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In this study, two wheat-derived cadmium (Cd)-immobilizing endophytic Pseudomonas paralactis M14 and Priestia megaterium R27 were evaluated for their effects on wheat tissue Cd uptake under hydroponic conditions. Then, the impacts of the biochar (BC), M14+R27 (MR), and BC+MR treatments on wheat Cd uptake and the mechanisms involved were investigated at the jointing, heading, and mature stages of wheat plants under field-plot conditions. A hydroponic experiment showed that the MR treatment significantly decreased the above-ground tissue Cd content compared with the M14 or R27 treatment. The BC+MR treatment reduced the grain Cd content by 51.5%-67.7% and Cd translocation factor at the mature stage of wheat plants and increased the organic matter-bound Cd content by 31%-75% in the rhizosphere soils compared with the BC or MR treatment. Compared with the BC or MR treatment, the relative abundances of the biomarkers associated with Gemmatimonas, Altererythrobacter, Gammaproteobacteria, Xanthomonadaceae, Phenylobacterium, and Nocardioides in the BC+MR-treated rhizosphere microbiome decreased and negatively correlated with the organic matter-bound Cd contents. In the BC+MR-treated root interior microbiome, the relative abundance of the biomarker belonging to Exiguobacterium increased and negatively correlated with the Cd translocation factor, while the relative abundance of the biomarker belonging to Pseudonocardiaceae decreased and positively correlated with the Cd translocation factor. Our findings suggested that the BC+MR treatment reduced Cd availability and Cd transfer through affecting the abundances of these specific biomarkers in the rhizosphere soil and root interior microbiomes, leading to decreased wheat grain Cd uptake in the contaminated soil.

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Introduction: With the rising demand for medical services and the associated burden, work-related stress and mental health issue have garnered increased attention among healthcare workers. Anxiety, cognitive impairment, and their comorbidities severely impact the physical and mental health as well as the work status of healthcare workers. The network analysis method was used to identify the anxiety and cognitive impairment among mental healthcare workers using the Generalized Anxiety Disorder Scale (GAD-7) and the Perceived Deficit Questionnaire for Depression (PDQ-D). We sought to identify the core symptoms associated with the comorbidity of anxiety and cognitive impairment in mental healthcare workers. Methods: The study was conducted by Shandong Daizhuang Hospital and Qingdao Mental Health Center in China from September 13, 2022, to October 25, 2022, involving a total of 680 healthcare workers as participants. GAD-7 and PDQ-D were utilized to assess anxiety and cognitive impairment, respectively. Regularized partial correlation network analysis was employed to examing the expected influence and predictability of each item within the network. Statistical analysis and visualization of the network were performed using R software. Results: The mean total score for anxiety was 3.25, while the mean total score for cognitive symptoms was 15.89. PDQ17 "Remembering numbers", PDQ12 "Trouble get started" and PDQ20 "Trouble make decisions" emerged as central symptoms in the anxiety-cognition network. GAD6 "Irritable", GAD5 "Restlessness" and GAD1 "Nervousness or anxiety" were identified as the most critical bridge symptoms connecting anxiety and cognition. Gender was found to be unrelated to the global strength of the network, edge weight distribution, or individual edge weights. Conclusion: Utilizing central and bridge symptoms (i.e., Remembering numbers, Trouble get started, Trouble make decisions, Irritable, Restlessness and Nervousness or anxiety) as primary intervention points may aid in mitigating the serious health consequences of anxiety, cognitive impairment, and comorbidities anxiety and cognitive impairment for mental healthcare workers.

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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that commonly affects children and adolescents with a poor prognosis. The terminal unfolded protein response (UPR) is an emerging anti-cancer approach, although its role in pediatric T-ALL remains unclear. In our pediatric T-ALL cohort from different centers, a lower QRICH1 expression was found associated with a worse prognosis of pediatric T-ALL. Overexpression of QRICH1 significantly inhibited cell proliferation and stimulated apoptosis of T-ALL both in vitro and in vivo. Upregulation of QRICH1 significantly downregulated 78 KDa glucose-regulated protein (GRP78) and upregulated CHOP, thus activating the terminal UPR. Co-overexpression of GRP78 in T-ALL cells overexpressing QRICH1 partially reverted the inhibited proliferation and stimulated apoptosis. QRICH1 bound to the residues Asp212 and Glu155 of the nucleotide-binding domain (NBD) of GRP78, thereby inhibiting its ATP hydrolysis activity. In addition, QRICH1 was associated with endoplasmic reticulum (ER) stress in T-ALL, and overexpression of QRICH1 reversed drug resistance. Overall, low QRICH1 expression is an independent risk factor for a poor prognosis of pediatric T-ALL. By inhibiting GRP78, QRICH1 suppresses pediatric T-ALL.

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Pseudomonas protegens is an important biocontrol agent with the ability to suppress plant pathogens and promote plant growth. P. protegens' ability to endure hyperosmotic stress is crucial to its effectiveness as a biocontrol agent. This study elucidated potassium's role and mechanism of action in enabling the hyperosmotic tolerance of P. protegens. Potassium was observed to significantly improve the growth of P. protegens under hyperosmotic conditions. Four functionally redundant potassium transporters, KdpA1, KdpA2, TrkH, and Kup, were identified in P. protegens, of which KdpA2 and TrkH were particularly important for its growth under hyperosmotic conditions. Potassium enhanced the biofilm formation and cell membrane stability of P. protegens under hyperosmotic conditions. In addition, we revealed that K+ stimulates the expression of several genes related to DNA damage repair in P. protegens under hyperosmotic conditions. Further experiments revealed that the DNA repair-related recG induced by potassium contributes to P. protegens' hyperosmotic tolerance. We also found that the sigma factor RpoN participates in the hyperosmotic adaptation of P. protegens. Furthermore, we revealed that the opuCABCD operon, whose expression is induced by potassium through RpoN, serves as the key pathway through which betaine, choline, and carnitine improve the hyperosmotic tolerance of P. protegens.

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This study aimed to explore the probiotic characteristics of Lacticaseibacillus rhamnosus SN21-1 and Lactiplantibacillus plantarum SN21-2 by genotype and phenotype analysis, assess their safety in vitro and in vivo, and investigate the effects of L. rhamnosus SN21-1 and L. plantarum SN21-2 on Salmonella typhimurium-infected broilers in an in vivo experiment. L. rhamnosus SN21-1 and L. plantarum SN21-2 showed antimicrobial activity against pathogens, including S. Typhimurium, resistance to simulated gastrointestinal digestive fluid, and adhesion to HT-29 cells. In addition, L. rhamnosus SN21-1 and L. plantarum SN21-2 showed no resistance to most common antimicrobial agents and no haemolysis in vitro. Whole-genome sequence analyses of L. rhamnosus SN21-1 and L. plantarum SN21-2 provided basic genomic information, functional genes underlying the probiotic characteristics, and evidence of safety. Furthermore, feeding with L. rhamnosus SN21-1 or L. plantarum SN21-2 for 28 d had no significant effect on the growth or blood biochemical parameters of the broilers, and hematoxylin-eosin staining revealed no liver, spleen, heart, or kidney damage. Additionally, L. rhamnosus SN21-1 or L. plantarum SN21-2 did not translocate to the blood, liver, spleen, heart, or kidney of the broilers. Moreover, L. rhamnosus SN21-1 and L. plantarum SN21-2 significantly reduced S. Typhimurium counts in the faeces and caecal contents of S. Typhimurium-infected broilers and reduced small intestinal bleeding in S. Typhimurium-infected broilers. Consequently, L. rhamnosus SN21-1 and L. plantarum SN21-2 have excellent probiotic characteristics and are safe for use as anti-S. typhimurium probiotics in broilers.

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INTRODUCTION: To evaluate the effects and safety of monoamine oxidase B inhibitors (MAO-B inhibitors) for early Parkinson's disease. METHODS: All studies assessed the efficacy of MAO-B inhibitors in patients with early Parkinson's disease were searched. Publications were screened and data were extracted according to predefined criteria. Rev Man 5.4 and Stata 14.0 software were used for statistical analysis. Outcomes assessed included change of Unified Parkinson's Disease Rating Scale (UPDRS) total score, UPDRS Part II score, UPDRS Part III score and the incidence of adverse events. RESULTS: Thirty trials were identified and included in this meta-analysis. Compared with placebo, rasagiline, selegiline, safinamide and zonisamide were significantly more effective, with a standardized mean difference (SMD) of -0.41, 95% confidence interval (CI) = -0.64 to -0.18, SMD =-0.38 (95% CI= -0.51 to -0.24), SMD=-0.37 (95%CI= -0.54 to -0.21) and SMD=-0.31 (95%CI= -0.57 to -0.05) on the UPDRS III score change respectively. The surface under the cumulative ranking (SUCRA) results showed that rasagiline ranked first in improving UPDRS II and UPDRS III, respectively. For safety outcomes, safinamide combination with dopaminergic treatment had lower risk of incurring any adverse events (risk ratio=0.1 95% CI= 0.01 to 0.2), no statistical difference in incidence of adverse events was observed amongst other MAO-B inhibitor regimes and placebo. CONCLUSION: In conclusion, rasagiline, selegiline, safinamide and zonisamide were effective compared to placebo in the treatment of early Parkinson's disease, but rasagiline was the most effective drug. As for safety, safinamide combination with dopaminergic treatment had lower risk of incurring any adverse events.

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Suillus is one of the most important genera of ectomycorrhizal fungi. As a model for studying host specificity, its molecular fragments and nuclear genome have been analyzed. However, its mitochondrial genome has not yet been reported. In this study, we assembled five mitogenomes of Suillus and analyzed and compared their basic characteristics. Owing to the large number of introns as well as intergenic regions, the mitogenomic lengths of species of Suillus were greater than those of other species of Boletales. We identified two main patterns of gene order arrangement in the members of the order Boletales. The Ka/Ks values of 15 protein-coding genes were <1 for the mitochondrial genes of 39 Boletales species, indicating their conserved evolution. Phylogenetic trees, reconstructed using the mitogenomes, indicated that the genus Suillus was monophyletic. Phylogenetic results based on the internal transcribed spacer region and mitogenome were used to confirm the distribution of Suillus placidus in China. The results showed that the mitogenome was superior in distinguishing species compared with a single molecular fragment. This is the first study to investigate the mitogenome of Suillus, enriching the mitogenome information and providing basic data for the phylogeny, resource conservation, and genetic diversity of this genus.

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Secondary flowering is the phenomenon in which a tree blooms twice or more times a year. Along with the development of blueberry (Vaccinium corymbosum L.) fruits in spring, a large number of secondary flowers on the strong upright spring shoots were noticed in blueberries planted in the greenhouse. To reveal the cause and possible regulatory mechanism of the phenomenon, we clarified the phenological characteristics of flower bud differentiation and development on the spring shoots by combining phenological phenotype with anatomical observation. Furthermore, the changes in carbohydrates, trehalose-6-phosphate (Tre6P), and the relationship among the key enzyme regulatory genes for Tre6P metabolism and the key regulatory genes for flower formation during the differentiation process of apical buds and axillary buds were investigated. The results showed that the process of flower bud differentiation and flowering of apical and axillary buds was consistent, accompanied by a large amount of carbohydrate consumption. This process was positively correlated with the expression trends of VcTPS1/2, VcSnRK1, VcFT, VcLFY2, VcSPL43, VcAP1, and VcDAM in general, and negatively correlated with that of VcTPP. In addition, there is a certain difference in the differentiation progress of flower buds between the apical and axillary buds. Compared with axillary buds, apical buds had higher contents of sucrose, fructose, glucose, Tre6P, and higher expression levels of VcTPS2, VcFT, VcSPL43, and VcAP1. Moreover, VcTPS1 and VcTPS2 were more closely related to the physiological substances (sucrose and Tre6P) in axillary bud and apical bud differentiation, respectively. It was suggested that sucrose and trehalose-6-phosphate play a crucial role in promoting flower bud differentiation in strong upright spring shoots, and VcTPS1 and VcTPS2 might play a central role in these activities. Our study provided substantial sight for further study on the mechanism of multiple flowering of blueberries and laid a foundation for the regulation and utilization of the phenomenon of multiple flowering in a growing season of perennial woody plants.

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BACKGROUND: Patients with craniofacial cancer frequently suffer from severe pain. The traditional intrathecal, oral, or intravenous analgesics could only provide insufficient pain relief with many side effects. Thus, a more effective analgesia approach is required. This study aimed to investigate the safety and efficacy of placing the catheter of an intrathecal morphine pump in the prepontine cistern for the treatment of craniofacial cancer pain. METHODS: We performed a retrospective study of patients with primary or metastatic craniofacial cancer pain who received the catheter placement of an intrathecal morphine pump into the prepontine cistern in eleven medical centers from September 2019 to December 2023. Friedman test and pairwise signed-rank test were used to evaluate the difference in numeric rating scale (NRS) scores, the number of breakthrough pain episodes, dose of intrathecal morphine, and dose of systemic morphine equivalents (oral, patch, intravenous) from preoperative period to postoperative days 1, 7, and 30. P values were corrected for multiple comparisons using Bonferroni test. RESULTS: The study included 33 patients. The median (interquartile range [IQR]) of NRS scores at days 1, 7, and 30 postimplant were 2.0 (1.0-3.5), 2.0 (1.0-2.0), and 1.0 (1.0-2.0), respectively, which was significantly lower than that before surgery (median, 8.0; IQR, 7.0-10.0; all P < .001). Compared to baseline number/d of breakthrough pain episodes (median, 6.0; IQR, 4.5-10.0), there was a progressive decrease in the number/d of breakthrough pain episodes at day 1, day 7, and day 30 postimplant, and the median (IQR) were 1.0 (0.0-3.0), 2.0 (0.0-3.0), and 0.0 (0.0-1.2), respectively (all P < .001). Approximately 78.8% and 96.7% of patients reported pain relief >50% at days 1 and 30 postimplant, respectively. Compared with that at day 1 postimplant, the proportion of patients with a pain relief rate >75% at day 30 postimplant also increased with continued intrathecal treatment. Compared to the dose of baseline systemic morphine equivalents (median, 228 mg.d-1; IQR, 120-408 mg.d-1), the dose of systemic morphine equivalents reduced significantly from 0(0-120) mg.d-1 at day 1 postimplant (P = .001), to 0 (0-0) mg.d-1 at days 7 and 30 postimplant (both P < .001). Few patients reported perioperative adverse events, including nausea, constipation, hypotension, urinary retention, dry mouth, headache, and sedation. No severe adverse events occurred. CONCLUSIONS: Placing the catheter tip of an intrathecal morphine pump into the prepontine cistern could effectively relieve refractory craniofacial cancer pain with an extremely low total morphine dose requirement and few adverse events. This procedure could be considered in patients with severe refractory craniofacial cancer pain.

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BACKGROUND: Chronic anemia, especially chemotherapy-induced anemia, is a common and intractable symptom. Puzzlingly, the conventional anemic treatment may lead to various side effects, and the mechanism of stress anemia remains unclear. METHODS: Here, peripheral blood, histopathological and transmission electron microscopical examination, colony forming test, flow cytometry, and qRT-PCR assay were used to investigate the effects of Angelia sinensis polysaccharide (ASP), one main active ingredient of Chinese herb medicine Angelica sinensis, on ameliorating 5-fluorouracil (5-FU)-induced stress anemia. RESULTS: We found that intraperitoneal injection to a C57BL/6J mouse ASP 100 mg/kg per day for consecutive 10 days or 14 days, remarkably accelerated the recovery of RBC, hemoglobin, and hematocrit in blood. ASP alleviated 5-FU-caused impairment of bone marrow cell and BFU-E enumeration. Meanwhile, ASP antagonized 5-FU promoting extramedullary erythropoiesis in the spleen, inducing splenomegaly due to stress erythroblastic islands, and occurrence of megakaryocytes and hematopoietic precursors in splenic colonies. ASP increased splenic stress BFU-E enumeration, driving BFU-E differentiation towards Pro-E and end-stage erythroblasts. Furthermore, ASP increased the number of F4/80+VCAM-1+ splenic erythroblastic island central macrophages, upregulating genetic expression of EPOR, Emp, VCAM-1, Hmox-1, Trf, TfR1, Fpn1, Spi-C, DNase2a, Tim4, MertK, and Klf1 in splenocytes. CONCLUSIONS: Our findings indicate that the possible mechanism of chemotherapy-induced anemia is related to stress erythroid maturation arrest. Whereas, ASP may promote stress erythroid differentiation via elevated EPO sensitivity in extramedullary hematopoietic organs and enhanced macrophage-mediated adhesion, iron homeostasis and transfer, and nuclear engulfment, which may represent a promising therapeutic strategy.

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Background and Purpose: Growth hormone-releasing hormone (GHRH) agonist, a 29-amino acid peptide, shows significant potential in treating myocardial infarction (MI) by aiding the repair of injured heart tissue. The challenge lies in the effective on-site delivery of GHRH agonist. This study explores the use of a targetable delivery system employing ROS-responsive PEG-PPS-PEG polymers to encapsulate and deliver GHRH agonist MR409 for enhanced therapeutic efficacy. Methods: We synthesized a self-assembling poly (ethylene glycol)-poly (propylene sulfide)-poly (ethylene glycol) polymer (PEG-PPS-PEG) amphiphilic polymer responsive to reactive oxygen species (ROS). The hydrophilic peptide GHRH agonist MR409 was encapsulated within these polymers to form nano PEG-PPS-PEG@MR409 vesicles (NPs). Cardiomyocyte apoptosis was induced under hypoxia and serum-free culture condition for 24 hours, and their production of ROS was detected by fluorescence dye staining. The cellular uptake of PEG-PPS-PEG@MR409 NPs was observed using fluorescence-labeled MR409. Targeting ability and therapeutic efficacy were evaluated using a mouse MI model. Results: PEG-PPS-PEG@MR409 NPs were efficiently internalized by cardiomyocytes, reducing ROS levels and apoptosis. These NPs exhibited superior targeting to the infarcted heart compared to naked MR409 peptide. With a reduced injection frequency (once every three days), PEG-PPS-PEG@MR409 NPs significantly promoted cardiac function recovery post-MI, matching the efficacy of daily MR409 injections. Conclusion: ROS-responsive PEG-PPS-PEG polymers provide a novel and effective platform for the targeted delivery of GHRH agonist peptides, improving cardiac function and offering a new approach for peptide therapy in MI treatment.

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Land subsidence caused by excessive groundwater withdrawal has become a global hazard, which demands further researches and the potential measures to control. Using the FlowTrac Ⅱ consolidation test system, six compression tests were designed to investigate the stress state and stress paths of sand within confined aquifers under conditions of withdrawal and recharging. The deformation characteristics of aquifer sand were studied under different withdrawal-recharging patterns. During pumping and recharge processes, sand deformation responses were observed to lag behind changes in applied stress. The characteristics of this hysteresis effect on deformation were summarized. The alternating phenomenon of rebound and compression of sand deformation under the recharging process is analyzed. When the recharging effect was relatively small than withdrawing effect under the stable withdrawal-recharging pattern, the compression deformation was observed in the recharging process. The research results provide a rational explanation for the continuous compression deformation of the aquifer during groundwater level recovery and offer experimental evidence for the rational design of artificial groundwater recharge in engineering construction.

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OBJECTIVE: To investigate the clinical characteristics and treatment of relapsed CD5+ diffuse large B-cell lymphoma (DLBCL). METHODS: The data of a patient with CD5+ DLBCL was collected, and its clinical characteristics and treatment outcome were analyzed. RESULTS: The patient developed hemophagocytic syndrome and achieved complete remission (CR) after 6 cycles of R-ECHOP chemotherapy, then relapsed. After 2 cycles of PD-1 inhibitor combined with lenalidomide treatment, the patient achieved CR again accompanied by a decrease of interleukin (IL)-10 expression level. After a total of 15 cycles of chemotherapy, the patient remained in CR for 24 months, and the level of IL-10 remained in the normal range. CONCLUSION: PD-1 inhibitor combined with lenalidomide regimen may be a new treatment for relapsed CD5+ DLBCL.

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A novel photoredox/nickel dual catalytic intermolecular alkylarylation of vinylarenes with tertiary and secondary alkyltrifluoroborates and aryl bromides is described, which affords 1,1-diarylalkane frameworks that are found in various natural products as well as functionalized molecules in good to excellent yield and regioselectivity through a radical relay process. Notably, this redox-neutral reaction could proceed efficiently with good tolerance of various substrates, including a great diversity of commercially available (hetero)aryl bromides, alkyltrifluoroborates, and vinylarenes.

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2,4,6-Trichloroanisole (2,4,6-TCA), a compound with a characteristic earthy odor, is a common source of odorous pollutants in drinking water and wine. However, research on its biological toxicity is limited. In this study, we used zebrafish as an indicator model to investigate the effects of 2,4,6-TCA exposure on morphological development, oxidative stress, apoptosis, heart rate, blood flow, and motility. We found that exposure to 2,4,6-TCA resulted in significant spinal, tail, and cardiac deformities in zebrafish larvae and promoted a pronounced oxidative stress response and extensive cell apoptosis, notably in the digestive tract, head, spine, and heart, ultimately leading to significant reductions in zebrafish heart rate, blood flow, and motility. Moreover, these effects became more pronounced with an increase in the concentration of 2,4,6-TCA to which the zebrafish were exposed. Furthermore, qPCR analysis revealed that exposure to 2,4,6-TCA promoted significant changes in the expression levels of genes associated with oxidative stress, apoptosis, cardiac development, and the nervous system, particularly key genes (p53, apaf1, casp9, and casp3) in the mitochondrial apoptotic pathway, which were significantly upregulated. Similarly, we detected significant upregulation of ache gene expression. These findings indicated that exposure to 2,4,6-TCA resulted in the accumulation of reactive oxygen species in zebrafish, induced strong oxidative stress responses, and triggered lipid peroxidation and extensive cell apoptosis. Cellular apoptosis, which mitochondrial signaling pathways may mediate, has been found to lead to malformations in zebrafish embryos, resulting in significant reductions in cardiac function and motility. To our knowledge, this is the first systematic assessment of the toxicity of 2,4,6-TCA, and our findings provide an important reference for risk assessment and early warning of 2,4,6-TCA exposure.

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Grass carp reovirus (GCRV) is the most virulent pathogen in the genus Aquareovirus, belonging to the family Spinareoviridae. Members of the Spinareoviridae family are known to replicate and assemble in cytoplasmic inclusion bodies termed viroplasms; however, the detailed mechanism underlying GCRV viroplasm formation and its specific roles in virus infection remains largely unknown. Here, we demonstrate that GCRV viroplasms form through liquid-liquid phase separation (LLPS) of the nonstructural protein NS80 and elucidate the specific role of LLPS during reovirus infection and immune evasion. We observe that viroplasms coalesce within the cytoplasm of GCRV-infected cells. Immunofluorescence and transmission electron microscopy indicate that GCRV viroplasms are membraneless structures. Live-cell imaging and fluorescence recovery after photobleaching assay reveal that GCRV viroplasms exhibit liquid-like properties and are highly dynamic structures undergoing fusion and fission. Furthermore, by using a reagent to inhibit the LLPS process and constructing an NS80 mutant defective in LLPS, we confirm that the liquid-like properties of viroplasms are essential for recruiting viral dsRNA, viral RdRp, and viral proteins to participate in viral genome replication and virion assembly, as well as for sequestering host antiviral factors for immune evasion. Collectively, our findings provide detailed insights into reovirus viroplasm formation and reveal the specific functions of LLPS during virus infection and immune evasion, identifying potential targets for the prevention and control of this virus. IMPORTANCE: Grass carp reovirus (GCRV) poses a significant threat to the aquaculture industry, particularly in China, where grass carp is a vital commercial fish species. However, detailed information regarding how GCRV viroplasms form and their specific roles in GCRV infection remains largely unknown. We discovered that GCRV viroplasms exhibit liquid-like properties and are formed through a physico-chemical biological phenomenon known as liquid-liquid phase separation (LLPS), primarily driven by the nonstructural protein NS80. Furthermore, we confirmed that the liquid-like properties of viroplasms are essential for virus replication, assembly, and immune evasion. Our study not only contributes to a deeper understanding of GCRV infection but also sheds light on broader aspects of viroplasm biology. Given that viroplasms are a universal feature of reovirus infection, inhibiting LLPS and then blocking viroplasms formation may serve as a potential pan-reovirus inhibition strategy.

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BACKGROUND: Depression is the leading cause of mortality among mental health disorders. Evidence about the associations of socioeconomic status, social activities, and loneliness with depression is scarce. We aimed to identify whether social activities and loneliness mediate the association between socioeconomic status and depression, and the extent of interactive or joint relationships between social activities, loneliness, and socioeconomic status on depression. METHODS: In this population-based, cross-national cohort study we used data from five nationally representative surveys across 24 countries between Feb 15, 2008, and Feb 27, 2019: the Health and Retirement Study (HRS); the English Longitudinal Study of Ageing (ELSA); the Survey of Health, Ageing and Retirement in Europe (SHARE); the China Health and Retirement Longitudinal Study (CHARLS); and the Mexican Health and Ageing Study (MHAS). We included participants who were aged 50 years and older with reported information on socioeconomic status, social activities, and loneliness at baseline, and who had been assessed at least twice. We excluded participants with depressive symptoms at baseline; those with missing data on depressive symptoms and covariates; and those lost to follow-up. We defined socioeconomic status as high and low using latent class analysis based on family income, education, and employment status. Depression was assessed using the Center for Epidemiological Studies Depression Scale (CES-D) or EURO-D. We applied Cox proportional hazard models to estimate the association of socioeconomic status with depression. We used random-effects models to obtain pooled results. Joint and interactive effects of socioeconomic status, social activities, and loneliness on depression were explored, and the mediating roles of social activities and loneliness in the association between socioeconomic status and depression were explored using causal mediation analysis. FINDINGS: A total of 69 160 participants were included in our study and, during a median follow-up of 5 years, a total of 20 237 participants developed depression with a pooled incidence of 7·2 (95% CI 4·4-10·0) per 100 person-years. Compared with participants with high socioeconomic status, those with low socioeconomic status had a higher risk of depression (pooled hazard ratio [HR] 1·34; 95% CI 1·23-1·44). The proportion of the associations between socioeconomic status and depression mediated by social activities and loneliness were 6·12% (1·14-28·45) and 5·54% (0·71-27·62), respectively. We only observed a significant multiplicative interaction of socioeconomic status and loneliness with depression (pooled HR 0·84; 0·79-0·90). Compared with participants with high socioeconomic status and who were socially active and not lonely, those with low socioeconomic status and who were socially inactive and lonely had a higher risk of depression (pooled HR 2·45; 2·08-2·82). INTERPRETATION: Social inactivity and loneliness positively mediated a small proportion of the association between socioeconomic status and depression, indicating that other approaches in addition to interventions targeting social isolation and loneliness are required to mitigate the risk of depression in older adults. Additionally, the joint effects of socioeconomic status, social activities, and loneliness highlight the benefits of simultaneous and integrated interventions to reduce the global burden of depression. FUNDING: National Natural Science Foundation of China.

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The study of drug-target interaction plays an important role in the process of drug development. The subject of DTI forecasting has advanced significantly in the last several years, yielding numerous significant research findings and methodologies. Heterogeneous data sources provide richer information and comprehensive perspectives for drug-target interaction prediction, so many existing methods rely on heterogeneous networks, and graph embedding technology becomes an important technology to extract information from heterogeneous networks. These approaches, however, are less concerned with potential noisy information in heterogeneous networks and more focused on the extent of information extraction in those networks. Based on this, a potential DTI predictive network model called FBRWPC is proposed in this paper. It uses a fine-grained similarity selection program to first integrate similarity on similar networks and then a bidirectional random walk graph embedding learning method with restart to obtain an updated drug target interaction matrix. Through the use of similarity selection and fine-grained selection similarity integration, the framework can effectively filter out the noise present in heterogeneous networks and enhance the model's prediction performance. The experimental findings demonstrate that, even after being split up into four distinct types of data sets, FBRWPC can still retain great prediction performance, a sign of the model's resilience and good generalization.

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Trichoderma harzianum T4 is a soil fungus that plays an important role in the biological control of plant diseases. The aim of this study was to functionally characterize the ß-1,6-glucanase gene Neg1 in T. harzianum T4 and to investigate the effect of its overexpression on biocontrol traits, especially antagonism against pathogenic fungi. We found that overexpression of Neg1 did not affect growth of T. harzianum but enhanced sporulation of T. harzianum T4 cultures. Generally, spores are closely related to the defense ability of defense fungi and can assist their proliferation and improve their colonization ability. Secondly, overexpression of Neg1 also increased the secretion level of various hydrolytic enzymes and enhanced the antagonistic ability against phytopathogenic fungi of Fusarium spp. The results suggest that Neg1 is a key gene for improving the biocontrol effect of T. harzianum T4, which contributes to a better understanding of the mechanism of action of T. harzianum T4 as a fungal biocontrol agent.

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Pseudomonas protegens can serve as an agricultural biocontrol agent. P. protegens often encounters hyperosmotic stress during industrial production and field application. The ability of P. protegens to withstand hyperosmotic stress is important for its application as a biocontrol agent. AlgU is a global regulator responsible for stress response and biocontrol ability. However, the specific regulatory role of AlgU in the hyperosmotic adaptation of P. protegens is poorly understood. In this study, we found that the AlgU mutation disrupted the hyperosmotic tolerance of P. protegens. Many genes and metabolites related to cell envelope formation were significantly downregulated in ΔalgU compared with that in the wild-type (WT) strain under hyperosmotic conditions, and we found that the algU mutation caused membrane integrity to be compromised and increased membrane permeability. Further experiments revealed that the cell envelope integrity protein TolA, which is regulated by AlgU, contributes to cell membrane stability and osmotic tolerance in P. protegens. In addition, several genes related to oxidative stress response were significantly downregulated in ΔalgU, and higher levels of intracellular reactive oxygen species were found in ΔalgU. Furthermore, we found that the synthesis of N-acetyl glutaminyl glutamine amide is directly regulated by AlgU and contributes to the hyperosmotic adaptation of P. protegens. This study revealed the mechanisms of AlgU's participation in osmotic tolerance in P. protegens, and it provides potential molecular targets for research on the hyperosmotic adaptation of P. protegens.IMPORTANCEIn this study, we found that the extracytoplasmic function sigma factor AlgU is essential for the survival of P. protegens under hyperosmotic conditions. We provided evidence supporting the roles of AlgU in influencing cell membrane stability, intracellular reactive oxygen species (ROS) accumulation, and dipeptide N-acetylglutaminylglutamine amide (NAGGN) synthesis in P. protegens under hyperosmotic conditions. Our findings revealed the mechanisms of AlgU's participation in hyperosmotic stress tolerance in P. protegens, and they provide potential molecular targets for research on the hyperosmotic adaptation of P. protegens, which is of value in improving the biocontrol ability of P. protegens.

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