent on a function of CD45^(+)COL1A1^(+)andαSMA^(+)cells.Our findings reveal that myeloid-derived fibrocytes play a pivotal role in NP fibrosis and may therefore be a target for modifying disc degeneration and promoting its repair.展开更多
Aging is one of the greatest risk factors for morbidity caused by the coronavirus disease 2019(COVID19).In older individuals,a dysregulated immune response to severe acute respiratory syndrome coronavirus 2(SARS-CoV-2...Aging is one of the greatest risk factors for morbidity caused by the coronavirus disease 2019(COVID19).In older individuals,a dysregulated immune response to severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection contributes to disease severity;however,the underlying mechanism remains elusive.In this study,we established an aging mouse model of COVID-19,successfully replicating the development of a relatively severe disease in older adults.Further single-cell transcriptome analysis revealed a distinct immune cell landscape in the infected lungs,accompanied by an over-activated inflammatory response,especially in aging mice.Compared to young mice,aging mice showed extensive neutrophil activation,NETosis,and a dramatic decrease in the number of alveolar macrophages(AMs).Moreover,as important executors of efferocytosis,AMs exhibited a low efferocytotic gene signature and downregulation of multiple efferocytosis receptors in aged mice.Further analysis indicated that the efferocytosis of neutrophils,whether undergoing apoptosis or NETosis,was compromised after SARS-CoV-2 infection.Since efferocytosis is a key process in inflammatory resolution,impaired efferocytosis may contribute to hyperinflammation in aging lungs.Our study reveals the characteristics and role of efferocytosis in aging mice after SARS-CoV-2 infection and provides valuable insights for the potential treatment of COVID-19.展开更多
基金funded by grants Pronaii 302979A1-S-9005 CONACyT (México) from RMDA。
文摘Dengue is an arboviral disease caused by the dengue virus,with 390 million infections reported annually worldwide.It is classified into two categories:dengue without or with warning signs and severe dengue.[1]Given the moderate efficacy of the dengue vaccine,[2]there is an urgent necessity to design host-directed therapeutic strategies,such as the repurposing of FDA-approved drugs,to combat dengue virus infection.
文摘BACKGROUND Acute pancreatitis(AP)is an emergency gastrointestinal disease that requires immediate diagnosis and urgent clinical treatment.An accurate assessment and precise staging of severity are essential in initial intensive therapy.AIM To explore the prognostic value of inflammatory markers and several scoring systems[Acute Physiology and Chronic Health Evaluation II,the bedside index of severity in AP(BISAP),Ranson’s score,the computed tomography severity index(CTSI)and sequential organ failure assessment]in severity stratification of earlyphase AP.METHODS A total of 463 patients with AP admitted to our hospital between 1 January 2021 and 30 June 2024 were retrospectively enrolled in this study.Inflammation marker and scoring system levels were calculated and compared between different severity groups.Relationships between severity and several predictors were evaluated using univariate and multivariate logistic regression models.Predictive ability was estimated using receiver operating characteristic curves.RESULTS Of the 463 patients,50(10.80%)were classified as having severe AP(SAP).The results revealed that the white cell count significantly increased,whereas the prognostic nutritional index measured within 48 hours(PNI48)and calcium(Ca^(2+))were decreased as the severity of AP increased(P<0.001).According to multivariate logistic regression,C-reactive protein measured within 48 hours(CRP_(48)),Ca^(2+)levels,and PNI48 were independent risk factors for predicting SAP.The area under the curve(AUC)values for the CRP_(48),Ca^(2+),PNI48,Acute Physiology and Chronic Health Evaluation II,sequential organ failure assessment,BISAP,CTSI,and Ranson scores for the prediction of SAP were 0.802,0.736,0.871,0.799,0.783,0.895,0.931 and 0.914,respectively.The AUC for the combined CRP_(48)+Ca^(2+)+PNI48 model was 0.892.The combination of PNI48 and Ranson achieved an AUC of 0.936.CONCLUSION Independent risk factors for developing SAP include CRP_(48),Ca^(2+),and PNI48.CTSI,BISAP,and the combination of PNI48 and the Ranson score can act as reliable predictors of SAP.
基金Chongqing Shapingba District Technology Innovation Project(Project No.:2024046)。
文摘Objective:To investigate the expression level of interleukin-17D(IL-17D)in the serum of patients with severe pneumonia and its correlation with disease severity.Methods:This study included 50 patients with severe pneumonia who were diagnosed and treated in the hospital from May 2024 to May 2025.The expression level of IL-17D in the serum of all patients was recorded.Patients were divided into severe and mild groups based on their disease severity.Gender,age,disease duration,presence of fever,atelectasis,pneumothorax,interleukin-2(IL-2),interleukin-4(IL-4),interleukin-6(IL-6),and interleukin-17D were selected as independent variables.Statistical software SPSS 22.00 was used for univariate analysis,and variables with statistical significance in the univariate analysis were included in a multivariate logistic regression analysis to determine the correlation between IL-17D and the severity of severe pneumonia.Results:The results of this study showed that the level of IL-17D in patients with severe pneumonia was significantly higher than the normal threshold.Univariate analysis indicated that atelectasis,IL-2,IL-6,and IL-17D were statistically significant(P<0.05)and could be considered as influencing factors for the severity of severe pneumonia.Multivariate logistic regression analysis revealed that atelectasis(OR=2.141,95%CI:1.684–2.391),IL-2(OR=2.884,95%CI:2.240–3.614),IL-6(OR=2.571,95%CI:2.190–2.943),and IL-17D(OR=2.416,95%CI:2.093–2.735)were positively correlated with the severity of severe pneumonia.Conclusion:The expression level of IL-17D in the serum of patients with severe pneumonia is higher than the normal threshold and is positively correlated with disease severity.
文摘The clinical treatment of severe trauma withsternoclavicular joint injury is challenging,primarilydue to the irregular shape of the bones surrounding thesternoclavicular joint,as well as the posterior clavicle beingclose to the aorta and mediastinal organs.^([1])These patientsnot only suffer direct injuries to the sternoclavicularjoint,but also frequently experience severe injuries toother body parts.The systemic physiological disordersand multi-organ dysfunction caused by severe traumaincrease the surgery di?culty and mortality risk.^([2])
基金supported by National Natural Science Foundation of China(81272737).
文摘Acute pancreatitis(AP)is a prevalent gastrointestinal disease necessitating hospitalization globally,with an annual incidence ranging from 13 to 45 per 100,000 individuals[1]and a mortality rate of 5%-10%.[2]While most cases follow a self-limiting course,approximately 20%-30%of cases progress to severe acute pancreatitis(SAP),characterized by pancreatic necrosis and multiorgan failure,with the mortality rate increasing to 36%-50%.
文摘BACKGROUND The imbalance of hormone levels in the body is closely related to the occurrence and progression of schizophrenia,especially thyroid hormones.AIM To study the relationship between triiodothyronine(T3),thyroxine(T4),free T3(FT3),free T4(FT4),thyroid stimulating hormone(TSH)and schizophrenia.METHODS In this study,100 schizophrenia patients were selected from our hospital between April 2022 and April 2024.Their clinical data were analyzed retrospectively.Based on the Positive and Negative Syndrome Scale(PANSS)score,patients were divided into mild(1-3 points,n=39),moderate(4 points,n=45),and severe groups(5-7 points,n=16).Additionally,55 healthy individuals served as a control group.Venous blood samples were collected to measure T3,T4,FT3,FT4,TSH,and cortisol concentrations,analyzing their relationship with PANSS scores.RESULTS The serum levels of T3,FT3,FT4,TSH and cortisol in the schizophrenia group were lower than those in the control group(P<0.05).With the increase of the severity of the disease,the concentrations of T3 and T4 decreased,while the con-centrations of TSH and cortisol increased(P<0.05).The concentrations of TSH and cortisol were positively correlated with the PANSS score,while T3 and T4 were negatively correlated with the PANSS score(P<0.05).The receiver ope-rating characteristic curve results showed that T3,T4,TSH,and cortisol had good efficacy in the diagnosis of schizophrenia.Logistic results showed that decreased T3 level,decreased T4 level,decreased TSH level and increased cortisol level may be independent risk factors for schizophrenia.CONCLUSION Thyroid hormone levels are associated with the severity of schizophrenia symptoms,which can provide new solutions for the diagnosis and treatment of schizophrenia.
基金supported by the National Natural Science Foundation of China(82102315).
文摘BACKGROUND:The lack of a stable,easy-to-operate animal model for severe trauma has hindered the research progress.The aim of this study is to develop a mouse model that replicates the pathophysiological conditions of severe trauma,providing a reliable research tool.METHODS:Male C57BL/6J mice(aged 8-10 weeks and weighting approximately 20 g)were used to establish the severe trauma model.Under anesthesia,a midshaft femoral fracture was created and packed with sterile cotton.A midline incision was made from the inguinal region to the sternum,exposing the abdominal organs for 30 min.The right femoral artery was cannulated to induce controlled blood loss at 30%,35%,40%,and 50%of the total blood volume.Survival rates were monitored for 24 h post-induction.In the mice that experienced 30%blood loss,the mean arterial pressure,body temperature,blood gas parameters,peripheral blood inflammatory markers,and major organ pathological changes were assessed.RESULTS:Mice with femoral fractures,soft tissue injuries,abdominal organ exposure,and 30%blood loss exhibited stable survival rates.Increased blood loss significantly reduced survival rates.Mean arterial pressure decreased initially,recovering within 0-15 min and returning to baseline by 50 min.Similarly,the body temperature decreased initially and gradually recovered to baseline within 50 min.Levels of peripheral blood inflammatory markers remained elevated for 12 h post-injury.Distant organs,including intestines,lungs,liver,spleen and kidneys,displayed varying degrees of injury.CONCLUSION:The established mouse model replicates the pathophysiological responses to severe trauma,indicating stability and reproducibility,which could be an useful tool for further trauma research.
基金supported by the National Natural Science Foundation of China(32170144 and 32470146).
文摘Severe fever with thrombocytopenia syndrome(SFTS)is a novel emerging acute infectious disease caused by severe fever with thrombocytopenia syndrome virus(SFTSV),characterized by high fever and thrombocytopenia.It has been proved that traditional Chinese medicine(TCM)has displayed definite therapeutic effects on viral hemorrhagic fever,indicating its potential to treat SFTS.In this study,SFTS-relative key targets were predicted via gene ontology(GO)analysis and kyoto encyclopedia of genes and genomes(KEGG)enrichment analysis.Molecular docking was then used to select stable binders.Molecules matched TCMs were identified,and a new prescription,Qingqi Guxue decoction(QQGX),was formulated to clear heat and nourish blood,with a resulting drug composition network.We explored the optimal drug proportion for QQGX.Through an in-depth study of molecular mechanisms,we found that QQGX induces S phase arrest by promoting the degradation of cyclin A2(CCNA2)and cyclin-dependent kinase 2(CDK2),thereby inhibiting SFTSV replication.Finally,we verified the effectiveness and safety of QQGX based on the mouse liver bile duct organoid model infected with SFTSV.In summary,our study prepared a TCM decoction using the method of network pharmacology.This decoction has a significant inhibitory effect on the replication of SFTSV and provides a new treatment strategy for hemorrhagic fever with TCM.
文摘BACKGROUND Coronavirus disease 2019(COVID-19)is strongly associated with an increased risk of thrombotic events,including severe outcomes such as pulmonary embolism.Elevated D-dimer levels are a critical biomarker for assessing this risk.In Gabon,early implementation of anticoagulation therapy and D-dimer testing has been crucial in managing COVID-19.This study hypothesizes that elevated Ddimer levels are linked to increased COVID-19 severity.AIM To determine the impact of D-dimer levels on COVID-19 severity and their role in guiding clinical decisions.METHODS This retrospective study analyzed COVID-19 patients admitted to two hospitals in Gabon between March 2020 and December 2023.The study included patients with confirmed COVID-19 diagnoses and available D-dimer measurements at admission.Data on demographics,clinical outcomes,D-dimer levels,and healthcare costs were collected.COVID-19 severity was classified as non-severe(outpatients)or severe(inpatients).A multivariable logistic regression model was used to assess the relationship between D-dimer levels and disease severity,with adjusted odds ratios(OR)and 95%CI.RESULTS A total of 3004 patients were included,with a mean age of 50.17 years,and the majority were female(53.43%).Elevated D-dimer levels were found in 65.81%of patients,and 57.21%of these experienced severe COVID-19.Univariate analysis showed that patients with elevated D-dimer levels had 3.33 times higher odds of severe COVID-19(OR=3.33,95%CI:2.84-3.92,P<0.001),and this association remained significant in the multivariable analysis,adjusted for age,sex,and year of collection.The financial analysis revealed a substantial burden,particularly for uninsured patients.CONCLUSION D-dimer predicts COVID-19 severity and guides treatment,but the high cost of anticoagulant therapy highlights the need for policies ensuring affordable access in resource-limited settings like Gabon.
文摘Background: Severe acute malnutrition (SAM) is one of the major public health problems associated with increased mortality in under-five children. In low-income countries, renal dysfunction (RD) contributes to about 34% mortality in under-five children with severe acute malnutrition. This study aimed to determine the impacts of severe acute malnutrition on the kidney among the admitted under-five children. Methods: In this prospective longitudinal observational study, a total of 190 children aged 6 to 59 months were enrolled from Iringa and Dodoma tertiary hospitals. Socio-demographic, clinical and laboratory data were collected using a structured questionnaire. Estimated Glomerular Filtration Rate (eGFR) and urine albumin creatinine ratio (uACR) were used to determine RD. Data analysis was done using SPSS version 26 and statistical significance was assumed for factors with p-value Results: Out of 190 children with severe acute malnutrition, 36 (19%) had renal dysfunction. Factors associated with RD in malnourished children were the history of local herbs used within one week (AOR = 5.85, 95% CI [1.41, 24.319], p = 0.0152), Acute watery diarrhea with severe dehydration (AOR = 2.15, 95% CI [1.033, 4.711], p = 0.0166), and positive urine leukocytes (AOR = 19.91, 95% CI [4.09, 96.989], p = 0.0002). At three months of follow up, out of 36 children with RD, 20 (55.56%) attained full recovery, while 4 (11.11%) developed chronic kidney disease (CKD). Children with RD had prolonged hospital stays for more than 14 days with a mean 12.25 ± 5.00 days compared to those with no RD with a mean 6.29 ± 1.68 days (p Conclusion: Renal dysfunction is common among children with severe acute malnutrition. It is associated with prolonged hospital stays and increased mortality. Further studies which can determine the burden of RD in children with severe acute malnutrition as compared to those with no severe acute malnutrition are needed.
基金supported by funding from the Medical Research Funding of Guangdong(No.A2022499 to QGX)the National Natural Science Foundation of China(No.82301796 to PL)the Guangdong Province Regional Joint Fund-Youth Fund Project of China(No.2022A1515111201 to PL).
文摘This study aimed to introduce a modified Byars staged procedure and investigate its application value in patients with severe hypospadias.We retrospectively analyzed the clinical data of patients with severe hypospadias admitted to the First Affiliated Hospital of Sun Yat-sen University(Guangzhou,China)between October 2012 and October 2022.In total,31 patients underwent the conventional Byars procedure(conventional group),and 45 patients underwent the modified Byars staged procedure(modified group).Our modified strategy was built upon the standard Byars procedure by incorporating glansplasty during the first stage and employing a Y-shaped flap in conjunction with a glandular tunnel for urethroplasty during the second stage.Notably,there were no statistically significant differences in the preoperative baseline characteristics,duration of surgery,amount of blood loss,or occurrence of postoperative complications,including urethral fistula,stricture and diverticulum,or penile curvature,between the conventional and modified groups.However,there was a significantly lower incidence of coronal sulcus fistula(0 vs 16.1%,P=0.02)and glans dehiscence(0 vs 12.9%,P=0.02)in the surgical group than that in the conventional group.In addition,the modified group exhibited a notably greater rate of normotopic urethral opening(100.0%vs 83.9%,P=0.01)and a higher mean score on the Hypospadias Objective Penile Evaluation(HOPE;mean±standard error of mean:8.6±0.2 vs 7.9±0.3,P=0.02)than did the conventional group.In conclusion,the modified Byars staged procedure significantly reduced the risks of glans dehiscence and coronal sulcus fistula.Consequently,it offers a promising approach for achieving favorable penile esthetics,thereby providing a reliable therapeutic option for severe hypospadias.
基金providing by the Shenzhen City Nanshan District Science and Technology Plan Project(Medical and Health Category)(Grant No.2018073)。
文摘Objective:To assess whether there is a correlation between CT scan severity score and pulmonary function in Interstitial Lung Disease,and provide a more reliable basis for clinical diagnosis and treatment.Materials and Methods:Sixty patients with clinical diagnosis of Interstitial Lung Disease(ILD)were collected,and chest CT and pulmonary function tests were performed at the same time.Here DLCO%and FEV1%were used as the pulmonary function indexes.The severity of the patients was assessed by CT scores as mild(range,1~10),moderate(range 11~20),and severe(range 21~30).Correlation analysis was carried out between CT score and pulmonary function index,and the lung function parameters of patients at three grades were compared between groups and pairwise among the means.Results:As per the CT severity classification,there were 13 mild cases,31 moderate cases,and 16 severe cases.CT score was negatively correlated with DLCO%and FEV1%.R value was-0.814 and-0.797,respectively;The comparison of the mean value of DLCO%and FEV1%among the three groups and the pairings of the mean value of DLCO%and FEV1%were statistically significant.Conclusion:There was good correlation between CT score of ILD and the pulmonary function index.The pulmonary function index of patients with different CT severity grading was statistically significant,which can provide a new basis for the clinical evaluation and diagnosis of the disease.
文摘A recent single-center retrospective study proposed novel combinations of hematological parameters and scoring systems for predicting severe acute pancre-atitis.While these combinations showed promising predictive performance,several limitations warrant consideration,including the lack of calibration,the absence of key inflammatory markers such as procalcitonin,and practical challenges in integrating these models into routine clinical workflows.To improve predictive accuracy and clinical applicability,prospective validation and the inclusion of additional variables are recommended.
文摘Acute pancreatitis(AP)is a complex and potentially life-threatening inflammatory condition with a highly variable clinical course,ranging from mild,selflimiting episodes to severe necrotizing forms.Among its common complications ascites has traditionally been viewed as a passive byproduct of peritoneal inflammation and enzymatic leakage with limited diagnostic or prognostic utility.However,growing evidence challenges this perspective,suggesting that ascitic fluid in AP represents a dynamic and clinically meaningful component of disease progression.In this editorial we reflected on the findings presented by Rao et al,who highlighted the diagnostic,prognostic,and therapeutic significance of ascitic fluid in AP.Easily accessible markers such as lactate dehydrogenase may provide early prognostic insight while emerging molecular biomarkers and cytokine pro-files offer promise for more precise risk stratification and individualized therapy.We argue that the systematic evaluation of ascitic fluid should be integrated into the clinical management of moderate to severe AP.Incorporating ascites analysis into standard diagnostic protocols may enhance early risk assessment,inform therapeutic decisions,and ultimately improve patient outcomes.Ascitic fluid should be recognized as a clinically valuable marker and an important source of information in the evolving landscape of AP care.
文摘This study examines the interaction between emotional states(anxiety and depression)and tinnitus severity in individuals undergoing a four-month sound therapy intervention.43 participants(28 males and 15 females)of a study on four-month sound therapy of tinnitus were recruited and their tinnitus severity(Tinnitus Handicap Inventory,THI,and Tinnitus Functional Index,TFI)and emotional state(Hospitalary Anxiety and Depression Scale,HADS)were assessed before and after finishing the treatment.The participants,predominantly with moderate tinnitus,showed a significant reduction in tinnitus-related distress,with a mean reduction of approximately 30 points on both the THI and the TFI.Analysis revealed significant gender differences,with women experiencing higher baseline tinnitus distress but higher response to sound therapy.Emotional state assessments revealed moderate levels of anxiety and depression at baseline,which decreased significantly after therapy,particularly in women.Correlational analyses revealed a strong relationship between changes in emotional state and tinnitus severity,with reductions in anxiety and depression associated with improved tinnitus outcomes.The results highlight the complex relationship between emotional well-being and tinnitus severity and underline the potential of sound therapy to alleviate both emotional distress and tinnitus symptoms.
基金Supported by Guangzhou Municipal Science and Technology Bureau,No.SL2024AD3JD0112.
文摘BACKGROUND Boerhaave syndrome,or spontaneous esophageal rupture,is a rare and lifethreatening emergency,typically caused by a sudden increase in esophageal pressure due to violent coughing or vomiting.Early diagnosis is challenging as its symptoms often resemble those of other diseases.Understanding its pathological features and treatment strategies is therefore critical for clinical practice.CASE SUMMARY This report describes a case of spontaneous esophageal rupture triggered by violent coughing in a 55-year-old male with a history of smoking and hypertension.Following severe coughing,the patient developed chest pain,vomiting,and respiratory distress.Initial clinical evaluation was inconclusive,with a suspected diagnosis of cardiovascular or gastrointestinal conditions.After further examination,the diagnosis of spontaneous esophageal rupture was confirmed.Chest X-ray,computed tomography,and endoscopy revealed a rupture in the lower esophagus,along with mediastinal abscess and pleural effusion.Laboratory tests showed mild infection markers.The patient underwent surgical repair of the esophageal rupture(approximately 3 cm in length)with mediastinal drainage.Postoperatively,the patient’s temperature normalized within 3 days,respiratory function improved,and pleural effusion significantly decreased.After two weeks of treatment,the patient was discharged without complications and had a favorable prognosis.The study suggests that while violent coughing is a rare trigger,it can lead to severe damage,and imaging techniques play a crucial role in diagnosis.CONCLUSION Spontaneous esophageal rupture presents significant diagnostic and therapeutic challenges.Early recognition and timely intervention are crucial for improving prognosis.This case highlights the importance of imaging and surgical treatment,offering new insights for managing similar cases and providing valuable clinical guidance.
基金Key-Area Research and Development Program of Guangdong (2020B1111200001)National Natural Science Foundation of China (42230105, U2142213, 42175167)。
文摘Taking short-duration heavy rainfall and convective wind gusts as examples, the present study examined the characteristics of radar reflectivity and several convective parameters. We analyzed nowcasting techniques by integrating a high-resolution numerical weather prediction model with these convective parameters. Based on the CMA-GD 1-km model and its assimilation system, we conducted repeated tests on radar reflectivity data assimilation and analyzed their impact on nowcasting accuracy. Based on these analyses, we proposed a method to improve model forecasts using the useful indicative information provided by high-frequency radar reflectivity data and convective parameters. The improved method was applied to the CMA-GD 1-km model for nowcasting tests. Evaluations from batch tests and case analysis show that the proposed method significantly reduced the model's false alarm rates and improved its nowcasting performance.
基金supported by the National Natural Science Foundation of China,No.32071033(to MT)Basic and Applied Basic Research Foundation of Guangdong Province,Nos.2023A1515010140(to MT),2022A1515140169(to MT),2022A1515111096(to ZC)+3 种基金Science and Technology Project of Guangzhou,Nos.202201010015(to YL),2023A03J0790(to TJ)Basic and Applied Basic Research Foundation of Guangzhou,No.2023A04J1285(to ZC)Medical Research Foundation of Guangdong Province,No.A2023147(to ZC)Health Science and Technology Project of Guangzhou,No.20221A011039(to TJ)。
文摘Post-translational modification of spastin enables precise spatiotemporal control of its microtubule severing activity.However,the detailed mechanism by which spastin turnover is regulated in the context of neurite outgrowth remains unknown.Here,we found that spastin interacted with ubiquitin and was significantly degraded by K48-mediated poly-ubiquitination.Cullin3 facilitated spastin degradation and ubiquitination.RING-box protein 1,but not RING-box protein 2,acted synergistically with Cullin3 protein to regulate spastin degradation.Overexpression of Culin3 or BRX1 markedly suppressed spastin expression,and inhibited spastin-mediated microtubule severing and promotion of neurite outgrowth.Moreover,USP14 interacted directly with spastin to mediate its deubiquitination.USP14 overexpression significantly increased spastin expression and suppressed its ubiquitination and degradation.Although co-expression of spastin and USP14 did not enhance microtubule severing,it did increase neurite length in hippocampal neurons.Taken together,these findings elucidate the intricate regulatory mechanisms of spastin turnover,highlighting the roles of the Cullin-3–Ring E3 ubiquitin ligase complex and USP14 in orchestrating its ubiquitination and degradation.The dynamic interplay between these factors governs spastin stability and function,ultimately influencing microtubule dynamics and neuronal morphology.These insights shed light on potential therapeutic targets for neurodegenerative disorders associated with spastin defects.
基金jointly General Research Fund(17121619)of the Research Grant Council of Hong KongGuangdong Basic and Applied Basic Research Foundation(2024A1515010104 and 2023A1515220095)Scientific Research Foundation of Peking University Shenzhen Hospital(KYQD202100X)。
文摘Fibrotic remodeling of nucleus pulposus(NP)leads to structural and mechanical anomalies of intervertebral discs that prone to degeneration,leading to low back pain incidence and disability.Emergence of fibroblastic cells in disc degeneration has been reported,yet their nature and origin remain elusive.In this study,we performed an integrative analysis of multiple single-cell RNA sequencing datasets to interrogate the cellular heterogeneity and fibroblast-like entities in degenerative human NP specimens.We found that disc degeneration severity is associated with an enrichment of fibrocyte phenotype,characterized by CD45 and collagen I dual positivity,and expression of myofibroblast markerα-smooth muscle actin.Refined clustering and classification distinguished the fibrocyte-like populations as subtypes in the NP cells-and immunocytes-clusters,expressing disc degeneration markers HTRA1 and ANGPTL4 and genes related to response to TGF-β.In injury-induced mouse disc degeneration model,fibrocytes were found recruited into the NP undergoing fibrosis and adopted a myofibroblast phenotype.Depleting the fibrocytes in CD11b-DTR mice in which myeloid-derived lineages were ablated by diphtheria toxin could markedly attenuate fibrous modeling and myofibroblast formation in the NP of the degenerative discs,and prevent disc height loss and histomorphological abnormalities.Marker analysis supports that disc degeneration progression is dependent on a function of CD45^(+)COL1A1^(+)andαSMA^(+)cells.Our findings reveal that myeloid-derived fibrocytes play a pivotal role in NP fibrosis and may therefore be a target for modifying disc degeneration and promoting its repair.
基金supported by the National Key Research and Development Program of China(NKPs)(2022YFC2604101).
文摘Aging is one of the greatest risk factors for morbidity caused by the coronavirus disease 2019(COVID19).In older individuals,a dysregulated immune response to severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection contributes to disease severity;however,the underlying mechanism remains elusive.In this study,we established an aging mouse model of COVID-19,successfully replicating the development of a relatively severe disease in older adults.Further single-cell transcriptome analysis revealed a distinct immune cell landscape in the infected lungs,accompanied by an over-activated inflammatory response,especially in aging mice.Compared to young mice,aging mice showed extensive neutrophil activation,NETosis,and a dramatic decrease in the number of alveolar macrophages(AMs).Moreover,as important executors of efferocytosis,AMs exhibited a low efferocytotic gene signature and downregulation of multiple efferocytosis receptors in aged mice.Further analysis indicated that the efferocytosis of neutrophils,whether undergoing apoptosis or NETosis,was compromised after SARS-CoV-2 infection.Since efferocytosis is a key process in inflammatory resolution,impaired efferocytosis may contribute to hyperinflammation in aging lungs.Our study reveals the characteristics and role of efferocytosis in aging mice after SARS-CoV-2 infection and provides valuable insights for the potential treatment of COVID-19.
