Pan-drug resistance and hypervirulence in a human fungal pathogen are enabled by mutagenesis induced by mammalian body temperature.

The continuing emergence of invasive fungal pathogens poses an increasing threat to public health. Here, through the China Hospital Invasive Fungal Surveillance Net programme, we identified two independent cases of human infection with a previously undescribed invasive fungal pathogen, Rhodosporidiobolus fluvialis, from a genus in which many species are highly resistant to fluconazole and caspofungin. We demonstrate that R. fluvialis can undergo yeast-to-pseudohyphal transition and that pseudohyphal growth enhances its virulence, revealed by the development of a mouse model. Furthermore, we show that mouse infection or mammalian body temperature induces its mutagenesis, allowing the emergence of hypervirulent mutants favouring pseudohyphal growth. Temperature-induced mutagenesis can also elicit the development of pan-resistance to three of the most commonly used first-line antifungals (fluconazole, caspofungin and amphotericin B) in different Rhodosporidiobolus species. Furthermore, polymyxin B was found to exhibit potent activity against the pan-resistant Rhodosporidiobolus mutants. Collectively, by identifying and characterizing a fungal pathogen in the drug-resistant genus Rhodosporidiobolus, we provide evidence that temperature-dependent mutagenesis can enable the development of pan-drug resistance and hypervirulence in fungi, and support the idea that global warming can promote the evolution of new fungal pathogens.

Catalytic [4+2]- and [4+4]-cycloaddition using furan-fused cyclobutanone as a privileged C4 synthon.

Cycloaddition reactions play a pivotal role in synthetic chemistry for the direct assembly of cyclic architectures. However, hurdles remain for extending the C4 synthon to construct diverse heterocycles via programmable [4+n]-cycloaddition. Here we report an atom-economic and modular intermolecular cycloaddition using furan-fused cyclobutanones (FCBs) as a versatile C4 synthon. In contrast to the well-documented cycloaddition of benzocyclobutenones, this is a complementary version using FCB as a C4 reagent. It involves a C-C bond activation and cycloaddition sequence, including a Rh-catalyzed enantioselective [4 + 2]-cycloaddition with imines and an Au-catalyzed diastereoselective [4 + 4]-cycloaddition with anthranils. The obtained furan-fused lactams, which are pivotal motifs that present in many natural products, bioactive molecules, and materials, are inaccessible or difficult to prepare by other methods. Preliminary antitumor activity study indicates that 6e and 6 f exhibit high anticancer potency against colon cancer cells (HCT-116, IC50 = 0.50 ± 0.05 µM) and esophageal squamous cell carcinoma cells (KYSE-520, IC50 = 0.89 ± 0.13 µM), respectively.

Trichinella spiralis Paramyosin Alleviates Collagen-Induced Arthritis in Mice by Modulating CD4+ T Cell Differentiation.

Rheumatoid arthritis (RA) is an autoimmune disease that significantly impacts quality of life by disrupting CD4+ T cell immune homeostasis. The identification of a low-side-effect drug for RA treatment is urgently needed. Our previous study suggests that Trichinella spiralis paramyosin (Ts-Pmy) has immunomodulatory effects, but its potential effect on CD4+ T cell response in RA remains unclear. In this study, we used a murine model to investigate the role of rTs-Pmy in regulating CD4+ T cell differentiation in collagen-induced arthritis (CIA). Additionally, we assessed the impact of rTs-Pmy on CD4+ T cell differentiation towards the Th1 and Th17 phenotypes, which are associated with inflammatory responses in arthritis, using in vitro assays. The results demonstrated that rTs-Pmy administration reduced arthritis severity by inhibiting Th1 and Th17 response while enhancing Treg response. Prophylactic administration of Ts-Pmy showed superior efficacy on CIA compared to therapeutic administration. Furthermore, in vitro assays demonstrated that rTs-Pmy could inhibit the differentiation of CD4+ T cells into Th1 and Th17 while inducing the production of Tregs, suggesting a potential mechanism underlying its therapeutic effects. This study suggests that Ts-Pmy may ameliorate CIA by restoring the immune balance of CD4+ T cells and provides new insights into the mechanism through which helminth-derived proteins exert their effects on autoimmune diseases.

The Plant PTM Viewer 2.0: in-depth exploration of plant protein modification landscapes.

Post-translational modifications (PTMs) greatly increase protein diversity and functionality. To help the plant research community interpret the ever-increasing number of reported PTMs, The Plant PTM Viewer (https://www.psb.ugent.be/PlantPTMViewer) provides an intuitive overview and tools to assess plant protein PTMs. This update includes 62 novel PTM profiling studies, adding a total of 112,000 modified peptides reporting plant PTMs, including 14 additional PTM types and three species (moss, tomato and soybean). Furthermore, an open modification re-analysis of a large-scale Arabidopsis thaliana mass spectrometry tissue atlas identified previously uncharted landscapes of lysine acylations predominant in seed and flower tissues and 3-phosphoglycerylation on glycolytic enzymes in plants. An extra 'protein list analysis' tool was developed for retrieval and assessing the enrichment of PTMs a protein list of interest. We conducted a protein list analysis on nuclear proteins, revealing a substantial number of redox modifications in the nucleus, confirming previous assumptions regarding the redox regulation of transcription. We encourage the plant research community to use PTM Viewer 2.0 for hypothesis testing and new target discovery and also to submit new data to expand the coverage of conditions, plant species, and PTM types, thereby enriching our understanding of plant biology.

RGS19 activates the MYH9/ß-catenin/c-Myc positive feedback loop in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common fatal cancers worldwide, and the identification of novel treatment targets and prognostic biomarkers is urgently needed because of its unsatisfactory prognosis. Regulator of G-protein signaling 19 (RGS19) is a multifunctional protein that regulates the progression of various cancers. However, the specific function of RGS19 in HCC remains unclear. The expression of RGS19 was determined in clinical HCC samples. Functional and molecular biology experiments involving RGS19 were performed to explore the potential mechanisms of RGS19 in HCC. The results showed that the expression of RGS19 is upregulated in HCC tissues and is significantly associated with poor prognosis in HCC patients. RGS19 promotes the proliferation and metastasis of HCC cells in vitro and in vivo. Mechanistically, RGS19, via its RGS domain, stabilizes the MYH9 protein by directly inhibiting the interaction of MYH9 with STUB1, which has been identified as an E3 ligase of MYH9. Moreover, RGS19 activates ß-catenin/c-Myc signaling via MYH9, and RGS19 is also a transcriptional target gene of c-Myc. A positive feedback loop formed by RGS19, MYH9, and the ß-catenin/c-Myc axis was found in HCC. In conclusion, our research revealed that competition between RGS19 and STUB1 is a critical mechanism of MYH9 regulation and that the RGS19/MYH9/ß-catenin/c-Myc feedback loop may represent a promising strategy for HCC therapy.

Electrocatalytic Nitrate Reduction on Metallic CoNi-Terminated Catalyst with Industrial-Level Current Density in Neutral Medium.

Green ammonia synthesis through electrocatalytic nitrate reduction reaction (eNO3RR) can serve as an effective alternative to the traditional energy-intensive Haber-Bosch process. However, achieving high Faradaic efficiency (FE) at industrially relevant current density in neutral medium poses significant challenges in eNO3RR. Herein, with the guidance of theoretical calculation, a metallic CoNi-terminated catalyst is successfully designed and constructed on copper foam, which achieves an ammonia FE of up to 100% under industrial-level current density and very low overpotential (-0.15 V versus reversible hydrogen electrode) in a neutral medium. Multiple characterization results have confirmed that the maintained metal atom-terminated surface through interaction with copper atoms plays a crucial role in reducing overpotential and achieving high current density. By constructing a homemade gas stripping and absorption device, the complete conversion process for high-purity ammonium nitrate products is demonstrated, displaying the potential for practical application. This work suggests a sustainable and promising process toward directly converting nitrate-containing pollutant solutions into practical nitrogen fertilizers.

Crystal structure of Trichinella spiralis calreticulin and the structural basis of its complement evasion mechanism involving C1q.

Helminths produce calreticulin (CRT) to immunomodulate the host immune system as a survival strategy. However, the structure of helminth-derived CRT and the structural basis of the immune evasion process remains unclarified. Previous study found that the tissue-dwelling helminth Trichinella spiralis produces calreticulin (TsCRT), which binds C1q to inhibit activation of the complement classical pathway. Here, we used x-ray crystallography to resolve the structure of truncated TsCRT (TsCRTΔ), the first structure of helminth-derived CRT. TsCRTΔ was observed to share the same binding region on C1q with IgG based on the structure and molecular docking, which explains the inhibitory effect of TsCRT on C1q-IgG-initiated classical complement activation. Based on the key residues in TsCRTΔ involved in the binding activity to C1q, a 24 amino acid peptide called PTsCRT was constructed that displayed strong C1q-binding activity and inhibited C1q-IgG-initiated classical complement activation. This study is the first to elucidate the structural basis of the role of TsCRT in immune evasion, providing an approach to develop helminth-derived bifunctional peptides as vaccine target to prevent parasite infections or as a therapeutic agent to treat complement-related autoimmune diseases.

An audio-semantic multimodal model for automatic obstructive sleep Apnea-Hypopnea Syndrome classification via multi-feature analysis of snoring sounds.

Introduction: Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) is a common sleep-related breathing disorder that significantly impacts the daily lives of patients. Currently, the diagnosis of OSAHS relies on various physiological signal monitoring devices, requiring a comprehensive Polysomnography (PSG). However, this invasive diagnostic method faces challenges such as data fluctuation and high costs. To address these challenges, we propose a novel data-driven Audio-Semantic Multi-Modal model for OSAHS severity classification (i.e., ASMM-OSA) based on patient snoring sound characteristics. Methods: In light of the correlation between the acoustic attributes of a patient's snoring patterns and their episodes of breathing disorders, we utilize the patient's sleep audio recordings as an initial screening modality. We analyze the audio features of snoring sounds during the night for subjects suspected of having OSAHS. Audio features were augmented via PubMedBERT to enrich their diversity and detail and subsequently classified for OSAHS severity using XGBoost based on the number of sleep apnea events. Results: Experimental results using the OSAHS dataset from a collaborative university hospital demonstrate that our ASMM-OSA audio-semantic multimodal model achieves a diagnostic level in automatically identifying sleep apnea events and classifying the four-class severity (normal, mild, moderate, and severe) of OSAHS. Discussion: Our proposed model promises new perspectives for non-invasive OSAHS diagnosis, potentially reducing costs and enhancing patient quality of life.

Application of deep eutectic solvents on extraction of flavonoids.

Deep eutectic solvents (DESs), as a new type of eco-friendly solvent, have attracted increasing attention on the extraction and separation of flavonoid compounds from various samples, owing to their excellent properties such as biodegradability and ease of handling with very low toxicity. This article provides a status review of the applications of DESs in the extraction of flavonoids, including the introduction of flavonoid compounds, the properties and superiority of DESs, and extraction methods (ultrasonic-assisted extraction, heating reflux extraction, matrix solid-phase dispersion, and solid-phase extraction). Finally, prospects and challenges in the application of DESs on extraction and separation are extensively elucidated and critically reviewed.

Risk factors and patterns for progression of fellow-eye myopic traction maculopathy: a 3-year retrospective cohort study.

AIMS: To investigate the effect of preretinal tractional structures (PTS) and posterior scleral structures (PSS) on myopic traction maculopathy (MTM) progression. METHODS: This retrospective cohort study included 185 fellow highly myopic eyes of 185 participants who underwent surgery for MTM. PTS included epiretinal membrane, incomplete posterior vitreous detachment and their combination. PSS included posterior staphyloma and dome-shaped macula (DSM). The MTM stage was graded according to the Myopic Traction Maculopathy Staging System. Optical coherence tomography was used to identify MTM progression, defined as an upgrade of MTM. The Kaplan-Meier method with log-rank test was used to assess MTM progression over the 3-year follow-up period. Risk factors for progression were identified using Cox regression analysis. RESULTS: MTM progression was observed in 48 (25.9%) eyes. Three-year progression-free survival (PFS) rates for eyes with PTS, staphyloma and DSM were 53.7%, 58.2% and 90.7%, respectively. Eyes with PTS and staphyloma exhibited lower 3-year PFS rates than those without PTS or staphyloma (P log-rank test =0.002 and <0.001), while eyes with DSM had a higher 3-year PFS rate than eyes without DSM (P log-rank test=0.01). Multivariate Cox regression analysis showed that PTS (HR, 3.23; p<0.001) and staphyloma (HR, 7.91; p<0.001) were associated with MTM progression, whereas DSM (HR, 0.23; p=0.046) was a protective factor. CONCLUSION: Both PTS and PSS play a critical role in the progression of MTM. Addressing these factors can aid in the management of MTM.

Efficacy and Safety of Surgical Peripheral Iridectomy, Goniosynechialysis, and Goniotomy for Advanced Primary Angle-closure Glaucoma without Cataract: One-year Results of a Multicenter Study.

PRCIS: The combination of surgical peripheral iridectomy, goniosynechialysis, and goniotomy is a safe and effective surgical approach for advanced primary angle-closure glaucoma without cataract. PURPOSE: To evaluate the efficacy and safety of surgical peripheral iridectomy (SPI), goniosynechialysis (GSL), and goniotomy (GT) in advanced primary angle-closure glaucoma (PACG) eyes without cataract. PATIENTS AND METHODS: A prospective multicenter observational study was performed for patients who underwent combined SPI, GSL, and GT for advanced PACG without cataract. Patients were assessed before and after the operation. Complete success was defined as achieving intraocular pressure (IOP) between 6-18 mm Hg with at least a 20% reduction compared to baseline, without the use of ocular hypotensive medications or reoperation. Qualified success adopted the same criteria but allowed medication use. Factors associated with surgical success were analyzed using logistic regression. RESULTS: A total of 61 eyes of 50 advanced PACG were included. All participants completed 12 months of follow-up. Thirty-six eyes (59.0%) achieved complete success, and 56 eyes (91.8%) achieved qualified success. Preoperative and postsurgical at 12 months mean IOPs were 29.7±7.7 and 16.1±4.8 mm Hg, respectively. The average number of ocular hypotensive medications decreased from 1.9 to 0.9 over 12 months. The primary complications included IOP spike (n=9), hyphema (n=7), and shallow anterior chamber (n=3). Regression analysis indicated that older age (odds ratio [OR]=1.09; P=0.043) was positively associated with complete success, while a mixed angle closure mechanism (OR=0.17; P=0.036) reduced success rate. CONCLUSIONS: The combination of SPI, GSL, and GT is a safe and effective surgical approach for advanced PACG without cataract. It has great potential as a first-line treatment option for these patients.

Development and Validation of a Nomogram Model to Predict Obstructive Sleep Apnea.

Objectives: Polysomnography was class I test for who was suspected of obstructive sleep apnea (OSA) which would cost lots of time and money. This study aimed to develop a nomogram model mainly based on oxygen and blood routine indicators to predict OSA. Methods: We retrospectively analyzed 685 patients with suspected OSA at our hospital. Multivariate analysis was used to construct a nomogram. The performance of the nomogram was assessed using calibration and discrimination. Results: The multivariate analysis identified age, gender, body mass index, mean pulse oxygen saturation, percent nighttime with oxygen saturation less than 90%, red blood cell, hematocrit, and red blood cell distribution width SD as significant factors (P < .05). A nomogram was created for the prediction of OSA using these clinical parameters and was internally validated using a bootstrapping method. Our nomogram model showed good discrimination and calibration in terms of predicting OSA, and had a C-index of 0.935 [95% confidence interval (CI), 0.917-0.954] according to the internal validation. Discrimination and calibration in the validation group were also good (C-index, 0.957; 95% CI, 0.930-0.984). Conclusion: The newly developed nomogram can effectively help physicians make better clinical decisions, which may save a lot of time and costs.

Establishment and clinical application of the HLA genotype database of platelet-apheresis donors in Suzhou.

The establishment of a platelet-apheresis donor database may provide a feasible solution to improve the efficacy of platelet transfusion in patients with immune platelet transfusion refractoriness (PTR). This study aimed to establish HLA genotype database in Suzhou, to provide HLA-I compatible platelets for PTR patients to ensure the safety and effectiveness of platelet transfusions. We used a polymerase chain reaction sequence-based typing (PCR-SBT) method to establish the database by performing high-resolution HLA-A, -B, and -C genotyping on 900 platelet-apheresis donors. HLA-I antibody was detected in patients using a Luminex device, and HLA-I gene matching was performed by an HLA-Matchmaker. We found that the highest frequency of the HLA-A allele was A*11:01 (17.06 %), followed by A*24:02 (14.67 %) and A*02:01 (13.61 %). The highest frequency of the HLA-B allele was B*46:01 (9.78 %), followed by B*40:01 (8.39 %) and B*13:02 (33 %). After the detection of platelet antibodies in 74 patients with immune PTR, we found 30 HLA-A antibodies and 48 HLA-B antibodies, and there were a variety of high frequency antibodies whose alleles were low in the donor database, such as HLA-A*68:02, and B*57:01. After avoiding donor-specific antibodies (DSA) matching, 102 of 209 platelet-compatible transfusions were effective, resulting in an effective rate of 48.8 %, which significantly improved the efficacy of platelet transfusion. The establishment of a platelet donor database is of great significance to improve the therapeutic effect of platelet transfusion in patients with hematologic disorder, and save blood resources, and it is also the premise and guarantee of precise platelet transfusion.

FSP1-mediated ferroptosis in cancer: from mechanisms to therapeutic applications.

Ferroptosis is a new discovered regulated cell death triggered by the ferrous ion (Fe2+)-dependent accumulation of lipid peroxides associated with cancer and many other diseases. The mechanism of ferroptosis includes oxidation systems (such as enzymatic oxidation and free radical oxidation) and antioxidant systems (such as GSH/GPX4, CoQ10/FSP1, BH4/GCH1 and VKORC1L1/VK). Among them, ferroptosis suppressor protein 1 (FSP1), as a crucial regulatory factor in the antioxidant system, has shown a crucial role in ferroptosis. FSP1 has been well validated to ferroptosis in three ways, and a variety of intracellular factors and drug molecules can alleviate ferroptosis via FSP1, which has been demonstrated to alter the sensitivity and effectiveness of cancer therapies, including chemotherapy, radiotherapy, targeted therapy and immunotherapy. This review aims to provide important frameworks that, bring the regulation of FSP1 mediated ferroptosis into cancer therapies on the basis of existing studies.

Naps and cardiovascular disease risk in different age and sex groups: evidence from a large community cohort.

STUDY OBJECTIVES: This study examined the relationship between naps and cardiovascular disease (CVD) events or death in different age and sex groups. METHODS: A total of 3069 participants stratified by age (<65, 65-74, and ≥75 years old) and sex, underwent Cox regression analysis to assess nap's impact on CVD risk. Restricted cubic spline plots (RCS) were used for dose-response relationships. RESULTS: Significant age-stratified interactions were found when exploring the associations between nap frequency or duration and CVD events (P interaction = 0.001, 0.036 respectively). Individuals younger than 65 years with higher nap frequency or longer nap duration had a significantly increased risk of CVD events (P < 0.001, P = 0.001 respectively). The age group of 65-74 years showed significant associations between CVD events and nap frequency or nap duration (P = 0.017, 0.016 respectively), together with nap duration and CVD deaths (P = 0.008). In the subgroup of females aged 65-74, significant associations were found between nap frequency or duration and CVD events (P = 0.006, 0.002 respectively). Nap frequency or duration was also significantly associated with CVD deaths (P =0.005, 0.010 respectively). CONCLUSIONS: This study underscores a noteworthy correlation between a higher frequency or longer duration of daytime nap and an increased susceptibility to CVD among individuals aged 65-74 years, particularly in females. However, further research is needed to better understand the underlying mechanisms.

GINS2 regulates temozolomide chemosensitivity via the EGR1/ECT2 axis in gliomas.

Temozolomide (TMZ), a DNA alkylating agent, has become the primary treatment for glioma, the most common malignancy of the central nervous system. Although TMZ-containing regimens produce significant clinical response rates, some patients inevitably suffer from inferior treatment outcomes or disease relapse, likely because of poor chemosensitivity of glioma cells due to a robust DNA damage response (DDR). GINS2, a subunit of DNA helicase, contributes to maintaining genomic stability and is highly expressed in various cancers, promoting their development. Here, we report that GINS2 was upregulated in TMZ-treated glioma cells and co-localized with γH2AX, indicating its participation in TMZ-induced DDR. Furthermore, GINS2 regulated the malignant phenotype and TMZ sensitivity of glioma cells, mostly by promoting DNA damage repair by affecting the mRNA stability of early growth response factor 1 (EGR1), which in turn regulates the transcription of epithelial cell-transforming sequence 2 (ECT2). We constructed a GINS2-EGR1-ECT2 prognostic model, which accurately predicted patient survival. Further, we screened Palbociclib/BIX-02189 which dampens GINS2 expression and synergistically inhibits glioma cell proliferation with TMZ. These findings delineate a novel mechanism by which GINS2 regulates the TMZ sensitivity of glioma cells and propose a promising combination therapy to treat glioma.

Plumbagin Regulates Snail to Inhibit Hepatocellular Carcinoma Epithelial-Mesenchymal Transition in vivo and in vitro.

Background/Aims: Plumbagin (PL) has been shown to effe ctively inhibit autophagy, suppressing invasion and migration of hepatocellular carcinoma (HCC) cells. However, the specific mechanism remains unclear. This study aimed to investigate the effect of PL on tumor growth factor (TGF)-ß-induced epithelial-mesenchymal transition (EMT) in HCC. Methods: Huh-7 cells were cultured, and in vivo models of EMT and HCC-associated lung metastasis were developed through tail vein and in situ injections of tumor cells. In vivo imaging and hematoxylin and eosin staining were used to evaluate HCC modeling and lung metastasis. After PL intervention, the expression levels of Snail, vimentin, E-cadherin, and N-cadherin in the liver were evaluated through immunohistochemistry and Western blot. An in vitro TGF-ß-induced cell EMT model was used to detect Snail, vimentin, E-cadherin, and N-cadherin mRNA levels through a polymerase chain reaction. Their protein levels were detected by immunofluorescence staining and Western blot. Results: In vivo experiments demonstrated that PL significantly reduced the expression of Snail, vimentin, and N-cadherin, while increasing the expression of E-cadherin at the protein levels, effectively inhibiting HCC and lung metastasis. In vitro experiments confirmed that PL up-regulated epithelial cell markers, down-regulated mesenchymal cell markers, and inhibited EMT levels in HCC cells. Conclusion: PL inhibits Snail expression, up-regulates E-cadherin expression, and down-regulates N-cadherin and vimentin expression, preventing EMT in HCC cells and reducing lung metastasis.

Human myiasis in Sub-Saharan Africa: A systematic review.

BACKGROUND: Human myiasis is a parasitic dipteran fly infestation that infects humans and vertebrates worldwide. However, the disease is endemic in Sub-Saharan Africa and Latin America. In Sub-Saharan Africa, it is under-reported and therefore its prevalence is unknown. This systematic review aims to elucidate the prevalence of human myiasis, factors that influence the infection, and myiasis-causing fly species in SSA. The review also dwelled on the common myiasis types and treatment methods of human myiasis. METHODS: Here, we collect cases of human myiasis in Sub-Saharan Africa based on literature retrieved from PubMed, Google Scholar and Science Direct from 1959 to 2022. A total of 75 articles and 157 cases were included in the study. The recommendations of PRISMA 2020 were used for the realization of this systematic review. RESULTS: In total, 157 cases of human myiasis in SSA were reviewed. Eleven fly species (Cordylobia anthropophaga, Cordylobia rodhaini, Dermatobia hominis, Lucilia cuprina, Lucilia sericata, Oestrus ovis, Sarcophaga spp., Sarcophaga nodosa, Chrysomya megacephala, Chrysomya chloropyga and Clogmia albipuntum) were found to cause human myiasis in SSA. Cordylobia anthropophaga was the most prevalent myiasis-causing species of the reported cases (n = 104, 66.2%). More than half of the reported cases were from travelers returning from SSA (n = 122, 77.7%). Cutaneous myiasis was the most common clinical presentation of the disease (n = 86, 54.7%). Females were more infected (n = 78, 49.6%) than males, and there was a higher infestation in adults than young children. CONCLUSION: The findings of this study reveals that international travelers to Sub-Saharan Africa were mostly infested therefore, we recommend that both international travelers and natives of SSA be enlightened by public health officers about the disease and its risk factors at entry points in SSA and the community level respectively. Clinicians in Sub-Saharan Africa often misdiagnose the disease and most of them lack the expertise to properly identify larvae, so we recommend the extensive use of molecular identification methods instead.

Association between gut microbiota and Hirschsprung disease: a bidirectional two-sample Mendelian randomization study.

Background: Several studies have pointed to the critical role of gut microbiota (GM) and their metabolites in Hirschsprung disease (HSCR) pathogenesis. However, the detailed causal relationship between GM and HSCR remains unknown. Methods: In this study, we used two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between GM and HSCR, based on the MiBioGen Consortium's genome-wide association study (GWAS) and the GWAS Catalog's HSCR data. Reverse MR analysis was performed subsequently, and the sensitivity analysis, Cochran's Q-test, MR pleiotropy residual sum, outlier (MR-PRESSO), and the MR-Egger intercept were used to analyze heterogeneity or horizontal pleiotropy. 16S rDNA sequencing and targeted mass spectrometry were developed for initial validation. Results: In the forward MR analysis, inverse-variance weighted (IVW) estimates suggested that Eggerthella (OR: 2.66, 95%CI: 1.23-5.74, p = 0.01) was a risk factor for HSCR, while Peptococcus (OR: 0.37, 95%CI: 0.18-0.73, p = 0.004), Ruminococcus2 (OR: 0.32, 95%CI: 0.11-0.91, p = 0.03), Clostridiaceae1 (OR: 0.22, 95%CI: 0.06-0.78, p = 0.02), Mollicutes RF9 (OR: 0.27, 95%CI: 0.09-0.8, p = 0.02), Ruminococcaceae (OR: 0.16, 95%CI: 0.04-0.66, p = 0.01), and Paraprevotella (OR: 0.45, 95%CI: 0.21-0.98, p = 0.04) were protective factors for HSCR, which had no heterogeneity or horizontal pleiotropy. However, reverse MR analysis showed that HSCR (OR: 1.02, 95%CI: 1-1.03, p = 0.049) is the risk factor for Eggerthella. Furthermore, some of the above microbiota and short-chain fatty acids (SCFAs) were altered in HSCR, showing a correlation. Conclusion: Our analysis established the relationship between specific GM and HSCR, identifying specific bacteria as protective or risk factors. Significant microbiota and SCFAs were altered in HSCR, underlining the importance of further study and providing new insights into the pathogenesis and treatment.

Objective sleep characteristics and hypertension: a community-based cohort study.

Objective: The link between sleep quality and hypertension risk is well-established. However, research on the specific dose-relationship between objective sleep characteristics and hypertension incidence remains limited. This study aims to explore the dose-relationship association between objective sleep characteristics and hypertension incidence. Methods: A community-based prospective cohort study design was employed using data from the Sleep Heart Health Study (SHHS). A total of 2,460 individuals were included in the study, of which 780 had hypertension. Baseline personal characteristics and medical history were collected. Objective sleep characteristics were obtained through polysomnography (PSG). Multivariate logistic regression models were utilized for analysis. Restricted cubic splines (RCS) were used to examine dose-relationship associations. Results: After adjusting for covariates, the percentage of total sleep duration in stage 2 (N2%) was positively associated with hypertension incidence, while the N3% was negatively associated with hypertension incidence Odds ratio (OR) = 1.009, 95% confidence interval (CI) [1.001, 1.018], P = 0.037; OR = 0.987, 95% CI: [0.979, 0.995], P = 0.028, respectively. For every 10% increase in N2 sleep, the risk of developing hypertension increases by 9%, while a 3% decrease in N3 sleep corresponds to a 0.1% increase in the incidence of hypertension. In the subgroup of non-depression, a positive association between N2% and hypertension was significant statistically (OR = 1.012, 95%CI, 1.002, 1.021, P = 0.013, Pinteraction = 0.013). RCS demonstrated that the risk of developing hypertension was lower when N2% ranged from 38% to 58% and rapidly increased thereafter (P = 0.002, non-linear P = 0.040). The lowest risk for hypertension incidence risk of N3% occurring at 25%, and a significant increase below 15% or above 40% (P = 0.001, non-linear P = 0.008). Conclusions: There's a negative association between N3% and the incidence of hypertension, and a positive association between N2% and the incidence of hypertension, particularly among non-depression individuals. These associations exhibit strong non-linear dose-response relationships.