BACKGROUND: The level of measurable residual disease (MRD) before and after transplantation is related to inferior transplant outcomes, and post-hematopoietic stem cell transplantation measurable residual disease (post-HSCT MRD) has higher prognostic value in determining risk than pre-hematopoietic stem cell transplantation measurable residual disease (pre-HSCT MRD). However, only a few work has been devoted to the risk factors for positive post-HSCT MRD in patients with acute lymphoblastic leukemia (ALL). This study evaluated the risk factors for post-HSCT MRD positivity in patients with ALL who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: A total of 1683 ALL patients from Peking University People's Hospital between January 2009 and December 2019 were enrolled to evaluate the cumulative incidence of post-HSCT MRD. Cox proportional hazard regression models were built for time-to-event outcomes. Multivariable analysis was performed to determine independent influencing factors from the univariable analysis. RESULTS: Both in total patients and in T-cell ALL or B-cell ALL, pediatric or adult, human leukocyte antigen-matched sibling donor transplantation or haploidentical SCT subgroups, positive pre-HSCT MRD was a risk factor for post-HSCT MRD positivity ( P  <0.001 for all). Disease status (complete remission 1 [CR1] vs . ≥CR2) was also a risk factor for post-HSCT MRD positivity in all patients and in the B cell-ALL, pediatric, or haploidentical SCT subgroups ( P  = 0.027; P  = 0.003; P  = 0.035; P  = 0.003, respectively). A risk score for post-HSCT MRD positivity was developed using the variables pre-HSCT MRD and disease status. The cumulative incidence of post-HSCT MRD positivity was 12.3%, 25.1%, and 38.8% for subjects with scores of 0, 1, and 2-3, respectively ( P  <0.001). Multivariable analysis confirmed the association of the risk score with the cumulative incidence of post-HSCT MRD positivity and relapse as well as leukemia-free survival and overall survival. CONCLUSION Our results indicated that positive pre-MRD and disease status were two independent risk factors for post-HSCT MRD positivity in patients with ALL who underwent allo-HSCT.
Humans ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology* ; Neoplasm, Residual ; Hematopoietic Stem Cell Transplantation/methods* ; Male ; Female ; Risk Factors ; Adolescent ; Adult ; Child ; Child, Preschool ; Young Adult ; Middle Aged ; Infant ; Transplantation, Homologous ; Proportional Hazards Models ; Retrospective Studies

ObjectiveTo investigate the mechanisms of mitochondrial dynamics and metabolic reprogramming in the treatment of diabetic nephropathy （DN） by Shenxiao Tongluo prescription via the peroxisome proliferator-activated receptor γ coactivator-1α （PGC-1α）/sirtuin-3 （SIRT3）/hypoxia-inducible factor-1α （HIF-1α） signaling pathway. MethodsSixty-five SD rats were randomized into a sham group （10 rats） and a modeling group （55 rats）， and the modeling rats underwent left nephrectomy and intraperitoneal injection of streptozotocin （35 mg·kg^-1） to prepare a DN model. After successful modeling， the rats were randomized into model， empagliflozin （10 mg·kg^-1）， and low-， medium-， and high-dose （7.656， 15.312， 30.624 g·kg^-1， respectively） Shenxiao Tongluo prescription groups. The urine microalbumin （UmAlb）， blood urea nitrogen （BUN）， and serum creatinine （SCr） levels of rats in each group were assessed after continuous gavage for 8 weeks. The corresponding kits were used to measure the levels of lactate， superoxide dismutase （SOD）， and malondialdehyde （MDA） in the kidney tissue. Hematoxylin-eosin staining， Masson staining， and periodic acid-Schiff staining were performed to observe the pathological changes in the kidney tissue. Transmission electron microscopy was employed to observe mitochondrial morphology. Immunohistochemistry was employed to determine the expression levels of dynamin-related protein 1 （DRP1） and pyruvate kinase M2 （PKM2） in the kidney tissue. Western blot was adopted to assess the protein levels of PGC-1α， SIRT3， HIF-1α， dynamin-related protein 1 （Drp1）， optic atrophy 1 （OPA1）， hexokinase 2 （HK2）， and pyruvate kinase M2 （PKM2） in the kidney tissue. ResultsCompared with the sham group， the model group showed elevated levels of UmAlb， BUN， SCr， lactate， and MDA， decreased SOD level （P<0.05）， glomerular hypertrophy， thickening of the mesangial basement membrane， vacuolar degeneration of renal tubular epithelial cells， and infiltration of renal interstitial inflammatory cells， oval mitochondria with disordered， blurred or disappearing cristae， down-regulated protein levels of PGC-1α， SIRT3， and OPA1， and up-regulated protein levels of HIF-1α， DRP1， HK2， and PKM2 （P<0.05）. Compared with the model group， the treatment in all the groups increased the body weight， lowered the levels of GLU， UmAlb， BUN， and MDA， raised the level of SOD， alleviated the pathological damage in the kidney tissue and mitochondrial damage， up-regulated the expression of PGC-1α， SIRT3， and OPA1， and down-regulated the expression of HIF-1α， DRP1， and PKM2 （P<0.05）. Empagliflozin and Shenxiao Tongluo prescription at medium and high doses lowered the levels of SCr and lactate and down-regulated the expression of HK2 （P<0.05）， which had no statistical significance in the low-dose Shenxiao Tongluo prescription group. ConclusionShenxiao Tongluo prescription may regulate mitochondrial dynamics and metabolic reprogramming by activating the PGC-1α/SIRT3/HIF-1α pathway， thereby alleviating oxidative damage in the kidney tissue and delaying the progression of DN.

ObjectiveTo investigate the mechanisms of mitochondrial dynamics and metabolic reprogramming in the treatment of diabetic nephropathy （DN） by Shenxiao Tongluo prescription via the peroxisome proliferator-activated receptor γ coactivator-1α （PGC-1α）/sirtuin-3 （SIRT3）/hypoxia-inducible factor-1α （HIF-1α） signaling pathway. MethodsSixty-five SD rats were randomized into a sham group （10 rats） and a modeling group （55 rats）， and the modeling rats underwent left nephrectomy and intraperitoneal injection of streptozotocin （35 mg·kg^-1） to prepare a DN model. After successful modeling， the rats were randomized into model， empagliflozin （10 mg·kg^-1）， and low-， medium-， and high-dose （7.656， 15.312， 30.624 g·kg^-1， respectively） Shenxiao Tongluo prescription groups. The urine microalbumin （UmAlb）， blood urea nitrogen （BUN）， and serum creatinine （SCr） levels of rats in each group were assessed after continuous gavage for 8 weeks. The corresponding kits were used to measure the levels of lactate， superoxide dismutase （SOD）， and malondialdehyde （MDA） in the kidney tissue. Hematoxylin-eosin staining， Masson staining， and periodic acid-Schiff staining were performed to observe the pathological changes in the kidney tissue. Transmission electron microscopy was employed to observe mitochondrial morphology. Immunohistochemistry was employed to determine the expression levels of dynamin-related protein 1 （DRP1） and pyruvate kinase M2 （PKM2） in the kidney tissue. Western blot was adopted to assess the protein levels of PGC-1α， SIRT3， HIF-1α， dynamin-related protein 1 （Drp1）， optic atrophy 1 （OPA1）， hexokinase 2 （HK2）， and pyruvate kinase M2 （PKM2） in the kidney tissue. ResultsCompared with the sham group， the model group showed elevated levels of UmAlb， BUN， SCr， lactate， and MDA， decreased SOD level （P<0.05）， glomerular hypertrophy， thickening of the mesangial basement membrane， vacuolar degeneration of renal tubular epithelial cells， and infiltration of renal interstitial inflammatory cells， oval mitochondria with disordered， blurred or disappearing cristae， down-regulated protein levels of PGC-1α， SIRT3， and OPA1， and up-regulated protein levels of HIF-1α， DRP1， HK2， and PKM2 （P<0.05）. Compared with the model group， the treatment in all the groups increased the body weight， lowered the levels of GLU， UmAlb， BUN， and MDA， raised the level of SOD， alleviated the pathological damage in the kidney tissue and mitochondrial damage， up-regulated the expression of PGC-1α， SIRT3， and OPA1， and down-regulated the expression of HIF-1α， DRP1， and PKM2 （P<0.05）. Empagliflozin and Shenxiao Tongluo prescription at medium and high doses lowered the levels of SCr and lactate and down-regulated the expression of HK2 （P<0.05）， which had no statistical significance in the low-dose Shenxiao Tongluo prescription group. ConclusionShenxiao Tongluo prescription may regulate mitochondrial dynamics and metabolic reprogramming by activating the PGC-1α/SIRT3/HIF-1α pathway， thereby alleviating oxidative damage in the kidney tissue and delaying the progression of DN.

Objective To analyze the structural and phylogenetic characteristics of the mitochondrial genome from Bulinus globosus, so as to provide a theoretical basis for classification and identification of species within the Bulinus genus, and to provide insights into understanding of Bulinus-schistosomes interactions and the mechanisms of parasite transmission. Methods B. globosus samples were collected from the Ruya River basin in Zimbabwe. Mitochondrial DNA was extracted from B. globosus samples and the corresponding libraries were constructed for high-throughput sequencing on the Illumina NovaSeq 6000 platform. After raw sequencing data were subjected to quality control using the fastp software, genome assembly was performed using the A5-miseq and SPAdes tools, and genome annotation was conducted using the MITOS online server. Circular maps and sequence plots of the mitochondrial genome were generated using the CGView and OGDRAW software, and the protein conservation motifs and structures were analyzed using the TBtools software. Base composition and codon usage bias were analyzed and visualized using the software MEGA X and the ggplot2 package in the R software. In addition, a phylogenetic tree was created in the software MEGA X after sequence alignment with the software MAFFT 7, and visualized using the software iTOL. Results The mitochondrial genome of B. globosus was a 13 730 bp double-stranded circular molecule, containing 2 ribosomal RNA (rRNA) genes, 22 transfer RNA (tRNA) genes, and 13 protein-coding genes, with a marked AT preference. The mitochondrial genome composition of B. globosus was similar to that of other species within the Bulinus genus. Phylogenetic analysis revealed that the complete mitochondrial genome sequence of B. globosus was clustered with B. truncatus, B. nasutus, and B. ugandae into the same evolutionary clade, and gene superfamily analysis showed that the metabolism-related proteins of B. globosus were highly conserved, notably the cytochrome c oxidase family, which showed a significant consistency. Conclusions This is the first whole mitochondrial genome sequencing to decode the compositional features of the mitochondrial genome of B. globosus from Zimbabwe and its evolutionary relationship within the Bulinus genus, which provides important insights for further understanding of the phylogeny and mitochondrial genome characteristics of the Bulinus genus.

Coronavirus-related diseases pose a significant challenge to the global health system. Given the diversity of coronaviruses and the unpredictable nature of disease outbreaks, the traditional "one bug, one drug" paradigm struggles to address the growing number of emerging crises. Therefore, there is an urgent need for therapeutic agents with broad-spectrum anti-coronavirus activity. Here, we provide evidence that ATV006, an anti-SARS-CoV-2 nucleoside analog targeting RNA-dependent RNA polymerase (RdRp), has broad antiviral activity against human and animal coronaviruses. Using mouse hepatitis virus (MHV) and human coronavirus NL63 (HCoV-NL63) as a model, we show that ATV006 has potent prophylactic and therapeutic activity against murine coronavirus infection in vivo. Remarkably, ATV006 successfully inhibits viral replication in mice even when administered 96 h after infection. Due to its oral bioavailability and potency against multiple coronaviruses, ATV006 has the potential to become a useful antiviral agent against SARS-CoV-2 and other circulating and emerging coronaviruses in humans and animals.

Objective To analyze the clinical characteristics and explore the potential mechanisms under-lying acute wheezing associated with respiratory syncytial virus(RSV)and human rhinovirus(HRV)infections in infants.Methods A retrospective analysis was conducted on 560 infants who consecutively presented to the emer-gency department of Qingdao University Affiliated Women and Children's Hospital between January 2022 and December 2024 with acute exacerbation of wheezing caused by RSV and/or HRV infection;these infants constituted the infection group.A control group of 120 healthy infants who underwent routine physical examinations at the same hospital during the same period was also included.Multiplex PCR amplification sequencing technology was employed to detect respiratory pathogens via nucleic acid analysis.The infection group was further classified into the RSV-only group(n=248),the HRV-only group(n=186),and the co-infection group(HRV+RSV,n=126).One-way analysis of variance(ANOVA)was used to compare body mass index(BMI),peripheral blood white blood cell(WBC)count,neutrophil count,lymphocyte count,C-reactive protein(CRP)levels,and concentrations of interleukin(IL)-1β,IL-6,Toll-like receptor 4(TLR4),NOD-like receptor protein 3(NLRP3)inflamma-some,and matrix metalloproteinase-9(MMP-9)across the groups.Additionally,comparisons were made regarding gender distribution,severity of wheezing,history of wheezing,history of eczema,parental allergic history,oxygen supplementation requirements,and presence of concurrent pulmonary infection among the infected infants.Based on wheezing severity,the infection group was further divided into a severe wheezing group and a mild wheezing group.Clinical characteristics and biological indicators were analyzed and compared between these two groups to identify potential independent risk factors.Pearson correlation analysis was performed to evaluate the association between peripheral blood levels of IL-6,NLRP3,and MMP-9 and the severity of acute wheezing exacerbation in children.Results A one-way ANOVA indicated statistically significant differences in WBC count,neutrophil count,CRP,IL-1β,IL-6,TLR4,NLRP3,and MMP-9 levels across the study groups(all P<0.001).Both the RSV and co-infection groups demonstrated significantly higher rates of severe wheezing,oxygen requirement,and prolonged wheezing duration compared to the HRV group(all P<0.05).Among these,the co-infection group exhibited the highest oxygen requirement rate,although the duration of wheezing was shorter than that observed in the RSV group(P<0.05).The incidence of concurrent pulmonary infection was significantly greater in the RSV group compared to the HRV group(P<0.05).Additionally,the proportion of infants with a prior history of wheez-ing was significantly higher in the RSV group than in both the HRV and co-infection groups(P<0.05).Both the RSV and co-infection groups showed a significantly higher prevalence of eczema history among infants compared to the HRV group(P<0.05).Moreover,the co-infection group had a significantly higher proportion of parental allergic history compared with both the RSV and HRV groups(P<0.05).Clinical data analysis stratified by wheezing severity revealed that RSV was the most commonly detected virus among the enrolled infants,particularly in those presenting with severe wheezing(χ2=3.940,P=0.002).The severe wheezing group exhibited significantly higher rates of prior wheezing,history of eczema,parental allergy,need for oxygen supplementation,and concurrent pulmonary infections compared to the mild wheezing group(P<0.001).Furthermore,the duration of wheezing was significantly prolonged in the severe group relative to the mild group(t=2.058,P=0.040).Levels of IL-6,NLRP3,and MMP-9 were also significantly elevated in the severe wheezing group(P<0.05).Multivariate logistic regression analysis revealed that RSV infection,along with elevated levels of IL-6,NLRP3,and MMP-9,were independent risk factors associated with severe wheezing(OR=3.217,1.023,1.022,and 1.056,respectively;all P<0.05).In children with RSV/HRV infection,the severity of acute wheezing demonstrated a positive correlation with NLRP3 and MMP-9 levels(P<0.05).The Pearson correlation coefficient between NLRP3 and MMP-9 was r=0.238(P<0.001),indicating a weak yet statistically significant positive relationship.Conclusions RSV may provoke more severe respiratory inflammatory responses and clinical manifestations compared to HRV.Individuals with a genetic predisposition to allergies or a pre-existing history of respiratory conditions may experience height-ened severity of wheezing following viral infection.The NLRP3 inflammasome may further intensify airway inflam-mation and remodeling through the promotion of MMP-9 release.These mechanisms may collectively contribute to the pathogenesis of acute wheezing episodes and subsequently influence the progression of respiratory diseases.

Objective To analyze the clinical characteristics and explore the potential mechanisms under-lying acute wheezing associated with respiratory syncytial virus(RSV)and human rhinovirus(HRV)infections in infants.Methods A retrospective analysis was conducted on 560 infants who consecutively presented to the emer-gency department of Qingdao University Affiliated Women and Children's Hospital between January 2022 and December 2024 with acute exacerbation of wheezing caused by RSV and/or HRV infection;these infants constituted the infection group.A control group of 120 healthy infants who underwent routine physical examinations at the same hospital during the same period was also included.Multiplex PCR amplification sequencing technology was employed to detect respiratory pathogens via nucleic acid analysis.The infection group was further classified into the RSV-only group(n=248),the HRV-only group(n=186),and the co-infection group(HRV+RSV,n=126).One-way analysis of variance(ANOVA)was used to compare body mass index(BMI),peripheral blood white blood cell(WBC)count,neutrophil count,lymphocyte count,C-reactive protein(CRP)levels,and concentrations of interleukin(IL)-1β,IL-6,Toll-like receptor 4(TLR4),NOD-like receptor protein 3(NLRP3)inflamma-some,and matrix metalloproteinase-9(MMP-9)across the groups.Additionally,comparisons were made regarding gender distribution,severity of wheezing,history of wheezing,history of eczema,parental allergic history,oxygen supplementation requirements,and presence of concurrent pulmonary infection among the infected infants.Based on wheezing severity,the infection group was further divided into a severe wheezing group and a mild wheezing group.Clinical characteristics and biological indicators were analyzed and compared between these two groups to identify potential independent risk factors.Pearson correlation analysis was performed to evaluate the association between peripheral blood levels of IL-6,NLRP3,and MMP-9 and the severity of acute wheezing exacerbation in children.Results A one-way ANOVA indicated statistically significant differences in WBC count,neutrophil count,CRP,IL-1β,IL-6,TLR4,NLRP3,and MMP-9 levels across the study groups(all P<0.001).Both the RSV and co-infection groups demonstrated significantly higher rates of severe wheezing,oxygen requirement,and prolonged wheezing duration compared to the HRV group(all P<0.05).Among these,the co-infection group exhibited the highest oxygen requirement rate,although the duration of wheezing was shorter than that observed in the RSV group(P<0.05).The incidence of concurrent pulmonary infection was significantly greater in the RSV group compared to the HRV group(P<0.05).Additionally,the proportion of infants with a prior history of wheez-ing was significantly higher in the RSV group than in both the HRV and co-infection groups(P<0.05).Both the RSV and co-infection groups showed a significantly higher prevalence of eczema history among infants compared to the HRV group(P<0.05).Moreover,the co-infection group had a significantly higher proportion of parental allergic history compared with both the RSV and HRV groups(P<0.05).Clinical data analysis stratified by wheezing severity revealed that RSV was the most commonly detected virus among the enrolled infants,particularly in those presenting with severe wheezing(χ2=3.940,P=0.002).The severe wheezing group exhibited significantly higher rates of prior wheezing,history of eczema,parental allergy,need for oxygen supplementation,and concurrent pulmonary infections compared to the mild wheezing group(P<0.001).Furthermore,the duration of wheezing was significantly prolonged in the severe group relative to the mild group(t=2.058,P=0.040).Levels of IL-6,NLRP3,and MMP-9 were also significantly elevated in the severe wheezing group(P<0.05).Multivariate logistic regression analysis revealed that RSV infection,along with elevated levels of IL-6,NLRP3,and MMP-9,were independent risk factors associated with severe wheezing(OR=3.217,1.023,1.022,and 1.056,respectively;all P<0.05).In children with RSV/HRV infection,the severity of acute wheezing demonstrated a positive correlation with NLRP3 and MMP-9 levels(P<0.05).The Pearson correlation coefficient between NLRP3 and MMP-9 was r=0.238(P<0.001),indicating a weak yet statistically significant positive relationship.Conclusions RSV may provoke more severe respiratory inflammatory responses and clinical manifestations compared to HRV.Individuals with a genetic predisposition to allergies or a pre-existing history of respiratory conditions may experience height-ened severity of wheezing following viral infection.The NLRP3 inflammasome may further intensify airway inflam-mation and remodeling through the promotion of MMP-9 release.These mechanisms may collectively contribute to the pathogenesis of acute wheezing episodes and subsequently influence the progression of respiratory diseases.

Objective To investigate the effects of microgravity environment on hibernating myoblasts.Methods Hibernating myoblasts were cultured under real and simulated microgravity conditions for 10 days.RNA-seq analysis and immunofluorescence are used to analysis the impact of microgravity environment on cell growth and gene expression of myoblasts.Results Under the microgravity conditions,genes associated with proliferation were upregulated.Under simulated microgravity,there were more and higher proportion of Ki67 positive cells compared to normal gravity conditions.Conclusion The microgravity environment promotes the proliferation of hibernating myoblasts.

Poly(dimethyl siloxane)(PDMS)is suitable for the fabrication of space cell culture chips.It is necessary to perform highly stable hydrophilic modification to promote cell adhesion on PDMS surface.We modified PDMS surface by oxygen plasma treatment combining with physical adsorption in this article.PDMS,which was treated with oxygen plasma and sequentially coated with Poly-L-lysine or collagen(PLL-ox-PDMS,COL-ox-PDMS)with various solution concentration and kept in different environmental conditions,were characterized by contact angle and surface energy measurements,and atomic force microscopy(AFM).Cell growth conditions on bare PDMS and modified PDMS were compared,and the numbers of live cells cultured for 1-3 days were evaluated.Experimental results indicate that higher solution concentration and low storage temperature benefit the hydrophilicity stability.The contact angles of PLL-ox-PDMS stored in 4℃and COL-ox-PDMS were close to 60°and 65°on day 25 and 14,respectively.Both modified PDMS surfaces are suitable for cell adhesion and proliferation,and no cell layer falls offin 10 days.The modification method is especially suitable for applications such as medium and long term space cell culture.

Critical care medicine-related treatment is an interdisciplinary and multi-professional process,often leading to secondary or concomitant mental disorders in clinical practice.Currently,there is no consensus on the pharmacological treatment of related mental illnesses in China.The Chinese Society of Psychosomatic Medicine collaborated with the Critical Care Medicine expert group to form a consensus writing expert group.After a systematic review of relevant literature,summarizing published domestic and foreign literature,and extensive discussions,the consensus was developed.The consensus elaborates on the principles and processes of the standardized use of psychotropic drugs in critical care medicine,as well as the clinical indications,precautions,and specific drug selection of various psychiatric medications,providing feasible suggestions and guidance for the clinical application of psychiatric medications in the intensive care unit.