Arsenic methylation and microbial communities in paddy soils under alternating anoxic and oxic conditions.

Arsenic (As) methylation in soils affects the environmental behavior of As, excessive accumulation of dimethylarsenate (DMA) in rice plants leads to straighthead disease and a serious drop in crop yield. Understanding the mobility and transformation of methylated arsenic in redox-changing paddy fields is crucial for food security. Here, soils including un-arsenic contaminated (N-As), low-arsenic (L-As), medium-arsenic (M-As), and high-arsenic (H-As) soils were incubated under continuous anoxic, continuous oxic, and consecutive anoxic/oxic treatments respectively, to profile arsenic methylating process and microbial species involved in the As cycle. Under anoxic-oxic (A-O) treatment, methylated arsenic was significantly increased once oxygen was introduced into the incubation system. The methylated arsenic concentrations were up to 2-24 times higher than those in anoxic (A), oxic (O), and oxic-anoxic (O-A) treatments, under which arsenic was methylated slightly and then decreased in all four As concentration soils. In fact, the most plentiful arsenite S-adenosylmethionine methyltransferase genes (arsM) contributed to the increase in As methylation. Proteobacteria (40.8%-62.4%), Firmicutes (3.5%-15.7%), and Desulfobacterota (5.3%-13.3%) were the major microorganisms related to this process. These microbial increased markedly and played more important roles after oxygen was introduced, indicating that they were potential keystone microbial groups for As methylation in the alternating anoxic (flooding) and oxic (drainage) environment. The novel findings provided new insights into the reoxidation-driven arsenic methylation processes and the model could be used for further risk estimation in periodically flooded paddy fields.

Exercise-promoted adiponectin secretion activates autolysosomes to protect the liver of ApoE-/- mice from a high-fat diet.

Fat is a "double-edged sword": while it is a necessary substance for the body, the long-term intake of excessive fat will cause obesity, with the liver subjected to lipotoxicity as it accumulates. It will then continue to deteriorate, eventually leading to liver failure, which is a negative impact of high-fat food intake. Research has shown that exercise can reverse the side effects of a chronic high-fat diet and help the body to mitigate the harmful effects of lipotoxicity. In our study, it was found that moderate-intensity cardio-training (MICT) and high-intensity interval exercise (HIIT) effectively protected the livers of high-fat diet (HFD) ApoE-/- mice against lipotoxicity. Previous results demonstrated that 12 weeks of HFD resulted in a significant elevation of CD36 in the livers of C57BL/6J mice, while knockdown of CD36 did not reduce the accumulation of fat in the liver. Therefore, we used ApoE-/- mice as experimental subjects. Although HFD caused the development of hyperlipidemia and atherosclerosis, it is interesting to note that, due to the knockdown of ApoE, the livers of ApoE-/- mice in the non-exercise group did not show significant lipid deposition; however, after 12 weeks of MICT and HIIT, the livers of ApoE-/- mice showed significant lipid deposition. After we analyzed the lipid metabolism in their livers, we found that this was caused by the promotion of transport of peripheral fat into the liver due to exercise. Moreover, 12 weeks of exercise effectively reduced atherosclerosis, and the livers of ApoE-/- mice in the exercise group were not damaged by lipotoxicity. The results showed that a 12-week exercise treatment activated AMPK in the livers of HFD ApoE-/- mice through the APN-AdipoR1 signaling pathway, improved hepatic lipid metabolism disorders, and promoted the nuclear translocation of TFEB to enhance autophagic-lysosomal lipid scavenging. After the peripheral lipid is input into the liver due to exercise, the energy generated through gluconeogenesis can be used to replenish the energy consumed by exercise and maintain the normal operation of various functions in the liver, based on which the high autophagic flux in the liver can be maintained and the lipid clearance rate can be enhanced to protect the liver from lipotoxicity.

Amplified photosynthetic responses to drought events offset the positive effects of warming on arid desert plants.

Ongoing warming will influence plant photosynthesis via thermal effects and by enhancing water deficit. As the primary limiting factor for the growth and development of plants in arid deserts, water may alter the potential warming effects on plant photosynthesis and lead to increased uncertainty in plant dynamics. Here, we used open-top chambers (OTCs) to evaluate the impacts of in situ warming (+0.5 and +1.5 °C) on the photosynthesis and growth of two representative desert plants, Artemisia ordosica and Grubovia dasyphylla, from wet to dry spells. The plant traits associated with photosynthetic diffusive and biochemical processes were also measured to explore the underlying mechanisms involved. Warming significantly increased the net photosynthetic rate (Anet) during wet spells under 1.5 °C warming in both plants, while only increased that of A. ordosica under 0.5 °C warming. During dry spells, Anet decreased both in A. ordosica and G. dasyphylla, with the rates of declining being 48 % and 41 %, respectively, higher than control under warming. Consequently, warming significantly amplified photosynthetic responses to drought events, which offset the positive warming effects during wet spells and led to unchanged plant biomass in both species. Besides, alterations in plant traits tended to be associated with positive warming effects during wet spells, and the negative effects of drought were mainly due to stomatal limitation. Our results emphasised that the potential benefits of warming during wet spells may be reversed during drought events. Thus, the adverse effects of ongoing warming on desert productivity may increase during dry spells in growing seasons and during dry years.

Design and synthesis of some novel structurally diverse thiochroman derivatives as fungicides against phytopathogenic fungi.

BACKGROUND: Plant diseases infected by pathogenic fungi have a devastating effect on global agricultural and food industry yields. The development of novel, environmentally friendly, and efficient fungicides is an important technique for preventing and combatting phytopathogenic fungi. RESULTS: Herein, 99 thiochroman-based derivatives containing hydroxyl, sulfoxide, sulfone, carbonyl, double bond, amino, imine, oxime, oxime ester, and amide moieties were synthesized. The antifungal activities of the target compounds against ten typical phytopathogenic fungi were also investigated. The bioassay results illustrated that most of the target compounds exhibited moderate to excellent antifungal effects against the tested fungi in vitro. Among these, thiochroman-oxime derivatives (12a-12m) exerted a promising inhibition effect, especially against Fusarium solani, Fusarium graminearum, Valsa mali, and Botrytis cinerea strains. Furthermore, the compounds 12f and 12g markedly suppressed the spore germination germ and tube growth. At the same time, they exerted excellent protective effects against potatoes infected by F. solani, making them superior to commercial fungicides Hymexazol and Chlorothalonil. Notably, the compounds 12d and 12f also showed excellent protective effects against cherry tomatoes infected by B. cinerea. Further mechanistic studies revealed that compound 12f exerted an antifungal effect by overtly altering the mycelium structure and remarkably increasing cell membrane permeability. Fortunately, the excellent bioactive compounds showed good safety against human hepatic cell lines (WRL-68). The preliminary structure-activity relationship analysis revealed that the introduction of hydroxyl or oxime fragments at the thiopyran ring might be significantly beneficial to antifungal activity. CONCLUSION: This study provides thiochroman compounds that can be used in the development of novel botanical fungicides for the management of phytopathogenic fungi. © 2024 Society of Chemical Industry.

Multiple Self-Powered Sensor-Integrated Mobile Manipulator for Intelligent Environment Detection.

A multiple self-powered sensor-integrated mobile manipulator (MSIMM) system was proposed to address challenges in existing exploration devices, such as the need for a constant energy supply, limited variety of sensed information, and difficult human-computer interfaces. The MSIMM system integrates triboelectric nanogenerator (TENG)-based self-powered sensors, a bionic manipulator, and wireless gesture control, enhancing sensor data usability through machine learning. Specifically, the system includes a tracked vehicle platform carrying the manipulator and electronics, including a storage battery and a microcontroller unit (MCU). An integrated sensor glove and terminal application (APP) enable intuitive manipulator control, improving human-computer interaction. The system responds to and analyzes various environmental stimuli, including the droplet and fall height, temperature, pressure, material type, angles, angular velocity direction, and acceleration amplitude and direction. The manipulator, fabricated using 3D printing technology, integrates multiple sensors that generate electrical signals through the triboelectric effect of mechanical motion. These signals are classified using convolutional neural networks for accurate environmental monitoring. Our database shows signal recognition and classification accuracy exceeding 94%, with specific accuracies of 100% for pressure sensors, 99.55% for angle sensors, and 98.66, 95.91, 96.27, and 94.13% for material, droplet, temperature, and acceleration sensors, respectively.

Asymptomatic infection and disappearance of clinical symptoms of COVID-19 infectors in China 2022-2023: a cross-sectional study.

To explore the clinical characteristics of patients infected with SARS-CoV-2 nationwide, especially the effect factors of asymptomatic infection and disappearance of clinical symptoms. A total of 66,448 COVID-19 patients in China who have been diagnosed by nucleic acid test or rapid antigen test were surveyed online (December 24, 2022 to January 16, 2023). Our cross-sectional study used descriptive analyses and binary Logistics regression model to assess the correlation between the clinical characteristics and relative factors, including age, gender, pre-existing conditions, reinfection, vaccination and treatment. A total of 64,515 valid questionnaires were collected. Among included participants, 5969 of which were asymptomatic. The symptoms were mainly upper respiratory symptoms, including dry and itchy throat (64.16%), sore throat (59.95%), hoarseness (57.90%), nasal congestion (53.39%). In binary Logistics regression model, we found that male, no pre-existing conditions, reinfection and vaccination have positive correlations with the appearance of asymptomatic COVID-19 patients. In Cox proportional-hazards regression model, considering all clinical symptoms disappeared in 14 days as outcome, we found that ≤ 60 years old, male, no pre-existing conditions, vaccination and adopted treatment have positive correlations with rapid amelioration of clinical symptoms in COVID-19 patients. The clinical symptoms of the participants were mainly upper respiratory symptoms which were according with the infection of Omicron variant. Factors including age, gender, pre-existing conditions and reinfection could influence the clinical characteristics and prognosis of COVID-19 patients. Importantly, vaccination has positive significance for the prevention and treatment of COVID-19. Lastly, the use of Chinese medicine maybe beneficial to COVID-19 patients, however, reasonable guidance is necessary.

Risk factors analysis of noninvasive positive pressure ventilation in inpatients with overlapping syndrome of chronic obstructive pulmonary disease combined with obstructive sleep apnea.

OBJECTIVE: The aim of the study was to analyze the clinical data of patients with chronic obstructive pulmonary disease and obstructive sleep apnea overlap syndrome (OS) during hospitalization and to evaluate the risk factors of patients treated with Non-Invasive Ventilation (NIV). METHODS: Demographic and clinical data of patients with confirmed OS during hospitalization were retrospectively collected. The patients were divided into two groups according to whether noninvasive ventilator was used during hospitalization, including OS treated with NIV (244 cases) and OS without NIV (239 cases). The t-test, χ 2 test, and Kaplan-Meier curve were used to compare the two groups, and multiple logistic regression was used to analyze the risk factors of NIV in patients with OS. RESULTS: Compared with the OS group without NIV, the pulmonary hypertension, lymphocyte count, and left ventricular ejection fraction% of OS patients with NIV were lower, whereas PCO2, uric acid, C-reactive protein, procalcitonin, and N-terminal pro-B-type natriuretic peptide were higher, with statistical differences (P < 0.05). During hospitalization and follow-up, OS patients with NIV had a longer hospital stay (P < 0.001), and there was no significant difference in the rate of readmission within 28 days. The logistic regression analysis showed that the history of diuretic use, previous history of noninvasive ventilator use, and ischemic heart disease were independent risk factors for NIV treatment in OS patients during hospitalization. CONCLUSION: Patients with OS undergoing NIV during hospitalization exhibited more severe overall illness and had prolonged hospital stays compared to OS patients not receiving NIV. History of diuretic use, history of NIV use, and ischemic heart disease are independent risk factors for NIV treatment in OS patients during hospitalization.

A double-sided coating paper antibacterial indicator card based on polyvinyl alcohol/sodium carboxymethyl cellulose-anthocyanins and chitosan-halloysite nanotubes loaded essential oil to monitor fish freshness.

This study developed a multifunctional paper-based freshness antibacterial indicator card by dual-sided coating on conventional filter paper. The indicator coating was composed of anthocyanins from purple cabbage, and polyvinyl alcohol and sodium carboxymethyl cellulose as substrates while the antibacterial coating contained halloysite nanotubes for loaded thyme essential oil and chitosan. FT-IR, XRD, and SEM analyses revealed that the components were well-mixed, and the paper was tightly bound to the coatings through hydrogen bonds. Additionally, the coating effectively filled the porous fiber gaps in the paper, significantly enhancing the mechanical properties of the paper. The tensile strength of the coated paper was enhanced from 14.28 MPa to a range of 42.25-47.71 MPa, and the bending resistance was increased from 0.35 N·mm to a range of 1.72-1.99 N·mm compared to the uncoated paper. The addition of anthocyanins provided excellent sensitivity to pH and ammonia for the indicator card. Furthermore, the coating including halloysite nanotubes for loaded thyme essential oil exhibited antimicrobial resistance against Escherichia coli and Staphylococcus aureus. When used on fresh carp, the antibacterial indicator card not only indicated the freshness of the carp but also extended the best before date of the fish meat by 1-2 days. The indicator exhibited the most pronounced color transformation and optimal freshness indication performance when the mass fraction of anthocyanins was 2 %.

Innovative Synthesis of Au Nanoparticle-Trapped Flexible Macrocrystals: Achieving Stable Black Crystal Wires with Broadband Absorption.

In optical materials, the development of absorbers for a wide spectrum is a focal point of research. A pivotal challenge lies in ensuring the stability and durability of optical absorbers, particularly at elevated temperatures. This study introduces a novel approach to creating absorbers with diverse colors, focusing on the synthesis and properties of black crystal wires. In contrast to black gold nanoparticle (Au NP) precipitates, which change color within hours under similar conditions, the method involves strategically trapping Au NPs within defects during the growth of single crystals. This results in black crystal wires that not only exhibit broadband absorption but also maintain exceptional stability even under prolonged exposure to high temperatures. The method also involves the controlled synthesis of colorless and red crystal wires. As a proof of concept, these stable black Au crystal wires demonstrate superior performance in photothermal conversion applications. The methodology, derived from the crystal growth process, presents a defect template that offers a novel approach to material design. Furthermore, these unique crystals, available in various colors, hold significant promise for a range of unexplored applications.

Correlation of psychological resilience with social support and coping style in Parkinson's disease: A cross-sectional study.

AIMS: To analyse the current status of psychological resilience in Parkinson's disease (PD) patients and its correlation with social support and coping style. DESIGN: A cross-sectional study. METHODS: PD patients hospitalized in a tertiary-level hospital in Shijiazhuang, Hebei Province, from March 2022 to March 2023 were selected for the study using the convenience sampling method. A general information questionnaire, psychological resilience scale, Medical Coping Modes Questionnaire and Perceived Social Support Scale were used to investigate 111 cases of PD. SPSS 25.0 software was used for statistical analysis. The data were analysed using independent samples t-test, one-way ANOVA, multiple linear regression analysis and the Pearson correlation coefficient. RESULTS: Parkinson's disease patients have a moderate level of psychological resilience. The results of the Pearson correlation analyses showed that the level of psychological resilience was positively correlated with social support and confrontation and was negatively correlated with avoidance and acceptance-resignation. The results of multiple linear regression analysis showed that social support and acceptance-resignation were the influencing factors of psychological resilience in PD patients. CONCLUSION: The psychological resilience of PD patients is at a moderate level. Social support and acceptance-resignation are the factors influencing the psychological resilience of PD patients. IMPACT STATEMENT: This study analysed the level of psychological resilience in PD patients and its correlation with social support and coping style from the perspective of positive psychology to provide some reference for targeted clinical interventions. Our study found that social support and acceptance-resignation are influential factors in psychological resilience in PD patients. Medical staff should encourage patients to face the disease positively and their social support should be increased in order to improve their level of psychological resilience. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Comparisons of laparoscopic and robotic pancreaticoduodenectomy using barbed and conventional sutures for pancreaticojejunostomy: a propensity score matching study.

BACKGROUND: There are limited data on the effect of different sutures and surgical approaches on the quality of pancreaticojejunostomy in minimally invasive pancreaticoduodenectomy (MIPD). This study compares the incidence of clinically relevant postoperative pancreatic fistula (CR-POPF) between the use of barbed sutures (BSs) and conventional sutures (CSs). METHODS: A retrospective cohort study was conducted on 253 consecutive patients who had undergone MIPD from July 2016 to April 2023. Patients were excluded if conversion to open surgery or open anastomosis was necessary. 220 patients were enrolled and divided into BS (n = 148) and CS (n = 72) groups. After 1:1 propensity score matching (PSM), 67 cases remained in each group. Univariate and multivariate analyses identified factors associated with CR-POPF. Comparisons were also made between laparoscopic (LPD) and robotic (RPD) pancreaticoduodenectomy. RESULTS: After PSM, BSs were associated with significantly lower rates of CR-POPF (7.5 vs. 22.4%, P = 0.015) and severe complications (Clavien-Dindo ≥ III) (7.5vs. 19.4%, P = 0.043). No significant differences were found in operative time, length of postoperative hospital stay, or other major morbidities. Multivariate analyses revealed BMI ≥ 22 kg/m2 (OR = 5.048, 95% CI: 1.256-20.287, P = 0.023) and the use of BSs (OR = 0.196, 95% CI: 0.059-0.653, P = 0.008) as the independent predictors of CR-POPF. There were no significant differences in postoperative outcomes between the LPD and RPD groups, but RPD was associated with significantly shorter operative time (402.8 min vs. 429.4 min, P = 0.015). CONCLUSIONS: In conclusion, using BSs for PJ during MIPD is feasible and has the potential to reduce CR-POPF and severe complications.

BRD4-specific PROTAC inhibits basal-like breast cancer partially through downregulating KLF5 expression.

Interest in the use of proteolysis-targeting chimeras (PROTACs) in cancer therapy has increased in recent years. Targeting bromodomain and extra terminal domain (BET) proteins, especially bromodomain-containing protein 4 (BRD4), has shown inhibitory effects on basal-like breast cancer (BLBC). However, the bioavailability of BRD4 PROTACs is restricted by their non-selective biodegradability and low tumor-targeting ability. We demonstrated that 6b (BRD4 PROTAC) suppresses BLBC cell growth by targeting BRD4, but not BRD2 and BRD3, for cereblon (CRBN)-mediated ubiquitination and proteasomal degradation. Compound 6b also inhibited expression of Krüppel-like factor 5 (KLF5) transcription factor, a key oncoprotein in BLBC, controlled by BRD4-mediated super-enhancers. Moreover, 6b inhibited HCC1806 tumor growth in a xenograft mouse model. The combination of 6b and KLF5 inhibitors showed additive effects on BLBC. These results suggest that BRD4-specific PROTAC can effectively inhibit BLBC by downregulating KLF5, and that 6b has potential as a novel therapeutic drug for BLBC.

The sEVs miR-487a/Notch2/GATA3 axis promotes osteosarcoma lung metastasis by inducing macrophage polarization toward the M2-subtype.

Small extracellular vesicles (sEVs) are important mediators of intercellular communication between tumor cells and their surrounding environment. Furthermore, the mechanisms by which miRNAs carried in tumor sEVs regulate macrophage polarization remain largely unknown. To concentrate sEVs, we used the traditional ultracentrifugation method. Western blot, NanoSight, and transmission electron microscopy were used to identify sEVs. To determine the function of sEVs-miR-487a, we conducted in vivo and in vitro investigations. The intercellular communication mechanism between osteosarcoma cells and M2 macrophages, mediated by sEVs carrying miR-487a, was validated using luciferase reporter assays, transwell assays, and Western blot analysis. In vitro, sEVs enriched in miR-487a and delivered miR-487a to macrophages, promoting macrophage polarization toward an M2-like type, which promotes proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of osteosarcoma cells. In vivo, sEVs enriched in miR-487a facilitate lung metastasis of osteosarcoma. Moreover, plasma miR-487a in sEVs was shown to be a potential biomarker applicable for osteosarcoma diagnosis. In summary, miR-487a derived from osteosarcoma cells can be transferred to macrophages via sEVs, then promote macrophage polarization towards an M2-like type by targeting Notch2 and activating the GATA3 pathway. In a feedback loop, the activation of macrophages accelerates epithelial-mesenchymal transition (EMT), which in turn promotes the migration, invasion, and lung metastasis of osteosarcoma cells. This reciprocal interaction between activated macrophages and osteosarcoma cells contributes to the progression of the disease. Our data demonstrate a new mechanism that osteosarcoma tumor cells derived exosomal-miR-487a which is involved in osteosarcoma development by regulating macrophage polarization in tumor microenvironment (TME).

HDAC1 and FOXK1 mediate EGFR-TKI resistance of non-small cell lung cancer through miR-33a silencing.

BACKGROUND: The development of acquired EGFR-TKI treatment resistance is still a major clinical challenge in the treatment of non-small cell lung cancer (NSCLC). This study aimed to investigate the role of HDAC1/FOXK1/miR-33a signaling in EGFR-TKI resistance. METHODS: The expression levels of miR-33a, HDAC1, and FOXK1 were examined using quantitative polymerase chain reaction (PCR) and bioinformatics analysis. Cell proliferation, migration, and apoptosis were explored by cell number assay, Transwell, and flow cytometry assays, respectively. After overexpression or knockdown of HDAC1, miR-33a expression in the cells, cell functions were tested. Immunoprecipitation and correlation analyses were used to evaluate the interaction between HDAC1 and FOXK1 protein. The tumor-suppressive role of miR-33a was investigated by animal experiments. RESULTS: The suppression of miR-33a increased TKI resistance by affecting cell proliferation, migration, and apoptosis in gefitinib-resistant cells. HDAC1 is the key upstream molecule that inhibits miR-33 expression. HDAC1 upregulation increased gefitinib resistance by its binding to FOXK1 in cells to silence miR-33a expression. MiR-33a overexpression exerts tumor-suppressive effects by negatively regulating ABCB7 and p70S6K1 expression. Moreover, overexpression of miR-33a inhibited tumor growth in a xenograft nude mouse model. CONCLUSIONS: HDAC1/FOXK1 upregulation and miR-33a silencing are new mechanisms of EGFR-TKI resistance in NSCLC.

High risk of low birth weight in couples with advanced paternal age in in vitro fertilization treatment.

BACKGROUND: With the development of socio-economic conditions and a shift in attitudes towards fertility, there has been a gradual increase in delayed childbearing since the 2000s. Age plays a significant role in the decline of fertility. However, we know very little about the association of paternal age with reproductive outcomes. OBJECTIVES: To investigate the correlation between advanced paternal age and semen quality, embryo quality, pregnancy, and neonatal outcomes in IVF cycles. MATERIALS AND METHODS: In this study, after excluding female partners aged ≥35 years, we analyzed data from 761 infertile couples who underwent in vitro fertilization cycles at the First Affiliated Hospital of USTC between June 2020 and March 2023. Cases were classified into three groups according to the age of the male: <35 years (530 infertile couples), 35 years ≤ paternal age <40 years (125 infertile couples), and ≥40 years (106 infertile couples). Then, we compared the general clinical data arising from in vitro fertilization cycles between the three groups, including semen parameters, embryonic parameters, and pregnancy and neonatal birth outcomes. RESULTS: Data analysis showed that the duration of infertility and the incidence of secondary infertility were significantly higher in paternal age ≥35 years groups than those aged <35 years (all p < 0.05). We also observed a significant difference between ≥40 years and <35 years groups in terms of the normal fertilization rate, high-quality embryo rate, clinical pregnancy rate, miscarriage rate, live birth rate, Apgar scores, and the low birth weight neonatal rate (all p < 0.05). The group with paternal age ≥40 years showed statistically significant differences in terms of clinical pregnancy rate, miscarriage rate, live birth rate, and low birth weight on multivariable logistic regression (all p < 0.05). CONCLUSION: The results of our study indicate that advanced paternal age (≥40 years) has a significant impact on the embryo quality, pregnancy outcome, and neonatal outcome. Paternal age over 40 years is a risk for in vitro fertilization success rate.

Risk factor patterns define social anxiety subtypes in adolescents with brain and clinical feature differences.

Social anxiety disorder (SAD) is one of the most common psychiatric disorders in adolescents. The heterogeneity of both symptoms and etiology is an essential source of difficulties in the treatment and prevention of SAD. The study aimed to identify subtypes of adolescent SAD based on etiology-related phenotype dimensions and examine symptom and brain associations of the subtypes. We used a deeply phenotyped sample (47 phenotype subscales from 13 measures) of adolescents with SAD (n = 196) and healthy controls (n = 109) to extract etiology-relevant risk factors, based on which we identified subtypes of SAD. We compared the subtypes on clinical characteristics and brain morphometrics and functional connectivity, and examined subtype-specific links between risk factors, brain aberrance, and clinical characteristics. We identified six etiology-relevant risk factors and two subtypes of adolescent SAD. One subtype showed mainly elevated negative emotionality trait and coping style and diminished positive emotionality trait and coping style, while the other additionally had significantly high environmental risk factors, more severe impairments in social functioning, and significant abnormalities in brain structure and function. There were subtype-specific links between the risk factor profiles, brain aberrance, and clinical characteristics. The finding suggests two etiology-based subtypes of adolescent SAD, providing novel insights to the diversity of pathological pathways and precise intervention strategies.

Structure-Activity Relationship Studies of Substituted 2-Phenyl-1,2,4-triazine-3,5(2H,4H)-dione Analogues: Development of Potent eEF2K Degraders against Triple-Negative Breast Cancer.

eEF2K, an atypical alpha-kinase, is responsible for regulating protein synthesis and energy homeostasis. Aberrant eEF2K function has been linked to various human cancers, including triple-negative breast cancer (TNBC). However, limited cellular activity of current eEF2K modulators impedes their clinical application. Based on the 2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione scaffold of our hits I4 and C1, structure-activity relationship analysis led to the discovery of several more active derivatives (e.g., 19, 34, and 36) in inhibiting the viability of TNBC cell line MDA-MB-231. Moreover, the most potent compound 36 significantly suppresses the viability, proliferation, and migration of both MDA-MB-231 and HCC1806 cell lines. Mechanistically, compound 36 has a high binding affinity for the eEF2K protein and effectively induces its degradation. Additionally, 36 exerts a comparable tumor-suppressive effect to paclitaxel in an MDA-MB-231 cell xenograft mouse model with no obvious toxicity, demonstrating that compound 36 could be developed as a potential novel therapeutic for TNBC treatment.

An essential role of the E3 ubiquitin ligase RNF126 in ensuring meiosis I completion during spermatogenesis.

INTRODUCTION: Homologous recombination repair during meiosis is essential for the exchange of genetic information between sister chromosomes, underpinning spermatogenesis and, consequently, fertility. The disruption of this process can lead to infertility, highlighting the importance of identifying the molecular actors involved. OBJECTIVES: This study aims to elucidate the role of the E3 ubiquitin ligase Rnf126 in spermatogenesis and its impact on fertility, particularly through its involvement in meiotic homologous recombination repair. METHODS: We used heterozygous and homozygous Rnf126 deletion models in mouse testes to examine the consequences on testicular health, sperm count, and the process of spermatogenesis. Additionally, we explored the association between RNF126 gene missense variants and nonobstructive male infertility in patients, with a focus on their functional impact on the protein's ubiquitin ligase activity. RESULTS: Rnf126 deletion led to testicular atrophy, disrupted seminiferous tubule structure, reduced sperm count, and spermatogenesis arrest at meiotic prophase I. Furthermore, male mice exhibited impaired homologous recombination repair and increased apoptosis within the seminiferous tubules. We identified four missense variants of the RNF126 (V68M, R241H, E261A, D253N) associated with male infertility. Specifically, the E261A and D253N variants, located in the RING domain, directly compromised the E3 ubiquitin ligase activity of RNF126. CONCLUSION: Our findings demonstrate the pivotal role of RNF126 in maintaining spermatogenesis and fertility, offering insights into the molecular mechanisms underlying male infertility. The identified RNF126 variants present novel targets for diagnostic and therapeutic strategies in treating nonobstructive male infertility.

Nanographene Oxide Promotes Angiogenesis by Regulating Osteoclast Differentiation and Platelet-Derived Growth Factor Secretion.

An imbalanced system of angiogenesis-osteoblasts-osteoclasts is regarded as the main factor in bone remodeling dysfunction diseases or osseointegration loss. Osteoclast precursors are the key cells that accelerate bone-specific angiogenesis and maintain normal osteoblast and osteoclast function. Graphene oxide is an effective scaffold surface modification agent with broad application prospects in bone tissue engineering. However, the effect of graphene oxide on the interaction between osteoclasts and angiogenesis has not yet been elucidated. In this study, a rat calvarial defect model was established and treated with an electrochemically derived nanographene oxide (ENGO) hydrogel. Higher angiogenesis and platelet-derived growth factor (PDGF) B in preosteoclasts were observed in the ENGO group compared with that in the control group. Moreover, in vitro experiments demonstrate the efficacy of ENGO in substantially reducing the expression of the receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclast-associated markers and inhibiting bone resorption activity. Additionally, ENGO enhances the secretion of the osteoclast-derived coupling factor PDGF-BB and promotes angiogenesis. Our investigation revealed the crucial role of isocitrate dehydrogenase 1 (IDH1) in the ENGO-mediated regulation of osteoclast differentiation and PDGF-BB secretion. The decreased expression of IDH1 reduces the level of histone lysine demethylase 7A (KDM7A) and subsequently increases the H3K9me2 level in the cathepsin K promoter region. In summary, we found that ENGO promotes angiogenesis by inhibiting the maturity of RANKL-induced osteoclasts and enhancing PDGF-BB secretion. These results indicate that ENGO holds promise for the application in fostering osteoclast-endothelial cell crosstalk, providing an effective strategy for treating bone resorption and osteoclast-related bone loss diseases.