[The effect of erbium laser pretreatment on bond strength between dentin and enamel and microleakage at the edge of CAD/CAM glass ionomer cement restorations for repairing tooth defects].

PURPOSE: To investigate the effects of erbium laser pretreatment on the bond strength of dentin and enamel,as well as microleakage at the edge of tooth defects repaired with computer-aided design (CAD) and computer-assisted manufacturing (CAM) glass-ceramic restorations for repairing dental defects. METHODS: A total of 62 fresh, nondecayed, nondiscoloration and noncracked wisdom teeth were collected from the Oral Surgery Clinic between January 2020 and January 2023. According to different pretreatment methods, they were randomly divided into two groups, erbium laser group and phosphoric acid group, with 31 teeth in each group. Each group was further divided into two subsets for bond strength testing (16 teeth) and microleakage testing (15 teeth).The shear bond strength between enamel and dentin of both groups was compared, as well as the degree and distribution of microleakage.Statistical analysis was performed with SPSS 17.0 software package. RESULTS: The shear bond strength between enamel and dentin of the erbium laser group was significantly higher than that of the phosphoric acid group (P＜0.05); the degree and distribution of microleakage at the lateral walls and gumline of the erbium laser group were significantly lower than those of the phosphoric acid group (P＜0.05). The scores of microleakage at the lateral walls of the erbium laser group mainly concentrated in grade 1 and 2, whereas those of the phosphoric acid group mainly concentrated in grade 2. There was significant difference in the distribution of lateral wall microleakage scores between the two groups (P＜0.05). The scores of microleakage at the gumline of the erbium laser group mainly concentrated in grade 1 and 2, whereas those of the phosphoric acid group mainly concentrated in grade 2 and 3. There was significant difference in the distribution of gumline microleakage scores between the two groups (P＜0.05). CONCLUSIONS: Erbium laser pretreatment can improve bonding strength between glass ionomer cement and dentin and enamel, reduce microleakage at the edge of CAD/CAM glass ionomer cement restorations, and enhance marginal fit.

Integrated metabolomic and transcriptomic analysis reveals variation in the metabolites of Dendrobium officinale, Dendrobium huoshanense, Dendrobium nobile.

INTRODUCTION: Dendrobium is a perennial herb of the genus Dendrobium in the orchid family. Generally, Dendrobium officinale (TP) and Dendrobium huoshanense (HS) are both considered to have the function of yin-nourishing, while Dendrobium nobile (JC) has better efficacy of heat-clearing. However, because of the wide variety of Dendrobium species, the classification and clinical application of Dendrobium are often confused clearly distinguished in different medicinal uses. OBJECTIVE: In order to compare the differentially accumulated metabolites (DAMs) and differentially expressed genes (DEGs) of the three Dendrobium. METHODS: We selected TP, HS, and JC cultivated on stone for metabolomic and transcriptomic analyses between 2 and 3 years. RESULTS: The results showed that a total of 489 metabolites were obtained, including 72 were DAMs. The 72 DAMs were mainly enriched in metabolic pathways and biosynthesis of secondary metabolites. Transcriptome analysis results showed that 1,038 annotated DEGs were identified among the three Dendrobium species. The comprehensive analysis showed that the three Dendrobium differed in the distribution of the content of four major active components: flavonoids, amino acids, alkaloids, and sugars and alcohols, among which the DAMs and DEGs were mainly enriched in metabolic pathways and secondary metabolite biosynthesis. CONCLUSION: In this study, metabolomics and transcriptomics were utilized to compare the differences among the three species of Dendrobium, to provide theoretical references for future research and selection of different species of Dendrobium based on different medicinal uses, and to lay the foundation for further research on the biosynthesis of flavonoids in Dendrobium.

Fine-grained subphenotypes in acute kidney injury populations based on deep clustering: Derivation and interpretation.

BACKGROUND: Acute kidney injury (AKI) is associated with increased mortality in critically ill patients. Due to differences in the etiology and pathophysiological mechanism, the current AKI criteria put it an embarrassment to evaluate clinical therapy and prognosis. OBJECTIVE: We aimed to identify subphenotypes based on routinely collected clinical data to expose the unique pathophysiologic patterns. METHODS: A retrospective study was conducted based on the Medical Information Mart for Intensive Care IV (MIMIC-IV) and the eICU Collaborative Research Database (eICU-CRD), and a deep clustering approach was conducted to derive subphenotypes. We conducted further analysis to uncover the underlying clinical patterns and interpret the subphenotype derivation. RESULTS: We studied 14,189 and 19,382 patients with AKI within 48 h of ICU admission in the two datasets, respectively. Through our approach, we identified seven distinct AKI subphenotypes with mortality heterogeneity in each cohort. These subphenotypes displayed significant variations in demographics, comorbidities, levels of laboratory measurements, and survival patterns. Notably, the subphenotypes could not be effectively characterized using the Kidney Disease: Improving Global Outcomes (KDIGO) criteria alone. Therefore, we uncovered the unique underlying characteristics of each subphenotype through model-based interpretation. To assess the usability of the subphenotypes, we conducted an evaluation, which yielded a micro-Area Under the Receiver Operating Characteristic (AUROC) of 0.81 in the single-center cohort and 0.83 in the multi-center cohort within 48-hour of admission. CONCLUSION: We derived highly characteristic, interpretable, and usable AKI subphenotypes that exhibited superior prognostic values.

The effect of childhood family adversity on adulthood depression among Chinese older migrant workers: gender differences in the mediating role of social-ecological systems.

BACKGROUND: Older migrant workers (OMWs) in China face unique challenges rooted in their early life experiences, which increase their vulnerability to psychological and behavioral problems in adulthood. By utilizing the cumulative disadvantage model and the social-ecological systems theory, this study explored the effect of childhood family adversity on adulthood depression in the mediating roles of OMWs' social-ecological microsystem and mesosystem and further examined gender differences in these associations. METHODS: Data were collected from the China Health and Retirement Longitudinal Study (CHARLS), involving a sample of 4,309 OMWs aged 50 and above. The measures included the Center for Epidemiological Research Depression Scale, childhood family adversity, socioeconomic status, marital quality, and physical and cognitive health. RESULTS: Childhood family adversity was positively associated with adulthood depression among OMWs. Social microsystem (physical and cognitive health) and mesosystem (marital quality and socioeconomic status) factors significantly mediated this relationship. Multi-group analysis revealed that the mediating effects of marital quality and socioeconomic status were stronger for female OMWs, while the mediating effects of physical and cognitive health were stronger for male OMWs. CONCLUSIONS: The findings suggest that childhood family adversity has a lasting impact on the mental health of OMWs, and that social-ecological systems factors play an important role in this relationship. The study also highlights the need for gender-specific interventions to address the mental health needs of OMWs.

Research Progress on Mechanical Strength of Rice Stalks.

As one of the most important food crops in the world, rice yield is directly related to national food security. Lodging is one of the most important factors restricting rice production, and the cultivation of rice varieties with lodging resistance is of great significance in rice breeding. The lodging resistance of rice is directly related to the mechanical strength of the stalks. In this paper, we reviewed the cell wall structure, its components, and its genetic regulatory mechanism, which improved the regulatory network of rice stalk mechanical strength. Meanwhile, we analyzed the new progress in genetic breeding and put forward some scientific problems that need to be solved in this field in order to provide theoretical support for the improvement and application of rice breeding.

Family and job microsystems as mediators between social integration and depression among rural-to-urban migrant workers in China: does having sons make a difference?

Background: Rural-to-urban migrant workers are a vulnerable group at risk of developing depression. Based on the social-ecological systems theory, this study investigates the impact of the lack of social integration on depression, considering the mediating roles of migrant workers' microsystems (family happiness and job burnout). Additionally, the study explores whether having sons influences these associations. Methods: The sample of 4,618 rural-to-urban migrant workers was obtained from the 2018 wave of the China Labor Force Dynamics Survey (CLDS). All the measures in the survey exhibited good reliability, including the Center for Epidemiological Research Depression Scale (CES-D), family happiness, job burnout, and social integration. The data were primarily analyzed using a structural equation model. Results: Social integration had a direct impact on depression among migrant workers. Additionally, it indirectly affected depression through the mediating roles of family happiness not job burnout. The moderating effect of having sons mainly occurred on the path from social integration to family happiness. Limitations: The cross-sectional design impeded the ability to draw causal inferences. Conclusion: This finding highlights the potential benefits of social integration and family happiness in promoting early prevention of depression among migrant workers. It indicates that the inclination toward having sons among migrant workers continues to impact their mental health.

Do Human Assertions Really Adhere Strictly to Norms? The Effect of Threatening Content in Information on Personalized Norm Perception.

Assertion is the use of declarative sentences to convey information, which necessitates meeting the "justified-belief norm" as a prerequisite. However, a significant amount of misinformation that did not meet these conditions was spread during COVID-19, leading to a reintroduction of the assertion norm. One possible hypothesis is that the threatening content of the misinformation influenced the perception of the norm. However, this remains unclear to researchers. Therefore, we conducted two experiments to investigate the effect of threatening content in information on individuals' perceptions of norms. In all the experiments, participants read backstories with and without threatening content, followed by answering assertion questions. It was observed that people do follow a looser assertion norm for information that contains threatening content. Additionally, further exploration revealed that threatening factors also lead individuals to more easily perceive the related content as truth and reduce the probability of being blamed. These two outcomes provide some explanation for the underlying mechanism of threatening factors' influence. The research results further refined the theory of assertion norms, offering a certain basis for information management.

Metabolomics analyses reveal the liver-protective mechanism of Wang's metabolic formula on metabolic-associated fatty liver disease.

Wang's metabolic formula (WMF) is a traditional Chinese medicine formula developed under the guidance of Professor Kungen Wang. WMF has been clinically utilized for several years. However, the therapeutic mechanism of WMF in treating metabolic-associated fatty liver disease (MAFLD) remains unclear. In this study, we performed phytochemical analysis on WMF using LC-MS. To study the role of WMF in MAFLD, we orally administered WMF (20.6 g/kg) to male MAFLD mice induced by a high-cholesterol high-fat diet (HCHFD). Then pathological, biochemical, and metabolomic analyses were performed. The main components of WMF are chlorogenic acid, geniposide, albiflorin, paeoniflorin, and calycosin-7-O-glucoside. MAFLD mice treated with WMF exhibited significant improvements in obesity, abnormal lipid metabolism, inflammation, and liver pathology. WMF decreased aspartate aminotransferase (AST), alanine aminotransferase (ALT), and triglyceride (TG) levels in the serum of MAFLD mice while increasing high-density lipoprotein cholesterol (HDL-c) levels. WMF lowered liver TG levels and inflammatory factors (IL-1ß, IL-6, TNF-α, and NF-κB). Metabolomic analysis of the liver annotated 78 differentially regulated metabolites enriched in four pathways: glycerophospholipid metabolism, retinol metabolism, PPAR signaling pathway, and choline metabolism. Western blot experiments showed that WMF increased the expression of PPAR-α, PPAR-ß, and RXR in the liver while decreasing the expression of RAR. The study demonstrates that WMF has a solid preventive and therapeutic effect on MAFLD. The anti-inflammatory and regulation of abnormal liver metabolism activities of WMF involve retinol metabolism and the PPAR signaling pathway.

Linkages between childhood emotional maltreatment and adulthood marital attitudes among rural first-generation college students in China: A latent profile analysis and multigroup comparisons.

BACKGROUND: Although there is a wealth of evidence indicating the enduring consequences of childhood emotional maltreatment (CEM) on social and relational functioning across life stages, little known about how CEM affects marital attitudes in emerging adulthood, particularly among rural first-generation college students (rural FGCS) at the critical stage of developing romantic relationships. OBJECTIVE: To explore whether differential patterns of CEM existed among rural FGCS in China during emerging adulthood. Furthermore, the study aims to examine the potential differences in the chain mediating role of CEM on the pathway to adulthood marital attitudes across different CEM profiles. PARTICIPANTS AND SETTING: Using a cluster sampling approach, a total of 3848 rural first-generation college freshmen (males = 39.2 %, mean age = 18.42 years) were recruited from three universities in China. METHODS: Latent profile analysis was utilized to identify potential patterns of CEM using Mplus version 7.4. Structural equation modeling and multigroup comparisons were then performed to investigate the association between CEM and attitudes towards marriage in emerging adulthood, utilizing AMOS 24.0. RESULTS: Three profiles of CEM was identified among rural FGCS: a low-CEM group (51.87 %), a moderate-CEM group (36.69 %), and a severe-CEM group (11.44 %). The association between CEM and adulthood marital attitudes was mediated by core self-evaluation and meaning in life. However, the mediation effects varied across the three CEM profiles. In the low-CEM group, core self-evaluation and meaning in life were observed to partially mediate the negative association between CEM and adulthood marital attitudes. On the other hand, in the moderate-CEM and severe-CEM groups, the relationship between CEM and adulthood marital attitudes was fully mediated by core self-evaluation. CONCLUSIONS: The study's findings suggest that CEM is a significant predictor of marital attitudes among rural FGCS during emerging adulthood, with the severity of emotional neglect and abuse being the primary distinguishing factor between different CEM profiles. Core self-evaluation plays an important role in this relationship. Future clinical interventions could benefit from focusing on enhancing core self-evaluation and meaning in life, particularly for those with CEM experiences.

Structural variant landscapes reveal convergent signatures of evolution in sheep and goats.

BACKGROUND: Sheep and goats have undergone domestication and improvement to produce similar phenotypes, which have been greatly impacted by structural variants (SVs). Here, we report a high-quality chromosome-level reference genome of Asiatic mouflon, and implement a comprehensive analysis of SVs in 897 genomes of worldwide wild and domestic populations of sheep and goats to reveal genetic signatures underlying convergent evolution. RESULTS: We characterize the SV landscapes in terms of genetic diversity, chromosomal distribution and their links with genes, QTLs and transposable elements, and examine their impacts on regulatory elements. We identify several novel SVs and annotate corresponding genes (e.g., BMPR1B, BMPR2, RALYL, COL21A1, and LRP1B) associated with important production traits such as fertility, meat and milk production, and wool/hair fineness. We detect signatures of selection involving the parallel evolution of orthologous SV-associated genes during domestication, local environmental adaptation, and improvement. In particular, we find that fecundity traits experienced convergent selection targeting the gene BMPR1B, with the DEL00067921 deletion explaining ~10.4% of the phenotypic variation observed in goats. CONCLUSIONS: Our results provide new insights into the convergent evolution of SVs and serve as a rich resource for the future improvement of sheep, goats, and related livestock.

Development and validation of an 18F-FDG PET/CT-based radiomics nomogram for predicting the prognosis of patients with esophageal squamous cell carcinoma.

RATIONALE AND OBJECTIVES: The aim of this study was to develop and validate a nomogram, integrating clinical factors and radiomics features, capable of predicting overall survival (OS) in patients diagnosed with esophageal squamous cell carcinoma (ESCC). METHODS: In this study, we retrospectively analyzed the case data of 130 patients with ESCC who underwent 18F-FDG PET/CT before treatment. Radiomics features associated with OS were screened by univariate Cox regression (p < 0.05). Further selection was performed by applying the least absolute shrinkage and selection operator Cox regression to generate the weighted Radiomics-score (Rad-score). Independent clinical risk factors were obtained by multivariate Cox regression, and a nomogram was constructed by combining Rad-score and independent risk factors. The predictive performance of the model for OS was assessed using the time-dependent receiver operating characteristic curve, concordance index (C-index), calibration curve, and decision curve analysis. RESULTS: Five radiomics features associated with prognosis were finally screened, and a Rad-score was established. Multivariate Cox regression analysis revealed that surgery and clinical M stage were identified as independent risk factors for OS in ESCC. The combined clinical-radiomics nomogram exhibited C-index values of 0.768 (95% CI: 0.699-0.837) and 0.809 (95% CI: 0.695-0.923) in the training and validation cohorts, respectively. Ultimately, calibration curves and decision curves for the 1-, 2-, and 3-year OS demonstrated the satisfactory prognostic prediction and clinical utility of the nomogram. CONCLUSION: The developed nomogram, leveraging 18F-FDG PET/CT radiomics and clinically independent risk factors, demonstrates a reliable prognostic prediction for patients with ESCC, potentially serving as a valuable tool for guiding and optimizing clinical treatment decisions in the future.

The effect of modified Qiyuan paste on mice with low immunity and sleep deprivation by regulating GABA nerve and immune system.

BACKGROUND: Low immunity and sleep disorders are prevalent suboptimal health conditions in contemporary populations, which render them susceptible to the infiltration of pathogenic factors. LJC, which has a long history in traditional Chinese medicine for nourishing the Yin and blood and calming the mind, is obtained by modifying Qiyuan paste. Dendrobium officinale Kimura et Migo has been shown to improve the immune function in sleep-deprived mice. In this study, based on the traditional Chinese medicine theory, LJC was prepared by adding D. officinale Kimura et Migo to Qiyuan paste decoction. METHODS: Indicators of Yin deficiency syndrome, such as back temperature and grip strength, were measured in each group of mice; furthermore, behavioral tests and pentobarbital sodium-induced sleep tests were performed. An automatic biochemical analyzer, enzyme-linked immunosorbent assay kit, and other methods were used to determine routine blood parameters, serum immunoglobulin (IgG, IgA, and IgM), cont (C3, C4), acid phosphatase (ACP) and lactate dehydrogenase (LDH) levels in the spleen, serum hemolysin, and delayed-type hypersensitivity (DTH) levels. In addition, serum levels of γ-aminobutyric acid (GABA) and glutamate (Glu) were detected using high-performance liquid chromatography (HPLC). Hematoxylin-eosin staining and Nissl staining were used to assess the histological alterations in the hypothalamus tissue. Western blot and immunohistochemistry were used to detect the expressions of the GABA pathway proteins GABRA1, GAD, GAT1, and GABAT1 and those of CD4+ and CD8+ proteins in the thymus and spleen tissues. RESULTS: The findings indicated that LJC prolonged the sleep duration, improved the pathological changes in the hippocampus, effectively upregulated the GABA content in the serum of mice, downregulated the Glu content and Glu/GABA ratio, enhanced the expressions of GABRA1, GAT1, and GAD, and decreased the expression of GABAT1 to assuage sleep disorders. Importantly, LJC alleviated the damage to the thymus and spleen tissues in the model mice and enhanced the activities of ACP and LDH in the spleen of the immunocompromised mice. Moreover, serum hemolysin levels and serum IgG, IgA, and IgM levels increased after LJC administration, which manifested as increased CD4+ content, decreased CD8+ content, and enhanced DTH response. In addition, LJC significantly increased the levels of complement C3 and C4, increased the number of white blood cells and lymphocytes, and decreased the percentage of neutrophils in the blood. CONCLUSIONS: LJC can lead to improvements in immunocompromised mice models with insufficient sleep. The underlying mechanism may involve regulation of the GABA/Glu content and the expression levels of GABA metabolism pathway-related proteins in the brain of mice, enhancing their specific and nonspecific immune functions.

Preparation of Al-doped mesoporous silica spheres (Al-MSSs) for the improvement of mechanical properties and aging resistance of dental resin composites.

OBJECTIVE: The purpose of this study was to synthesize Al-doped mesoporous silica spheres (Al-MSSs) and evaluate the effect of them as functional fillers on the mechanical properties and aging resistance of dental resin composites. METHODS: Al-MSSs were prepared by a two-step method. The effect of Al-MSSs on the performance of the composites was evaluated using neat resin matrix, commercial composites 3M Z350XT and samples containing mesoporous silica spheres (MSSs) and nonporous silica spheres (NSSs) as control. The neat resin matrix consisted of resin monomer (Bisphenol A glycerolate dimethacrylate/triethylene glycol dimethacrylate, 49.5/49.5, wt%) and photoinitiator (camphor quinone/Ethyl-4-dimethylaminobenzoate, 0.2/0.8, wt%). The mechanical properties (flexural strength, flexural modulus, compressive strength and microhardness) of them were evaluated by a universal testing machine and microhardness tester. The mechanical stabilities of the prepared composites in wet environment were evaluated by immersing them in deionized water at 37 °C. In addition, we evaluated the effect of Al-MSSs on other properties of the dental resin composites such as polymerization shrinkage, degree of conversion, curing depth, contact angle, water sorption and solubility according to ISO 4049: 2019. RESULTS: The synthesized Al-MSSs possessed good dispersibility with an average particle size of about 505 ± 16 nm. The mechanical properties of resin composites gradually increased with the increase of the loading amounts of inorganic fillers. The reinforcing effect of Al-MSSs was similar to that of MSSs and better than that of the NSSs groups at the same filler loading. After aging in deionized water at 37 °C for 30 days, the mechanical properties of all resin composites decreased. However, the decrease percentage of the composites filled with Al-MSSs was significantly lower than the other groups, indicating that the stability of the dental composites in wet environments was significantly improved by the Al-MSSs fillers. Furthermore, Al-MSSs had no obvious influence on the biocompatibility and other properties of dental resins. SIGNIFICANCE: The prepared Al-MSSs could effectively improve the mechanical properties and aging resistance without sacrificing other physic-chemical properties of dental resin composites.

Clinical influencing factors of vital pulp therapy on pulpitis permanent teeth with 2 calcium silicate-based materials: A randomized clinical trial.

BACKGROUND: Compared with traditional root canal therapy (RCT), vital pulp therapy (VPT) is a personalized and minimally invasive method for the treatment of pulpitis caused by dental caries. However, there are still no clear guidelines for VPT because high-quality randomized clinical trials are scarce. This prospective cohort study evaluated the clinical efficacy of VPT with the light-curable calcium silicate-based material TheraCal LC (TH) and bioceramic material iRoot BP Plus (BP) in reversible and irreversible pulpitis permanent teeth with carious exposures. METHODS: 115 teeth with reversible or irreversible pulpitis caused by deep care were randomly divided into 2 groups. TheraCal LC and iRoot BP Plus were used for the pulp capping. Direct pulp capping (DPC), partial pulpotomy (PP) and full pulpotomy (FP) were performed based on observation of the exposed pulp. Postoperative discomforts were enquired and recorded via follow-up phone calls. Clinical and radiographic evaluations were performed 3, 6, and 12 months postoperatively. RESULTS: The overall clinical success rate in the first year was 90.4% (47/52) in both groups. The TH group required less operating time, showed lower levels of pain, and had shorter pain duration post-operative (P < .001). According to the binary logistic regression model, preoperative pain duration was significantly correlated with the prognosis of VPT (P = .011). CONCLUSION: VPT with TheraCal LC and iRoot BP Plus in pulpitis permanent carious teeth both achieved good clinical outcomes, and TheraCal LC can be easily operated for clinical use. Preoperative pain duration of the affected tooth might have a significant correlation with the prognosis of VPT.

Simultaneous detection of dental caries and fissure sealant in intraoral photos by deep learning: a pilot study.

BACKGROUND: Deep learning, as an artificial intelligence method has been proved to be powerful in analyzing images. The purpose of this study is to construct a deep learning-based model (ToothNet) for the simultaneous detection of dental caries and fissure sealants in intraoral photos. METHODS: A total of 1020 intraoral photos were collected from 762 volunteers. Teeth, caries and sealants were annotated by two endodontists using the LabelMe tool. ToothNet was developed by modifying the YOLOX framework for simultaneous detection of caries and fissure sealants. The area under curve (AUC) in the receiver operating characteristic curve (ROC) and free-response ROC (FROC) curves were used to evaluate model performance in the following aspects: (i) classification accuracy of detecting dental caries and fissure sealants from a photograph (image-level); and (ii) localization accuracy of the locations of predicted dental caries and fissure sealants (tooth-level). The performance of ToothNet and dentist with 1year of experience (1-year dentist) were compared at tooth-level and image-level using Wilcoxon test and DeLong test. RESULTS: At the image level, ToothNet achieved an AUC of 0.925 (95% CI, 0.880-0.958) for caries detection and 0.902 (95% CI, 0.853-0.940) for sealant detection. At the tooth level, with a confidence threshold of 0.5, the sensitivity, precision, and F1-score for caries detection were 0.807, 0.814, and 0.810, respectively. For fissure sealant detection, the values were 0.714, 0.750, and 0.731. Compared with ToothNet, the 1-year dentist had a lower F1 value (0.599, p < 0.0001) and AUC (0.749, p < 0.0001) in caries detection, and a lower F1 value (0.727, p = 0.023) and similar AUC (0.829, p = 0.154) in sealant detection. CONCLUSIONS: The proposed deep learning model achieved multi-task simultaneous detection in intraoral photos and showed good performance in the detection of dental caries and fissure sealants. Compared with 1-year dentist, the model has advantages in caries detection and is equivalent in fissure sealants detection.

Association between gut microbiota and central retinal artery occlusion: A two-sample Mendelian randomization study.

PURPOSE: The gut microbiota might be closely related to central retinal artery occlusion (CRAO), but the causality has not been well defined. Two-sample Mendelian randomization (MR) study was used to reveal the potential causal effect between the gut microbiota and CRAO. METHODS: Data for gut microbiota were obtained from the genome-wide association studies of the Dutch Microbiome Project (DMP) (n = 7738) and the MiBioGen consortium (n = 18,340), and data on CRAO were obtained from samples of FinnGen project (546 cases and 344,569 controls). Causalities of exposures and outcomes were explored mainly using the inverse variance weighted method. In addition, multiple sensitivity analyses including MR-Egger, weighted median (WM), simple mode, weighted mode, and MR Pleiotropy RESidual Sum and Outlier were simultaneously applied to validate the final results. RESULTS: We identified three microbial pathways (two risk factors/one protective factor) and seven microbial taxa (two risk factors/five protective factors) associated with CRAO in the DMP study. Based on the data from the MiBioGen consortium, we identified seven microbial taxa (two risk factors/five protective factors) associated with CRAO, including the Eubacterium genus, which was consistently identified as a risk factor in both the DMP and the MiBioGen consortium MR analyses. CONCLUSION: Our study implicates the potential causal effects of specific microbial taxa and pathways on CRAO, potentially providing new insights into the prevention and treatment of CRAO through specific gut microbial taxa and pathway. Since our conclusion is a hypothesis derived from secondary genome-wide association studies (GWAS) data analysis, further research is needed for confirmation.

A time-resolved multi-omics atlas of transcriptional regulation in response to high-altitude hypoxia across whole-body tissues.

High-altitude hypoxia acclimatization requires whole-body physiological regulation in highland immigrants, but the underlying genetic mechanism has not been clarified. Here we use sheep as an animal model for low-to-high altitude translocation. We generate multi-omics data including whole-genome sequences, time-resolved bulk RNA-Seq, ATAC-Seq and single-cell RNA-Seq from multiple tissues as well as phenotypic data from 20 bio-indicators. We characterize transcriptional changes of all genes in each tissue, and examine multi-tissue temporal dynamics and transcriptional interactions among genes. Particularly, we identify critical functional genes regulating the short response to hypoxia in each tissue (e.g., PARG in the cerebellum and HMOX1 in the colon). We further identify TAD-constrained cis-regulatory elements, which suppress the transcriptional activity of most genes under hypoxia. Phenotypic and transcriptional evidence indicate that antenatal hypoxia could improve hypoxia tolerance in offspring. Furthermore, we provide time-series expression data of candidate genes associated with human mountain sickness (e.g., BMPR2) and high-altitude adaptation (e.g., HIF1A). Our study provides valuable resources and insights for future hypoxia-related studies in mammals.

Antibiotic influx and efflux in Pseudomonas aeruginosa: Regulation and therapeutic implications.

Pseudomonas aeruginosa is a notorious multidrug-resistant pathogen that poses a serious and growing threat to the worldwide public health. The expression of resistance determinants is exquisitely modulated by the abundant regulatory proteins and the intricate signal sensing and transduction systems in this pathogen. Downregulation of antibiotic influx porin proteins and upregulation of antibiotic efflux pump systems owing to mutational changes in their regulators or the presence of distinct inducing molecular signals represent two of the most efficient mechanisms that restrict intracellular antibiotic accumulation and enable P. aeruginosa to resist multiple antibiotics. Treatment of P. aeruginosa infections is extremely challenging due to the highly inducible mechanism of antibiotic resistance. This review comprehensively summarizes the regulatory networks of the major porin proteins (OprD and OprH) and efflux pumps (MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY) that play critical roles in antibiotic influx and efflux in P. aeruginosa. It also discusses promising therapeutic approaches using safe and efficient adjuvants to enhance the efficacy of conventional antibiotics to combat multidrug-resistant P. aeruginosa by controlling the expression levels of porins and efflux pumps. This review not only highlights the complexity of the regulatory network that induces antibiotic resistance in P. aeruginosa but also provides important therapeutic implications in targeting the inducible mechanism of resistance.

Molecular Insights into the Effects of F16L and F19L Substitutions on the Conformation and Aggregation Dynamics of Human Calcitonin.

Human calcitonin (hCT) regulates calcium-phosphorus metabolism, but its amyloid aggregation disrupts physiological activity, increases thyroid carcinoma risk, and hampers its clinical use for bone-related diseases like osteoporosis and Paget's disease. Improving hCT with targeted modifications to mitigate amyloid formation while maintaining its function holds promise as a strategy. Understanding how each residue in hCT's amyloidogenic core affects its structure and aggregation dynamics is crucial for designing effective analogues. Mutants F16L-hCT and F19L-hCT, where Phe residues in the core are replaced with Leu as in nonamyloidogenic salmon calcitonin, showed different aggregation kinetics. However, the molecular effects of these substitutions in hCT are still unclear. Here, we systematically investigated the folding and self-assembly conformational dynamics of hCT, F16L-hCT, and F19L-hCT through multiple long-time scale independent atomistic discrete molecular dynamics (DMD) simulations. Our results indicated that the hCT monomer primarily assumed unstructured conformations with dynamic helices around residues 4-12 and 14-21. During self-assembly, the amyloidogenic core of hCT14-21 converted from dynamic helices to ß-sheets. However, substituting F16L did not induce significant conformational changes, as F16L-hCT exhibited characteristics similar to those of wild-type hCT in both monomeric and oligomeric states. In contrast, F19L-hCT exhibited substantially more helices and fewer ß-sheets than did hCT, irrespective of their monomers or oligomers. The substitution of F19L significantly enhanced the stability of the helical conformation for hCT14-21, thereby suppressing the helix-to-ß-sheet conformational conversion. Overall, our findings elucidate the molecular mechanisms underlying hCT aggregation and the effects of F16L and F19L substitutions on the conformational dynamics of hCT, highlighting the critical role of F19 as an important target in the design of amyloid-resistant hCT analogs for future clinical applications.

ProteoMutaMetrics: machine learning approaches for solute carrier family 6 mutation pathogenicity prediction.

The solute carrier transporter family 6 (SLC6) is of key interest for their critical role in the transport of small amino acids or amino acid-like molecules. Their dysfunction is strongly associated with human diseases such as including schizophrenia, depression, and Parkinson's disease. Linking single point mutations to disease may support insights into the structure-function relationship of these transporters. This work aimed to develop a computational model for predicting the potential pathogenic effect of single point mutations in the SLC6 family. Missense mutation data was retrieved from UniProt, LitVar, and ClinVar, covering multiple protein-coding transcripts. As encoding approach, amino acid descriptors were used to calculate the average sequence properties for both original and mutated sequences. In addition to the full-sequence calculation, the sequences were cut into twelve domains. The domains are defined according to the transmembrane domains of the SLC6 transporters to analyse the regions' contributions to the pathogenicity prediction. Subsequently, several classification models, namely Support Vector Machine (SVM), Logistic Regression (LR), Random Forest (RF), and Extreme Gradient Boosting (XGBoost) with the hyperparameters optimized through grid search were built. For estimation of model performance, repeated stratified k-fold cross-validation was used. The accuracy values of the generated models are in the range of 0.72 to 0.80. Analysis of feature importance indicates that mutations in distinct regions of SLC6 transporters are associated with an increased risk for pathogenicity. When applying the model on an independent validation set, the performance in accuracy dropped to averagely 0.6 with high precision but low sensitivity scores.