Association between non-scarring alopecia and hypothyroidism: a bidirectional two-sample Mendelian randomization study.

Background: Non-scarring alopecia is typically represented by two main types: alopecia areata (AA) and androgenetic alopecia (AGA). While previous observational studies have indicated a link between non-scarring alopecia and hypothyroidism, the precise causal relationship remains uncertain. To determine the potential links between non-scarring alopecia and hypothyroidism, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis. Methods: We used independent genetic instruments from the FinnGen consortium for AA (682 cases, 361,140 controls) and AGA (195 cases, 201,019 controls) to investigate the association with hypothyroidism in the UK Biobank study (22,687 cases, 440,246 controls). The primary analysis was performed using the inverse variance-weighted method. Complementary approaches were employed to evaluate the pleiotropy and heterogeneity. Results: Genetically predicted AA exhibited a positive causal effect on hypothyroidism (odds ratio [OR], 1.0017; 95% confidence interval [CI], 1.0004-1.0029; P = 0.0101). Additionally, hypothyroidism was found to be strongly correlated with an increase in the risk of AA (OR, 45.6839; 95% CI, 1.8446-1131.4271, P = 0.0196). However, no causal relationship was demonstrated between AGA and hypothyroidism. A sensitivity analysis validated the integrity of these causal relationships. Conclusion: This MR study supports a bidirectional causal link between AA and hypothyroidism. Nevertheless, additional research is needed to gain a more thorough comprehension of the causal relationship between non-scarring alopecia and hypothyroidism.

Intercropping fruit trees in tea plantation improves soil properties and the formation of tea quality components.

Intercropping has been recommended as a beneficial cropping practice for improving soil characteristic and tea quality. However, there is limited research on the effects of intercropping fruit trees on soil chemical properties, soil aggregate structure, and tea quality components. In this study, intercropping fruit trees, specifically loquats and citrus, had a significant impact on the total available nutrients, AMN, and AP in soil. During spring and autumn seasons, the soil large-macroaggregates (>2 mm) proportion increased by 5.93% and 19.03%, as well as 29.23% and 19.14%, respectively, when intercropping loquats and citrus. Similarly, intercropping waxberry resulted in a highest small-macroaggregates (0.25 mm-2 mm) proportion at 54.89% and 77.32%. Soil aggregate stability parameters of the R0.25, MWD, and GMD were generally considered better soil aggregate stability indicators, and significantly improved in intercropping systems. Intercropping waxberry with higher values for those aggregate stability parameters and lower D values, showed a better soil aggregate distribution, while intercropping loquats and citrus at higher levels of AMN and AP in different soil aggregate sizes. As the soil aggregate sizes increased, the AMN and AP contents gradually decreased. Furthermore, the enhanced levels of amino acids were observed under loquat, waxberry, and citrus intercropping in spring, which increased by 27.98%, 27.35%, and 26.21%, respectively. The contents of tea polyphenol and caffeine were lower under loquat and citrus intercropping in spring. These findings indicated that intercropping fruit trees, specifically loquat and citrus, have immense potential in promoting the green and sustainable development of tea plantations.

Efficacy and safety of oral ibrexafungerp in Chinese patients with vulvovaginal candidiasis: a phase III, randomized, double-blind study.

PURPOSE: To evaluate the efficacy and safety of oral ibrexafungerp (HS-10366) versus placebo in Chinese patients with vulvovaginal candidiasis (VVC). METHODS: A double-blind, placebo-controlled, randomized, multicenter phase III study was conducted in symptomatic VVC patients. Patients received (2:1) twice-daily oral ibrexafungerp 300 mg or matching placebo for 1 day. The primary endpoint was clinical cure (vulvovaginal signs and symptoms [VSS] score = 0) at test-of-cure (TOC) on day 11 ± 3. The secondary endpoints included mycological eradication, overall response, and clinical improvement (VSS score ≤ 1) at TOC, and vulvovaginal symptom resolution at follow-up on day 25 ± 4. RESULTS: In total, 360 patients were included in the modified intention-to-treat set (defined as positive Candida cultured and receiving at least one study drug; 239 for ibrexafungerp, 121 for placebo). Compared with placebo, patients receiving ibrexafungerp had a significantly higher proportion of clinical cure (51.0% vs. 25.6%), mycological eradication (55.6% vs. 18.2%), overall response (33.9%, vs. 8.3%) at TOC and complete symptom resolution (74.5% vs. 39.7%, all P < 0.001) at follow-up. Subgroup analysis of clinical cure indicated that patients with C. albicans could benefit from ibrexafungerp over placebo. A similar benefit trend was also observed in those with non-albicans Candida by post-hoc analysis. Further analyses revealed similar efficacy of ibrexafungerp between patients with fluconazole non-susceptible C. albicans and fluconazole susceptible C. albicans regarding clinical cure and mycological eradication. Ibrexafungerp was generally well tolerated. Adverse events were primarily gastrointestinal and were mainly mild in severity. CONCLUSIONS: As a first-in-class antifungal agent, ibrexafungerp demonstrated promising efficacy and favorable safety for VVC treatment in Chinese patients. CHINADRUGTRIALS.ORG. CN REGISTRY NUMBER: CTR20220918.

Molecularly thin, two-dimensional all-organic perovskites.

Recently, the emergence of all-organic perovskites with three-dimensional (3D) structures has expanded the potential applications of perovskite materials. However, the synthesis and utilization of all-organic perovskites in 2D form remain largely unexplored because the design principle has not been developed. We present the successful synthesis of a metal-free 2D layered perovskite, denoted as the Choi-Loh van der Waals phase (CL-v phase), with the chemical formula A2B2X4, where A represents a larger-sized cation compared to B and X denotes an anion. The CL-v phase exhibits a van der Waals gap enabled by interlayer hydrogen bonding and can be exfoliated or grown as molecularly thin 2D organic crystals. The dielectric constants of the CL-v phase range from 4.8 to 5.5 and we demonstrate their potential as gate dielectrics for thin-film transistors.

Dithiophosphinylation of Allenyl Acetates: Access to 1,2-Bis(diphenylphosphino)ethane-Type Bidentate Ligands.

1,2-Bis(diphenylphosphino)ethanes (DPPEs) are versatile and immensely important ligands in transition metal catalysts. Here we report the dithiophosphinylation of readily available allenyl acetates to give DPPEs in high yields and regioselectivity. This protocol features a broad substrate scope and mild conditions, avoiding the use of transition metals and air-sensitive sources of phosphorus. Mechanism studies indicate that the reaction was accomplished via an SN2'-type addition-elimination followed by a 1,4-addition step.

Exposure to Endocrine-Disrupting Chemicals and Congenital Heart Diseases: The Pooled Results Based on the Current Evidence.

The relationships between maternal exposure to endocrine-disrupting chemicals (EDCs) and congenital heart diseases (CHD) are not elucidated yet. The exposure levels of EDCs are generally estimated based on self-reported questionnaires or occupational exposure evaluations in the literature. Therefore, a study based on epidemiological data from human biospecimens is required to provide stronger evidence between maternal exposure to EDC and CHD. Embase, Pubmed, Scopus, and the Cochrane Library databases were searched for related research which provided risk estimates regarding the relationships between maternal EDC exposure and CHD in human offspring. Baseline characteristics and outcomes of CHD were extracted from each included study. Odds ratios (ORs) with 95% confidence intervals (CIs) were pooled to calculate the overall estimates of CHD. Subgroup and meta-regression analyses were performed to identify the sources of heterogeneity. Bootstrapping techniques were used in analyses where several studies originated from a similar population. A total of seventeen studies were involved in the meta-analyses. Maternal EDC exposure was significantly related to CHD in offspring (OR 2.15; 95%CI 1.64 to 2.83). EDC exposure was significantly associated with septal defects (OR 2.34; 95%CI 1.77 to 3.10), conotruncal defects (OR 2.54; 95%CI 1.89 to 3.43), right ventricular outflow tract obstruction (OR 2.65; 95%CI 1.73 to 4.07), left ventricular outflow tract obstruction (OR 3.58; 95%CI 2.67 to 4.79), anomalous pulmonary venous return (OR 2.31; 95%CI 1.34 to 4.00), and other heart defects (OR 2.49; 95%CI 1.75 to 3.54). In addition, maternal exposure to heavy metals, which included lead (OR 2.19; 95%CI 1.29 to 3.71), cadmium (OR 1.81; 95%CI 1.28 to 2.56), mercury (OR 2.23; 95%CI 1.13 to 4.44), and manganese (OR 2.65; 95%CI 1.48 to 4.74), increased risks for CHD significantly. In conclusion, based on the latest evidence, maternal EDC exposure may increase CHD risks in human offspring, especially in heavy metal exposure conditions.

Pontryagin's Minimum Principle-Guided RL for Minimum-Time Exploration of Spatiotemporal Fields.

This article studies the trajectory planning problem of an autonomous vehicle for exploring a spatiotemporal field subject to a constraint on cumulative information. Since the resulting problem depends on the signal strength distribution of the field, which is unknown in practice, we advocate the use of a model-free reinforcement learning (RL) method to find the solution. Given the vehicle's dynamical model, a critical (and open) question is how to judiciously merge the model-based optimality conditions into the model-free RL framework for improved efficiency and generalization, for which this work provides some positive results. Specifically, we discretize the continuous action space by leveraging analytic optimality conditions for the minimum-time optimization problem via Pontryagin's minimum principle (PMP). This allows us to develop a novel discrete PMP-based RL trajectory planning algorithm, which learns a planning policy faster than those based on a continuous action space. Simulation results: 1) validate the effectiveness of the PMP-based RL algorithm and 2) demonstrate its advantages, in terms of both learning efficiency and the vehicle's exploration time, over two baseline methods for continuous control inputs.

Real-world evidence from a retrospective study on suicide during depression: clinical characteristics, treatment patterns and disease burden.

BACKGROUND: Suicide stands as both a primary symptom and the direst outcome of major depressive disorder (MDD). The scarcity of effective treatment strategies makes managing MDD patients with suicide especially challenging. Hence, it is crucial to investigate disease characteristics and efficacious therapeutic strategies for these patients, drawing insights from disease databases and real-world data. METHODS: In this retrospective study, MDD patients hospitalized between January 2013 and December 2020 were investigated using Electronic Health Records (EHR) data from Beijing Anding Hospital. The study enrolled 4138 MDD patients with suicidal ideation or behavior (MDS) and 3848 without (MDNS). Demographic data, clinical attributes, treatment approaches, disease burden, and re-hospitalization within one year of discharge were extracted and compared. RESULTS: Patients in the MDS group were predominantly younger and female, exhibiting a higher prevalence of alcohol consumption, experiencing frequent life stress events, and having an earlier onset age. Re-hospitalizations within six months post-discharge in the MDS group were significantly higher than in the MDNS group (11.36% vs. 8.91%, p < 0.001). Moreover, a more considerable fraction of MDS patients underwent combined electroconvulsive therapy treatment (56.72% vs. 43.71%, p < 0.001). Approximately 38% of patients in both groups were prescribed two or more therapeutic regimes, and over 90% used antidepressants, either alone or combined. Selective serotonin reuptake inhibitors (SSRIs) were the predominant choice in both groups. Furthermore, antidepressants were often prescribed with antipsychotics or mood stabilizers. When medication alterations were necessary, the favoured options involved combination with antipsychotics or transitioning to alternative antidepressants. Yet, in the MDS group, following these initial modifications, the addition of mood stabilizers tended to be the more prioritized alternative. CONCLUSIONS: MDD patients with suicidal ideation or behaviour displayed distinctive demographic and clinical features. They exhibited intricate treatment patterns, a pronounced burden of illness, and an increased likelihood of relapse.

Multi-omics study reveals different pathogenesis of the generation of skin lesions in SLE and IDLE patients.

Lupus erythematosus (LE) is a heterogeneous, antibody-mediated autoimmune disease. Isolate discoid LE (IDLE) and systematic LE (SLE) are traditionally regarded as the two ends of the spectrum, ranging from skin-limited damage to life-threatening multi-organ involvement. Both belong to LE, but IDLE and SLE differ in appearance of skin lesions, autoantibody panels, pathological changes, treatments, and immunopathogenesis. Is discoid lupus truly a form of LE or is it a completely separate entity? This question has not been fully elucidated. We compared the clinical data of IDLE and SLE from our center, applied multi-omics technology, such as immune repertoire sequencing, high-resolution HLA alleles sequencing and multi-spectrum pathological system to explore cellular and molecular phenotypes in skin and peripheral blood from LE patients. Based on the data from 136 LE patients from 8 hospitals in China, we observed higher damage scores and fewer LE specific autoantibodies in IDLE than SLE patients, more uCDR3 sharing between PBMCs and skin lesion from SLE than IDLE patients, elevated diversity of V-J recombination in IDLE skin lesion and SLE PBMCs, increased SHM frequency and class switch ratio in IDLE skin lesion, decreased SHM frequency but increased class switch ratio in SLE PBMCs, HLA-DRB1*03:01:01:01, HLA-B*58:01:01:01, HLA-C*03:02:02:01, and HLA-DQB1*02:01:01:01 positively associated with SLE patients, and expanded Tfh-like cells with ectopic germinal center structures in IDLE skin lesions. These findings suggest a significant difference in the immunopathogenesis of skin lesions between SLE and IDLE patients. SLE is a B cell-predominate systemic immune disorder, while IDLE appears limited to the skin. Our findings provide novel insights into the pathogenesis of IDLE and other types of LE, which may direct more accurate diagnosis and novel therapeutic strategies.

Facile fabrication of temperature/pH dual sensitive hydrogels based on cellulose and polysuccinimide through aqueous amino-succinimide reaction.

A temperature/pH dual sensitive hydrogel with a semi-interpenetrating network (semi-IPN) structure was synthesized through an aqueous amino-succinimide reaction between water-soluble polysuccinimide and polyethyleneimine in the presence of thermosensitive cellulose derivatives. Single-factor experiments were carried out to optimize the preparation conditions of the semi-IPN hydrogel. The swelling behavior and cytotoxicity assay of the hydrogel were tested. Finally, taking 5- fluorouracil (5-Fu) as a model drug, the release performance of the 5-Fu-loaded hydrogel was investigated. The results indicated that the swelling ratio (SR) first decreased and then increased when the pH of the solutions ascended from 2 to 10. The SR decreased with the increase in temperature. In addition, the swelling behavior of the hydrogel was reversible and reproducible under different pH values and temperatures. The prepared hydrogels had good cytocompatibility. The release behavior of 5-Fu was most consistent with the Korsmeyer-Peppas model and followed the case II diffusion. The acidic environment was beneficial for the release of 5-Fu. The preparation process of the semi-IPN hydrogel is simple and the reaction can proceed quickly in water. The strategy introduced here has great potential for application in the preparation of drug carriers.

Shear damage mechanisms of jointed rock mass: a macroscopic and mesoscopic study.

The joints are existing throughout the underground rock mass. It is of great significance to investigate the shear performance of the rock mass to maintain the stability of the underground structure. In this study, we conducted orthogonal tests to determine the proportion of rock-like materials, and used JRC curves to make specimen molds and then prepare the specimens. We conducted straight shear tests and uniaxial compression tests to determine the various mechanical parameters of the rock-like materials. Next, we carried out the compression and shear tests to investigate the shear characteristics of the specimens, and study the damage pattern and shear strength of the jointed rock mass under different confining pressures and roughness levels. The mesoscopic displacements in the shear process of joints were analyzed by using ABAQUS. The test results show that the effect of the confining pressure on the shear strength of the joint plane is relatively obvious, and a larger confining pressure indicates a larger shear strength. The effects of different joint plane roughness and shear rated on the shear characteristics of the joint plane are also significant. The mesoscopic displacement difference inside the joint plane with higher roughness is relatively large, and the stress concentration phenomenon is obvious and lasts longer, which leads to the faster destruction of the specimen with higher roughness and the higher destruction degree. Therefore, we suggest that the priority should be given to the reinforcement of jointed rock mass with high roughness during the construction to prevent sudden destabilization and failure.

Recent advances in mesenchymal stem cell therapy for myocardial infarction.

Myocardial infarction refers to the ischemic necrosis of myocardium, characterized by a sharp reduction or interruption of blood flow in the coronary arteries due to the coronary artery occlusion, resulting in severe and prolonged ischemia in the corresponding myocardium and ultimately leading to ischemic necrosis of the myocardium. Given its high risk, it is considered as one of the most serious health threats today. In current clinical practice, multiple approaches have been explored to diminish myocardial oxygen consumption and alleviate symptoms, but notable success remains elusive. Accumulated clinical evidence has showed that the implantation of mesenchymal stem cell for treating myocardial infarction is both effective and safe. Nevertheless, there persists controversy and variability regarding the standardizing MSC transplantation protocols, optimizing dosage, and determining the most effective routes of administration. Addressing these remaining issues will pave the way of integration of MSCs as a feasible mainstream cardiac treatment.

Integrative Single Cell Atlas Revealed Intratumoral Heterogeneity Generation from an Adaptive Epigenetic Cell State in Human Bladder Urothelial Carcinoma.

Intratumor heterogeneity (ITH) of bladder cancer (BLCA) contributes to therapy resistance and immune evasion affecting clinical prognosis. The molecular and cellular mechanisms contributing to BLCA ITH generation remain elusive. It is found that a TM4SF1-positive cancer subpopulation (TPCS) can generate ITH in BLCA, evidenced by integrative single cell atlas analysis. Extensive profiling of the epigenome and transcriptome of all stages of BLCA revealed their evolutionary trajectories. Distinct ancestor cells gave rise to low-grade noninvasive and high-grade invasive BLCA. Epigenome reprograming led to transcriptional heterogeneity in BLCA. During early oncogenesis, epithelial-to-mesenchymal transition generated TPCS. TPCS has stem-cell-like properties and exhibited transcriptional plasticity, priming the development of transcriptionally heterogeneous descendent cell lineages. Moreover, TPCS prevalence in tumor is associated with advanced stage cancer and poor prognosis. The results of this study suggested that bladder cancer interacts with its environment by acquiring a stem cell-like epigenomic landscape, which might generate ITH without additional genetic diversification.

Unraveling the evolutionary origin of the complex Nuclear Receptor Element (cNRE), a cis-regulatory module required for preferential expression in the atrial chamber.

Cardiac function requires appropriate proteins in each chamber. Atria requires slow myosin to act as reservoirs, while ventricles demand fast myosin for swift pumping. Myosins are thus under chamber-biased cis-regulation, with myosin gene expression imbalances leading to congenital heart dysfunction. To identify regulatory inputs leading to cardiac chamber-biased expression, we computationally and molecularly dissected the quail Slow Myosin Heavy Chain III (SMyHC III) promoter that drives preferential expression to the atria. We show that SMyHC III gene states are orchestrated by a complex Nuclear Receptor Element (cNRE) of 32 base pairs. Using transgenesis in zebrafish and mice, we demonstrate that preferential atrial expression is achieved by a combinatorial regulatory input composed of atrial activation motifs and ventricular repression motifs. Using comparative genomics, we show that the cNRE might have emerged from an endogenous viral element through infection of an ancestral host germline, revealing an evolutionary pathway to cardiac chamber-specific expression.

The Causal Relationship between Plasma Myeloperoxidase Levels and Respiratory Tract Infections: A Bidirectional Mendelian Randomization Study.

Background: Observational researches reported the underlying correlation of plasma myeloperoxidase (MPO) concentration with respiratory tract infections (RTIs), but their causality remained unclear. Here, we examined the cause-effect relation between plasma MPO levels and RTIs. Materials and Methods: Datasets of plasma MPO levels were from the Folkersen et al. study (n = 21,758) and INTERVAL study (n = 3,301). Summarized data for upper respiratory tract infection (URTI) (2,795 cases and 483,689 controls) and lower respiratory tract infection (LRTI) in the intensive care unit (ICU) (585 cases and 430,780 controls) were from the UK Biobank database. The primary method for Mendelian randomization (MR) analysis was the inverse variance weighted approach, with MR-Egger and weighted median methods as supplements. Cochrane's Q test, MR-Egger intercept test, MR pleiotropy residual sum and outliers global test, funnel plots, and leave-one-out analysis were used for sensitivity analysis. Results: We found that plasma MPO levels were positively associated with URTI (odds ratio (OR) = 1.135; 95% confidence interval (CI) = 1.011-1.274; P=0.032) and LRTI (ICU) (OR = 1.323; 95% CI = 1.006-1.739; P=0.045). The consistent impact direction is shown when additional plasma MPO level genome-wide association study datasets are used (URTI: OR = 1.158; 95% CI = 1.072-1.251; P < 0.001; LRTI (ICU): OR = 1.216; 95% CI = 1.020-1.450; P=0.030). There was no evidence of a causal effect of URTI and LRTI (ICU) on plasma MPO concentration in the reverse analysis (P > 0.050). The sensitivity analysis revealed no violations of MR presumptions. Conclusions: Plasma MPO levels may causally affect the risks of URTI and LRTI (ICU). In contrast, the causal role of URTI and LRTI (ICU) on plasma MPO concentration was not supported in our MR analysis. Further studies are needed to identify the relationship between RTIs and plasma MPO levels.

Correlation between inflammatory factors, autophagy protein levels, and infection in granulation tissue of diabetic foot ulcer.

OBJECTIVE: To observe the expression of inflammatory factors and autophagy-related proteins in granulation tissue of diabetic foot ulcer (DFU) patients and analyze their relationship with infection. METHODS: This is a retrospective cohort study. One hundred and fifty-two patients with DFU in our hospital from July 2020 to March 2022 were selected as the DFU group, including 98 cases in infection stage group and 54 cases in infection control group. The patients were further graded as the mild (51 cases), the moderate (65 cases), and the severe infection group (36 cases) according to the Wagner grading criteria. Sixty-seven patients with foot burns during the same period were selected as the control group. The distribution of pathogenic bacteria on the ulcer surface was examined using fully automated bacterial analyzer. The expression of inflammatory factors (procalcitonin [PCT], tumor necrosis factor-α [TNF-α], and interleukin-6 [IL-6]) was valued by real-time fluorescence quantitative PCR (qRT-PCR). Protein expression was measured by immunohistochemistry (IHC). The correlation was analyzed by Pearson. RESULTS: The surface infection of DFU patients was mostly induced by gram-negative and gram-positive bacteria, with Pseudomonas aeruginosa predominating among the Gram-negative bacteria and Staphylococcus aureus among the gram-positive bacteria. The infection stage group had higher content of PCT, TNF-α, and IL-6 and lower content of Beclin-1 and LC3 than the infection control group (p < .001). The levels of PCT, TNF-α, and IL-6 in the DFU patients with cardiovascular events were higher than those in the nonoccurrence group (p < .001). Glycated hemoglobin in patients with DFU was positively correlated with PCT, TNF-α, and IL-6 levels (p < .05), and negatively correlated with Beclin-1 and LC3 levels (p < .001). CONCLUSION: P. aeruginosa and S. aureus were predominant bacterial in DFU infections. Inflammatory factor and autophagy protein expression were closely correlated with the degree of infection.

Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations.

DNA methyltransferases DNMT3A- and DNMT3B-mediated DNA methylation critically regulate epigenomic and transcriptomic patterning during development. The hotspot DNMT3A mutations at the site of Arg822 (R882) promote polymerization, leading to aberrant DNA methylation that may contribute to the pathogenesis of acute myeloid leukemia (AML). However, the molecular basis underlying the mutation-induced functional misregulation of DNMT3A remains unclear. Here, we report the crystal structures of the DNMT3A methyltransferase domain, revealing a molecular basis for its oligomerization behavior distinct to DNMT3B, and the enhanced intermolecular contacts caused by the R882H or R882C mutation. Our biochemical, cellular, and genomic DNA methylation analyses demonstrate that introducing the DNMT3B-converting mutations inhibits the R882H-/R882C-triggered DNMT3A polymerization and enhances substrate access, thereby eliminating the dominant-negative effect of the DNMT3A R882 mutations in cells. Together, this study provides mechanistic insights into DNMT3A R882 mutations-triggered aberrant oligomerization and DNA hypomethylation in AML, with important implications in cancer therapy.