Drug repurposing opportunities for chronic kidney disease.

The development of targeted drugs for the early prevention and management of chronic kidney disease (CKD) is of great importance. However, the success rates and cost-effectiveness of traditional drug development approaches are extremely low. Utilizing large sample genome-wide association study data for drug repurposing has shown promise in many diseases but has not yet been explored in CKD. Herein, we investigated actionable druggable targets to improve renal function using large-scale Mendelian randomization and colocalization analyses. We combined two population-scale independent genetic datasets and validated findings with cell-type-dependent eQTL data of kidney tubular and glomerular samples. We ultimately prioritized two drug targets, opioid receptor-like 1 and F12, with potential genetic support for restoring renal function and subsequent treatment of CKD. Our findings explore the potential pathological mechanisms of CKD, bridge the gap between the molecular mechanisms of pathogenesis and clinical intervention, and provide new strategies in future clinical trials of CKD.

All-in-one porous membrane enables full protection in guided bone regeneration.

The sophisticated hierarchical structure that precisely combines contradictory mechanical and biological characteristics is ideal for biomaterials, but it is challenging to achieve. Herein, we engineer a spatiotemporally hierarchical guided bone regeneration (GBR) membrane by rational bilayer integration of densely porous N-halamine functionalized bacterial cellulose nanonetwork facing the gingiva and loosely porous chitosan-hydroxyapatite composite micronetwork facing the alveolar bone. Our GBR membrane asymmetrically combine stiffness and flexibility, ingrowth barrier and ingrowth guiding, as well as anti-bacteria and cell-activation. The dense layer has a mechanically matched space maintenance capacity toward gingiva, continuously blocks fibroblasts, and prevents bacterial invasion with multiple mechanisms including release-killing, contact-killing, anti-adhesion, and nanopore-blocking; the loose layer is ultra-soft to conformally cover bone surfaces and defect cavity edges, enables ingrowth of osteogenesis-associated cells, and creates a favorable osteogenic microenvironment. As a result, our all-in-one porous membrane possesses full protective abilities in GBR.

Causal effects of gut microbiota on the risk of periodontitis: a two-sample Mendelian randomization study.

Introduction: The oral cavity and the gut tract are interconnected, and both contain abundant natural microbiota. Gut microbiota may interact with oral flora and participate in the development of periodontitis. However, the specific role of certain gut microbiota taxa for periodontitis has not been investigated. Mendelian Randomization is an ideal method to explore causal relationships avoiding reverse causality and potential confounding factors. Thus, we conducted a two-sample Mendelian Randomization study to comprehensively reveal the potential genetic causal effect of gut microbiota on periodontitis. Methods: SNPs strongly associated with 196 gut microbiota taxa (18,340 individuals) were selected as instrument variables, and periodontitis (17,353 periodontitis cases and 28,210 controls) was used as the outcome. The causal effect was analyzed via random effect inverse variance-weighted, weighted median, and MR-Egger. The sensitivity analyses were conducted using Cochran's Q tests, funnel plots, leave-one-out analyses, and MR-Egger intercept tests. Results: Nine gut microbiota taxa (Prevotella 7, Lachnospiraceae UCG-008, Enterobacteriales, Pasteurellales, Enterobacteriaceae, Pasteurellaceae, Bacteroidales S24.7 group, Alistipes, and Eisenbergiella) are predicted to play a causal role in enhancing the risk of periodontitis (p< 0.05). Besides, two gut microbiota taxa (Butyricicoccus and Ruminiclostridium 6) have potentially inhibitive causal effects on the risk of periodontitis (p< 0.05). No significant estimation of heterogeneity or pleiotropy is detected. Conclusion: Our study demonstrates the genetic causal effect of 196 gut microbiota taxa on periodontitis and provides guidance for the clinical intervention of periodontitis.

Band-Aid-Like Self-Fixed Barrier Membranes Enable Superior Bone Augmentation.

In guided bone regeneration surgery, a barrier membrane is usually used to inhibit soft tissue from interfering with osteogenesis. However, current barrier membranes usually fail to resist the impact of external forces on bone-augmented region, thus causing severe displacement of membranes and their underlying bone graft materials, eventually leading to unsatisfied bone augmentation. Herein, a new class of local double-layered adhesive barrier membranes (ABMs) is developed to successfully immobilize bone graft materials. The air-dried adhesive hydrogel layers with suction-adhesion properties enable ABMs to firmly adhere to the wet bone surface through a "stick-and-use" band-aid-like strategy and effectively prevent the displacement of membranes and the leakage of bone grafts in uncontained bone defect treatment. Furthermore, the strategy is versatile for preparing diverse adhesive barrier membranes and immobilizing different bone graft materials for various surgical regions. By establishing such a continuous barrier for the bone graft material, this strategy may open a novel avenue for designing the next-generation barrier membranes.

Causal effects of gut microbiota on the risk of chronic kidney disease: a Mendelian randomization study.

Background: Previous studies have reported that gut microbiota is associated with an increased risk of chronic kidney disease (CKD) progression. However, whether gut microbiota has a causal effect on the development of CKD has not been revealed. Thus, we aimed to analyze the potential causal effect of gut microbiota on the risk of CKD using mendelian randomization (MR) study. Materials and Methods: Independent single nucleotide polymorphisms closely associated with 196 gut bacterial taxa (N = 18340) were identified as instrumental variables. Two-sample MR was performed to evaluate the causal effect of gut microbiota on CKD (N = 480698), including inverse-variance-weighted (IVW) method, weighted median method, MR-Egger, mode-based estimation and MR-PRESSO. The robustness of the estimation was tested by a series of sensitivity analyses including Cochran's Q test, MR-Egger intercept analysis, leave-one-out analysis and funnel plot. Statistical powers were also calculated. Results: The genetically predicted higher abundance of order Desulfovibrionales was causally associated with an increased risk of CKD (odds ratio = 1.15, 95% confidence interval: 1.05-1.26; p = 0.0026). Besides, we also detected potential causalities between nine other taxa (Eubacterium eligens group, Desulfovibrionaceae, Ruminococcaceae UCG-002, Deltaproteobacteria, Lachnospiraceae UCG-010, Senegalimassilia, Peptostreptococcaceae, Alcaligenaceae and Ruminococcus torques group) and CKD (p < 0.05). No heterogeneity or pleiotropy was detected for significant estimates. Conclusion: We found that Desulfovibrionales and nine other taxa are associated with CKD, thus confirming that gut microbiota plays an important role in the pathogenesis of CKD. Our work also provides new potential indicators and targets for screening and prevention of CKD.

Causal relationship between physical activity, leisure sedentary behaviors and COVID-19 risk: a Mendelian randomization study.

BACKGROUND: The 2019 coronavirus disease pandemic (COVID-19) poses an enormous threat to public health worldwide, and the ensuing management of social isolation has greatly decreased opportunities for physical activity (PA) and increased opportunities for leisure sedentary behaviors (LSB). Given that both PA and LSB have been established as major influencing factors for obesity, diabetes and cardiometabolic syndrome, whether PA/LSB in turn affects the susceptibility to COVID-19 by disrupting metabolic homeostasis remains to be explored. In this study, we aimed to systematically evaluate the causal relationship between PA/LSB and COVID-19 susceptibility, hospitalization and severity using a Mendelian randomization study. METHODS: Data were obtained from a large-scale PA dataset (N = 377,000), LSB dataset (N = 422,218) and COVID-19 Host Genetics Initiative (N = 2,586,691). The causal effects were estimated with inverse variance weighted, MR-Egger, weighted median and MR-PRESSO. Sensitivity analyses were implemented with Cochran's Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis and the funnel plot. Risk factor analyses were further conducted to investigate the potential mediators. RESULTS: Genetically predicted accelerometer-assessed PA decreased the risk for COVID-19 hospitalization (OR = 0.93, 95% CI 0.88-0.97; P = 0.002), while leisure television watching significantly increased the risk of COVID-19 hospitalization (OR = 1.55, 95% CI 1.29-1.88; P = 4.68 × 10-6) and disease severity (OR = 1.85, 95% CI 1.33-2.56; P = 0.0002) after Bonferroni correction. No causal effects of self-reported moderate to vigorous physical activity (MVPA), accelerometer fraction of accelerations > 425 milligravities, computer use or driving on COVID-19 progression were observed. Risk factor analyses indicated that the above causal associations might be mediated by several metabolic risk factors, including smoking, high body mass index, elevated serum triglyceride levels, insulin resistance and the occurrence of type 2 diabetes. CONCLUSION: Our findings supported a causal effect of accelerometer-assessed PA on the reduced risk of COVID-19 hospitalization as well as television watching on the increased risk of COVID-19 hospitalization and severity, which was potentially mediated by smoking, obesity and type 2 diabetes-related phenotypes. Particular attention should be given to reducing leisure sedentary behaviors and encouraging proper exercise during isolation and quarantine for COVID-19.

Causal relationship between 14 site-specific cancers and venous thromboembolism.

Background: It has been observed that cancer and venous thromboembolism (VTE) are associated, but anticancer therapy may violate the causality. Therefore, this study aimed to elucidate the causal relationship of various cancers to VTE using Mendelian randomization (MR). Methods: Three MR methods were used to estimate causal effects: Inverse variance weighted (IVW), MR-Egger and weighted median. Sensitivity analyses included Cochran's Q-test, MR-Egger intercept test and MR-PRESSO. Gene ontology enrichment analysis was performed to elucidate the underlying mechanisms of VTE development in cancer patients. Results: The primary IVW approach showed that non-Hodgkin's lymphoma (NHL) might increase the risk of VTE (odds ratio [OR]: 1.20, 95% confidence interval [95% CI]: 1.00-1.44, p = 0.045), while melanoma possibly reduced the risk of VTE (OR: 0.89, 95% CI: 0.82-0.97, p = 0.006), although there was no significance after adjustment for multiple testing. No association was observed between VTE risk and other site-specific cancers. Gene ontology enrichment analysis revealed that vitamin D played an important role in the development of VTE in cancer patients. Conclusions: Our findings suggested that genetically predicted NHL was associated with higher VTE risk, whereas melanoma had lower VTE risk compared with other site-specific cancers. Moreover, this study suggested that anticancer therapy and increased extensive examination might play a more important role in VTE development than the nature of cancer.

Long-lasting renewable antibacterial porous polymeric coatings enable titanium biomaterials to prevent and treat peri-implant infection.

Peri-implant infection is one of the biggest threats to the success of dental implant. Existing coatings on titanium surfaces exhibit rapid decrease in antibacterial efficacy, which is difficult to promisingly prevent peri-implant infection. Herein, we report an N-halamine polymeric coating on titanium surface that simultaneously has long-lasting renewable antibacterial efficacy with good stability and biocompatibility. Our coating is powerfully biocidal against both main pathogenic bacteria of peri-implant infection and complex bacteria from peri-implantitis patients. More importantly, its antibacterial efficacy can persist for a long term (e.g., 12~16 weeks) in vitro, in animal model, and even in human oral cavity, which generally covers the whole formation process of osseointegrated interface. Furthermore, after consumption, it can regain its antibacterial ability by facile rechlorination, highlighting a valuable concept of renewable antibacterial coating in dental implant. These findings indicate an appealing application prospect for prevention and treatment of peri-implant infection.