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BackgroundDiabetic peripheral neuropathy (DPN) is a common chronic complication of diabetes, while the underlying molecular mechanisms are still unclear. The aim of this study was to screen the key genes and the roles of immune infiltration in DPN using bioinformatics analysis.MethodsDPN mice datasets including GSE222778, GSE11343, GSE70852, GSE27382, and GSE34889 were retrieved from the GEO database. Data of human DPN were retrieved from the dbGaP. The differentially expressed genes (DEGs) were selected and further analyzed by using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and Gene Set Enrichment Analysis (GSEA) to find the shared key pathway. Protein–protein interaction networks were built in shared mouse and human DEGs. The hub genes were selected and verified in vitro using high- glucose-treated PC12 cells and Schwann cells. The single-sample GSEA (ssGSEA) algorithm was used to analyze the proportions of infiltrating immune cells in human DPN and the subsequent correlations with hub genes.ResultsA total of 323 mouse DEGs and 501 human DEGs were selected, and they were found significantly enriched in immune-related biological functions and pathways. A total of 13 DEGs were found shared in mice and human DPN datasets, and among them, there were 7 hub genes, namely, PLAUR, S100A8, IL7R, CXCL13, SRPX2, CD300LB, and CFI. The expression of Cfi, S100a8, Cxcl13, and Cd300lb was consistently confirmed in vitro. The scores of neutrophils and NK CD56bright cells varied most significantly by immune cell infiltration analysis (p < 0.01). Furthermore, the selected hub genes were found to be highly correlated with the immune infiltration.ConclusionOur study indicated the importance of immune dysregulations in DPN and identified several hub genes through combined analysis in mice and human DPN samples, thus providing potential diagnostic and therapeutic targets in the future.

ObjectivesMetagenomic next-generation sequencing (mNGS) is emerging as a novel diagnostic technology for various infectious diseases; however, limited studies have investigated its application in etiological diagnosis of early onset pneumonia (EOP) among patients undergoing extracorporeal cardiopulmonary resuscitation (ECPR) following in-hospital cardiac arrest (IHCA), The clinical significance of early mNGS in predicting short-term prognosis of IHCA patients after ECPR remains unclear.MethodsThis retrospective study included 76 patients with IHCA who underwent ECPR at the First Affiliated Hospital of Zhengzhou University from January 2018 to December 2022. Baseline characteristics and etiological data of all patients during their hospitalization were collected and statistically analyzed. The primary outcome of this study was the diagnosis of EOP, while the secondary outcomes included successful extracorporeal membrane oxygenation (ECMO) weaning and survival at discharge. Additionally, the characteristics of bronchoalveolar lavage fluid (BALF) flora in these patients were compared by analyzing both mNGS results and culture results.ResultsMultivariate logistic regression were employed to analyze the predictors of ECMO weaning failure, mortality at discharge, and the incidence of EOP. Ultimately, patients with lower SOFA scores on admission [OR (95%CI): 1.447 (1.107-1.890), p=0.007] and those who underwent early mNGS testing within 48 hours after ECPR [OR (95%CI): 0.273 (0.086-0.865), p=0.027] demonstrated a higher probability of successful weaning from ECMO. Patients with higher SOFA scores on admission [OR (95%CI): 2.404 (1.422-4.064), p=0.001], and elevated lactate levels [OR (95%CI): 1.176 (1.017-1.361), p=0.029] exhibited an increased likelihood of mortality at discharge. Furthermore, early mNGS detection [OR (95%CI): 0.186 (0.035-0.979), p=0.047], and lower CRP levels (48h-7d after ECMO) [OR (95%CI):1.011 (1.003-1.019), p=0.006] were associated with a reduced incidence of EOP. In addition, the pathogens detected by mNGS within 48 hours after ECPR were mainly oral colonizing bacteria and viruses, and viruses were in the majority, while all BALF cultures were negative. In contrast, between 48 hours and 7 days after ECPR, BALF cultures were positive in all EOP patients.ConclusionsEarly mNGS testing to identify microbial flora facilitates timely adjustment of antibiotic regimens, thereby reducing the incidence of EOP and improving short-term prognosis in patients undergoing ECPR following IHCA.

Ovarian cancer is one of the most common gynecological malignancies. The current first-line treatment strategies for advanced ovarian cancer include surgery, chemotherapy, and maintenance therapy. Bevacizumab and poly (ADP-ribose) polymerase inhibitors (PARPi) are primary maintenance treatments for advanced ovarian cancer. Previously, many patients declined these therapies before medicare coverage because of high costs. Bevacizumab and apatinib are anti-tumor angiogenic agents. In this case study, we describe a patient with advanced ovarian cancer who underwent neoadjuvant chemotherapy, interval debulking surgery, and adjuvant chemotherapy. She declined bevacizumab and PARPi maintenance therapy owing to the prohibitive expenses. The patient was administered off-label apatinib and achieved a progression-free survival of 54 months. Thus, apatinib may offer substantial therapeutic value as a first-line maintenance therapy in advanced ovarian cancer.

BackgroundPast studies have demonstrated that diabetic neuropathy is related to sarcopenia, but the further causal relation is still unclear. We sought to investigate the causal relationship by combining data from cross-sectional and Mendelian randomization (MR) studies.MethodsThe genome-wide association studies data were collected from the UK Biobank and the European Working Group on Sarcopenia to conduct a bi-directional two-sample MR study to explore the causality between diabetic neuropathy and relevant clinical traits of sarcopenia, including appendicular lean mass (ALM), walking speed and low hand grip strength. The inverse-variance weighted and various sensitivity analyses were used to obtain MR estimates. We also enrolled a total of 196 Type 2 diabetes patients from April 2021 to April 2024 and divided them into the Distal peripheral neuropathy (DPN) group (n=51) and non-DPN group (n=145) via vibration perception threshold (VPT) and neuropathy deficit score. Logistic regression and ROC curve analysis were used to investigate the relationship between DPN and relevant sarcopenia clinical features.ResultsAccording to a forward MR analysis, decreased walking speed (OR: 0.04, 95% confidence interval (CI): 0.01-0.16; P

IntroductionAs a widely used traditional Chinese medicine with hot property, aconite can significantly promote energy metabolism. However, it is unclear whether the gut microbiota and bile acids contribute to the energy metabolism-promoting properties of aconite. The aim of this experiment was to verify whether the energy metabolism-promoting effect of aconite aqueous extract (AA) is related to gut microbiota and bile acid (BA) metabolism.MethodsThe effect of AA on energy metabolism in rats was detected based on body weight, body temperature, and adipose tissue by HE staining and immunohistochemistry. In addition, 16S rRNA high-throughput sequencing and targeted metabolomics were used to detect changes in gut microbiota and BA concentrations, respectively. Antibiotic treatment and fecal microbiota transplantation (FMT) were also performed to demonstrate the importance of gut microbiota.ResultsRats given AA experienced an increase in body temperature, a decrease in body weight, and an increase in BAT (brown adipose tissue) activity and browning of WAT (white adipose tissue). Sequencing analysis and targeted metabolomics indicated that AA modulated gut microbiota and BA metabolism. The energy metabolism promotion of AA was found to be mediated by gut microbiota, as demonstrated through antibiotic treatment and FMT. Moreover, the energy metabolism-promoting effect of aconite is associated with the bile acid receptor TGR5 (Takeda G-protein-coupled receptor 5)-UCP1 (uncoupling protein 1) signaling pathway.ConclusionThe energy metabolism-promoting effect of aconite is associated with gut microbiota and bile acid receptor TGR5-UCP1 signaling.

BackgroundThe clinical efficacy of allergen-specific immunotherapy (AIT) for Alternaria alternata (A. alt) and Dermatophagoides farinae (Der f) extracts remains largely unknown in China. We sought to retrospectively evaluate the efficacy caused by AIT agents manufactured in China of patients who are sensitized to A. alt and Der f.MethodsPatients aged 5–27 years with asthma and perennial allergic rhinitis (AR), and AIT with A. alt and Der f were recruited, and then classified into two groups: A. alt-AIT (n = 31) and A. alt + Der f-AIT group (n = 39). All data were gathered retrospectively, including biological parameters, pulmonary function, and symptom and medication scores.Results70 patients who underwent A. alt and Der f AIT were enrolled. A significant improvement was observed in the values of FEV1% (P

IntroductionResearch has demonstrated that higher social support is associated with better psychological health, quality of life, cognition, activities of daily living, and social participation, but the relationship between social support and sleep quality remains unknown. This study aims to investigate the mediating effects of anxiety and depression in the relationship between social support and sleep among community-dwelling patients with schizophrenia.MethodPurposive sampling was used to collect face-to-face data from 1,107 community-dwelling patients with schizophrenia in Chengdu, Sichuan Province, China, between April and July 2023. The Athens Insomnia Scale (AIS) was used to assess sleep quality; the Generalized Anxiety Disorder 7-item scale (GAD-7) was utilized to evaluate anxiety symptoms; and the Patient Health Questionnaire-9 (PHQ-9) was employed to assess depressive symptoms. The mediating effect of anxiety and depression symptoms was assessed using the bootstrap method via Model 6 (Serial multiple mediator model) of the SPSS PROCESS macro.ResultsAmong the 1,107 participants, the proportions of people with schizophrenia experiencing anxiety, depressive symptoms, and poor sleep quality were 22.8, 37.7, and 42.1%, respectively. Mediation analyses indicated that although social support had no direct effect on sleep quality, anxiety and depressive symptoms fully mediated the relationship between social support and sleep quality.ConclusionPatients with schizophrenia experience low levels of social support and poor sleep quality. To enhance the sleep quality of individuals with schizophrenia, all levels of society (government, medical institutions, and communities) must pay more attention to mental health. Implementing diverse intervention measures to strengthen social support and improve symptoms of anxiety and depression should be considered. This approach may potentially lead to an improvement in sleep quality among individuals with schizophrenia.

With the rapid global spread of COVID-19 and the continuous emergence of variants, there is an urgent need to develop safe and effective vaccines. Here, we developed a novel mRNA vaccine, HC009, based on new formulation by the QTsome delivery platform. Immunogenicity results showed that the prime-boost immunization strategy with HC009 was able to induce robust and durable humoral immunity, as well as Th1-biased cellular responses in rodents or non-human primates (NHPs). After further challenge with live SARS-CoV-2 virus, HC009 provided adequate protection against virus infection in hACE2 transgenic mice. Therefore, HC009 could provide significant immune protection against SARS-CoV-2.

BackgroundThe burden on society grows as the number of individuals with cognitive impairment rises. Numerous research have discovered a connection between cognitive impairment and the gut-brain axis, which is useful in examining the pathophysiology of cognitive impairment and potential therapeutic approaches. As a result, this article explores developments and trends in the research concerning the gut-brain axis and cognitive impairment through a bibliometric analysis of the contributions made by various countries/regions, institutions, authors, and journals.MethodsWe looked for articles on gut-brain axis and cognitive impairment from 2014 to 2023 in the Web of Science Core Collection. For the descriptive analysis, figures and tables were taken using GraphPad Prism 6 and WPS Office 2024. For the visual analysis of the countries/regions, institutions, authors, and keywords, VOSviewer was utilized.ResultsWe obtained 458 publications from 1 January 2014 to 9 September 2023. The country with the most publications (175, 38.21%) was China. The country with the greatest total number of citations (3,138, 17.22%) was the United States of America. The highest number of articles (15, 3.26%) was issued by Zhejiang University. The most published first author is Karsas M. In this field, Nutrients have published the most articles (24). The most often occurring keywords include “Alzheimer’s disease,” “cognitive impairment,” “gut microbiota,” “inflammation,” “diet,” etc. “Stroke,” “tau,” “probiotics,” “exercise,” “fecal microbiota transplantation,” etc. emerged later.ConclusionAn increasing amount of research has focused on the connection between cognitive impairment and the gut-brain axis. In this area, the United States of America and China have both made significant contributions. The author team’s collaboration has to be improved. Our study contributes to understanding the field’s current state and predicting its future trend.

Gut barrier is not only part of the digestive organ but also an important immunological organ for the hosts. The disruption of gut barrier can lead to various diseases such as obesity and colitis. In recent years, traditional Chinese medicine (TCM) has gained much attention for its rich clinical experiences enriched in thousands of years. After orally taken, TCM can interplay with gut microbiota. On one hand, TCM can modulate the composition and function of gut microbiota. On the other hand, gut microbiota can transform TCM compounds. The gut microbiota metabolites produced during the actions of these interplays exert noticeable pharmacological effects on the host especially gut barrier. Recently, a large number of studies have investigated the repairing and fortifying effects of TCM on gut barriers from the perspective of gut microbiota and its metabolites. However, no review has summarized the mechanism behand this beneficiary effects of TCM. In this review, we first briefly introduce the unique structure and specific function of gut barrier. Then, we summarize the interactions and relationship amidst gut microbiota, gut microbiota metabolites and TCM. Further, we summarize the regulative effects and mechanisms of TCM on gut barrier including physical barrier, chemical barrier, immunological barrier, and microbial barrier. At last, we discuss the effects of TCM on diseases that are associated gut barrier destruction such as ulcerative colitis and type 2 diabetes. Our review can provide insights into TCM, gut barrier and gut microbiota.

Ethnopharmacological relevance: Pulsatilla decoction (PD) is a classical prescription for the treatment of ulcerative colitis. Previous studies have demonstrated that the therapeutic efficacy of PD is closely associated with the activation of Farnesoid X receptor (FXR). The activity of FXR is regulated by apical sodium-dependent bile acid transporter (ASBT), and the FXR-ASBT cascade reaction, centered around bile acid receptor FXR, plays a pivotal role in maintaining bile acid metabolic homeostasis to prevent the occurrence and progression of ulcerative colitis (UC).Aim of the study: To elucidate the underlying mechanism by which PD exerts its proteactive effects against Dextran Sulfate Sodium Salt (DSS)-induced ulcerative colitis, focusing on the modulation of FXR and ASBT.Materials and methods: To establish a model of acute ulcerative colitis, BALB/C mice were administered 3.5% DSS in their drinking water for consecutive 7 days. The disease activity index (DAI) was employed to evaluate the clinical symptoms exhibited by each group of mice. Goblet cell expression in colon tissue was assessed using glycogen schiff periodic acid-Schiff (PAS) and alcian blue staining techniques. Inflammatory cytokine expression in serum and colonic tissues was examined through enzyme-linked immunosorbent assay (ELISA). A PCR Array chip was utilized to screen 88 differential genes associated with the FXR-ASBT pathway in UC treatment with PD. Western blotting (WB) analysis was performed to detect protein expression levels of differentially expressed genes in mouse colon tissue.Results: The PD treatment effectively reduced the Disease Activity Index (DAI) score and mitigated colon histopathological damage, while also restoring weight and colon length. Furthermore, it significantly alleviated the severity of ulcerative colitis (UC), regulated inflammation, modulated goblet cell numbers, and restored bile acid balance. Additionally, a PCR Array analysis identified 21 differentially expressed genes involved in the FXR-ASBT pathway. Western blot results demonstrated significant restoration of FXR, GPBAR1, CYP7A1, and FGF15 protein expression levels following PD treatment; moreover, there was an observed tendency towards increased expression levels of ABCB11 and RXRα.Conclusion: The therapeutic efficacy of PD in UC mice is notable, potentially attributed to its modulation of bile acid homeostasis, enhancement of gut barrier function, and attenuation of intestinal inflammation.

BackgroundYishen-Tongbi Decoction (YSTB), a traditional Chinese prescription, has been used to improve syndromes of rheumatoid arthritis (RA) for many years. Previous research has shown that YSTB has anti-inflammatory and analgesic properties. However, the underlying molecular mechanism of the anti-RA effects of YSTB remains unclear.Purpose and study designThe purpose of this research was to investigate how YSTB affected mice with collagen-induced arthritis (CIA) and RAW264.7 cells induced with lipopolysaccharide (LPS).ResultsThe findings show that YSTB could significantly improve the clinical arthritic symptoms of CIA mice (mitigate paw swelling, arthritis score, thymus and spleen indices, augment body weight), downregulated expression of pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), IL-6 and IL-17, while upregulated the level of anti-inflammatory like IL-10 and transforming growth factor-β (TGF-β). Meanwhile, YSTB inhibits bone erosion and reduces inflammatory cell infiltration, synovial proliferation, and joint destruction in CIA mice. In addition, we found that YSTB was able to suppress the LPS-induced inflammation of RAW264.7 cells, which was ascribed to the suppression of nitric oxide (NO) production and reactive oxygen species formation (ROS). YSTB also inhibited the production of inducible nitric oxide synthase and reduced the releases of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in LPS-induced RAW264.7 cells. Furthermore, the phosphorylation expression of JAK2, JAK3, STAT3, p38, ERK and p65 protein could be suppressed by YSTB, while the expression of SOCS3 could be activated.ConclusionTaken together, YSTB possesses anti-inflammatory and prevention bone destruction effects in RA disease by regulating the JAK/STAT3/SOCS3 signaling pathway.

Fagopyrum dibotrys, belonging to the family Polygonaceae and genus Fagopyrum, is used in traditional Chinese medicine and is rich in beneficial components, such as flavonoids. As its abundant medicinal value has become increasingly recognized, its excessive development poses a considerable challenge to wild germplasm resources, necessitating artificial cultivation and domestication. Considering these factors, a high-quality genome of F. dibotrys was assembled and the evolutionary relationships within Caryophyllales were compared, based on which 58 individual samples of F. dibotrys were re-sequenced. We found that the samples could be categorized into three purebred populations and regions distributed at distinct elevations. Our varieties were cultivated from the parental populations of the subpopulation in central Yunnan. F. dibotrys is speculated to have originated in the high-altitude Tibetan Plateau region, and that its combination with flavonoids can protect plants against ultraviolet radiation; this infers a subpopulation with a high accumulation of flavonoids. This study assembled a high-quality genome and provided a theoretical foundation for the future introduction, domestication, and development of cultivated varieties of F. dibotrys.

IntroductionThe pattern of extraocular muscle involvement in ocular myasthenia gravis varies across different reports, diverging from our own observations. Thus, we employed two novel tools to discern this pattern.MethodsA retrospective analysis was conducted to collect and organize clinical data from 43 patients diagnosed with ocular myasthenia gravis. Each patient underwent both the computerized diplopia test and the Ocular Motor Nerve Palsy Scale assessment to evaluate the involvement of extraocular muscles.ResultsAmong the patients, there were 30 male and 13 female individuals, with a total of 113 affected extraocular muscles identified. Among all the affected extraocular muscles, the involvement of the levator palpebrae superioris muscle accounted for 35.40%, medial rectus muscle 7.7%, lateral rectus muscle 16.81%, superior rectus muscle 13.27%, inferior rectus muscle 12.39%, superior oblique muscle 1.77%, and inferior oblique muscle 2.65% of the total affected extraocular muscles. The positivity rates of the Neostigmine test were 89.19%, AChR antibody detection was 59.38%, and repetitive nerve stimulation was 34.38%. The AChR antibody positive rate among patients with only diplopia was 100%; among those with only ptosis, it was 80%; and among those with both diplopia and ptosis, it was 86.67%.ConclusionThe involvement of the extraocular muscles is not uniform. The levator palpebrae superioris exhibits the highest incidence rate, followed by the four rectus muscles and two oblique muscles. The inferior oblique involvement typically occurs when four or more EOMs are affected. Moreover, the levator palpebrae superioris and medial rectus show a higher tendency for bilateral involvement compared with other extraocular muscles.

Treatment of glomerulonephritis presents several challenges, including limited therapeutic options, high costs, and potential adverse reactions. As a recognized Chinese patent medicine, Tripterygium wilfordii poly-glycosides (TWP) have shown promising benefits in managing autoimmune diseases. To evaluate clinical effectiveness and safety of TWP in treating glomerulonephritis, we systematically searched PubMed, Cochrane Library, Web of Science, and Embase databases for controlled studies published up to 12 July 2023. We employed weighted mean difference and relative risk to analyze continuous and dichotomous outcomes. This meta-analysis included 16 studies that included primary membranous nephropathy (PMN), type 2 diabetic kidney disease (DKD), and Henoch-Schönlein purpura nephritis (HSPN). Analysis revealed that additional TWP administration improved patients’ outcomes and total remission rates, reduced 24-h urine protein (24hUP) and decreased relapse events. The pooled results demonstrated the non-inferiority of TWP to glucocorticoids in achieving total remission, reducing 24hUP, and converting the phospholipase A2 receptor (PLA2R) status to negative. For DKD patients, TWP effectively reduced 24hUP levels, although it did not significantly improve the estimated glomerular filtration rate (eGFR). Compared to valsartan, TWP showed comparable improvements in 24hUP and eGFR levels. In severe cases of HSPN in children, significant clinical remission and a reduction in 24hUP levels were observed with the addition of TWP treatment. TWP did not significantly increase the incidence of adverse reactions. Therefore, TWP could offer therapeutic benefits to patients with PMN, DKD, and severe HSPN, with a minimal increase in the risk of side effects.

BackgroundScrub typhus, caused by the Orientia tsutsugamushi (Ot), is a widespread vector-borne disease transmitted by chigger mites. Hemophagocytic lymphohistiocytosis (HLH) is considered to be one of the potentially severe complications. The diagnosis of scrub typhus-associated HLH may be overlooked due to the non-specific clinical characteristics and the absence of pathognomonic eschar.Case presentationWe obtained clinical data from two patients in the South of Sichuan, China. The first case involved a 6-year-old girl who exhibited an unexplained fever and was initially diagnosed with sepsis, HLH, and pulmonary infection. The other patient presented a more severe condition characterized by multiple organ dysfunction and was initially diagnosed with septic shock, sepsis, HLH, acute kidney injury (AKI), and pulmonary infection. At first, a specific examination for scrub typhus was not performed due to the absence of a characteristic eschar. Conventional peripheral blood cultures yielded negative results in both patients, and neither of them responded to routine antibiotics. Fortunately, the causative pathogen Orientia tsutsugamushi (Ot) was detected in the plasma samples of both patients using metagenomics next-generation sequencing (mNGS) and further confirmed by polymerase chain reaction. Subsequently, they both were treated with doxycycline and recovered quickly.ConclusionThe unbiased mNGS provided a clinically actionable diagnosis for an uncommon pathogen-associated infectious disease that had previously evaded conventional diagnostic approaches.

IntroductionThe uridine diphosphate (UDP)-glycosyltransferase (UGT) family is the largest glycosyltransferase family, which is involved in the biosynthesis of natural plant products and response to abiotic stress. UGT has been studied in many medicinal plants, but there are few reports on Platycodon grandiflorus. This study is devoted to genome-wide analysis of UGT family and identification of UGT genes involved in drought stress of Platycodon grandiflorus (PgUGTs).MethodsThe genome data of Platycodon grandiflorus was used for genome-wide identification of PgUGTs, online website and bioinformatics analysis software was used to conduct bioinformatics analysis of PgUGT genes and the genes highly responsive to drought stress were screened out by qRT-PCR, these genes were cloned and conducted bioinformatics analysis.ResultsA total of 75 PgUGT genes were identified in P.grandiflorus genome and clustered into 14 subgroups. The PgUGTs were distributed on nine chromosomes, containing multiple cis-acting elements and 22 pairs of duplicate genes were identified. Protein-protein interaction analysis was performed to predict the interaction between PgUGT proteins. Additionally, six genes were upregulated after 3d under drought stress and three genes (PGrchr09G0563, PGrchr06G0523, PGrchr06G1266) responded significantly to drought stress, as confirmed by qRT-PCR. This was especially true for PGrchr06G1266, the expression of which increased 16.21-fold after 3d of treatment. We cloned and conducted bioinformatics analysis of three candidate genes, both of which contained conserved motifs and several cis-acting elements related to stress response, PGrchr06G1266 contained the most elements.DiscussionPgGT1 was confirmed to catalyze the C-3 position of platycodin D and only eight amino acids showed differences between gene PGr008G1527 and PgGT1, which means PGr008G1527 may be able to catalyze the C-3 position of platycodin D in the same manner as PgGT1. Seven genes were highly expressed in the roots, stems, and leaves, these genes may play important roles in the development of the roots, stems, and leaves of P. grandiflorus. Three genes were highly responsive to drought stress, among which the expression of PGrchr06G1266 was increased 16.21-fold after 3d of drought stress treatment, indicating that PGrchr06G1266 plays an important role in drought stress tolerance. To summarize, this study laied the foundation to better understand the molecular bases of responses to drought stress and the biosynthesis of platycodin.

C1GALT1 plays a pivotal role in colorectal cancer (CRC) development and progression through its involvement in various molecular mechanisms. This enzyme is central to the O-glycosylation process, producing tumor-associated carbohydrate antigens (TACA) like Tn and sTn, which are linked to cancer metastasis and poor prognosis. The interaction between C1GALT1 and core 3 synthase is crucial for the synthesis of core 3 O-glycans, essential for gastrointestinal health and mucosal barrier integrity. Aberrations in this pathway can lead to CRC development. Furthermore, C1GALT1's function is significantly influenced by its molecular chaperone, Cosmc, which is necessary for the proper folding of T-synthase. Dysregulation in this complex interaction contributes to abnormal O-glycan regulation, facilitating cancer progression. Moreover, C1GALT1 affects downstream signaling pathways and cellular behaviors, such as the epithelial-mesenchymal transition (EMT), by modifying O-glycans on key receptors like FGFR2, enhancing cancer cell invasiveness and metastatic potential. Additionally, the enzyme's relationship with MUC1, a mucin protein with abnormal glycosylation in CRC, highlights its role in cancer cell immune evasion and metastasis. Given these insights, targeting C1GALT1 presents a promising therapeutic strategy for CRC, necessitating further research to develop targeted inhibitors or activators. Future efforts should also explore C1GALT1's potential as a biomarker for early diagnosis, prognosis, and treatment response monitoring in CRC, alongside investigating combination therapies to improve patient outcomes.

The metabolic disease hyperuricemia (HUA) is caused by presence of excessive serum uric acid (UA), which leads to an increased risk of chronic kidney disease and gout. As a widely used traditional Chinese medicine, Euodiae fructus (ER) has strong anti-inflammatory and analgesic effects, however, its therapeutic effects on HUA and gout have not been investigated. To investigate the potential effects and underlying mechanisms, the effect of ER on proinflammatory cytokines and NLRP3 inflammasome activation was studied in mouse bone marrow macrophages. Moreover, a mouse model of HUA and gouty arthritis was established by coadministration of potassium oxonate (PO) and monosodium urate crystals to mice fed a high-fat diet (HFD) for 37 consecutive days. Oral administration of ER aqueous extract was given 1 hour later after the injection of PO for 10 days. Our study showed that ER is a powerful NLRP3 inhibitor in mouse macrophages. Most importantly, ER (0.75 g/kg) treatment substantially decreased the ankle joint thickness ratio, serum UA, creatinine and blood urea nitrogen levels (p < 0.05). Additionally, ER (0.75 g/kg) dramatically reversed the increases in renal urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) as well as the decreases in organic anion transporter 1 (OAT1) and ATP binding cassette subfamily G member 2 (ABCG2) levels (p < 0.05). Moreover, ER (0.75 g/kg) markedly ameliorated the production of the serum inflammatory cytokines IL-1β and TNF-α (p < 0.01), and improved the activation of NLRP3 inflammasome signaling in the kidneys. Taken together, these data indicate that ER, a powerful and specific NLRP3 inhibitor, has multiple anti-HUA, anti-gout and anti-inflammatory effects. Our investigation is designed to experimentally support the conventional use of ER-containing classical herbal formulas in the treatment of HUA-related disorders and may add a new dimension to the clinical application of ER.

Objective: The article aims to provide genetic counseling to a family with two children who were experiencing growth and developmental delays.Methods: Clinical information of the proband was collected. Peripheral blood was collected from core family members to identify the initial reason for growth and developmental delays by whole exome sequencing (WES) and Sanger sequencing. To ascertain the consequences of the newly discovered variants, details of the variants detected were analyzed by bioinformatic tools. Furthermore, we performed in vitro experimentation targeting SNX14 gene expression to confirm whether the variants could alter the expression of SNX14.Results: The proband had prenatal ultrasound findings that included flattened frontal bones, increased interocular distance, widened bilateral cerebral sulci, and shortened long bones, which resulted in subsequent postnatal developmental delays. The older sister also displayed growth developmental delays and poor muscle tone. WES identified compound heterozygous variants of c.712A>T (p.Arg238Ter) and .2744A>T (p.Gln915Leu) in the SNX14 gene in these two children. Both are novel missense variant that originates from the father and mother, respectively. Sanger sequencing confirmed this result. Following the guideline of the American College of Medical Genetics and Genomics (ACMG), the SNX14 c.712A>T (p.Arg238Ter) variant was predicted to be pathogenic (P), while the SNX14 c.2744A>T (p.Gln915Leu) variant was predicted to be a variant of uncertain significance (VUS). The structural analysis revealed that the c.2744A>T (p.Gln915Leu) variant may impact the stability of the SNX14 protein. In vitro experiments demonstrated that both variants reduced SNX14 expression.Conclusion: The SNX14 gene c.712A>T (p.Arg238Ter) and c.2744A>T (p.Gln915Leu) were identified as the genetic causes of growth and developmental delay in two affected children. This conclusion was based on the clinical presentations of the children, structural analysis of the mutant protein, and in vitro experimental validation. This discovery expands the range of SNX14 gene variants and provides a foundation for genetic counseling and guidance for future pregnancies in the affected children’s families.

We report a case of well-differentiated papillary mesothelial tumor (WDPMT) diagnosed using internal thoracoscopic biopsy in a patient who has suffered from recurrent pleural effusions for over 35 years together with a history of elevated CA125. We hope to provide a case for the diagnosis of this rare benign and preinvasive pleural tumor and recommend that internal thoracoscopy may be a good choice in these recurrent pleural effusion patients especially for those minimal lesions not easily detected using CT scan.

Immunotherapy has been developed, which harnesses and enhances the innate powers of the immune system to fight disease, particularly cancer. PD-1 (programmed death-1) and PD-L1 (programmed death ligand-1) are key components in the regulation of the immune system, particularly in the context of cancer immunotherapy. PD-1 and PD-L1 are regulated by PTMs, including phosphorylation, ubiquitination, deubiquitination, acetylation, palmitoylation and glycosylation. PROTACs (Proteolysis Targeting Chimeras) are a type of new drug design technology. They are specifically engineered molecules that target specific proteins within a cell for degradation. PROTACs have been designed and demonstrated their inhibitory activity against the PD-1/PD-L1 pathway, and showed their ability to degrade PD-1/PD-L1 proteins. In this review, we describe how PROTACs target PD-1 and PD-L1 proteins to improve the efficacy of immunotherapy. PROTACs could be a novel strategy to combine with radiotherapy, chemotherapy and immunotherapy for cancer patients.

BackgroundSocioeconomic status inequality is an important variable in the emergence of urological diseases in humans. This study set out to investigate the association between the prevalence of overactive bladder (OAB) and the poverty income ratio (PIR) that served as a more influential indicator of socioeconomic status compared to education and occupation.MethodData from the National Health and Nutrition Examination Survey (NHANES) conducted from 2007 to 2020 were used in this cross-sectional study. The association between the PIR and OAB was examined using weighted multivariate logistic regression and weighted restricted cubic splines (RCS). Additionally, interaction analysis was used for investigation to the connections between PIR and OAB in various covariate groups in order to confirm the stability of the results.ResultsWe observed a noteworthy inverse association between PIR and OAB after adjusting for potential confounding variables (OR = 0.87, 95% CI, 0.84–0.90, p

Emotional disorders, such as anxiety and depression, represent a major societal problem; however, the underlying neurological mechanism remains unknown. The ventral lateral septum (LSv) is implicated in regulating processes related to mood and motivation. In this study, we found that LSv GABAergic neurons were significantly activated in mice experiencing chronic social defeat stress (CSDS) after exposure to a social stressor. We then controlled LSv GABAergic neuron activity using a chemogenetic approach. The results showed that although manipulation of LSv GABAergic neurons had little effect on anxiety-like behavioral performances, the activation of LSv GABAergic neurons during CSDS worsened social anxiety during a social interaction (SI) test. Moreover, LSv GABAergic neurons showed strong projections to the paraventricular nucleus (PVN) of the hypothalamus, which is a central hub for stress reactions. Remarkably, while activation of GABAergic LSv–PVN projections induced social anxiety under basal conditions, activation of this pathway during CSDS alleviated social anxiety during the SI test. On the other hand, the chemogenetic manipulation of LSv GABAergic neurons or LSvGABA–PVN projections had no significant effect on despair-like behavioral performance in the tail suspension test. Overall, LS GABAergic neurons, particularly the LSv GABAergic–PVN circuit, has a regulatory role in pathological anxiety and is thus a potential therapeutic target for the treatment of emotional disorders.

BackgroundL-carnitine therapy for idiopathic sperm abnormalities exhibits variable effectiveness, and currently, there are no established criteria to predict patient response. This study investigated correlations between seminal plasma markers and semen parameters to identify biomarkers that can guide indications for L-carnitine therapy indications in patients with idiopathic sperm abnormalities.MethodsA retrospective review was conducted on 223 male patients with idiopathic oligoasthenoteratospermia, who sought medical attention at our clinic between January 2020 and October 2022. These patients underwent a pretreatment seminal plasma biochemical analysis, followed by a three-month continuous L-carnitine treatment. The correlation between seminal plasma biochemical parameters and pretreatment semen parameters was analyzed. Semen quality was compared between cases with normal and abnormal seminal plasma biochemical parameters, both pretreatment and posttreatment. The correlation between the changes in semen parameters after treatment and seminal plasma biochemical parameters were investigated.ResultsCorrelation analyses revealed significant associations between all pretreatment semen parameters and seminal plasma biochemical markers, except for liquefying time and the ratio of normal morphology. Subgroup analysis, stratified by seminal fructose, zinc, citric acid, and neutral glycosidase levels, demonstrated that abnormal groups exhibited significantly different levels of semen parameters compared with the normal groups. The changing difference and changing ratio in the ratio of forward motile sperm showed a negative correlation with seminal fructose levels (r=-0.165 and -0.144). The changing difference in semen volume was negatively correlated with the level of seminal neutral glycosidase (r=-0.158). The changing ratio in semen volume, sperm concentration, total sperm count, and count of forward motile sperm all exhibited negative correlations with the levels of seminal neutral glycosidase (range from -0.178 to -0.224).ConclusionSeminal plasma biochemical markers, particularly fructose and neutral glycosidase, may serve as valuable indicators for determining the eligibility of patients with idiopathic sperm abnormalities for L-carnitine therapy.

BackgroundThis study aims to investigate the changes in circulating dipeptidyl peptidase-4 (DPP-4) activity following short-term intensive insulin therapy (SIIT) in newly diagnosed type 2 diabetes (T2D) patients and to assess its potential in predicting long-term remission.MethodsNinety-five patients underwent SIIT for 2-3 weeks to attain and sustain near-normal glycemia. Insulin was then discontinued, and patients were followed for a year to evaluate glycemic outcomes. Biochemical tests, serum DPP-4 activity, and mixed meal tolerance tests were conducted at baseline, post-SIIT, and the 3-month follow-up.ResultsDPP-4 activity decreased from 44.08 ± 9.58 to 40.53 ± 8.83 nmol/min/mL after SIIT (P

Colorectal cancer is the third most common type of cancer worldwide and has become one of the major human disease burdens. In clinical practice, the treatment of colorectal cancer has been closely related to the use of irinotecan. Irinotecan combines with many other anticancer drugs and has a broader range of drug combinations. Combination therapy is one of the most important means of improving anti-tumor efficacy and overcoming drug resistance. Reasonable combination therapy can lead to better patient treatment options, and inappropriate combination therapy will increase patient risk. For the colorectal therapeutic field, the significance of combination therapy is to improve the efficacy, reduce the adverse effects, and improve the ease of treatment. Therefore, we explored the clinical advantages of its combination therapy based on mechanism or metabolism and reviewed the rationale basis and its limitations in conducting exploratory clinical trials on irinotecan combination therapy, including the results of clinical trials on the combination potentiation of cytotoxic drugs, targeted agents, and herbal medicine. We hope that these can evoke more efforts to conduct irinotecan in the laboratory for further studies and evaluations, as well as the possibility of more in-depth development in future clinical trials.

Research on ocean ambient noise is highly important for environment monitoring, marine mammal protection, underwater communication and navigation. In this paper, we present the long-term statistics and wind dependence of near-bottom and deep-sea ambient noise in the northwest South China Sea, at a depth of 1240 m. The data were collected from 11th July 2022 to 31st December 2022 together with local wind speeds ranging from 1 to 58 knots (two typhoons involved), and the processing frequency band is between 20 and 2000 Hz. The long-term mean noise level is calculated along with its skewness, kurtosis and percentile distributions. Diurnal and monthly average of noise levels are analyzed, and the large fluctuations in lower (≤100 Hz) and higher (≥400 Hz) frequencies are respectively caused by the variation of the number of nearby and distant ships and the diverse distributions of the windspeeds in individual months. We find that the noise level in winter (Dec.) is 10~11 dB higher than that in summer (Jul.) at higher frequencies. The probability densities of noise levels in the situation of a fixed wind speed are likely to obey the Burr distributions in low frequencies (50 and 100 Hz) and the Weibull distributions in high frequencies (400 and 1000 Hz). In addition, the mean noise levels for different Beaufort scales match well with the 5-dB-addtion Wenz curves, and a mathematic relationship is acquired between the noise level and wind speed in the experimental site. The results are of great representativeness, and are significant to data-driven noise modelling, evaluation and improvement of sonar performance in the region of South China Sea with an incomplete deep-water sound channel.

The liver serves as a vital regulatory hub for various physiological processes, including sugar, protein, and fat metabolism, coagulation regulation, immune system maintenance, hormone inactivation, urea metabolism, and water-electrolyte acid-base balance control. These functions rely on coordinated communication among different liver cell types, particularly within the liver’s fundamental hepatic lobular structure. In the early stages of liver development, diverse liver cells differentiate from stem cells in a carefully orchestrated manner. Despite its susceptibility to damage, the liver possesses a remarkable regenerative capacity, with the hepatic lobule serving as a secure environment for cell division and proliferation during liver regeneration. This regenerative process depends on a complex microenvironment, involving liver resident cells, circulating cells, secreted cytokines, extracellular matrix, and biological forces. While hepatocytes proliferate under varying injury conditions, their sources may vary. It is well-established that hepatocytes with regenerative potential are distributed throughout the hepatic lobules. However, a comprehensive spatiotemporal model of liver regeneration remains elusive, despite recent advancements in genomics, lineage tracing, and microscopic imaging. This review summarizes the spatial distribution of cell gene expression within the regenerative microenvironment and its impact on liver regeneration patterns. It offers valuable insights into understanding the complex process of liver regeneration.

The liver, as the body’s primary organ for maintaining internal balance, is composed of numerous hexagonal liver lobules, each sharing a uniform architectural framework. These liver lobules serve as the basic structural and functional units of the liver, comprised of central veins, hepatic plates, hepatic sinusoids, and minute bile ducts. Meanwhile, within liver lobules, distinct regions of hepatocytes carry out diverse functions. The in vitro construction of liver lobule models, faithfully replicating their structure and function, holds paramount significance for research in liver development and diseases. Presently, two primary technologies for constructing liver lobule models dominate the field: 3D bioprinting and microfluidic techniques. 3D bioprinting enables precise deposition of cells and biomaterials, while microfluidics facilitates targeted transport of cells or other culture materials to specified locations, effectively managing culture media input and output through micro-pump control, enabling dynamic simulations of liver lobules. In this comprehensive review, we provide an overview of the biomaterials, cells, and manufacturing methods employed by recent researchers in constructing liver lobule models. Our aim is to explore strategies and technologies that closely emulate the authentic structure and function of liver lobules, offering invaluable insights for research into liver diseases, drug screening, drug toxicity assessment, and cell replacement therapy.

Based on a case study of digital games, this paper explores the politics between power and digital capital ingrained in the rapidly expanding Chinese cyberspace. The results show that digital capital and power in cyberspace form a paradoxical relationship that produces four sorts of politics: alliance, semi-alliance, disjunction, and semi-disjunction. Chinese modernity, as well as China's unique capital structure and governance system, have contributed to these politics. It is these politics that have given rise to a more decentralized regulatory system, brought freedom and autonomy to cyberspace, and maximized the Chinese government's power. Then digital capitalists in cyberspace can weave digital technology quickly into various social practices and make full use of netizens' creativity. Consequently, the politics between the Chinese government and digital capitalists in cyberspace not only triggered an unexpected social transformation but also opened up a different path for Chinese digital technology.

At present, the global urbanization process is accelerating, with the climate changing constantly and extreme weather increasing. In this background, urban flood disasters caused by rainstorms frequently occur in China. Therefore, a disaster risk analysis model based on a bow-tie Bayesian network was established to analyze the risk of waterlogging disasters. First, the waterlogging accident was analyzed, the intermediate and basic events that caused the accident were identified, and the accident tree was drawn. According to the intuitive nature of the fault tree, it was transformed into a Bayesian network, and in the meantime, a posteriori probability analysis of nodes was performed to further obtain the critical importance of basic events. By analyzing the importance of the basic events of waterlogging disasters, the key basic events that lead to disasters were proposed. Finally, the bow-tie model was used to analyze the importance of the hazards, and a strategy for the prevention and control of accidents was proposed. The results show that the major accident node of urban waterlogging accidents is the unsafe state of the urban environment, and the management and control of the urban environment should be strengthened to improve the prevention and control of urban waterlogging, e.g., pre-disaster prevention.

Acute high-altitude hypoxia can lead to intestinal damage and changes in gut microbiota. Sustained and reliable oxygen enrichment can resist hypoxic damage at high altitude to a certain extent. However, it remains unclear whether oxygen enrichment can protect against gut damage and changes in intestinal flora caused by acute altitude hypoxia. For this study, eighteen male Sprague–Dawley rats were divided into three groups, control (NN), hypobaric hypoxic (HH), and oxygen-enriched (HO). The NN group was raised under normobaric normoxia, whereas the HH group was placed in a hypobaric hypoxic chamber simulating 7,000 m for 3 days. The HO group was exposed to oxygen-enriched air in the same hypobaric hypoxic chamber as the HH group for 12 h daily. Our findings indicate that an acute HH environment caused a fracture of the crypt structure, loss of epithelial cells, and reduction in goblet cells. Additionally, the structure and diversity of bacteria decreased in richness and evenness. The species composition at Phylum and Genus level was characterized by a higher ratio of Firmicutes and Bacteroides and an increased abundance of Lactobacillus with the abundance of Prevotellaceae_NK3B31_group decreased in the HH group. Interestingly, after oxygen enrichment intervention, the intestinal injury was significantly restrained. This was confirmed by an increase in the crypt depth, intact epithelial cell morphology, increased relative density of goblet cells, and higher evenness and richness of the gut microbiota, Bacteroidetes and Prevotellaceae as the main microbiota in the HO group. Finally, functional analysis showed significant differences between the different groups with respect to different metabolic pathways, including Amino acid metabolism, energy metabolism, and metabolism. In conclusion, this study verifies, for the first time, the positive effects of oxygen enrichment on gut structure and microbiota in animals experiencing acute hypobaric hypoxia.

Minimal residual disease (MRD) refers to a very small number of residual tumor cells in the body during or after treatment, representing the persistence of the tumor and the possibility of clinical progress. Circulating tumor DNA (ctDNA) is a DNA fragment actively secreted by tumor cells or released into the circulatory system during the process of apoptosis or necrosis of tumor cells, which emerging as a non-invasive biomarker to dynamically monitor the therapeutic effect and prediction of recurrence. The feasibility of ctDNA as MRD detection and the revolution in ctDNA-based liquid biopsies provides a potential method for cancer monitoring. In this review, we summarized the main methods of ctDNA detection (PCR-based Sequencing and Next-Generation Sequencing) and their advantages and disadvantages. Additionally, we reviewed the significance of ctDNA analysis to guide the adjuvant therapy and predict the relapse of lung, breast and colon cancer et al. Finally, there are still many challenges of MRD detection, such as lack of standardization, false-negatives or false-positives results make misleading, and the requirement of validation using large independent cohorts to improve clinical outcomes.

Atrial fibrillation (AF) is a common arrhythmia in clinic, and its incidence is increasing year by year. In today's increasingly prevalent society, ageing poses a huge challenge to global healthcare systems. AF not only affects patients' quality of life, but also causes thrombosis, heart failure and other complications in severe cases. Although there are some measures for the diagnosis and treatment of AF, specific serum markers and targeted therapy are still lacking. In recent years, ncRNAs have become a hot topic in cardiovascular disease research. These ncRNAs are not only involved in the occurrence and development of AF, but also in pathophysiological processes such as myocardial infarction and atherosclerosis, and are potential biomarkers of cardiovascular diseases. We believe that the understanding of the pathophysiological mechanism of AF and the study of diagnosis and treatment targets can form a more systematic diagnosis and treatment framework of AF and provide convenience for individuals with AF and the society.

BackgroundProgrammed death receptor 1 (PD-1) inhibition has shown durable response and mild adverse events (AEs) in adult malignancies. However, data on the clinical activity of PD-1 inhibition in pediatric patients are lacking. We comprehensively assessed the efficacy and safety of PD-1 inhibitor-based regimens for pediatric malignancies.MethodsWe conducted a real-world, multi-institutional, retrospective analysis of pediatric malignancies treated with PD-1 inhibitor-based regimens. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). The secondary endpoints included disease control rate (DCR), duration of response (DOR), and AEs. The Kaplan–Meier method was used to calculate PFS and DOR. The National Cancer Institute Common Toxicity Criteria for AEs (version 5.0) were used to grade toxicity.ResultsA total of 93 and 109 patients were evaluated for efficacy and safety, respectively. For all efficacy-evaluable patients, PD-1 inhibitor monotherapy, combined chemotherapy, combined histone deacetylase inhibitor, and combined vascular endothelial growth factor receptor tyrosine kinase inhibitor cohorts, the ORR and DCR were 53.76%/81.72%, 56.67%/83.33%, 54.00%/80.00%, 100.00%/100.00%, and 12.50%/75.00%, respectively; the median PFS and DOR were 17.6/31.2 months, not achieved/not achieved, 14.9/31.2 months, 17.6/14.9 months, and 3.7/1.8 months, respectively; the incidence rate of AEs were 83.49%, 55.26%, 100.00%, 80.00%, and 100.00%, respectively. One patient in the PD-1 inhibitor-combined chemotherapy cohort discontinued treatment due to diabetic ketoacidosis.ConclusionsThis largest retrospective analysis demonstrate that PD-1 inhibitor-based regimens are potentially effective and tolerable in pediatric malignancies. Our findings provide references for future clinical trials and practice of PD-1 inhibitors in pediatric cancer patients.

Viburnum japonicum is a rare plant species and endemic to the coastal region of Eastern Asia with extremely small populations. Within mainland China, this species can be only found in narrow habitats of the northeast coastal islands of Zhejiang Province. However, there are scarce conservation genetic studies on V. japonicum, which has limited the effective conservation and management of this rare species. Here, 51 individuals in four natural populations covering the Chinese geographic range of the species were sampled to assess the genetic diversity and population structure. A total of 445,060 high-quality single nucleotide polymorphisms (SNPs) were identified using double digest restriction-site associated sequencing (ddRAD-seq). The overall average values of observed heterozygosity (Ho), expected heterozygosity (He), and average nucleotide diversity (π), were 0.2207, 0.2595, and 0.2741, respectively. The DFS-2 population exhibited the highest level of genetic diversity among all the populations. Genetic differentiation between populations was moderate (FST = 0.1425), and there was selfing between populations (FIS = 0.1390, S = 24.52%). Of the total genetic variation, 52.9% was found among populations through AMOVA analysis. The Mantel test (r = 0.982, p = 0.030) combined with analyses of the Maximum Likelihood (ML) phylogenetic tree, ADMIXTURE, and principal component analysis (PCA), revealed that populations of V. japonicum were genetically segregated and significantly correlated with their geographical distribution. Our study demonstrated that V. japonicum maintained a medium level of genetic diversity and differentiation with a strong population structure, and the results were mainly affected by its island distribution pattern and self-crossing characteristics. These results provide insights into the genetic diversity and population history of V. japonicum, critical information for conserving and sustainably developing its genetic resources.

ObjectiveThis study explored the impact of childhood trauma on adolescent cyberbullying and the mediating roles of emotional intelligence and online social anxiety between them.MethodsThe Childhood Trauma Scale, Emotional Intelligence Scale, and Chinese Brief Version of the Social Media User Social Anxiety Scale and Cyber Bullying Scale were used to assess 1,046 adolescents [boys: 297, girls: 749, average age = 15.79 years] from four schools in Shandong Province, China. SPSS 25.0 and AMOS 24.0 were used for statistical analysis.Results(1) Childhood trauma was positively associated with adolescents’ cyberbullying; (2) Emotional intelligence and online social anxiety played partial mediating roles in the relationship between childhood trauma and cyberbullying; (3) Emotional intelligence and online social anxiety played a chain mediating role in the relationship between childhood trauma and cyberbullying.ConclusionThis study reveals the relationship and mediating mechanisms between childhood trauma and cyberbullying. It provides implications for the theory and prevention of cyberbullying.

Camellia oleifera Abel. is an economically important woody edible-oil species that is mainly cultivated in hilly areas of South China. The phosphorus (P) deficiency in the acidic soils poses severe challenges for the growth and productivity of C. oleifera. WRKY transcription factors (TFs) have been proven to play important roles in biological processes and plant responses to various biotic/abiotic stresses, including P deficiency tolerance. In this study, 89 WRKY proteins with conserved domain were identified from the C. oleifera diploid genome and divided into three groups, with group II further classified into five subgroups based on the phylogenetic relationships. WRKY variants and mutations were detected in the gene structure and conserved motifs of CoWRKYs. Segmental duplication events were considered as the primary driver in the expanding process of WRKY gene family in C. oleifera. Based on transcriptomic analysis of two C. oleifera varieties characterized with different P deficiency tolerances, 32 CoWRKY genes exhibited divergent expression patterns in response to P deficiency stress. qRT-PCR analysis demonstrated that CoWRKY11, -14, -20, -29 and -56 had higher positive impact on P-efficient CL40 variety compared with P-inefficient CL3 variety. Similar expression trends of these CoWRKY genes were further observed under P deficiency with longer treatment period of 120d. The result indicated the expression sensitivity of CoWRKYs on the P-efficient variety and the C. oleifera cultivar specificity on the P deficiency tolerance. Tissue expression difference showed CoWRKYs may play a crucial role in the transportation and recycling P in leaves by affecting diverse metabolic pathways. The available evidences in the study conclusively shed light on the evolution of the CoWRKY genes in C. oleifera genome and provided a valuable resource for further investigation of functional characterization of WRKY genes involved to enhance the P deficiency tolerance in C. oleifera.

COVID-19 induces acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and leads to severe immunological changes that threatens the lives of COVID-19 victims. Studies have shown that both the regulatory T cells and macrophages were deranged in COVID-19-induced ALI. Herbal drugs have long been utilized to adjust the immune microenvironment in ALI. However, the underlying mechanisms of herbal drug mediated ALI protection are largely unknown. This study aims to understand the cellular mechanism of a traditional Chinese medicine, Qi-Dong-Huo-Xue-Yin (QD), in protecting against LPS induced acute lung injury in mouse models. Our data showed that QD intrinsically promotes Foxp3 transcription via promoting acetylation of the Foxp3 promoter in CD4+ T cells and consequently facilitates CD4+CD25+Foxp3+ Tregs development. Extrinsically, QD stabilized β-catenin in macrophages to expedite CD4+CD25+Foxp3+ Tregs development and modulated peripheral blood cytokines. Taken together, our results illustrate that QD promotes CD4+CD25+Foxp3+ Tregs development via intrinsic and extrinsic pathways and balanced cytokines within the lungs to protect against LPS induced ALI. This study suggests a potential application of QD in ALI related diseases.

Introduction: Aconite is a form of traditional Chinese medicine (TCM) that has been widely used to treat diarrhea for thousands of years. However, it is not clear whether the anti-diarrhea role of aconite aqueous extract (AA) is associated with regulation of the gut microbiota or with bile acid (BA) metabolism. This study aimed to confirm whether AA exerts its anti-diarrhea effects by regulating the gut microbiota and BA metabolism.Methods: The therapeutic effect of AA in a mouse model of diarrhea was measured based on analysis of body weight, fecal water content, diarrhea scores, intestinal propulsion rate, colonic pathology, and colonic immunohistochemistry. In addition, 16S rRNA high-throughput sequencing was conducted to analyze the effect of AA on the gut microbiota, and targeted metabolomics was employed to analyze the effect of AA on metabolism of BAs.Results: The results showed that treatment with AA reduced fecal water content and diarrhea scores, inhibited intestinal propulsion rate and pathological changes in the colon, and increased AQP3 and AQP4 content in the colon. In addition, AA was found to be capable of regulating the gut microbiota. Effects included increasing its richness (according to the ACE and Chao1 indices); altering the gut microbiota community structure (PCA, PCoA, and NMDS); increasing the relative abundance of norank_f_Muribaculaceae, Ruminococcus, Lachnospiraceae_NK4A136_group, Prevotellaceae_UCG-001, and norank_f_norank_o_Clostridia_UCG-014; and decreasing the relative abundance of Escherichia-Shigella, unclassified_f_Ruminococcaceae, Ruminococcus_torques_group, and Parasutterella. More importantly, AA significantly increased fecal TCA (a primary BA) and DCA, LCA, GDCA, dehydro-LCA, and 12-keto-LCA (secondary BAs), thus restoring BA homeostasis. Moreover, AA increased the ratios of DCA/CA, DCA/TCA, and LCA/CDCA and decreased the ratios of TLCA/LCA, GLCA/LCA, and TUDCA/UDCA.Conclusion: The anti-diarrhea effect of AA was associated with restoration of the gut microbiota and BA metabolism-related homeostasis. The results of this study provide insights into the application of AA and the treatment of diarrhea.

This paper evaluates LFS (LICOM Forecast System) forecasts and compares them with other marine forecast systems under the IVTT (Intercomparison and Validation Task Team) Class 4 framework. LFS delivers real-time daily forecasts driven by the GFS (Global Forecast System) atmospheric analyses and surface forecasts. The nudging method in LFS provides the initial state for forecasting, with only the temperature and salinity restored towards the Mercator PSY4 daily analyses. Assessments show that LFS demonstrates a reasonably good capability in short-term marine environment forecast. For the leading 1-6 days forecasts, the root mean square error (RMSE) ranges between 0.53-0.63°C, 0.57-0.66°C and 0.12-0.13 psu for the sea surface temperature, temperature, and salinity profiles, respectively. The overall performance is comparable to other major marine forecast systems, with a slight advantage in forecasting the temperature and salinity profiles. Different nudging time scales are applied to the upper ocean and deep ocean to preserve the effects of mesoscale processes and correct the large-scale biases in temperature and salinity. However, the absence of other observational constraints, such as the sea level height, significantly affects the regional forecast features. Further analyses are required to improve the performance, and the integration of an assimilation system into LFS is urgently needed.

BackgroundAtractylodes macrocephala Koidz. (AM) is a functional food with strong ant-colitis activity. AM volatile oil (AVO) is the main active ingredient of AM. However, no study has investigated the improvement effect of AVO on ulcerative colitis (UC) and the bioactivity mechanism also remains unknown. Here, we investigated whether AVO has ameliorative activity on acute colitis mice and its mechanism from the perspective of gut microbiota.MethodsAcute UC was induced in C57BL/6 mice by dextran sulfate sodium and treated with the AVO. Body weight, colon length, colon tissue pathology, and so on were assessed. The gut microbiota composition was profiled using 16s rRNA sequencing and global metabolomic profiling of the feces was performed. The results showed that AVO can alleviate bloody diarrhea, colon damage, and colon inflammation in colitis mice. In addition, AVO decreased potentially harmful bacteria (Turicibacter, Parasutterella, and Erysipelatoclostridium) and enriched potentially beneficial bacteria (Enterorhabdus, Parvibacter, and Akkermansia). Metabolomics disclosed that AVO altered gut microbiota metabolism by regulating 56 gut microbiota metabolites involved in 102 KEGG pathways. Among these KEGG pathways, many metabolism pathways play an important role in maintaining intestine homeostasis, such as amino acid metabolism (especially tryptophan metabolism), bile acids metabolism, and retinol metabolism.ConclusionIn conclusion, our study indicated that AVO can be expected as novel prebiotics to treat ulcerative colitis, and modulating the composition and metabolism of gut microbiota may be its pharmacological mechanism.

ObjectiveThere is growing evidence of a relationship between anti-seizure medication (ASM) use and the risk of dementia. This study examined this association using a meta-analysis approach.MethodsPubMed, EMBASE, and Cochrane Library were systematically searched for peer-reviewed observational studies published up to February 2023. Study quality was evaluated using the Newcastle-Ottawa Scale, and an overall odds ratio (OR) was pooled using fixed or random-effects models.ResultsThe analysis included 9 publications with 10 studies. The results showed that overall ASM exposure was associated with an increased risk of dementia [OR: 1.09, 95% confidence interval (CI): 1.03–1.15; P = 0.003] in general population. However, this association disappeared (OR: 1.02, 95% CI: 0.97–1.07; P = 0.361) when the study data adjusted for drug indications were pooled. Subgroup analysis based on individual drugs found only a positive association among those exposed to valproate, carbamazepine, and clonazepam. Furthermore, an increased risk was found in patients with bipolar disorder exposed to ASMs (OR: 1.43, 95% CI: 1.07–1.92; P = 0.015).ConclusionsThe statistically significant association between ASM and dementia in general population may be driven by unmeasured confounding or several individual first-generation ASMs. However, a higher risk of dementia was observed among bipolar disorder patients treated with ASMs. Given the few included studies and evidence of high heterogeneity, further larger, prospective studies that control for important confounders are needed to verify our findings.

Diabetic nephropathy (DN), the leading cause of end-stage renal disease, is the most significant microvascular complication of diabetes and poses a severe public health concern due to a lack of effective clinical treatments. Autophagy is a lysosomal process that degrades damaged proteins and organelles to preserve cellular homeostasis. Emerging studies have shown that disorder in autophagy results in the accumulation of damaged proteins and organelles in diabetic renal cells and promotes the development of DN. Autophagy is regulated by nutrient-sensing pathways including AMPK, mTOR, and Sirt1, and several intracellular stress signaling pathways such as oxidative stress and endoplasmic reticulum stress. An abnormal nutritional status and excess cellular stresses caused by diabetes-related metabolic disorders disturb the autophagic flux, leading to cellular dysfunction and DN. Here, we summarized the role of autophagy in DN focusing on signaling pathways to modulate autophagy and therapeutic interferences of autophagy in DN.

Background: Several studies performed thus far indicate that neuroinflammation may be one of the mechanisms underlying the pathogenesis of neuropathic pain (NP). Autophagy, as an adaptive response, has been regarded as an active process of removing the inflammatory stimulus and restoring homeostatic balance. Resolution of inflammation is a biochemical process mediated by the so-called aspirin-triggered specialized proresolving lipid mediators (AT-SPMs), which are thought to exert protective effects in NP. Recent studies have proposed mechanisms in models of inflammatory disorders and showed a relationship between resolution of inflammation and autophagy. This study aimed to validate the functional effects of Aspirin-triggered Resolvin D1 (AT-RvD1) on in vitro and in vivo models of inflammation and to determine their roles in the regulation of autophagy and activation of the Nod-like receptor protein 3 (NLRP3) inflammasome signaling pathway.Methods: An NP model was established using L5-6 spinal nerve ligation (SNL) and a model of tumor necrosis factor alpha (TNF-α)-stimulated primary microglia was established to evaluate the effect of SPMs. Western blotting was used to detect the level of NLRP3 inflammasomes complexes proteins (NLRP3, ASC, and Caspase-1) and autophagy-related proteins (LC3B, and Beclin1). Immunofluorescence staining was used to understand the autophagy and NLRP3 inflammasome activation process. The behavioral changes in rats were analyzed using paw withdrawal thresholds (PWT) and paw withdrawal latency (PWL) test.Results: Our results showed that AT-SPMs significantly upregulated the activation of autophagy, which was characterized by an increase in the ratio of LC3B-II/I and accumulation of ATG5 and Beclin1. AT-RvD1 showed a dose-dependent decrease in the upregulated PWT and PWL induced by SNL and suppressed the expression of the NLRP3 inflammasome protein and the production of its corresponding downstream proinflammatory factors. Additionally, AT-RvD1 induced the activation of autophagy of the microglia and decreased the expression of the NLRP3 inflammasome protein and the accumulation of proinflammatory factors in TNF-ɑ-challenged microglia.Conclusion: Thus, these results showed that AT-RvD1 may be a potential alternative therapeutic strategy for the prevention or treatment of NP by inhibition of the NLRP3 inflammasome signaling pathway by targeting the induction of autophagy.

ObjectiveLime application and understory plant clearance are two common forest management methods employed to increase forest productivity in subtropical regions. However, the effect of these two management methods, or their combined application, on soil respiration in forest plantation settings is still not fully understood.MethodsHere, a field experiment was conducted to determine how lime application, understory clearance, and their combined application, would impact total soil respiration (Rs), autotrophic respiration (Ra), and heterotrophic respiration (Rh) in a Chinese subtropical Eucalyptus plantation. Changes in soil microclimate and microbial community (PLFAs), as well as Eucalyptus fine root biomass were also assessed.ResultsLime application stimulated Rh, but decreased Ra of understory vegetation (primarily Dicranopteris dichotoma), thus consequently inhibiting Rs. Understory clearance also reduced Rs, primarily due to reductions in soil PLFAs and associated Rh, and Ra of understory vegetation. Since the increase in Rh induced by lime application was greater than the decrease in Rh caused by understory clearance, the combined application of lime application and understory clearance decreased Rs primarily by reducing understory root respiration.ConclusionOur observations suggest that understory plants can modulate the effect of lime application on Rs, highlighting the important role of understory vegetation in regulating soil carbon cycling in subtropical Eucalyptus plantations. We concluded that the potential interactive effects should be considered in developing management practices that optimize the yield and sustainability of subtropical plantations.

ObjectivesThere is an ongoing debate about the restrictive inattentive (RI) presentation of attention deficit hyperactivity disorder (ADHD). The current study aimed to systematically investigate the clinical, neuropsychological, and brain functional characteristics of children with ADHD restrictive inattentive presentation.MethodsA clinical sample of 789 children with or without ADHD participated in the current study and finished clinical interviews, questionnaires, and neuropsychological tests. Those individuals with a diagnosis of ADHD were further divided into three subgroups according to the presentation of inattentive and/or hyperactive/impulsive symptoms, the ADHD-RI, the ADHD-I (inattentive), and the ADHD-C (combined) groups. Between-group comparisons were carried out on each clinical and neuropsychological measure using ANCOVA, with age and sex as covariates. Bonferroni corrections were applied to correct for multiple comparisons. Two hundred twenty-seven of the subjects also went through resting-state functional magnetic resonance imaging scans. Five ADHD-related brain functional networks, including the default mode network (DMN), the dorsal attention network (DAN), the ventral attention network, the executive control network, and the salience network, were built using predefined regions of interest (ROIs). Voxel-based group-wise comparisons were performed.ResultsCompared with healthy controls, all ADHD groups presented more clinical problems and weaker cognitive function. Among the ADHD groups, the ADHD-C group had the most clinical problems, especially delinquent and aggressive behaviors. Regarding cognitive function, the ADHD-RI group displayed the most impaired sustained attention, and the ADHD-C group had the worst response inhibition function. In terms of brain functional connectivity (FC), reduced FC in the DMN was identified in the ADHD-C and the ADHD-I groups but not the ADHD-RI group, compared to the healthy controls. Subjects with ADHD-I also presented decreased FC in the DAN in contrast to the control group. The ADHD-RI displayed marginally significantly lower FC in the salience network compared to the ADHD-I and the control groups.ConclusionThe ADHD-RI group is distinguishable from the ADHD-I and the ADHD-C groups. It is characterized by fewer externalizing behaviors, worse sustained attention, and better response inhibition function. The absence of abnormally high hyperactive/impulsive symptoms in ADHD-RI might be related to less impaired brain function in DMN, but potentially more impairment in the salience network.

BackgroundThis experimental study aimed to determine the dynamic changes in myocardial strain and microvascular perfusion in diabetic rats by comprehensive echocardiography while evaluating the effect of dapagliflozin (DAPA).Materials and methodsMale Sprague–Dawley rats (n = 128) were randomly divided into four groups based on the presence or absence of a high-fat diet and streptozotocin-induced diabetes with or without DAPA treatment (n = 32/group). Serial conventional ultrasound, two-dimensional speckle tracking echocardiography (2D-STE) and myocardial contrast echocardiography (MCE) were performed at 2, 4, 6, and 8 weeks, and left ventricular global longitudinal strain (GLS), myocardial blood flow velocity (MBFV), myocardial blood flow (MBF), and myocardial blood volume (MBV) were determined. All animals were sacrificed immediately after the last echo measurement for histopathological assessment.ResultsDespite similar conventional Doppler-echo indexes among the groups at 2, 4, 6, and 8 weeks (p > 0.05), left ventricular GLS, MBFV, MBF, and MBV were decreased at 8 weeks in diabetic rats (p < 0.05) as detected by both 2D-STE and MCE. These indexes were significantly improved at 6 and 8 weeks after treatment with DAPA for diabetic rats (p < 0.05), reaching similar values observed in non-diabetic controls. DAPA treatment was associated with increased myocardial vacuolization and microvessel density and reduced interstitial fibrosis in diabetic rats.ConclusionsCombined 2D-STE and MCE is sensitive for detecting left ventricular deformity and impaired microvascular perfusion in prediabetes and the early stage of diabetes mellitus. DAPA exerts a beneficial effect on protecting myocardial perfusion in diabetic rats.