The varicella-zoster virus ORF16 protein promotes both the nuclear transport and the protein abundance of the viral DNA polymerase subunit ORF28.

Although all herpesviruses utilize a highly conserved replication machinery to amplify their viral genomes, different members may have unique strategies to modulate the assembly of their replication components. Herein, we characterize the subcellular localization of seven essential replication proteins of varicella-zoster virus (VZV) and show that several viral replication enzymes such as the DNA polymerase subunit ORF28, when expressed alone, are localized in the cytoplasm. The nuclear import of ORF28 can be mediated by the viral DNA polymerase processivity factor ORF16. Besides, ORF16 could markedly enhance the protein abundance of ORF28. Noteworthily, an ORF16 mutant that is defective in nuclear transport still retained the ability to enhance ORF28 abundance. The low abundance of ORF28 in transfected cells was due to its rapid degradation mediated by the ubiquitin-proteasome system. We additionally reveal that radicicol, an inhibitor of the chaperone Hsp90, could disrupt the interaction between ORF16 and ORF28, thereby affecting the nuclear entry and protein abundance of ORF28. Collectively, our findings imply that the cytoplasmic retention and rapid degradation of ORF28 may be a key regulatory mechanism for VZV to prevent untimely viral DNA replication, and suggest that Hsp90 is required for the interaction between ORF16 and ORF28.

A plant NLR receptor employs ABA central regulator PP2C-SnRK2 to activate antiviral immunity.

Defence against pathogens relies on intracellular nucleotide-binding, leucine-rich repeat immune receptors (NLRs) in plants. Hormone signaling including abscisic acid (ABA) pathways are activated by NLRs and play pivotal roles in defence against different pathogens. However, little is known about how hormone signaling pathways are activated by plant immune receptors. Here, we report that a plant NLR Sw-5b mimics the behavior of the ABA receptor and directly employs the ABA central regulator PP2C-SnRK2 complex to activate an ABA-dependent defence against viral pathogens. PP2C4 interacts with and constitutively inhibits SnRK2.3/2.4. Behaving in a similar manner as the ABA receptor, pathogen effector ligand recognition triggers the conformational change of Sw-5b NLR that enables binding to PP2C4 via the NB domain. This receptor-PP2C4 binding interferes with the interaction between PP2C4 and SnRK2.3/2.4, thereby releasing SnRK2.3/2.4 from PP2C4 inhibition to activate an ABA-specific antiviral immunity. These findings provide important insights into the activation of hormone signaling pathways by plant immune receptors.

Unravel the Supremacy of Klebsiella variicola over Native Microbial Strains for Aroma-Enhancing Compound Production in Reconstituted Tobacco Concentrate through Metagenomic Analysis.

Sensory attributes strongly influence consumers' preferences for products. The inoculation of the Klebsiella variicola H8 strain in a reconstituted tobacco leaf concentrate (RTLC) solution increased neutral aroma-enhancing compound (NAEC) production by 45%, decreased the nicotine level by 25%, decreased the water-soluble total sugar content by ~36%, and improved the sensory quality by 5.71%. The production of NAECs such as dihydrokiwi lactone (DHKL: 192.86%), 1,2,3,4-tetrahydro-1,1,6-trimethylnaphthalene (THTMN: 177.77%), 2,4-di-tert-butylphenol (DTBP: 25%), 4-oxoisofolkone (OIFK: 116.66%,) 1,9-heptadecadiene-4,6-diyn-3-ol (HDD: 116.67%), ß-damastrone (BDS: 116.67), and megastigmatrienone A (MSTA: 116.67%) was increased. A metagenomics analysis of the microbial community in the fermented RTLC (FRTLC) was performed to elucidate the mechanism by which NAECs were produced. As a result, 24 groups of functional genes were identified, and among them, five families of carbohydrate-active enzymes, (i) glycoside hydrolase (GH), (ii) glycosyltransferase (GT), (iii) polysaccharide lyase (PL), (iv) carbohydrate esterase (CE), and (v) auxiliary active enzyme (AA), were found to be positively correlated with the production of NAECs. However, among the GHs, the GHs annotated from the H8 strain chromosome displayed the highest relative abundance and a positive correlation with the production of NAECs. Specifically, the GH13-14, GH13-20, GH13-38, GH13-25, GH13-10, GH42, and GH28 genes of the H8 strain were relatively more abundant and were key contributors to the production of NAECs. The correlation analyses revealed that the H8 strain plays a leading role among all the microorganisms in FRTLC in the production of NAECs. Our findings support the application of Klebsiella variicola in NAEC production and a reduction in nicotine content in tobacco products.

Functions and novel regulatory mechanisms of key glycolytic enzymes in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive vascular disease characterized by remodeling of the pulmonary vasculature and elevated pulmonary arterial pressure, ultimately leading to right heart failure and death. Despite its clinical significance, the precise molecular mechanisms driving PAH pathogenesis warrant confirmation. Compelling evidence indicates that during the development of PAH, pulmonary vascular cells exhibit a preference for energy generation through aerobic glycolysis, known as the "Warburg effect", even in well-oxygenated conditions. This metabolic shift results in imbalanced metabolism, increased proliferation, and severe pulmonary vascular remodeling. Exploring the Warburg effect and its interplay with glycolytic enzymes in the context of PAH has yielded current insights into emerging drug candidates targeting enzymes and intermediates involved in glucose metabolism. This sheds light on both opportunities and challenges in the realm of antiglycolytic therapy for PAH.

Burnout and depression in college students.

Research on burnout has garnered considerable attention since its inception. However, the ongoing debate persists regarding the conceptual model of burnout and its relationship with depression. Thus, we conducted a network analysis to determine the dimensional structure of burnout and the burnout-depression overlap. The Maslach Burnout Inventory-Student Survey and Patient Health Questionnaire-9 were used to measure burnout and depression among 1096 college students. We constructed networks for burnout, depression, and a burnout-depression co-occurrence network. The results showed that cynicism symptom was the most central to the burnout network. In the co-occurrence network, depressive symptoms ("anhedonia", "fatigue") and burnout symptom ("doubting the significance of studies") were the most significant in causing burnout-depression comorbidity. Community detection revealed three communities within burnout symptoms, aligning closely with their three dimensions identified through factor analysis. Additionally, there was no overlap between burnout and depression. In conclusion, our findings support a multidimensional structure of burnout, affirming it as a distinct concept separate from depression. Cynicism, rather than exhaustion, plays the most important role in burnout and the burnout-depression comorbidity.

Association of changes in plant-based diet consumption with all-cause mortality among older adults in China: a prospective study from 2008 to 2019.

OBJECTIVES: To examine the association of changes in plant-based diet consumption with all-cause mortality among older adults in China. DESIGN: Cohort study. SETTING: This cohort study of 11 years used data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS), a long-term, nationwide survey covering 23 provinces in China. PARTICIPANTS: A total of 7843 older participants aged ≥60 years were included in this study. MEASUREMENTS: Changes in plant-based diets consumption (2008-2011) were assessed by 3 graded plant-based diet indices, including an overall plant-based diet index (PDI), a healthful plant-based diet index (hPDI), and an unhealthful plant-based diet index (uPDI). The main outcome was all-cause mortality. Multivariable-adjusted Cox proportional-hazards models were fitted to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) of mortality for changes in PDI, hPDI, and uPDI. RESULTS: A total of 7843 participants (mean [SD] age, 82.2 [10.9] years; 3588 [45.7%] men) were included in this study. During a median (IQR) of 9 (5-10) years of follow-up, 3749 deaths were documented. Compared with older adults whose plant-based diet indices were relatively stable, older adults with the greatest decrease (quintile 1) in PDI, hPDI, and uPDI had respectively 32% (95% CI, 19%-47%) higher, 21% (95% CI, 9%-33%) higher, and 10% (95% CI, 4%-21%) lower risk of death. Compared with older adults whose diet indices were relatively stable, older adults with the greatest increase (quintile 5) in uPDI had a 13% higher risk of death (95% CI, 1%-21%), while no significant associations of the increased PDI and hPDI with all-cause mortality were observed. CONCLUSION: Maintaining the consumption of overall and healthful plant-based diets, and decreasing the consumption of an unhealthful plant-based diet can be beneficial in preventing or delaying premature death among Chinese older adults.

Correlation between Combined Urinary Metal Exposure and Grip Strength under Three Statistical Models: A Cross-sectional Study in Rural Guangxi.

Objective: This study aimed to investigate the potential relationship between urinary metals copper (Cu), arsenic (As), strontium (Sr), barium (Ba), iron (Fe), lead (Pb) and manganese (Mn) and grip strength. Methods: We used linear regression models, quantile g-computation and Bayesian kernel machine regression (BKMR) to assess the relationship between metals and grip strength. Results: In the multimetal linear regression, Cu (ß = -2.119), As (ß = -1.318), Sr (ß = -2.480), Ba (ß = 0.781), Fe (ß = 1.130) and Mn (ß = -0.404) were significantly correlated with grip strength ( P < 0.05). The results of the quantile g-computation showed that the risk of occurrence of grip strength reduction was -1.007 (95% confidence interval: -1.362, -0.652; P < 0.001) when each quartile of the mixture of the seven metals was increased. Bayesian kernel function regression model analysis showed that mixtures of the seven metals had a negative overall effect on grip strength, with Cu, As and Sr being negatively associated with grip strength levels. In the total population, potential interactions were observed between As and Mn and between Cu and Mn ( P interactions of 0.003 and 0.018, respectively). Conclusion: In summary, this study suggests that combined exposure to metal mixtures is negatively associated with grip strength. Cu, Sr and As were negatively correlated with grip strength levels, and there were potential interactions between As and Mn and between Cu and Mn.

Effects of grafting on chemical constituents, toxicological properties, antithrombotic activity, and myocardial infarction protection of styrax secreted from the trunk of Liquidambar orientalis Mill.

Styrax, the balsam refined from the trunk of Liquidambar orientalis Mill. has a variety of applications in the perfumery and medical industry, especially for use in traditional Chinese medicine. However, the resources of styrax are in shortage due to being endangered of this plant. Grafting can improve the adaptability of plants to unfavorable environmental conditions. We tried to graft the L. orientalis Mill. on L. formosana Hance which was widely distributed in Jiangsu and Zhejiang provinces of China in an attempt to obtain styrax from grafted L. orientalis Mill. (grafted styrax, SG). Whether SG can become an alternative application of commercially available styrax (SC) need be further investigated. The components of SG were analyzed by GC-MS, and the results showed that the chromatograms of SG, SC, and styrax standard (SS) were consistent. The ration of 12 major chemical components based peak area in SG, SC, and SS were 93.95%, 94.24%, and 95.86% respectively. The assessment of toxicity, antithrombotic activity, and myocardial infarction protection of SG and SC was evaluated by using the zebrafish model, the results showed that SG and SC have the similar toxicological properties as evidenced by acute toxicity test, developmental toxicity and teratogenicity, and long-term toxicity test. Both SG and SC significantly decreased the thrombosis and increased blood flow velocity of zebrafish induced by adrenaline hydrochloride, inhibited myocardial apoptosis, myocardial infarction and myocardial inflammation in zebrafish induced by isoproterenol hydrochloride. Moreover, SG had an obvious improvement effect on cardiac output, while SC has no effect. Collectively, SG is similar to SC in chemical composition, toxicological properties, antithrombotic activity, and myocardial infarction protection effects, and may be used as a substitute for styrax to reduce the collection for wild L. orientalis Mill. and increase the available styrax resources.

Phylogeny and molecular evolution of the first local monkeypox virus cluster in Guangdong Province, China.

The first local mpox outbreak in Guangdong Province, China occurred in June 2023. However, epidemiological data have failed to quickly identify the source and transmission of the outbreak. Here, phylogeny and molecular evolution of 10 monkeypox virus (MPXV) genome sequences from the Guangdong outbreak were characterized, revealing local silent transmissions that may have occurred in Guangdong whose mpox outbreaks suggested a molecular epidemiological correlation with Portugal and several regions of China during the same period. The lineage IIb C.1, which includes all 10 MPXV from Guangdong, shows consistent temporal continuity in both phylogenetic characteristics and unique molecular evolutionary mutation spectrum, reflected in the continuous increase of single nucleotide polymorphisms (SNPs) and shared mutations over time. Compared with the Japan MPXV, the Guangdong MPXV showed higher genomic nucleotide differences and separated 14 shared mutations from the B.1 lineage, comprising 6 non-synonymous mutations in genes linked to host regulation, virus infection, and virus life cycle. The unique mutation spectrum with temporal continuity in IIb C.1, related to apolipoprotein B mRNA-editing catalytic polypeptide-like 3, promotes rapid viral evolution and diversification. The findings contribute to understanding the ongoing mpox outbreak in China and offer insights for developing joint prevention and control strategies.

Choosing the right animal model for osteomyelitis research: Considerations and challenges.

Osteomyelitis is a debilitating bone disorder characterized by an inflammatory process involving the bone marrow, bone cortex, periosteum, and surrounding soft tissue, which can ultimately result in bone destruction. The etiology of osteomyelitis can be infectious, caused by various microorganisms, or noninfectious, such as chronic nonbacterial osteomyelitis (CNO) and chronic recurrent multifocal osteomyelitis (CRMO). Researchers have turned to animal models to study the pathophysiology of osteomyelitis. However, selecting an appropriate animal model that accurately recapitulates the human pathology of osteomyelitis while controlling for multiple variables that influence different clinical presentations remains a significant challenge. In this review, we present an overview of various animal models used in osteomyelitis research, including rodent, rabbit, avian/chicken, porcine, minipig, canine, sheep, and goat models. We discuss the characteristics of each animal model and the corresponding clinical scenarios that can provide a basic rationale for experimental selection. This review highlights the importance of selecting an appropriate animal model for osteomyelitis research to improve the accuracy of the results and facilitate the development of novel treatment and management strategies.

Urantide alleviates atherosclerosis-related liver and kidney injury via the Wnt/ß-catenin signaling pathway in ApoE(-/-) mice.

OBJECTIVE: To investigate the role of urantide in the prevention and treatment of atherosclerosis (AS)-related liver and kidney injury by antagonizing the urotensin II/urotensin receptor (UII/UT) system and regulating the Wnt/ß-catenin signaling pathway. METHODS: Atherosclerotic ApoE-/- mice were treated with 20 mg/kg, 30 mg/kg, and 40 mg/kg urantide for 14 days. RESULTS: When ApoE-/- mice developed AS, significant pathological changes occurred in the liver and kidney, and the UII/UT system in tissue was highly activated; furthermore, the Wnt/ß-catenin signalling pathway was activated, and proteins related to this signalling pathway, such as GSK-3ß, AXIN2, CK­1, and APC, were significantly downregulated. After urantide treatment, the pathological damage to the liver and kidney was effectively improved, the activity of the UII/UT system was effectively inhibited, and the expression of the Wnt/ß-catenin signalling pathway and related proteins was restored. Wnt/ß-catenin signals were mainly localized in the cytoplasm, renal tubules, and interstitium. CONCLUSION: Urantide could improve AS-related liver and kidney injury by antagonizing the UII/UT system, and the improvements in liver and kidney function in atherosclerotic ApoE-/- mice may be related to inhibition of the Wnt/ß-catenin signalling pathway.

[Effects of Modified Biochar-Supported Zero-Valent Iron on the Removal of Trichloroethylene and Responses of Microbial Community in Soil].

Trichloroethylene is a typical organic contaminant that has widely existed in industry sites and groundwater. Biochar-supported zero-valent iron material has been used to remove trichloroethylene in groundwater; however, it could affect the microbial communities in aquifer soil, leading to changes in the environmental behavior of trichloroethylene. In this study, biochar was prepared under oxygen-limited conditions and modified by NaOH and HNO3 agents. Then, a modified biochar-supported zero-valent iron composite (BC composites) was synthesized using ball milling technology. The effects of BC composites on the removal of trichloroethylene and the responses of the microbial community were investigated under the condition of simulated aquifer soil. The results showed that the specific surface areas of BC composites were increased after the modification with NaOH. The highest removal rate of trichloroethylene was observed in the BC_2 treatment, up to 90.01%. Except in the BC_1 treatment, the diversity and abundance of soil microorganisms were increased, and the microbial community structure was changed after the addition of different BC composites, in which Bacillus, Thiobacillus, and Pseudomonas might have been the potential degrading bacteria of trichloroethylene. The abundance of Thiobacillus and Pseudomonas increased under the BC_2 treatment, which was favorable to the removal of trichloroethylene. The stabilization of the microbial community structure was probably maintained by Nocardioideas, Thermincola, Lysobacter, Gemmatimonas, Microvirga, and Pseudomonas. According to the predictive analysis of microbial metabolic pathways, the abundance of xenobiotics biodegradation and metabolism genes and the folding, sorting, and degradation of genes were the highest under the BC_2 treatment. Thus, the NaOH-modified BC composite could prompt the removal of trichloroethylene in simulated aquifer soil, probably due to the increase in the abundance of soil-degrading bacteria and the expression of degradation genes, demonstrating that the NaOH-modified BC composite could be used for the remediation of the organic-contaminated industry sites as a new composite material.

Trithiocyanurate-functionalized hydrochar for effectively removing methylene blue and Pb (II) cationic pollutants.

Functionalization can change the physicochemical properties of hydrochar and improve its ability to adsorb pollutants. Herein, a trithiocyanurate-functionalized hydrochar (TTHC) was obtained from acylation of chloroacetyl chloride and hydrochar and modification with trithiocyanuric acid in alkaline conditions. TTHC can efficiently remove cationic methylene blue (MB) and Pb(II) from wastewater. The removal can be expressed with pseudo-second-order kinetic and Langmuir models. The MB and Pb(II) removed uptakes by TTHC at 298 K exceeded 909.9 and 182.8 mg g-1 respectively, and the removal rates reached 90% and 98% within 120 min respectively. Characterizations show TTHC is functionalized with trithiocyanurate, and rich in thiolate and aromaticity, and tends to adsorb MB/Pb(II) via multiple adsorption mechanisms. After five sorption-desorption regeneration cycles, TTHC maintained 80% and 99% adsorption capacities for MB and Pb(II) respectively. Therefore, TTHC is a promising efficient sorbent for removing MB and Pb(II) from effluents.

INPP5E regulates CD3ζ enrichment at the immune synapse by phosphoinositide distribution control.

The immune synapse, a highly organized structure formed at the interface between T lymphocytes and antigen-presenting cells (APCs), is essential for T cell activation and the adaptive immune response. It has been shown that this interface shares similarities with the primary cilium, a sensory organelle in eukaryotic cells, although the roles of ciliary proteins on the immune synapse remain elusive. Here, we find that inositol polyphosphate-5-phosphatase E (INPP5E), a cilium-enriched protein responsible for regulating phosphoinositide localization, is enriched at the immune synapse in Jurkat T-cells during superantigen-mediated conjugation or antibody-mediated crosslinking of TCR complexes, and forms a complex with CD3ζ, ZAP-70, and Lck. Silencing INPP5E in Jurkat T-cells impairs the polarized distribution of CD3ζ at the immune synapse and correlates with a failure of PI(4,5)P2 clearance at the center of the synapse. Moreover, INPP5E silencing decreases proximal TCR signaling, including phosphorylation of CD3ζ and ZAP-70, and ultimately attenuates IL-2 secretion. Our results suggest that INPP5E is a new player in phosphoinositide manipulation at the synapse, controlling the TCR signaling cascade.

NLRs derepress MED10b- and MED7-mediated repression of jasmonate-dependent transcription to activate immunity.

Plant intracellular nucleotide-binding domain, leucine-rich repeat-containing receptors (NLRs) activate a robust immune response upon detection of pathogen effectors. How NLRs induce downstream immune defense genes remains poorly understood. The Mediator complex plays a central role in transducing signals from gene-specific transcription factors to the transcription machinery for gene transcription/activation. In this study, we demonstrate that MED10b and MED7 of the Mediator complex mediate jasmonate-dependent transcription repression, and coiled-coil NLRs (CNLs) in Solanaceae modulate MED10b/MED7 to activate immunity. Using the tomato CNL Sw-5b, which confers resistance to tospovirus, as a model, we found that the CC domain of Sw-5b directly interacts with MED10b. Knockout/down of MED10b and other subunits including MED7 of the middle module of Mediator activates plant defense against tospovirus. MED10b was found to directly interact with MED7, and MED7 directly interacts with JAZ proteins, which function as transcriptional repressors of jasmonic acid (JA) signaling. MED10b-MED7-JAZ together can strongly repress the expression of JA-responsive genes. The activated Sw-5b CC interferes with the interaction between MED10b and MED7, leading to the activation of JA-dependent defense signaling against tospovirus. Furthermore, we found that CC domains of various other CNLs including helper NLR NRCs from Solanaceae modulate MED10b/MED7 to activate defense against different pathogens. Together, our findings reveal that MED10b/MED7 serve as a previously unknown repressor of jasmonate-dependent transcription repression and are modulated by diverse CNLs in Solanaceae to activate the JA-specific defense pathways.

The Association Between Solid Fuel Use and Visual Impairment Among Middle-Aged and Older Chinese Adults: Nationwide Population-Based Cohort Study.

BACKGROUND: Indoor air pollution has been reported to have adverse effects on the eye; however, the health effects of exposure to cooking with solid fuels on visual impairment remain unclear in China. OBJECTIVE: We aimed to examine the association between cooking with solid fuels and visual impairment, including distance visual impairment (DVI) and near visual impairment (NVI). METHODS: Data were obtained from the China Health and Retirement Longitudinal Study, a nationwide survey of adults aged over 45 years who were enrolled in 2011 (Wave 1) and followed up in Wave 2 (2013), Wave 3 (2015), and Wave 4 (2018). We used Cox proportional hazards models to determine the association between solid fuels use and visual impairment. Additionally, the impact of switching cooking fuel types on vision function were examined through wave-specific data analysis (Wave 1 and Wave 4). Interaction and subgroup analyses were performed to explore the potential effect modifiers. Data were collected using the stratified multistage random sampling method and further analyzed using SPSS 27.0 and R 4.2.1 statistical software packages. RESULTS: A total of 9559 middle-aged and older Chinese adults without visual impairment at baseline were included in the study, with 51.2% (n=4914) of the participants reporting that they cooked with solid fuels. During the follow-up period, 2644 (27.5%) and 3130 (32.6%) participants developed DVI and NVI, respectively. Compared with the clean fuel users, participants who cooked with solid fuels had a higher risk of DVI (hazards ratio [HR] 1.38, 95% CI 1.28-1.50) and NVI (HR 1.18, 95% CI 1.10-1.27). In addition, switching the cooking fuel type from clean to solid fuels was associated with an elevated risk of DVI (HR 1.51, 95% CI 1.15-1.98) and NVI (HR 1.39, 95% CI 1.06-1.82) compared to persistently using clean fuels during the follow-up period, although no protective effect of switching from solid to clean fuels on NVI was found (P=.52). In subgroup analysis, we found that cooking with solid fuels increased the risk of DVI in participants younger than 65 years (HR 1.41, 95% CI 1.28-1.55), men (HR 1.45, 95% CI 1.28-1.65), urban residents (HR 1.41, 95% CI 1.08-1.75), and smokers (HR 1.43, 95% CI 1.25-1.64). By contrast, negative effects of cooking with solid fuels on NVI were found in nonsmokers (HR 1.21, 95% CI 1.11-1.33) and urban residents (HR 1.20, 95% CI 1.10-1.37). CONCLUSIONS: Cooking with solid fuels was associated with an increased risk of visual impairment among middle-aged and older Chinese adults. These findings indicate that promoting the utilization of clean fuels is conducive to reducing the burden of visual impairment for the public.

[Correlation Between the Diversity Characteristics of Groundwater Bacterial Community and Environmental Factors in Typical Industrial Areas].

In order to investigate the composition and diversity of groundwater bacterial communities in typical industrial areas in Shanghai, the Illumina MiSeq high-throughput technology was adopted to explore the correlation and response mechanism of groundwater bacterial communities and environmental factors in typical industries, combined with the analysis of groundwater tri-nitrogen, heavy metals, organic matter, and other indicators. The results showed that the ammonia nitrogen in the groundwater of the petrochemical industry was 64.49%, 32.46%, and 113.91% higher than that of the textile industry, metal products industry, and other industries (P<0.05), respectively. The main detectable indicators of organic matter were total petroleum hydrocarbons (TPH) and volatile phenol. The mass concentration of volatile phenol in groundwater of the petrochemical industry was significantly higher than that of the textile industry, metal products industry, and other industries (P<0.05). The mass concentration of arsenic in the metal products industry was 49.26% and 50.59% higher than that in the petrochemical industry and other industries (P<0.05), respectively. Chloride, manganese, sulfate, etc., were significantly different in different industries (P<0.05). The Shannon index of groundwater in the textile industry was the highest at 3.14, whereas the Shannon index and Ace index of the groundwater in the metal products industry were as low as at 2.42 and 960.46, respectively. The dominant bacterial phylum in groundwater in the industrial area was Proteobacteria, accounting for 80.05%-86.18%. Arsenic, mercury, TPH, etc. were the main influencing factors in groundwater in industrial areas, whereas the nitrifying bacteria, denitrifying bacteria, and organic matter-degrading bacteria were mostly related to groundwater environmental factors. The results of this study can provide theoretical support for groundwater pollution risk management and microbial remediation in petrochemical and metal product industrial areas.

Single hormone or synthetic agonist induces Gs/Gi coupling selectivity of EP receptors via distinct binding modes and propagating paths.

To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize the same hormone, and 2) different cellular effectors couple to the same hormone-receptor pair [R.P. Xiao, Sci STKE 2001, re15 (2001); L. Hein, J. D. Altman, B.K. Kobilka, Nature 402, 181-184 (1999); Y. Daaka, L. M. Luttrell, R. J. Lefkowitz, Nature 390, 88-91 (1997)]. Not only these questions lie in the heart of hormone actions and receptor signaling but also dissecting mechanisms underlying these questions could offer therapeutic routes for refractory diseases, such as kidney injury (KI) or X-linked nephrogenic diabetes insipidus (NDI). Here, we identified that Gs-biased signaling, but not Gi activation downstream of EP4, showed beneficial effects for both KI and NDI treatments. Notably, by solving Cryo-electron microscope (cryo-EM) structures of EP3-Gi, EP4-Gs, and EP4-Gi in complex with endogenous prostaglandin E2 (PGE2)or two synthetic agonists and comparing with PGE2-EP2-Gs structures, we found that unique primary sequences of prostaglandin E2 receptor (EP) receptors and distinct conformational states of the EP4 ligand pocket govern the Gs/Gi transducer coupling selectivity through different structural propagation paths, especially via TM6 and TM7, to generate selective cytoplasmic structural features. In particular, the orientation of the PGE2 ω-chain and two distinct pockets encompassing agonist L902688 of EP4 were differentiated by their Gs/Gi coupling ability. Further, we identified common and distinct features of cytoplasmic side of EP receptors for Gs/Gi coupling and provide a structural basis for selective and biased agonist design of EP4 with therapeutic potential.

An investigation of the relationships between suicidal ideation, psychache, and meaning in life using network analysis.

BACKGROUND: Previous studies have investigated the relationships between psychache or meaning in life and suicidal ideation based on sum score of corresponding scale. However, this practice has hampered the fine-grained understanding of their relationships. This network analysis study aimed to conduct a dimension-level analysis of these constructs and the relationships among them in a joint framework, and identify potential intervention targets to address suicidal ideation. METHODS: Suicidal ideation, psychache, and meaning in life were measured using self-rating scales among 738 adults. A network of suicidal ideation, psychache, and meaning in life was constructed to investigate the connections between dimensions and calculate the expected influence and bridge expected influence of each node. RESULTS: "Psychache" was positively linked to "sleep" and "despair", while "presence of meaning in life" had negative associations with "psychache", "despair", and "pessimism". The most important central nodes were "sleep" and "despair", and the critical bridge nodes were "presence of meaning in life" and "psychache". CONCLUSION: These preliminary findings uncover the pathological pathways underlying the relationships between psychache, meaning in life, and suicidal ideation. The central nodes and bridge nodes identified may be potential targets for effectively preventing and intervening against the development and maintenance of suicidal ideation.

Sodium-Glucose Cotransporter 2 Inhibitors First Strategy Improve Decongestion in Patients with Symptomatic Heart Failure and Reduced Ejection Fraction When Compared to Angiotensin Receptor Neprilysin Inhibitor First Strategy.

BACKGROUND: Angiotensin receptor neprilysin inhibitor (ARNI) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) are emerging medical treatments for decompensated heart failure (HF) with reduced ejection fraction. In clinical practice, the combination of ARNI and SGLT2i cannot be administered owing to the poor hemodynamic status in patients with HF with reduced ejection fraction (HFrEF). This study aimed to compare different strategies of HF management for ARNI first or SGLT2i first in such a population. METHODS: From January 2016 to December 2021, 165 patients were diagnosed with HFrEF and New York Heart Association functional class ≥II and already received optimal medical treatment. Ninety-five patients received the ARNI-first strategy, and 70 patients received the SGLT2i-first strategy according to the physician's choice. Age, sex, hemodynamic condition, etiologies of HF, comorbidities, serum creatinine, N-terminal pro-B-type natriuretic peptide (NT-ProBNP), echocardiographic parameters, and clinical outcomes were compared between the ARNI and SGLT2i-first strategy groups. RESULTS: In the SGLT2i-first group, the median interval between the addition of the second medication was longer (ARNI-first vs. SGLT2i-first; 74 [49-100] days vs. 112 [86-138] days; p = 0.044). Improvement in left ventricular ejection fraction (LVEF), change in left atrial dimension, and change in left ventricular end-diastolic and end-systolic volume (LVESV) did not differ between the two groups. The incidence of HF hospitalization, cardiovascular mortality, and all-cause mortality did not differ between the two groups. A non-significant trend of lower NT-proBNP levels (ARNI-first vs. SGLT2i-first; 1383 [319-2507] pg/mL vs. 570 [206-1314] pg/mL; p = 0.055) and significantly higher discontinuation rate of diuretic agents (ARNI-first vs. SGLT2i- first; 6.8% vs. 17.5%; p = 0.039) were noted in the SGLT2i-first group. When early combination (≤14D) compared to late combination (>14D), better positive remodeling of LVESV presented significantly in early combination subgroups. CONCLUSIONS: In patients with symptomatic HFrEF, SGLT2i-first strategy may provide a higher possibility of discontinuing diuretic agents than the ARNI-first strategy. Changes in LV performance, progression of renal function, and clinical outcomes did not differ between the two groups. Early combination (≤14D) provided better LV remodeling.