ObjectiveTo explore the regulatory effect of Ganluqingwen prescription on inflammation and immunity by observing the clinical efficacy of Ganluqingwen prescription in the treatment of community-acquired pneumonia （CAP）， so as to provide a clinical basis for the treatment of CAP by traditional Chinese medicine （TCM）. MethodsA randomized controlled trial was conducted by selecting patients who were diagnosed with CAP and identified as wind-heat attacking lungs in Xinjiang Uygur Autonomous Region Hospital of TCM from January 2024 to May 2024 and assigning the patients to a control group （treated by western medicine treatment） or an experimental group （treated by Ganluqingwen prescription combined with western medicine）. The data of the enrolled patients before treatment， for three-day treatment， for seven-day treatment， and for 14-day treatment were collected， including basic information， medical history， pneumonia severity index （PSI） classification， and distribution and difference of laboratory and imaging information indexes. The peripheral blood specimens were collected from the patients. and the changes of inflammatory factors in peripheral blood were detected by using enzyme-linked immunosorbent assay （ELISA） reagent kits and flow-type multifactor microarrays to evaluate the clinical safety and efficacy of Ganluqingwen prescription in CAP. ResultsCompared with those in the groups before treatment， the total scores of TCM syndromes significantly decreased in both groups （P<0.05）. Compared with those in the control group after treatment， the total scores of TCM syndromes decreased more significantly in the experimental group （P<0.05）. Compared with the control group after treatment， the experimental group displayed a significantly reduced number of days of fever in patients （P<0.05）. Compared with those in the groups before treatment， the leukocyte， neutrophil counts， C-reactive protein （CRP）， procalcitonin （PCT）， interleukin （IL）-6， alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， creatinine （Cr）， creatine kinase （CK）， and creatine kinase isoenzymes （CK-MB） in both groups decreased （P<0.05） after treatment. Compared with that in the control group after treatment， the decrease of leukocyte， neutrophil counts， CRP， PCT， IL-6， ALT， AST， Cr， CK， and CK-MB was more pronounced in the experimental group （P<0.05）. Compared with those in the group before treatment， the partial pressure of carbon dioxide increased in the experimental group for 3 d of treatment （P<0.05）， and the standard alkali residual， actual alkali residual， standard bicarbonate concentration， and actual bicarbonate concentration increased in the experimental group for 7 d of treatment （P<0.05）. Compared with that in the group before treatment， D-dimer decreased in the control group for 7 d of treatment （P<0.05）. D-dimer and activated partial thromboplastin time （APTT） decreased in the experimental group for 3 d of treatment （P<0.05）， and D-dimer， fibrinogen （FIB）， and APTI significantly decreased in the group for 7 d of treatment （P<0.05）. Compared with the group for 3 d of treatment， the experimental group for 7 d of treatment showed decreased FIB （P<0.05）. Compared with those in the groups before treatment， the levels of inflammatory factors IL-4， IL-10， and IL-13 were elevated in the peripheral blood of the two groups after treatment， and the levels of B lymphocyte chemoattractant （BLC）， interferon gamma-induced protein 10 （IP-10）， tumor necrosis factor-alpha （TNF-α）， interferon-gamma （IFN-γ）， monocyte chemoattractant protein-1 （MCP-1）， CRP， IL-2， IL-6， IL-8， IL-17， IL-22， and IL-23p19 were significantly reduced （P<0.01）. Compared with the control group after treatment， the experimental group exhibited more significant improvement in indexes above （P<0.01）. ConclusionThe group treated by Ganluqingwen prescription combined with western medicine shows more significant effects on reducing total scores of TCM syndromes， lowering the ability of leukocyte and neutrophil counts， decreasing BLC， IP-10， TNF-α， IFN-γ， MCP-1， CRP， IL-2， IL-6， IL-8， IL-17， IL-22， and IL-23p19 in the peripheral blood of the patients， and elevating levels of IL-4， IL-10， and IL-13 than the group treated by western drugs alone.

ObjectiveTo explore the regulatory effect of Ganluqingwen prescription on inflammation and immunity by observing the clinical efficacy of Ganluqingwen prescription in the treatment of community-acquired pneumonia （CAP）， so as to provide a clinical basis for the treatment of CAP by traditional Chinese medicine （TCM）. MethodsA randomized controlled trial was conducted by selecting patients who were diagnosed with CAP and identified as wind-heat attacking lungs in Xinjiang Uygur Autonomous Region Hospital of TCM from January 2024 to May 2024 and assigning the patients to a control group （treated by western medicine treatment） or an experimental group （treated by Ganluqingwen prescription combined with western medicine）. The data of the enrolled patients before treatment， for three-day treatment， for seven-day treatment， and for 14-day treatment were collected， including basic information， medical history， pneumonia severity index （PSI） classification， and distribution and difference of laboratory and imaging information indexes. The peripheral blood specimens were collected from the patients. and the changes of inflammatory factors in peripheral blood were detected by using enzyme-linked immunosorbent assay （ELISA） reagent kits and flow-type multifactor microarrays to evaluate the clinical safety and efficacy of Ganluqingwen prescription in CAP. ResultsCompared with those in the groups before treatment， the total scores of TCM syndromes significantly decreased in both groups （P<0.05）. Compared with those in the control group after treatment， the total scores of TCM syndromes decreased more significantly in the experimental group （P<0.05）. Compared with the control group after treatment， the experimental group displayed a significantly reduced number of days of fever in patients （P<0.05）. Compared with those in the groups before treatment， the leukocyte， neutrophil counts， C-reactive protein （CRP）， procalcitonin （PCT）， interleukin （IL）-6， alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， creatinine （Cr）， creatine kinase （CK）， and creatine kinase isoenzymes （CK-MB） in both groups decreased （P<0.05） after treatment. Compared with that in the control group after treatment， the decrease of leukocyte， neutrophil counts， CRP， PCT， IL-6， ALT， AST， Cr， CK， and CK-MB was more pronounced in the experimental group （P<0.05）. Compared with those in the group before treatment， the partial pressure of carbon dioxide increased in the experimental group for 3 d of treatment （P<0.05）， and the standard alkali residual， actual alkali residual， standard bicarbonate concentration， and actual bicarbonate concentration increased in the experimental group for 7 d of treatment （P<0.05）. Compared with that in the group before treatment， D-dimer decreased in the control group for 7 d of treatment （P<0.05）. D-dimer and activated partial thromboplastin time （APTT） decreased in the experimental group for 3 d of treatment （P<0.05）， and D-dimer， fibrinogen （FIB）， and APTI significantly decreased in the group for 7 d of treatment （P<0.05）. Compared with the group for 3 d of treatment， the experimental group for 7 d of treatment showed decreased FIB （P<0.05）. Compared with those in the groups before treatment， the levels of inflammatory factors IL-4， IL-10， and IL-13 were elevated in the peripheral blood of the two groups after treatment， and the levels of B lymphocyte chemoattractant （BLC）， interferon gamma-induced protein 10 （IP-10）， tumor necrosis factor-alpha （TNF-α）， interferon-gamma （IFN-γ）， monocyte chemoattractant protein-1 （MCP-1）， CRP， IL-2， IL-6， IL-8， IL-17， IL-22， and IL-23p19 were significantly reduced （P<0.01）. Compared with the control group after treatment， the experimental group exhibited more significant improvement in indexes above （P<0.01）. ConclusionThe group treated by Ganluqingwen prescription combined with western medicine shows more significant effects on reducing total scores of TCM syndromes， lowering the ability of leukocyte and neutrophil counts， decreasing BLC， IP-10， TNF-α， IFN-γ， MCP-1， CRP， IL-2， IL-6， IL-8， IL-17， IL-22， and IL-23p19 in the peripheral blood of the patients， and elevating levels of IL-4， IL-10， and IL-13 than the group treated by western drugs alone.

Persistent infection with high-risk human papillomavirus(HR-HPV) is the primary etiological factor in cervical lesions and cervical cancer. Toll-like receptors(TLRs), as important pattern recognition receptors of the innate immune system, play a key role in the persistence of cervical HR-HPV infection. The "latent pathogen theory" in traditional Chinese medicine(TCM) holds that latent pathogens have both "latent" and "triggered" characteristics, which closely resemble the persistent infection and latent pathogenic potential of cervical HR-HPV. Guided by the "latent pathogen theory" and using contemporary immunological techniques, this paper explores the bidirectional immunomodulatory effects of TLRs in the persistence of cervical HR-HPV infection and their relationship with latent pathogens. The results indicate that TLRs play a crucial role in immune recognition and modulation. Dysregulation and overactivation of TLRs can induce chronic inflammation, allowing cervical HR-HPV to persist and evade immune detection. TLR dysfunction, coupled with a deficiency in healthy Qi that prevents the expulsion of pathogens, is a critical factor in the pathogenicity of latent pathogens. Restoring healthy Qi to modulate the immune functions of TLRs emerges as an important strategy for clearing cervical HR-HPV infection. By harmonizing the spleen and kidney and regulating immune balance, it is possible to reverse cervical HR-HPV infection, providing a scientific basis for clinical research.
Humans ; Toll-Like Receptors/genetics* ; Female ; Papillomavirus Infections/genetics* ; Papillomaviridae/immunology* ; Persistent Infection/genetics* ; Uterine Cervical Neoplasms/immunology* ; Animals ; Medicine, Chinese Traditional ; Cervix Uteri/immunology* ; Human Papillomavirus Viruses

Extensive studies have identified potential adverse effects on semen quality of obesity, based on body mass index, but the association between body fat distribution, a more relevant indicator for obesity, and semen quality remains less clear. We conducted a longitudinal study of 4304 sperm donors from the Guangdong Provincial Human Sperm Bank (Guangzhou, China) during 2017-2021. A body composition analyzer was used to measure total and local body fat percentage for each participant. Generalized estimating equations were employed to assess the association between body fat percentage and sperm count, motility, and morphology. We estimated that each 10% increase in total body fat percentage (estimated change [95% confidence interval, 95% CI]) was significantly associated with a 0.18 × 10 6 (0.09 × 10 6 -0.27 × 10 6 ) ml and 12.21 × 10 6 (4.52 × 10 6 -19.91 × 10 6 ) reduction in semen volume and total sperm count, respectively. Categorical analyses and exposure-response curves showed that the association of body fat distribution with semen volume and total sperm count was stronger at higher body fat percentages. In addition, the association still held among normal weight and overweight participants. We observed similar associations for upper limb, trunk, and lower limb body fact distributions. In conclusion, we found that a higher body fat distribution was significantly associated with lower semen quality (especially semen volume) even in men with a normal weight. These findings provide useful clues in exploring body fat as a risk factor for semen quality decline and add to evidence for improving semen quality for those who are expected to conceive.
Humans ; Male ; Adult ; Semen Analysis ; China ; Body Fat Distribution ; Longitudinal Studies ; Sperm Count ; Sperm Motility ; Body Mass Index ; Tissue Donors ; Obesity/complications* ; Spermatozoa ; Young Adult ; Middle Aged ; East Asian People

This article reports the clinical features and gene mutation types of a large family with Nascimento form of syndromic X-linked intellectual developmental disorder (MRXSN), involving 9 individuals across 3 generations, and a literature review was conducted. In this family, 9 individuals had similar manifestations including mental retardation and unusual facies, and 4 of them had passed away. Genetic testing showed that the proband had the deletion of exons 2-3 of the UBE2A gene, which was inherited from the mother. Fluorescent quantitative polymerase chain reaction showed that the proband and his uncle had the deletion of exons 2-3 of the UBE2A gene; the proband's mother, grandmother, and great-aunt had a heterozygous deletion of exons 2-3 of the UBE2A gene; the proband's father, sister, and aunt had a normal copy number of exons 2-3 of the UBE2A gene. The 34 patients reported in the literature had diverse clinical phenotypes, and UBE2A gene mutations (22/34, 65%) and large fragment deletions (12/34, 35%) were the main mutation types. Moderate to severe mental retardation (34/34, 100%), speech and language impairment (33/34, 97%), and unusual facies (32/34, 94%) were the main clinical manifestations of MRXSN patients. The disease has obvious phenotypic heterogeneity, and early diagnosis facilitates optimal prenatal and postnatal management to improve reproductive outcomes.
Humans ; Male ; Ubiquitin-Conjugating Enzymes/genetics* ; Female ; X-Linked Intellectual Disability/genetics* ; Gene Deletion ; Child ; Pedigree ; Child, Preschool ; Adult

BACKGROUND: The association of systemic inflammatory response index (SIRI) with prognosis of coronary artery disease (CAD) patients has never been investigated in a large sample with long-term follow-up. This study aimed to explore the association of SIRI with all-cause and cause-specific mortality in a nationally representative sample of CAD patients from United States. METHODS: A total of 3386 participants with CAD from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 were included in this study. Cox proportional hazards model, restricted cubic spline (RCS), and receiver operating characteristic curve (ROC) were performed to investigate the association of SIRI with all-cause and cause-specific mortality. Piece-wise linear regression and sensitivity analyses were also performed. RESULTS: During a median follow-up of 7.7 years, 1454 all-cause mortality occurred. After adjusting for confounding factors, higher lnSIRI was significantly associated with higher risk of all-cause (HR = 1.16, 95% CI: 1.09-1.23) and CVD mortality (HR = 1.17, 95% CI: 1.05-1.30) but not cancer mortality (HR = 1.17, 95% CI: 0.99-1.38). The associations of SIRI with all-cause and CVD mortality were detected as J-shaped with threshold values of 1.05935 and 1.122946 for SIRI, respectively. ROC curves showed that lnSIRI had robust predictive effect both in short and long terms. CONCLUSIONS SIRI was independently associated with all-cause and CVD mortality, and the dose-response relationship was J-shaped. SIRI might serve as a valid predictor for all-cause and CVD mortality both in the short and long terms.

T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy with a poor prognosis, despite advancements in treatment. Many patients struggle with relapse or refractory disease. Investigating the role of the super-enhancer (SE) regulated gene ubiquitin-specific protease 20 (USP20) in T-ALL could enhance targeted therapies and improve clinical outcomes. Analysis of histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) data from six T-ALL cell lines and seven pediatric samples identified USP20 as an SE-regulated driver gene. Utilizing the Cancer Cell Line Encyclopedia (CCLE) and BloodSpot databases, it was found that USP20 is specifically highly expressed in T-ALL. Knocking down USP20 with short hairpin RNA (shRNA) increased apoptosis and inhibited proliferation in T-ALL cells. In vivo studies showed that USP20 knockdown reduced tumor growth and improved survival. The USP20 inhibitor GSK2643943A demonstrated similar anti-tumor effects. Mass spectrometry, RNA-Seq, and immunoprecipitation revealed that USP20 interacted with hypoxia-inducible factor 1 subunit alpha (HIF1A) and stabilized it by deubiquitination. Cleavage under targets and tagmentation (CUT&Tag) results indicated that USP20 co-localized with HIF1A, jointly modulating target genes in T-ALL. This study identifies USP20 as a therapeutic target in T-ALL and suggests GSK2643943A as a potential treatment strategy.

Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

Objective:To explore the clinical and genetic characteristics of three children with Hyperekplexia.Methods:Three children who were diagnosed with Hyperekplexia at the Third Affiliated Hospital of Zhengzhou University between June 2018 and March 2020 were selected as the study subjects. Clinical data of the three children were collected. All children were subjected to whole exome sequencing. Pathogenicity of candidate variants were verified by Sanger sequencing and bioinformatic analysis.Results:The three children were all males, and had presented exaggerated startle reflexes and generalized stiffness in response to unexpected auditory or tactile stimulation, or had frequent traumatic falls following exaggerated startle. All children had shown positive nose-tapping reflex, though EEG and cranial MRI exams were all negative. Whole exome sequencing revealed that two children had harbored homozygous variants of the GLRB gene, of which the c. 1017_c.1018insAG (p.G340Rfs*14) was unreported previously. The third child had harbored compound heterozygous variants of the GLRA1 gene, among which the c.1262T>A (p.IIe421Asn) variant showed an unreported autosomal recessive inheritance. All children had responded well to clonazepam treatment. Conclusion:Patients with Hyperekplexia have typical clinical manifestations. Early clinical identification and genetic analysis can facilitate their diagnosis.

Objective:To report the results of national surveillance on the distribution and antimicrobial resistance profile of clinical Gram-negative bacteria isolates from bloodstream infections in China in 2022.Methods:The clinical isolates of Gram-negative bacteria from blood cultures in member hospitals of national bloodstream infection Bacterial Resistant Investigation Collaborative System（BRICS）were collected during January 2022 to December 2022. Antibiotic susceptibility tests were conducted by agar dilution or broth dilution methods recommended by Clinical and Laboratory Standards Institute（CLSI）. WHONET 5.6 and SPSS 25.0 software were used to analyze the data.Results:During the study period，9 035 strains of Gram-negative bacteria were collected from 51 hospitals，of which 7 895（87.4%）were Enterobacteriaceae and 1 140（12.6%）were non-fermenting bacteria. The top 5 bacterial species were Escherichia coli（ n=4 510，49.9%）， Klebsiella pneumoniae（ n=2 340，25.9%）， Pseudomonas aeruginosa（ n=534，5.9%）， Acinetobacter baumannii complex（ n=405，4.5%）and Enterobacter cloacae（ n=327，3.6%）. The ESBLs-producing rates in Escherichia coli， Klebsiella pneumoniae and Proteus spp. were 47.1%（2 095/4 452），21.0%（427/2 033）and 41.1%（58/141），respectively. The prevalence of carbapenem-resistant Escherichia coli（CREC）and carbapenem-resistant Klebsiella pneumoniae（CRKP）were 1.3%（58/4 510）and 13.1%（307/2 340）；62.1%（36/58）and 9.8%（30/307）of CREC and CRKP were resistant to ceftazidime/avibactam combination，respectively. The prevalence of carbapenem-resistant Acinetobacter baumannii（CRAB）complex was 59.5%（241/405），while less than 5% of Acinetobacter baumannii complex was resistant to tigecycline and polymyxin B. The prevalence of carbapenem-resistant Pseudomonas aeruginosa（CRPA）was 18.4%（98/534）. There were differences in the composition ratio of Gram-negative bacteria in bloodstream infections and the prevalence of main Gram-negative bacteria resistance among different regions，with statistically significant differences in the prevalence of CRKP and CRPA（ χ2=20.489 and 20.252， P<0.001）. The prevalence of CREC，CRKP，CRPA，CRAB，ESBLs-producing Escherichia coli and Klebsiella pneumoniae were higher in provinicial hospitals than those in municipal hospitals（ χ2=11.953，81.183，10.404，5.915，12.415 and 6.459， P<0.01 or <0.05），while the prevalence of CRPA was higher in economically developed regions（per capita GDP ≥ 92 059 Yuan）than that in economically less-developed regions（per capita GDP <92 059 Yuan）（ χ2=6.240， P=0.012）. Conclusions:The proportion of Gram-negative bacteria in bloodstream infections shows an increasing trend，and Escherichia coli is ranked in the top，while the trend of CRKP decreases continuously with time. Decreasing trends are noted in ESBLs-producing Escherichia coli and Klebsiella pneumoniae. Low prevalence of carbapenem resistance in Escherichia coli and high prevalence in CRAB complex have been observed. The composition ratio and antibacterial spectrum of bloodstream infections in different regions of China are slightly different，and the proportion of main drug resistant bacteria in provincial hospitals is higher than those in municipal hospitals.