Leveraging trans-ethnic genetic risk scores to improve association power for complex traits in underrepresented populations.

Trans-ethnic genome-wide association studies have revealed that many loci identified in European populations can be reproducible in non-European populations, indicating widespread trans-ethnic genetic similarity. However, how to leverage such shared information more efficiently in association analysis is less investigated for traits in underrepresented populations. We here propose a statistical framework, trans-ethnic genetic risk score informed gene-based association mixed model (GAMM), by hierarchically modeling single-nucleotide polymorphism effects in the target population as a function of effects of the same trait in well-studied populations. GAMM powerfully integrates genetic similarity across distinct ancestral groups to enhance power in understudied populations, as confirmed by extensive simulations. We illustrate the usefulness of GAMM via the application to 13 blood cell traits (i.e. basophil count, eosinophil count, hematocrit, hemoglobin concentration, lymphocyte count, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, monocyte count, neutrophil count, platelet count, red blood cell count and total white blood cell count) in Africans of the UK Biobank (n = 3204) while utilizing genetic overlap shared in Europeans (n = 746 667) and East Asians (n = 162 255). We discovered multiple new associated genes, which had otherwise been missed by existing methods, and revealed that the trans-ethnic information indirectly contributed much to the phenotypic variance. Overall, GAMM represents a flexible and powerful statistical framework of association analysis for complex traits in underrepresented populations by integrating trans-ethnic genetic similarity across well-studied populations, and helps attenuate health inequities in current genetics research for people of minority populations.

Identification of BMAL1-Regulated circadian genes in mouse liver and their potential association with hepatocellular carcinoma: Gys2 and Upp2 as promising candidates.

Identification and functional analysis of key genes regulated by the circadian clock system will provide a comprehensive understanding of the underlying mechanisms through which circadian clock disruption impairs the health of living organisms. The initial phase involved bioinformatics analysis, drawing insights from three RNA-seq datasets (GSE184303, GSE114400, and GSE199061) derived from wild-type mouse liver tissues, which encompassed six distinct time points across a day. As expected, 536 overlapping genes exhibiting rhythmic expression patterns were identified. By intersecting these genes with differentially expressed genes (DEGs) originating from liver RNA-seq data at two representative time points (circadian time, CT: CT2 and CT14) in global Bmal1 knockout mice (Bmal1-/-), hepatocyte-specific Bmal1 knockout mice (L-Bmal1-/-), and their corresponding control groups, 80 genes potentially regulated by BMAL1 (referred to as BMAL1-regulated genes, BRGs) were identified. These genes were significantly enriched in glycolipid metabolism, immune response, and tumorigenesis pathways. Eight BRGs (Nr1d1, Cry1, Gys2, Homer2, Serpina6, Slc2a2, Nmrk1, and Upp2) were selected to validate their expression patterns in both control and L-Bmal1-/- mice livers over 24 h. Real-time quantitative polymerase chain reaction results demonstrated a comprehensive loss of rhythmic expression patterns in the eight selected BRGs in L-Bmal1-/- mice, in contrast to the discernible rhythmic patterns observed in the livers of control mice. Additionally, significant reductions in the expression levels of these selected BRGs, excluding Cry1, were also observed in L-Bmal1-/- mice livers. Chromatin immunoprecipitation (ChIP)-seq (GSE13505 and GSE39860) and JASPAR analyses validated the rhythmic binding of BMAL1 to the promoter and intron regions of these genes. Moreover, the progression of conditions, from basic steatosis to non-alcoholic fatty liver disease, and eventual malignancy, demonstrated a continuous gradual decline in Bmal1 transcripts in the human liver. Combining the aforementioned BRGs with DEGs derived from human liver cancer datasets identified Gys2 and Upp2 as potential node genes bridging the circadian clock system and hepatocellular carcinoma (HCC). In addition, CCK8 and wound healing assays demonstrated that the overexpression of human GYS2 and UPP2 proteins inhibited the proliferation and migration of HepG2 cells, accompanied by elevated expression of p53, a tumor suppressor protein. In summary, this study systematically identified rhythmic genes in the mouse liver, and a subset of circadian genes potentially regulated by BMAL1. Two circadian genes, Gys2 and Upp2, have been proposed and validated as potential candidates for advancing the prevention and treatment of HCC.

Incorporating genetic similarity of auxiliary samples into eGene identification under the transfer learning framework.

BACKGROUND: The term eGene has been applied to define a gene whose expression level is affected by at least one independent expression quantitative trait locus (eQTL). It is both theoretically and empirically important to identify eQTLs and eGenes in genomic studies. However, standard eGene detection methods generally focus on individual cis-variants and cannot efficiently leverage useful knowledge acquired from auxiliary samples into target studies. METHODS: We propose a multilocus-based eGene identification method called TLegene by integrating shared genetic similarity information available from auxiliary studies under the statistical framework of transfer learning. We apply TLegene to eGene identification in ten TCGA cancers which have an explicit relevant tissue in the GTEx project, and learn genetic effect of variant in TCGA from GTEx. We also adopt TLegene to the Geuvadis project to evaluate its usefulness in non-cancer studies. RESULTS: We observed substantial genetic effect correlation of cis-variants between TCGA and GTEx for a larger number of genes. Furthermore, consistent with the results of our simulations, we found that TLegene was more powerful than existing methods and thus identified 169 distinct candidate eGenes, which was much larger than the approach that did not consider knowledge transfer across target and auxiliary studies. Previous studies and functional enrichment analyses provided empirical evidence supporting the associations of discovered eGenes, and it also showed evidence of allelic heterogeneity of gene expression. Furthermore, TLegene identified more eGenes in Geuvadis and revealed that these eGenes were mainly enriched in cells EBV transformed lymphocytes tissue. CONCLUSION: Overall, TLegene represents a flexible and powerful statistical method for eGene identification through transfer learning of genetic similarity shared across auxiliary and target studies.

Viral communities in a pH>10 serpentinite-like environment: insight into diversity and potential roles in modulating the microbiomes by bioactive vitamin B9 synthesis.

Viral communities exist in a variety of ecosystems and play significant roles in mediating biogeochemical processes, whereas viruses inhabiting strongly alkaline geochemical systems remain underexplored. In this study, the viral diversity, potential functionalities, and virus-host interactions in a strongly alkaline environment (pH = 10.4-12.4) exposed to the leachates derived from the serpentinization-like reactions of smelting slags were investigated. The viral populations (e.g., Herelleviridae, Queuovirinae, and Inoviridae) were closely associated with the dominating prokaryotic hosts (e.g., Meiothermus, Trueperaceae, and Serpentinomonas) in this ultrabasic environment. Auxiliary metabolic genes (AMGs) suggested that viruses may enhance hosts' fitness by facilitating cofactor biosynthesis, hydrogen metabolism, and carbon cycling. To evaluate the activity of synthesis of essential cofactor vitamin B9 by the viruses, a viral folA (vfolA) gene encoding dihydrofolate reductase (DHFR) was introduced into a thymidine-auxotrophic strain Escherichia coli MG1655 ΔfolA mutant, which restored the growth of the latter in the absence of thymidine. Notably, the homologs of the validated vDHFR were globally distributed in the viromes across various ecosystems. The present study sheds new light on the unique viral communities in hyperalkaline ecosystems and their potential beneficial impacts on the coexisting microbial consortia by supplying essential cofactors. IMPORTANCE: This study presents a comprehensive investigation into the diversity, potential functionalities, and virus-microbe interactions in an artificially induced strongly alkaline environment. Functional validation of the detected viral folA genes encoding dihydrofolate reductase substantiated the synthesis of essential cofactors by viruses, which may be ubiquitous, considering the broad distribution of the viral genes associated with folate cycling.

Tepidibacillus marianensis sp. nov., a novel heterotrophic iron-reducing bacterium isolated from Mariana Trench sediment.

A novel chemoheterotrophic iron-reducing micro-organism, designated as strain LSZ-M11000T, was isolated from sediment of the Marianas Trench. Phylogenetic analysis based on the 16S rRNA gene revealed that strain LSZ-M11000T belonged to genus Tepidibacillus, with 97 % identity to that of Tepidibacillus fermentans STGHT, a mesophilic bacterium isolated from the Severo-Stavropolskoye underground gas storage facility in Russia. The polar lipid profile of strain LSZ-M11000T consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, as well as other unidentified phospholipids and lipids. The major fatty acids were C16 : 0 (28.4 %), C18 : 0 (15.8 %), iso-C15 : 0 (12.9 %), and anteiso-C15 : 0 (12.0 %). Strain LSZ-M11000T had no menaquinone. Genome sequencing revealed that the genome size of strain LSZ-M11000T was 2.97 Mb and the DNA G+C content was 37.9 mol%. The average nucleotide identity values between strain LSZ-M11000T and its close phylogenetic relatives, Tepidibacillus fermentans STGHT and Tepidibacillus decaturensis Z9T, were 76.4 and 72.6 %, respectively. The corresponding DNA-DNA hybridization estimates were 20.9 and 23.4 %, respectively. Cells of strain LSZ-M11000T were rod-shaped (1.0-1.5×0.3-0.5 µm). Using pyruvate as an electron donor, it was capable of reducing KMnO4, MnO2, As(V), NaNO3, NaNO2, Na2SO4, Na2S2O3, and K2Cr2O7. Based on phenotypic, genotypic, and phylogenetic evidence, strain LSZ-M11000T is proposed to be a novel strain of the genus Tepidibacillus, for which the name Tepdibacillus marianensis is proposed. The type strain is LSZ-M11000T (=CCAM 1008T=JCM 39431T).

Association of cigarette smoking, smoking cessation with the risk of cardiometabolic multimorbidity in the UK Biobank.

BACKGROUND: To investigate the association between cigarette smoking, smoking cessation and the trajectory of cardiometabolic multimorbidity (CMM), and further to examine the association of age at smoking initiation and smoking cessation with CMM. METHODS: This study included 298,984 UK Biobank participants without cardiometabolic diseases (CMDs) (including type 2 diabetes, coronary heart diseases, stroke, and hypertension) at baseline. Smoking status was categorized into former, current, and never smokers, with age at smoking initiation and smoking cessation as a proxy for current and former smokers. The multi-state model was performed to evaluate the association between cigarette smoking, smoking cessation and CMM. RESULTS: During a median follow-up of 13.2 years, 59,193 participants developed first cardiometabolic disease (FCMD), 14,090 further developed CMM, and 16,487 died. Compared to former smokers, current smokers had higher risk at all transitions, with hazard ratio (95% confidence interval) = 1.59 (1.55 ∼ 1.63) vs. 1.18 (1.16 ∼ 1.21) (P = 1.48 × 10- 118) from health to FCMD, 1.40 (1.33 ∼ 1.47) vs. 1.09 (1.05 ∼ 1.14) (P = 1.50 × 10- 18) from FCMD to CMM, and 2.87 (2.72 ∼ 3.03) vs. 1.38 (1.32 ∼ 1.45) (P < 0.001) from health, 2.16 (1.98 ∼ 2.35) vs. 1.25 (1.16 ∼ 1.34) (P = 1.18 × 10- 46) from FCMD, 2.02 (1.79 ∼ 2.28) vs. 1.22 (1.09 ∼ 1.35) (P = 3.93 × 10- 17) from CMM to death; whereas quitting smoking reduced the risk attributed to cigarette smoking by approximately 76.5% across all transitions. Reduced risks of smoking cessation were also identified when age at quitting smoking was used as a proxy for former smokers. CONCLUSIONS: Cigarette smoking was associated with a higher risk of CMM across all transitions; however, smoking cessation, especially before the age of 35, was associated with a significant decrease in CMM risk attributed to cigarette smoking.

Target-regulated photoactivities of CdS/Ni-MOF heterojunction with [Ru(bpy)2dppz]2+ intercalator: a bisphenol A photoelectrochemical aptasensor.

Bisphenol A (BPA), an important endocrine disrupting compound, has infiltrated human daily lives through electronic devices, food containers, and children's toys. Developing of novel BPA assay methods with high sensitivity holds tremendous importance in valuing the pollution state. Here, we constructed an ultrasensitive photoelectrochemical (PEC) aptasensor for BPA determination by regulating photoactivities of CdS/Ni-based metal-organic framework (CdS/Ni-MOF) with [Ru(bpy)2dppz]2+ sensitizer. CdS/Ni-MOF spheres exhibited excellent photocatalytic performance, serving as a potential sensing platform for the construction of target recognition process. [Ru(bpy)2dppz]2+ were embedded into DNA double-stranded structure, functioning as sensitizer for modulating the signal response of the developed PEC aptasensor. The proposed PEC sensor exhibited outstanding analytical performances, including a wide linear range (0.1 to 1000.0 nM), low detection limit (0.026 nM, at 3σ/m), excellent selectivity, and high stability. This work provides a perspective for the design of ideal photosensitive materials and signal amplification strategies and extends their application in environment analysis.

Ligand-Controlled Electroreduction of CO2 to Formate over Facet-Defined Bimetallic Sulfide Nanoplates.

CO2 reduction (CO2R) catalyzed by an efficient, stable, and earth-abundant electrocatalyst offers an attractive means to store energy derived from renewable sources. Here, we describe the synthesis of facet-defined Cu2SnS3 nanoplates and the ligand-controlled CO2R property. We show that thiocyanate-capped Cu2SnS3 nanoplates possess excellent selectivity toward formate over a wide range of potentials and current densities, attaining a maximum formate Faradaic efficiency of 92% and partial current densities as high as 181 mA cm-2 when tested using a flow cell with gas-diffusion electrode. In situ spectroscopic measurements and theoretical calculations reveal that the high formate selectivity originates from favorable adsorption of HCOO* intermediates on cationic Sn sites that are electronically modulated by thiocyanates bound to adjacent Cu sites. Our work illustrates that well-defined multimetallic sulfide nanocrystals with tailored surface chemistries could provide a new avenue for future CO2R electrocatalyst design.

Pharmacological Activities of Lonicerae japonicae flos and Its Derivative-"Chrysoeriol" in Skin Diseases.

Chrysoeriol is an active ingredient derived from the Chinese medicinal herb (CMH) "Lonicerae japonicae flos" in the dried flower bud or bloomed flower of Lonicera japonica Thunberg. Dermatoses are the most common diseases in humans, including eczema, acne, psoriasis, moles, and fungal infections, which are temporary or permanent and may be painless or painful. Topical corticosteroids are widely used in Western medicine, but there are some side effects when it is continuously and regularly utilized in a large dosage. Chrysoeriol is a natural active ingredient, nontoxic, and without any adverse reactions in the treatment of dermatological conditions. METHODS: Nine electronic databases were searched, including WanFang Data, PubMed, Science Direct, Scopus, Web of Science, Springer Link, SciFinder, and China National Knowledge Infrastructure (CNKI), without regard to language constraints. The pharmacological activities of chrysoeriol from Lonicerae japonicae flos to fight against skin diseases were explained and evaluated through the literature review of either in vitro or in vivo studies. RESULTS: Chrysoeriol decreased the mRNA levels of proinflammatory cytokines IL-6, IL-1ß, and TNF-α. These were transcriptionally regulated by NF-κB and STAT3 to combat skin inflammation. It also showed promising actions in treating many skin ailments including wound healing, depigmentation, photoprotection, and antiaging. CONCLUSION: The cutaneous route is the best delivery approach to chrysoeriol across the skin barrier. However, toxicity, dosage, and safety assessments of chrysoeriol in a formulation or nanochrysoeriol on the human epidermis for application in skin diseases must be further investigated.

Oxygen Vacancies Boosted Hydronium Intercalation: A Paradigm Shift in Aluminum-Based Batteries.

In aqueous aluminum-ion batteries (AAIBs), the insertion/extraction chemistry of Al3+ often leads to poor kinetics, whereas the rapid diffusion kinetics of hydronium ions (H3O+) may offer the solution. However, the presence of considerable Al3+ in the electrolyte hinders the insertion reaction of H3O+. Herein, we report how oxygen-deficient α-MoO3 nanosheets unlock selective H3O+ insertion in a mild aluminum-ion electrolyte. The abundant oxygen defects impede the insertion of Al3+ due to excessively strong adsorption, while allowing H3O+ to be inserted/diffused through the Grotthuss proton conduction mechanism. This research advances our understanding of the mechanism behind selective H3O+ insertion in mild electrolytes.

What Is the Rate-Limiting Step of Oxygen Reduction Reaction on Fe-N-C Catalysts?

Oxygen reduction reaction (ORR) is essential to various renewable energy technologies. An important catalyst for ORR is single iron atoms embedded in nitrogen-doped graphene (Fe-N-C). However, the rate-limiting step of the ORR on Fe-N-C is unknown, significantly impeding understanding and improvement. Here, we report the activation energies of all of the steps, calculated by ab initio molecular dynamics simulations under constant electrode potential. In contrast to the common belief that a hydrogenation step limits the reaction rate, we find that the rate-limiting step is oxygen molecule replacing adsorbed water on Fe. This occurs through concerted motion of H2O desorption and O2 adsorption, without leaving the site bare. Interestingly, despite being an apparent "thermal" process that is often considered to be potential-independent, the barrier reduces with the electrode potential. This can be explained by stronger Fe-O2 binding and weaker Fe-H2O binding at a lower potential, due to O2 gaining electrons and H2O donating electrons to the catalyst. Our study offers new insights into the ORR on Fe-N-C and highlights the importance of kinetic studies in heterogeneous electrochemistry.

Ultrasensitive photoelectrochemical detection of glutathione based on the multifunctional catalytic properties of phosphotungstic acid.

A novel photoelectrochemical (PEC) sensor was constructed for the highly sensitive detection of reduced glutathione (GSH) based on the multiple catalytic properties of phosphotungstic acid (PTA). In this work, the catalytic properties of PTA were applied to PEC sensing for the first time and interpreted in detail. First, PTA as an electron acceptor can inhibit the complexation of photogenerated electron-hole pairs in p-Cu2O, thus significantly increasing the photogenerated current of p-type semiconductor material Cu2O. Secondly, when GSH is oxidized to oxidized glutathione (GSSG) by photogenerated holes on the photocathode, PTA is able to reduce GSSG to GSH by transferring protons, forming a redox cycle regeneration process of GSH. Finally, the relatively large amount of PTA in the background solution was able to pre-oxidize interfering substances such as L-cysteine and ascorbic acid, which improved the selectivity of the method. Under the optimal experimental conditions, the linear range of the PEC sensor response to GSH was 0.050-100 nmol L-1, with a detection limit as low as 0.017 nmol L-1 (S/N = 3), which can be applied to the detection of GSH content in cell lysate samples.

Microbial Contributions to Iodide Enrichment in Deep Groundwater in the North China Plain.

Microorganisms play crucial roles in the global iodine cycling through iodine oxidation, reduction, volatilization, and deiodination. In contrast to iodate formation in radionuclide-contaminated groundwater by the iodine-oxidizing bacteria, microbial contribution to the formation of high level of iodide in geogenic high iodine groundwater is poorly understood. In this study, our results of comparative metagenomic analyses of deep groundwater with typical high iodide concentrations in the North China Plain revealed the existence of putative dissimilatory iodate-reducing idrABP1P2 gene clusters in groundwater. Heterologous expression and characterization of an identified idrABP1P2 gene cluster confirmed its functional role in iodate reduction. Thus, microbial dissimilatory iodate reduction could contribute to iodide formation in geogenic high iodine groundwater. In addition, the identified iron-reducing, sulfur-reducing, sulfur-oxidizing, and dehalogenating bacteria in the groundwater could contribute to the release and production of iodide through the reductive dissolution of iron minerals, abiotic iodate reduction of derived ferrous iron and sulfide, and dehalogenation of organic iodine, respectively. These microbially mediated iodate reduction and organic iodine dehalogenation processes may also result in the transformation among iodine species and iodide enrichment in other geogenic iodine-rich groundwater systems worldwide.

Abiotic and Biotic Reduction of Iodate Driven by Shewanella oneidensis MR-1.

Iodate (IO3-) can be abiotically reduced by Fe(II) or biotically reduced by the dissimilatory Fe(III)-reducing bacterium Shewanella oneidensis (MR-1) via its DmsEFAB and MtrCAB. However, the intermediates and stoichiometry between the Fe(II) and IO3- reaction and the relative contribution of abiotic and biotic IO3- reduction by biogenic Fe(II) and MR-1 in the presence of Fe(III) remain unclear. In this study, we found that abiotic reduction of IO3- by Fe(II) produced intermediates HIO and I- at a ratio of 1:2, followed by HIO disproportionation to I- and IO3-. Comparative analyses of IO3- reduction by MR-1 wild type (WT), MR-1 mutants deficient in DmsEFAB or MtrCAB, and Shewanella sp. ANA-3 in the presence of Fe(III)-citrate, Fe(III) oxides, or clay minerals showed that abiotic IO3- reduction by biogenic Fe(II) predominated under iron-rich conditions, while biotic IO3- reduction by DmsEFAB played a more dominant role under iron-poor conditions. Compared to that in the presence of Fe(III)-citrate, MR-1 WT reduced more IO3- in the presence of Fe(III) oxides and clay minerals. The observed abiotic and biotic IO3- reduction by MR-1 under Fe-rich and Fe-limited conditions suggests that Fe(III)-reducing bacteria could contribute to the transformation of iodine species and I- enrichment in natural iodine-rich environments.

Bacterial Sulfate Reduction Facilitates Iodine Mobilization in the Deep Confined Aquifer of the North China Plain.

Bacterial sulfate reduction plays a crucial role in the mobilization of toxic substances in aquifers. However, the role of bacterial sulfate reduction on iodine mobilization in geogenic high-iodine groundwater systems has been unexplored. In this study, the enrichment of groundwater δ34SSO4 (15.56 to 69.31‰) and its significantly positive correlation with iodide and total iodine concentrations in deep groundwater samples of the North China Plain suggested that bacterial sulfate reduction participates in the mobilization of groundwater iodine. Similar significantly positive correlations were further observed between the concentrations of iodide and total iodine and the relative abundance of the dsrB gene by qPCR, as well as the composition and abundance of sulfate-reducing bacteria (SRB) predicted from 16S rRNA gene high-throughput sequencing data. Subsequent batch culture experiments by the SRB Desulfovibrio sp. B304 demonstrated that SRB could facilitate iodine mobilization through the enzyme-driven biotic and sulfide-driven abiotic reduction of iodate to iodide. In addition, the dehalogenation of organoiodine compounds by SRB and the reductive dissolution of iodine-bearing iron minerals by biogenic sulfide could liberate bound or adsorbed iodine into groundwater. The role of bacterial sulfate reduction in iodine mobilization revealed in this study provides new insights into our understanding of iodide enrichment in iodine-rich aquifers worldwide.

ATF4 renders human T-cell acute lymphoblastic leukemia cell resistance to FGFR1 inhibitors through amino acid metabolic reprogramming.

Abnormalities of FGFR1 have been reported in multiple malignancies, suggesting FGFR1 as a potential target for precision treatment, but drug resistance remains a formidable obstacle. In this study, we explored whether FGFR1 acted a therapeutic target in human T-cell acute lymphoblastic leukemia (T-ALL) and the molecular mechanisms underlying T-ALL cell resistance to FGFR1 inhibitors. We showed that FGFR1 was significantly upregulated in human T-ALL and inversely correlated with the prognosis of patients. Knockdown of FGFR1 suppressed T-ALL growth and progression both in vitro and in vivo. However, the T-ALL cells were resistant to FGFR1 inhibitors AZD4547 and PD-166866 even though FGFR1 signaling was specifically inhibited in the early stage. Mechanistically, we found that FGFR1 inhibitors markedly increased the expression of ATF4, which was a major initiator for T-ALL resistance to FGFR1 inhibitors. We further revealed that FGFR1 inhibitors induced expression of ATF4 through enhancing chromatin accessibility combined with translational activation via the GCN2-eIF2α pathway. Subsequently, ATF4 remodeled the amino acid metabolism by stimulating the expression of multiple metabolic genes ASNS, ASS1, PHGDH and SLC1A5, maintaining the activation of mTORC1, which contributed to the drug resistance in T-ALL cells. Targeting FGFR1 and mTOR exhibited synergistically anti-leukemic efficacy. These results reveal that FGFR1 is a potential therapeutic target in human T-ALL, and ATF4-mediated amino acid metabolic reprogramming contributes to the FGFR1 inhibitor resistance. Synergistically inhibiting FGFR1 and mTOR can overcome this obstacle in T-ALL therapy.

Long-term influence of air pollutants on morbidity and all-cause mortality of cardiometabolic multi-morbidity: A cohort analysis of the UK Biobank participants.

BACKGROUND: The effects of air pollutants on cardiometabolic diseases (CMDs) have been widely explored, whereas their influences on cardiometabolic multi-morbidity (CMM) were not clear. METHODS: We employed the UK Biobank cohort (N = 317,160) to study the association between six air pollutants (PM2.5, PM10, PM2.5-10, PM2.5abs, NO2, and NOx) and four CMDs including type II diabetes (T2D), coronary artery disease (CAD), stroke and hypertension. CMM was defined as occurrence of two or more of the four diseases. Multi-state Cox models were performed to estimate hazard ratio (HR) and its 95% confidence interval (95%CI). RESULTS: During a median follow-up of 12.8 years, 52,211 participants developed only one CMD, 15,446 further developed CMM, and 16,861 ultimately died. It was demonstrated that per interquartile range increase (IQR) increases in PM2.5, PM10, PM2.5-10, PM2.5abs, NO2, and NOx would increase 12% (9%-15%), 4% (1%-7%), 3% (1%-6%), 7% (4%-10%), 11% (8%-15%) and 10% (7%-13%) higher risk of developing one CMD from health baseline; 7% (2%-12%), 8% (3%-13%), 6% (2%-11%), 10% (5%-15%), 13% (7%-18%) and 10% (5%-15%) greater risk of occurring CMM from one CMD baseline; and 11% (-2%∼26%), 22% (7%-38%), 17% (3%-32%), 31% (16%-49%), 33% (17%-51%) and 32% (17%-50%) larger risk of causing death from CMM baseline, respectively. CONCLUSIONS: We revealed that people living in areas with high air pollution suffered from higher hazard of CMD, CMM and all-cause mortality; our findings implied keeping clean air was an effective approach to prevent or mitigate initiation, progression, and death from healthy to CMDs and from CMDs to CMM.

Influence of social deprivation on morbidity and all-cause mortality of cardiometabolic multi-morbidity: a cohort analysis of the UK Biobank cohort.

BACKGROUND: The relation of social deprivation with single cardiometabolic disease (CMD) was widely investigated, whereas the association with cardiometabolic multi-morbidity (CMM), defined as experiencing more than two CMDs during the lifetime, is poorly understood. METHODS: We analyzed 345,417 UK Biobank participants without any CMDs at recruitment to study the relation between social deprivation and four CMDs including type II diabetes (T2D), coronary artery disease (CAD), stroke and hypertension. Social deprivation was measured by Townsend deprivation index (TDI), and CMM was defined as occurrence of two or more of the above four diseases. Multivariable Cox models were performed to estimate hazard ratios (HRs) per one standard deviation (SD) change and in quartile (Q1-Q4, with Q1 as reference), as well as 95% confidence intervals (95% CIs). RESULTS: During the follow up, 68,338 participants developed at least one CMD (median follow up of 13.2 years), 16,225 further developed CMM (median follow up of 13.4 years), and 18,876 ultimately died from all causes (median follow up of 13.4 years). Compared to Q1 of TDI (lowest deprivation), the multivariable adjusted HR (95%CIs) of Q4 (highest deprivation) among participants free of any CMDs was 1.23 (1.20 ~ 1.26) for developing one CMD, 1.42 (1.35 ~ 1.48) for developing CMM, and 1.34 (1.27 ~ 1.41) for all-cause mortality. Among participants with one CMD, the adjusted HR (95%CIs) of Q4 was 1.30 (1.27 ~ 1.33) for developing CMM and 1.34 (1.27 ~ 1.41) for all-cause mortality, with HR (95%CIs) = 1.11 (1.06 ~ 1.16) for T2D patients, 1.07 (1.03 ~ 1.11) for CAD patients, 1.07 (1.00 ~ 1.15) for stroke patients, and 1.24 (1.21 ~ 1.28) for hypertension patients. Among participants with CMM, TDI was also related to the risk of all-cause mortality (HR of Q4 = 1.35, 95%CIs 1.28 ~ 1.43). CONCLUSIONS: We revealed that people living with high deprived conditions would suffer from higher hazard of CMD, CMM and all-cause mortality.

Clinical effects of multi-oil versus pure soybean oil-based lipid emulsions for preterm infants: An observational study.

BACKGROUND AND OBJECTIVES: Conventional soybean oil-based intravenous lipid emulsions (SO-ILEs) have high polyunsaturated fatty acid (PUFA) contents and phytosterols that may have adverse effects in preterm infants. Recently, the multi-oil-based intravenous lipid emulsion (MO-ILE), SMOFlipid, has been widely utilized in the neonatal intensive care unit (NICU), but significant benefits over SO-ILEs in low gestational age neonates have yet to be demonstrated. This study was performed to compare the effects of the SO-ILE, Intralipid, and the MO-ILE, SMOFlipid, on neonatal health outcomes in preterm infants. METHODS AND STUDY DESIGN: We performed a retrospective review of preterm infants born at gestational week (GW) <32 receiving parenteral nutrition for longer durations (≥14 d) in the NICU between 2016 and 2021. The primary aim of this study was to investigate differences in morbidity between preterm infants receiving SMOFlipid and Intralipid. RESULTS: A total of 262 preterm infants were included in the analysis, with 126 receiving SMOFlipid and 136 receiving Intralipid. The SMOFlipid group had lower rates of ROP (23.8% vs 37.5%, respectively; p=0.017), although the rate of ROP was not different in multivariate regression analysis. The length of hospi-tal stay was significantly shorter in the SMOFlipid than SO-ILE group (median [IQR]=64.8 [37] vs 72.5 [49] days; p<0.001). CONCLUSIONS: The use of SMOFlipid as the lipid emulsion was associated with higher clinical efficacy than SO-ILE in preterm infants.

Electroreduction Enables Regioselective 1,2-Diarylation of Alkenes with Two Electrophiles.

Precisely introducing two similar functional groups into bulk chemical alkenes represents a formidable route to complex molecules. Especially, the selective activation of two electrophiles is in crucial demand, yet challenging for cross-electrophile-coupling. Herein, we demonstrate a redox-mediated electrolysis, in which aryl nitriles are both aryl radical precursors and redox-mediators, enables an intermolecular alkene 1,2-diarylation with a remarkable regioselectivity, thereby avoiding the involvement of transition-metal catalysts. This transformation utilizes cyanoarene radical anions for activating various aryl halides (including iodides, bromides, and even chlorides) and affords 1,2-diarylation adducts in up to 83 % yield and >20 : 1 regioselectivity with more than 80 examples, providing a feasible approach to complex bibenzyl derivatives.