Amorphous Ni-Fe-Mo Oxides Coupled with Crystalline Metallic Domains for Enhanced Electrocatalytic Oxygen Evolution by Promoted Lattice-Oxygen Participation.

The crystalline/amorphous heterophase nanostructures are promising functional materials for biomedicals, catalysis, energy conversion, and storage. Despite great progress is achieved, facile synthesis of crystalline metal/amorphous multinary metal oxides nanohybrids remains challenging, and their electrocatalytic oxygen evolution reaction (OER) performance along with the catalytic mechanism are not systematically investigated. Herein, two kinds of ultrafine crystalline metal domains coupled with amorphous Ni-Fe-Mo oxides heterophase nanohybrids, including Ni/Ni0.5-a Fe0.5 Mo1.5 Ox and Ni-FeNi3 /Ni0.5-b Fe0.5-y Mo1.5 Ox , are fabricated through controllable reduction of amorphous Ni0.5 Fe0.5 Mo1.5 Ox precursors by simply tuning the amount of used reductant. Due to the suited component in metal domains, the special structure with dense crystalline/amorphous interfaces, and strong electronic coupling of their components, the resultant Ni-FeNi3 /Ni0.5-b Fe0.5-y Mo1.5 Ox nanohybrids show greatly enhanced OER activity with a low overpotential (278 mV) to reach 10 mA cm-2 current density and ultrahigh turnover frequency (38160 h-1 ), outperforming Ni/Ni0.5-a Fe0.5 Mo1.5 Ox , Ni0.5 Fe0.5 Mo1.5 Ox precursors, commercial IrO2 , and most of recently reported OER catalysts. Also, such Ni-FeNi3 /Ni0.5-b Fe0.5-y Mo1.5 Ox nanohybrids manifest good catalytic stability. As revealed by a series of spectroscopy and electrochemical analyses, their OER mechanism follows the lattice-oxygen-mediated (LOM) pathway. This work may shed light on the design of advanced heterophase nanohybrids, and promote their applications in water splitting, metal-air batteries, or other clean energy fields.

Interference with SPARC inhibits Benzophenone-3 induced ferroptosis in osteoarthritis: Evidence from bioinformatics analyses and biological experimentation.

The aim of this study is to conduct a thorough evaluation of the association between Benzophenone-3 (BP-3) exposure and OA, offering critical insights into the underlying mechanisms involved. The National Health and Nutrition Examination Survey (NHANES) database was utilized to investigate the correlation between BP-3 and osteoarthritis. Proteomic sequencing from clinical sample and the PharmMapper online tool were employed to predict the biological target of BP-3. Cellular molecular assays and transfection studies were performed to verify the prediction from bioinformatics analyses. Through cross-sectional analysis of the NHANES database, we identified BP-3 as a risk factor for OA development. The results of proteomic sequencing showed that Secreted Protein Acidic and Rich in Cysteine (SPARC) was significantly elevated in the area of damage compared to the undamaged area. SPARC was also among the potential biological targets of BP-3 predicted by the online program. Through in vitro cell experiments, we further determined that the toxicological effects of BP-3 may be due to SPARC, which elevates intracellular GPX4 levels, activates the glutathione system, and promotes lipid peroxidation to mitigate ferroptosis. Inhibiting SPARC expression has been shown to reduce inflammation and ferroptosis in OA contexts. This research provides an expansive understanding of BP-3's influence on osteoarthritis development. We have identified SPARC as a potent target for combating chondrocyte ferroptosis in BP-3-associated osteoarthritis.

Cross-talks between gut microbiota and tobacco smoking: a two-sample Mendelian randomization study.

BACKGROUND: Considerable evidence has been reported that tobacco use could cause alterations in gut microbiota composition. The microbiota-gut-brain axis also in turn hinted at a possible contribution of the gut microbiota to smoking. However, population-level studies with a higher evidence level for causality are lacking. METHODS: This study utilized the summary-level data of respective genome-wide association study (GWAS) for 211 gut microbial taxa and five smoking phenotypes to reveal the causal association between the gut microbiota and tobacco smoking. Two-sample bidirectional Mendelian randomization (MR) design was deployed and comprehensively sensitive analyses were followed to validate the robustness of results. We further performed multivariable MR to evaluate the effect of neurotransmitter-associated metabolites on observed associations. RESULTS: Our univariable MR results confirmed the effects of smoking on three taxa (Intestinimonas, Catenibacterium, and Ruminococcaceae, observed from previous studies) with boosted evidence level and identified another 13 taxa which may be causally affected by tobacco smoking. As for the other direction, we revealed that smoking behaviors could be potential consequence of specific taxa abundance. Combining with existing observational evidence, we provided novel insights regarding a positive feedback loop of smoking through Actinobacteria and indicated a potential mechanism for the link between parental smoking and early smoking initiation of their children driven by Bifidobacterium. The multivariable MR results suggested that neurotransmitter-associated metabolites (tryptophan and tyrosine, also supported by previous studies) probably played a role in the action pathway from the gut microbiota to smoking, especially for Actinobacteria and Peptococcus. CONCLUSIONS: In summary, the current study suggested the role of the specific gut microbes on the risk for cigarette smoking (likely involving alterations in metabolites) and in turn smoking on specific gut microbes. Our findings highlighted the hazards of tobacco use for gut flora dysbiosis and shed light on the potential role of specific gut microbiota for smoking behaviors.

Phase-Controlled Synthesis of Nickel-Iron Nitride Nanocrystals Armored with Amorphous N-Doped Carbon Nanoparticles Nanocubes for Enhanced Overall Water Splitting.

Transition metal nitrides (TMNs) nanostructures possess distinctive electronic, optical, and catalytic properties, showing great promise to apply in clean energy, optoelectronics, and catalysis fields. Nonetheless, phase-regulation of NiFe-bimetallic nitrides nanocrystals or nanohybrid architectures confronts challenges and their electrocatalytic overall water splitting (OWS) performances are underexplored. Herein, novel pure-phase Ni2+ x Fe2- x N nanocrystals armored with amorphous N-doped carbon (NC) nanoparticles nanocubes (NPNCs) are obtained by controllable nitridation of NiFe-Prussian-blue analogues derived oxides/NC NPNCs under Ar/NH3 atmosphere. Such Ni2+ x Fe2- x N/NC NPNCs possess mesoporous structures and show enhanced electrocatalytic activity in 1 m KOH electrolyte with the overpotential of 101 and 270 mV to attain 10 and 50 mA cm-2 current toward hydrogen and oxygen evolution reactions, outperforming their counterparts (mixed-phase NiFe2 O4 /Ni3 FeN/NC and NiFe oxides/NC NPNCs). Remarkably, utilizing them as bifunctional catalysts, the assembled Ni2+ x Fe2- x N/NC||Ni2+ x Fe2- x N/NC electrolyzer only needs 1.51 V cell voltage for driving OWS to approach 10 mA cm-2 water-splitting current, exceeding their counterparts and the-state-of-art reported bifunctional catalysts-based devices, and Pt/C||IrO2 couples. Additionally, the Ni2+ x Fe2- x N/NC||Ni2+ x Fe2- x N/NC manifests excellent durability for OWS. The findings presented here may spur the development of advanced TMNs nanostructures by combining phase, structure engineering, and hybridization strategies and stimulate their applications toward OWS or other clean energy fields.

Causal association of adipokines with osteoarthritis: a Mendelian randomization study.

OBJECTIVE: This two-sample Mendelian randomization study aimed to delve into the effects of genetically predicted adipokine levels on OA. METHODS: Summary statistic data for OA originated from a meta-analysis of a genome-wide association study with an overall 50 508 subjects of European ancestry. Publicly available summary data from four genome-wide association studies were exploited to respectively identify instrumental variables of adiponectin, leptin, resistin, chemerin and retinol-blinding protein 4. Subsequently, Mendelian randomization analyses were conducted with inverse variance weighted (IVW), weighted median and Mendelian randomization-Egger regression. Furthermore, sensitivity analyses were then conducted to assess the robustness of our results. RESULTS: The positive causality between genetically predicted leptin level and risk of total OA was indicated by IVW [odds ratio (OR): 2.40, 95% CI: 1.13-5.09] and weighted median (OR: 2.94, 95% CI: 1.23-6.99). In subgroup analyses, evidence of potential harmful effects of higher level of adiponectin (OR: 1.28, 95% CI: 1.01-1.61 using IVW), leptin (OR: 3.44, 95% CI: 1.18-10.03 using IVW) and resistin (OR: 1.18, 95% CI: 1.03-1.36 using IVW) on risk of knee OA were acquired. However, the mentioned effects on risk of hip OA were not statistically significant. Slight evidence was identified supporting causality of chemerin and retinol-blinding protein 4 for OA. The findings of this study were verified by the results from sensitivity analysis. CONCLUSIONS: An association between genetically predicted leptin level and risk of total OA was identified. Furthermore, association of genetically predicted levels of adiponectin, leptin and resistin with risk of knee OA were reported.

Phthalates exposure is associated with non-alcoholic fatty liver disease among US adults.

PURPOSE: Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease in the western countries. We aimed to ascertain the relationship of urinary phthalates concentrations with presence of NAFLD among US adults. METHODS: A cross-sectional analysis of data from National Health and Nutrition Examination Survey (NHANES) during 2003-2016 was performed. NAFLD was predicted by Hepatic Steatosis Index (HSI) and US Fatty Liver Index (US FLI), respectively. The logistic regression models were conducted to evaluate associations of urinary phthalates with NAFLD by adjustment for other covariates. RESULTS: Of the 4206 participants (mean age 47.99 years old; 50.06% men), risk of suspected NAFLD was increased in those with higher concentrations of urinary phthalates. The results of multivariate models suggested that urinary phthalate metabolites MEOHP (odds ratio [OR] = 1.56, 95% confidence interval [CI] = 1.08-2.24), MEHHP (OR = 1.55, 95% CI = 1.09-2.21), MECPP (OR = 1.44, 95% CI = 1.06-1.95) and the mixtures of nine phthalates (OR = 1.58, 95%CI = 1.18-2.11) were positively related to NAFLD defined by HSI; the similar significant associations were observed for MEHHP (OR = 1.98, 95% CI = 1.32-2.97) when NAFLD was determined based upon US FLI ≥30. In subgroup analyses, the positive associations of urinary phthalates concentrations with NAFLD risk remained robust both in males and females, whereas only in individuals aged <60 years. CONCLUSIONS: Phthalates exposure was independently associated with NAFLD both in males and females, regardless of being defined using HSI or US FLI.

Exposure to phthalates is associated with grip strength in US adults.

The potential association of exposure to phthalates with muscle strength was reported in previous animal experiments. However, their association was rarely directly investigated in general populations. Thus, we aimed to ascertain the association of exposure to phthalates with grip strength using cross-sectional analysis which included 2436 individuals aged ≥ 20 years from the National Health and Nutrition Examination Survey (NHANES) during 2011-2014. The multivariable linear regression models were performed with the adjustment of related covariates. The results suggested that a one-unit increase in log-transformed phthalate metabolites (µg/g creatinine) was inversely associated with grip strength, including Mono-(2-ethyl)-hexyl phthalate (ß: -2.727 kg, 95% CI: -3.452, -2.002), Mono-(2-ethyl-5-hydroxyhexyl) phthalate (ß: -3.721 kg, 95% CI: -4.836, -2.607), Mono-(2-ethyl-5-oxohexl) phthalate (ß: -4.669 kg, 95% CI: -5.761, -3.577), Mono-2-ethyl-5-carboxypentyl phthalate (ß: -4.756 kg, 95% CI: -5.957, -3.554), Mono-carboxyoctyl phthalate (ß: -1.324 kg, 95% CI: -2.412, -0.235), Mono-carboxynonyl phthalate (ß: -2.036 kg, 95% CI: -3.185, -0.886), Mono-benzyl phthalate (ß: -2.940 kg, 95% CI: -3.853, -2.026), Mono-n-butyl phthalate (ß: -2.100 kg, 95% CI: -3.474, -0.726), Mono-isobutyl phthalate (ß: -2.982 kg, 95% CI: -4.331, -1.633), and Mono-ethyl phthalate (ß: -1.709 kg, 95% CI: -2.368, -1.050). In subgroup analyses, the associations remained largely unchanged when the samples were stratified by gender and age; However they became ambiguous among underweight subjects when the samples were stratified by BMI status. Overall, exposure to phthalates was inversely associated with grip strength among US adults, regardless of their genders and ages. The suggestive potential BMI status-specific effects of phthalates on grip strength were observed.

Associations of urinary levels of phenols and parabens with osteoarthritis among US adults in NHANES 2005-2014.

Phenols and parabens are two major classes of endocrine-disrupting compounds (EDCs) that may be related to multiple human diseases. However, there has been no studies examining the association between phenols as well as parabens and osteoarthritis (OA). We assessed the link between urinary concentrations of triclosan (TCS), benzophenone-3 (BP-3), bisphenol A (BPA), and parabens with OA based on the data collected from National Health and Nutrition Examination Survey in multivariable logistic regression models. Among all the 7114 participants included, the weighted percentage of OA was 12.11% (n = 807). Compared with participants at tertile 1, those at tertile 2 of urinary BP-3, and tertile 3 of urinary BP-3 were more likely to show increased OA prevalence in a fully adjusted model, with odd ratio (OR) as 1.34 [95% confidence interval (CI): 1.01-1.78], 1.55 (95 CI%: 1.17-2.06), and 1.66 (95 CI%: 1.23-2.24), respectively. In subgroup analyses stratified by potential confounders, various subgroups remained to show statistically significant positive association between urinary BP-3 and OA prevalence. Otherwise, we observed no statistically significant associations between urinary TCS, BPA or parabens with OA. In conclusion, this serves as the first study in which we found that the urinary concentration of BP-3 was positively correlated to prevalence of OA among the US population.

Odorant binding protein 2 reduces imidacloprid susceptibility of Diaphorina citri.

The Asian citrus psyllid, Diaphorina citri, is the principal vector of Huanglongbing pathogen Candidatus Liberibacter asiaticus (CLas), which causes severe economic losses to citrus industry worldwide. Use of broad-spectrum insecticides to control D. citri has resulted in considerable resistance development. Specific chemosensory proteins such as odorant binding proteins (OBPs) are potentially involved in reduced insecticide susceptibility. However, functional data on the contribution of OBPs to reduced susceptibility of D. citri are unavailable. We found that DcitOBP2 was stably expressed in different developmental stages and highly expressed in the legs, head and cuticle of D. citri. Expression of DcitOBP2 was significantly induced by 12 to 48 h of imidacloprid exposure and ranged from a 1.34- to 2.44-fold increase. RNAi of DcitOBP2 increased the susceptibility of D. citri adults to imidacloprid. The purified recombinant protein of DcitOBP2 expressed in Escherichia coli showed strong in vitro binding activity (Kd = 62.39 nM) to imidacloprid using microscale thermophoresis technology (MST). DcitOBP2 also had strong binding ability to thiamethoxam and dinotefuran but it had no response to abamectin, fenpropathrin and chlorpyrifos. The results showed that DcitOBP2 can interact with several neonicotinoid insecticides. This suggests that DcitOBP2 is involved in the decreased susceptibility of D. citri to imidacloprid. Our data reveal a new function of insect OBPs as a buffering protein that helps insects survive insecticide exposure. Our investigation may also aid in the development of new methods for resistance management of D. citri.

Component-controlled synthesis of PdxSny nanocrystals on carbon nanotubes as advanced electrocatalysts for oxygen reduction reaction.

Pd-based bimetallic or multimetallic nanocrystals are considered to be potential electrocatalysts for cathodic oxygen reduction reaction (ORR) in fuel cells. Although much advance has been made, the synthesis of component-controlled Pd-Sn alloy nanocrystals or corresponding nanohybrids is still challenging, and the electrocatalytic ORR properties are not fully explored. Herein, component-controlled synthesis of PdxSny nanocrystals (including Pd3Sn, Pd2Sn, Pd3Sn2, and PdSn) has been realized, which are in situ grown or deposited on pre-treated multi-walled carbon nanotubes (CNTs) to form well-coupled nanohybrids (NHs) by a facile one-pot non-hydrolytic system thermolysis method. In alkaline media, all the resultant PdxSny/CNTs NHs are effective at catalyzing ORR. Among them, the Pd3Sn/CNTs NHs exhibit the best catalytic activity with the half-wave potential of 0.85 V (vs. RHE), good cyclic stability, and excellent methanol-tolerant capability due to the suited Pd-Sn alloy component and its strong interaction or efficient electronic coupling with CNTs. This work is conducive to the advancement of Pd-based nanoalloy catalysts by combining component engineering and a hybridization strategy and promoting their application in clean energy devices.

Porous Flower-Like Nanoarchitectures Derived from Nickel Phosphide Nanocrystals Anchored on Amorphous Vanadium Phosphate Nanosheet Nanohybrids for Superior Overall Water Splitting.

Transition metal phosphides (TMPs) and phosphates (TM-Pis) nanostructures are promising functional materials for energy storage and conversion. Nonetheless, controllable synthesis of crystalline/amorphous heterogeneous TMPs/TM-Pis nanohybrids or related nanoarchitectures remains challenging, and their electrocatalytic applications toward overall water splitting (OWS) are not fully explored. Herein, the Ni2 P nanocrystals anchored on amorphous V-Pi nanosheet based porous flower-like nanohybrid architectures that are self-supported on carbon cloth (CC) substrate (Ni2 P/V-Pi/CC) are fabricated by conformal oxidation and phosphorization of pre-synthesized NiV-LDH/CC. Due to the unique microstructures and strong synergistic effects of crystalline Ni2 P and amorphous V-Pi components, the obtained Ni2 P/V-Pi/CC owns abundant active sites, suitable surface/interface electronic structure and optimized adsorption-desorption of reaction intermediates, resulting in outstanding electrocatalytic performances toward hydrogen and oxygen evolution reactions in alkaline media. Correspondingly, the assembled Ni2 P/V-Pi/CC||Ni2 P/V-Pi/CC electrolyzer only needs an ultralow cell voltage (1.44 V) to deliver 10 mA cm-2 water-splitting currents, exceeding its counterparts, recently reported bifunctional catalysts-based devices, and Pt/C/CC||IrO2 /CC pairs. Moreover, the Ni2 P/V-Pi/CC||Ni2 P/V-Pi/CC manifests remarkable stability. Also, such device shows a certain prospect for OWS in acidic media. This work may spur the development of TMPs/TMPis-based nanohybrid architectures by combining structure and phase engineering, and push their applications in OWS or other clean energy options.

Candidatus Liberibacter asiaticus influences the emergence of the Asian citrus psyllid Diaphorina citri by regulating key cuticular proteins.

The Asian citrus psyllid, Diaphorina citri, is the primary vector of the HLB pathogen, Candidatus Liberibacter asiaticus (CLas). The acquisition of CLas shortens the developmental period of nymphs, accelerating the emergence into adulthood and thereby facilitating the spread of CLas. Cuticular proteins (CPs) are involved in insect emergence. In this study, we investigated the molecular mechanisms underlying CLas-promoted emergence in D. citri via CP mediation. Here, a total of 159 CP genes were first identified in the D. citri genome. Chromosomal location analysis revealed an uneven distribution of these CP genes across the 13 D. citri chromosomes. Proteomic analysis identified 54 differentially expressed CPs during D. citri emergence, with 14 CPs exhibiting significant differential expression after CLas acquisition. Five key genes, Dc18aa-1, Dc18aa-2, DcCPR-24, DcCPR-38 and DcCPR-58, were screened from the proteome and CLas acquisition. The silencing of these 5 genes through a modified feeding method significantly reduced the emergence rate and caused various abnormal phenotypes, indicating the crucial role that these genes play in D. citri emergence. This study provides a comprehensive overview of the role of CPs in D. citri and reveals that CLas can influence the emergence process of D. citri by regulating the expression of CPs. These key CPs may serve as potential targets for future research on controlling huanglongbing (HLB) transmission.

Causal Relationship between Gut Microbiota and Gout: A Two-Sample Mendelian Randomization Study.

Gout is a form of prevalent and painful inflammatory arthritis characterized by elevated serum urate (SUA) levels. The gut microbiota (GM) is believed to influence the development of gout and SUA levels. Our study aimed to explore the causal relationship between GM composition and gout, as well as SUA levels, utilizing a two-sample Mendelian Randomization (MR) approach. A total of 196 GM taxa from five levels were available for analysis. We identified five taxa associated with SUA levels and 10 taxa associated with gout. In reverse MR analysis, we discovered that gout affected the composition of five GM taxa, while SUA levels influenced the composition of 30 GM taxa. Combining existing research, our study unveiled a potential negative feedback loop between phylum Actinobacteria and SUA levels, establishing connections with gout. We also proposed two novel associations connecting GM taxa (genus Faecalibacterium and genus Prevotella9), SUA levels, and gout. These findings provide compelling evidence of causal relationships between specific GM taxa with SUA levels and gout, contributing valuable insights for the treatment of gout.

Body color plasticity of Diaphorina citri reflects a response to environmental stress.

Body color polyphenism is common in Diaphorina citri. Previous studies compared physiological characteristics in D. citri, but the ecological and biological significance of its body color polyphenism remains poorly understood. We studied the ecological and molecular effects of stressors related to body color in D. citri. Crowding or low temperature induced a high proportion of gray morphs, which had smaller bodies, lower body weight, and greater susceptibility to the insecticide dinotefuran. We performed transcriptomic and metabolomics analysiis of 2 color morphs in D. citri. Gene expression dynamics revealed that the differentially expressed genes were predominantly involved in energy metabolism, including fatty acid metabolism, amino acid metabolism, and carbohydrate metabolism. Among these genes, plexin, glycosidase, phospholipase, take out, trypsin, and triacylglycerol lipase were differentially expressed in 2 color morphs, and 6 hsps (3 hsp70, hsp83, hsp90, hsp68) were upregulated in gray morphs. The metabolome data showed that blue morphs exhibited a higher abundance of fatty acid and amino acid, whereas the content of carbohydrates was elevated in gray morphs. This study partly explains the body color polyphenism of D. citri and provides insights into the molecular changes of stress response of D. citri.

Association between urinary phthalate levels and chronic pain in US adults, 1999-2004: A nationally representative survey.

Introduction: Chronic pain is a public health concern throughout the world. Ascertaining and managing its risk factors helps develop well-directed treatment plans and prevention strategies. Phthalates (PAEs) exposure leads to various health problems. The present study aims to explore the potential correlation between urinary PAEs metabolites and chronic pain in adults. Methods: The study population data were extracted from the National Health and Nutrition Examination Survey (NHANES) conducted from 1999 to 2004 in the United States. Seven urinary PAEs metabolites were used to assess long-term PAEs exposure. The assessment of chronic pain was determined by a self-report questionnaire. Weighted analyses were conducted to consider the complex sampling design. Models were adjusted by demographic data and lifestyle factors. Urinary PAEs metabolites were assessed as both continuous and categorical variables. Tertile 1 was considered as the reference. Stratified analyses were performed by gender and pain site. All data analyses were conducted with STATA, version 15.1. P < 0.05 was considered with statistical significance. Results: A total of 4,196 participants were considered in our final analysis. Chronic pain prevalence reached 52.19% (n = 2,138) among the participants, with women accounting for a large proportion (57.75% vs. 42.25%). After multivariable logistic regression analysis, a higher prevalence of chronic pain was observed among participants in the third tertile of mono-(2-ethyl)-hexyl phthalate (MEHP) (OR = 1.23, 95% CI = 1.02-1.48, P = 0.034) and mono-benzyl phthalate (MBzP) (OR = 1.28, 95% CI = 1.04-1.58, P = 0.022) in our adjusted model. The logtransformed concentration of MBzP also showed a significant association with chronic pain prevalence (OR = 1.09, 95% CI = 1.01-1.18, P = 0.036) in the adjusted model. In further analysis, the positive correlations of urinary phthalate metabolites with chronic pain remained robust when stratified by gender and chronic pain site. Conclusions: Our findings presented a positive correlation between urinary PAEs metabolites and chronic pain among adult participants, and more causal research should be conducted to ascertain the interactions between the two and to expound their underlying mechanisms.

Integrating population-level and cell-based signatures for drug repositioning.

Drug repositioning presents a streamlined and cost-efficient way to expand the range of therapeutic possibilities. Furthermore, drugs with genetic evidence are more likely to progress successfully through clinical trials towards FDA approval. Exploiting these developments, single gene-based drug repositioning methods have been implemented, but approaches leveraging the entire spectrum of molecular signatures are critically underexplored. Most multi-gene-based approaches rely on differential gene expression (DGE) analysis, which is prone to identify the molecular consequence of disease and renders causal inference challenging. We propose a framework TReD (Transcriptome-informed Reversal Distance) that integrates population-level disease signatures robust to reverse causality and cell-based drug-induced transcriptome response profiles. TReD embeds the disease signature and drug profile in a high-dimensional normed space, quantifying the reversal potential of candidate drugs in a disease-related cell screen assay. The robustness is ensured by evaluation in additional cell screens. For an application, we implement the framework to identify potential drugs against COVID-19. Taking transcriptome-wide association study (TWAS) results from four relevant tissues and three DGE results as disease features, we identify 37 drugs showing potential reversal roles in at least four of the seven disease signatures. Notably, over 70% (27/37) of the drugs have been linked to COVID-19 from other studies, and among them, eight drugs are supported by ongoing/completed clinical trials. For example, TReD identifies the well-studied JAK1/JAK2 inhibitor baricitinib, the first FDA-approved immunomodulatory treatment for COVID-19. Novel potential candidates, including enzastaurin, a selective inhibitor of PKC-beta which can be activated by SARS-CoV-2, are also identified. In summary, we propose a comprehensive genetics-anchored framework integrating population-level signatures and cell-based screens that can accelerate the search for new therapeutic strategies.

Association of urinary phthalate metabolites with sarcopenia in US adults: NHANES 1999-2006.

Phthalates have been extensively detected in environmental and biological matrices. Exposure to phthalates is implicated in various human diseases. In this study, we conducted a cross-sectional study to determine whether urinary phthalate metabolite concentrations were correlated with prevalence of sarcopenia in US adult population. We included 3562 participants with detailed information on skeletal muscle mass and urinary phthalate metabolites based on National Health and Nutrition Examination Survey (NHANES) 1999-2006 data. A total of 7 main phthalate metabolites were analyzed in the urine sample of each participant. Appendicular skeletal muscle mass (ASM) was measured using dual-energy X-ray absorptiometry. Multivariable linear regression models were conducted following adjustment for multiple covariates. ASM adjusted by body mass index (ASM/BMI) was calculated, and sarcopenia was defined as the lowest quintile for ASM/BMI value. Compared with participants in quartile 1, those in quartile 2 of urinary mono-n-butyl phthalate (MnBP) and quartile 4 of urinary monobenzyl phthalate (MBzP) had decreased ASM/BMI. Urinary MnBP in quartile 4, as well as urinary MBzP in quartile 2, was shown to be significantly correlated with higher sarcopenia prevalence. In subgroup analysis, negative association of MBzP with ASM/BMI was observed in both males and females, while this negative association was only observed in males for MnBP. Females with higher urinary monoethyl phthalate (MEP) concentrations had higher sarcopenia risk. Taken together, the present study found several urinary phthalate metabolites were positively associated with sarcopenia prevalence in US adult population. These findings indicated phthalate exposure might be an important environmental risk factor contributing to sarcopenia development.

The gender-specific adverse association of polycyclic aromatic hydrocarbons on skeletal muscle mass and strength in the general adults and the possible mechanisms in experimental rats.

Whether polycyclic aromatic hydrocarbons (PAHs) exposure is associated with muscle mass and muscle strength has been scantly investigated. The cross-sectional associations of urinary PAH metabolites with appendicular skeletal muscle mass and hand grip strength in adults were first investigated in the National Health and Nutrition Examination Survey (NHANES). Laboratory study was further carried out to examine the effect of PAHs on skeletal muscle mass and strength. 2742 and 2462 US adults were finally analyzed for muscle mass and muscle strength, respectively. In male participants, urinary PAH metabolites were found to show an inverse relationship with muscle mass and grip strength. In female participants, no significant relationship was found between urinary PAH metabolites with muscle mass or grip strength. In male Sprague-Dawley (SD) rats, administration of B [a]P induced muscle atrophy when compared with the control. However, muscle mass and strength were not significantly altered in female rats. The variations in muscle morphology parameters were accompanied by significant decrease in plasma testosterone levels in the B [a]P-treated male rats. Testosterone co-treatment significantly mitigated B [a]P mediated damages in skeletal muscle in male rats. The results of the present study indicate that there may be a gender-specific causal relationship between the PAHs and muscle atrophy.

Vitamin D Status and Risk of All-Cause and Cause-Specific Mortality in Osteoarthritis Patients: Results from NHANES III and NHANES 2001-2018.

Objectives: The role of Vitamin D (VD) in calcium balance and bone health makes VD a vital factor in osteoarthritis (OA). Studies that have evaluated the effect of VD on OA patients have mainly been performed on a short-term basis. In this analysis, we aimed to evaluate whether VD was associated with mortality, a long-term outcome, in OA patients. Methods: Participants with self-reported OA from NHANES III and NHANES 2001−2018 were included. Associations of 25(OH)D concentrations with mortality risk were assessed continuously using restricted cubic splines and by categories (i.e., <25.0, 25.0−49.9, 50.0−74.9, and ≥75.0 nmol/L) using the Cox regression model. Sensitivity and stratified analyses were performed to evaluate the robustness of the results. Results: A total of 4570 patients were included, of which 1388 died by 31 December 2019. An L-shaped association was observed between 25(OH)D concentrations and all-cause mortality, whereas an inverse association was found for cardiovascular disease (CVD) mortality. The adjusted hazard ratios (95% confidence intervals) across four categories were 1.00 (reference), 0.49 (0.31, 0.75), 0.45 (0.29, 0.68), and 0.43 (0.27, 0.69) for all-cause mortality and 1.00 (reference), 0.28 (0.14, 0.59), 0.25 (0.12, 0.51), and 0.24 (0.11, 0.49) for CVD-specific mortality; no significant associations were found for cancer-specific mortality. Similar results were observed when stratified and sensitivity analyses were performed. Conclusions: Compared with patients with insufficient or deficient serum 25(OH)D, those with sufficient 25(OH)D concentrations had a lower risk of all-cause and CVD mortality, supporting a beneficial role of VD on a long-term basis.

Association of a novel antisense lncRNA TP73-AS1 polymorphisms and expression with colorectal cancer susceptibility and prognosis.

BACKGROUND: TP73-AS1 is a novel antisense long noncoding RNA and plays an important role in cell proliferation and cancer development. However, the link between TP73-AS1 and colorectal cancer (CRC) has not yet been reported. OBJECTIVE: To explore the association of genetic variants in TP73-AS1 and its expression with CRC susceptibility and prognosis. METHODS: A case-control study (including 507 CRC cases and 503 controls) and bioinformatics analysis were conducted. RESULTS: rs9800 polymorphism was significantly related to higher risk in CRC [adjusted odds ratio (AOR) = 1.33, 95% confidence interval (CI) = 1.02-1.75, P = 0.034 in heterozygote codominant model]. There was no difference between TP73-AS1 polymorphisms and different tumor node metastasis (TNM) stages in the adjusted model. Moreover, TP73-AS1 expression level was positively related to different TNM stages. After adjusted for age, gender and TNM, higher TP73-AS1 expression levels were related to shorter recurrence-free survival time [hazard ratio (HR) = 1.66, 95% CI = 1.02-2.71, P = 0.043]. CONCLUSION: TP73-AS1 polymorphisms and expression may be associated with susceptibility and prognosis of CRC.