Serum uric acid is inversely associated with lung function in US adults.

The relationship between serum uric acid and lung function has been controversial. This study aims to determine whether there is an independent relationship between serum uric acid and lung function in the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2012. Serum uric acid was considered the exposure variable, and lung function (FEV1 and FVC) was the outcome variable. Multivariable linear regression was conducted with adjustments for potential confounders. The total number of participants from NHANES (2007-2012) was 30,442, of which 7514 were included in our analysis after applying exclusion criteria. We observed that serum uric acid was negatively associated with FEV1 and FVC after adjusting for confounders (ß for FEV1 [- 24.77 (- 36.11, - 13.43)] and FVC [- 32.93 (- 47.42, - 18.45)]). Similarly, serum uric acid showed a negative correlation with FEV1 and FVC after adjusting for confounding variables both in male and female populations. The relationship between serum uric acid and FEV1 and FVC remained consistent and robust in various subgroups within both male and female populations, including age, race, BMI, alcohol consumption, smoking status, and income-poverty ratio. Serum uric acid is negatively associated with FEV1 and FVC in the US general healthy population. This negative relationship is significant in both the male and female populations.

Oral Simnotrelvir for Adult Patients with Mild-to-Moderate Covid-19.

BACKGROUND: Simnotrelvir is an oral 3-chymotrypsin-like protease inhibitor that has been found to have in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and potential efficacy in a phase 1B trial. METHODS: In this phase 2-3, double-blind, randomized, placebo-controlled trial, we assigned patients who had mild-to-moderate coronavirus disease 2019 (Covid-19) and onset of symptoms within the past 3 days in a 1:1 ratio to receive 750 mg of simnotrelvir plus 100 mg of ritonavir or placebo twice daily for 5 days. The primary efficacy end point was the time to sustained resolution of symptoms, defined as the absence of 11 Covid-19-related symptoms for 2 consecutive days. Safety and changes in viral load were also assessed. RESULTS: A total of 1208 patients were enrolled at 35 sites in China; 603 were assigned to receive simnotrelvir and 605 to receive placebo. Among patients in the modified intention-to-treat population who received the first dose of trial drug or placebo within 72 hours after symptom onset, the time to sustained resolution of Covid-19 symptoms was significantly shorter in the simnotrelvir group than in the placebo group (180.1 hours [95% confidence interval {CI}, 162.1 to 201.6] vs. 216.0 hours [95% CI, 203.4 to 228.1]; median difference, -35.8 hours [95% CI, -60.1 to -12.4]; P = 0.006 by Peto-Prentice test). On day 5, the decrease in viral load from baseline was greater in the simnotrelvir group than in the placebo group (mean difference [±SE], -1.51±0.14 log10 copies per milliliter; 95% CI, -1.79 to -1.24). The incidence of adverse events during treatment was higher in the simnotrelvir group than in the placebo group (29.0% vs. 21.6%). Most adverse events were mild or moderate. CONCLUSIONS: Early administration of simnotrelvir plus ritonavir shortened the time to the resolution of symptoms among adult patients with Covid-19, without evident safety concerns. (Funded by Jiangsu Simcere Pharmaceutical; ClinicalTrials.gov number, NCT05506176.).

Identification of alternative splicing associated with clinical features: from pan-cancers to genitourinary tumors.

Background: Alternative splicing events (ASEs) are vital causes of tumor heterogeneity in genitourinary tumors and many other cancers. However, the clinicopathological relevance of ASEs in cancers has not yet been comprehensively characterized. Methods: By analyzing splicing data from the TCGA SpliceSeq database and phenotype data for all TCGA samples from the UCSC Xena database, we identified differential clinical feature-related ASEs in 33 tumors. CIBERSORT immune cell infiltration data from the TIMER2.0 database were used for differential clinical feature-related immune cell infiltration analysis. Gene function enrichment analysis was used to analyze the gene function of ASEs related to different clinical features in tumors. To reveal the regulatory mechanisms of ASEs, we integrated race-related ASEs and splicing quantitative trait loci (sQTLs) data in kidney renal clear cell carcinoma (KIRC) to comprehensively assess the impact of SNPs on ASEs. In addition, we predicted regulatory RNA binding proteins in bladder urothelial carcinoma (BLCA) based on the enrichment of motifs around alternative exons for ASEs. Results: Alternative splicing differences were systematically analyzed between different groups of 58 clinical features in 33 cancers, and 30 clinical features in 24 cancer types were identified to be associated with more than 50 ASEs individually. The types of immune cell infiltration were found to be significantly different between subgroups of primary diagnosis and disease type. After integrating ASEs with sQTLs data, we found that 63 (58.9%) of the race-related ASEs were significantly SNP-correlated ASEs in KIRC. Gene function enrichment analyses showed that metastasis-related ASEs in KIRC mainly enriched Rho GTPase signaling pathways. Among those ASEs associated with metastasis, alternative splicing of GIT2 and TUBB3 might play key roles in tumor metastasis in KIRC patients. Finally, we identified several RNA binding proteins such as PCBP2, SNRNP70, and HuR, which might contribute to splicing differences between different groups of neoplasm grade in BLCA. Conclusion: We demonstrated the significant clinical relevance of ASEs in multiple cancer types. Furthermore, we identified and validated alternative splicing of TUBB3 and RNA binding proteins such as PCBP2 as critical regulators in the progression of urogenital cancers.

Integrating bioinformatic analysis and detailed experiments reveal an EMT-related biomarker for clear cell renal cell carcinoma.

BACKGROUND: Epithelial-mesenchymal transition (EMT) is associated with early recurrence and a poor prognosis in clear cell renal cell carcinoma (ccRCC). Studies have shown that EMT-related genes play an important regulatory role in tumor invasion, metastasis, and drug resistance, but the biological functions of EMT-related genes in ccRCC have not been specifically described. METHODS: The mRNA and clinicopathological data of 532 ccRCC and 72 normal samples were downloaded from The Cancer Genome Atlas as a training set. The gene expression matrix and survival data of 91 and 101 ccRCC samples were obtained from the International Cancer Genome Consortium and the ArrayExpress databases as validation sets, respectively. Univariate Cox analysis was used to identify and cluster prognostic genes, and multivariate Cox was performed to construct a prognostic signature. Moreover, CIBERSORT and CellMiner were used to assess immune cell infiltration and prognostic gene-drug sensitivity of the signature, respectively. Most importantly, we performed detailed experiments to verify the oncogenic function of a significant gene, OLFML2B, in vitro and in vivo. RESULTS: We constructed a prognostic signature including seven genes and divided patients into high-risk and low-risk groups. The prognosis of the high-risk group was significantly worse than that of the low-risk group through Kaplan-Meier survival analysis. Interestingly, significant differences were observed in clinical characteristics and immune cell infiltration between the two groups. In addition, a significant correlation was found between the expression of prognostic genes and the sensitivity of tumor cells to chemotherapeutics. Most importantly, OLFML2B was proved to contribute to the proliferation and metastasis of ccRCC through detailed functional experiments in vitro and in vivo, and its prognostic efficacy for ccRCC patients was affirmed. CONCLUSION: We identified the prognostic signature of seven genes based on EMT-related genes as prognostic biomarkers for ccRCC. Besides, OLFML2B was validated as a potential diagnostic and therapeutic target for ccRCC by our detailed experiments.

Role of human papillomavirus and associated viruses in bladder cancer: An updated review.

Bladder cancer (BC) is a complex disease affecting the urinary system and is regulated by several carcinogenic factors. Viral infection is one such factor that has attracted extensive attention in BC. Human papillomavirus (HPV) is the most common sexually transmitted infection, and although multiple researchers have explored the role of HPV in BC, a consensus has not yet been reached. In addition, HPV-associated viruses (e.g., human immunodeficiency virus, herpes simplex virus, BK virus, and JC virus) appear to be responsible for the occurrence and progression of BC. This study systematically reviews the relationship between HPV-associated viruses and BC to elucidate the role of these viruses in the onset and progression of BC. In addition, the study aims to provide a greater insight into the biology of HPV-associated viruses, and assess potential strategies for treating virus-induced BC. The study additionally focuses on the rapid development of oncolytic viruses that provide a potentially novel option for the treatment of BC.

Epidemiology and Association Rules Analysis for Pulmonary Tuberculosis Cases with Extrapulmonary Tuberculosis from Age and Gender Perspective: A Large-Scale Retrospective Multicenter Observational Study in China.

Background: Tuberculosis (TB), a multisystemic disease with protean presentation, remains a major global health problem. Although concurrent pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) cases are commonly observed clinically, knowledge regarding concurrent PTB-EPTB is limited. Here, a large-scale multicenter observational study conducted in China aimed to study the epidemiology of concurrent PTB-EPTB cases by diagnostically defining TB types and then implementing association rules analysis. Methods: The retrospective study was conducted at 21 hospitals in 15 provinces in China and included all inpatients with confirmed TB diagnoses admitted from Jan 2011 to Dec 2017. Association rules analysis was conducted for cases with concurrent PTB and various types of EPTB using the Apriori algorithm. Results: Evaluation of 438,979TB inpatients indicated PTB was the most commonly diagnosed (82.05%) followed by tuberculous pleurisy (23.62%). Concurrent PTB-EPTB was found in 129,422 cases (29.48%) of which tuberculous pleurisy was the most common concurrent EPTB type observed. The multivariable logistic regression models demonstrated that odds ratios of concurrent PTB-EPTB cases varied by gender and age group. For PTB cases with concurrent EPTB, the strongest association was found between PTB and concurrent bronchial tuberculosis (lift = 1.09). For EPTB cases with concurrent PTB, the strongest association was found between pharyngeal/laryngeal tuberculosis and concurrent PTB (lift = 1.11). Confidence and lift values of concurrent PTB-EPTB cases varied with gender and age. Conclusions: Numerous concurrent PTB-EPTB case types were observed, with confidence and lift values varying with gender and age. Clinicians should screen for concurrent PTB-EPTB in order to improve treatment outcomes.

Metabolic changes in kidney stone disease.

Kidney stone disease (KSD) is one of the earliest medical diseases known, but the mechanism of its formation and metabolic changes remain unclear. The formation of kidney stones is a extensive and complicated process, which is regulated by metabolic changes in various substances. In this manuscript, we summarized the progress of research on metabolic changes in kidney stone disease and discuss the valuable role of some new potential targets. We reviewed the influence of metabolism of some common substances on stone formation, such as the regulation of oxalate, the release of reactive oxygen species (ROS), macrophage polarization, the levels of hormones, and the alternation of other substances. New insights into changes in substance metabolism changes in kidney stone disease, as well as emerging research techniques, will provide new directions in the treatment of stones. Reviewing the great progress that has been made in this field will help to improve the understanding by urologists, nephrologists, and health care providers of the metabolic changes in kidney stone disease, and contribute to explore new metabolic targets for clinical therapy.

Advancements and Challenges in Reductive Conversion of Carbon Dioxide via Thermo-/Photocatalysis.

Carbon dioxide (CO2) is the major greenhouse gas and also an abundant and renewable carbon resource. Therefore, its chemical conversion and utilization are of great attraction for sustainable development. Especially, reductive conversion of CO2 with energy input has become a current hotspot due to its ability to access fuels and various important chemicals. Nowadays, the controllable CO2 hydrogenation to formic acid and alcohols using sustainable H2 resources has been regarded as an appealing solution to hydrogen storage and CO2 accumulation. In addition, photocatalytic CO2 reduction to CO also provides a potential way to utilize this greenhouse gas efficiently. Besides direct CO2 hydrogenation, CO2 reductive functionalization integrates CO2 reduction with subsequent C-X (X = N, S, C, O) bond formation and indirect transformation strategies, enlarging the diverse products derived from CO2 and promoting CO2 reductive conversion into a new stage. In this Perspective, the progress and challenges of CO2 reductive conversion, including hydrogenation, reductive functionalization, photocatalytic reduction, and photocatalytic reductive functionalization are summarized and discussed along with the key issues and future trends/directions in this field. We hope this Perspective can evoke intense interest and inspire much innovation in the promise of CO2 valorization.

Peripheral Lymphocyte Count and Viral Clearance in COVID-19.

The objective of the study was to investigate whether the peripheral lymphocyte count was independently negative association with viral clearance time of SARS-CoV-2 in Chinese patients with COVID-19. Total 202 patients were chosen for the last data analysis. The patients' mean age was 41.39±12.47 years. Male was accounted for 48.51% and female was 51.49% respectively. The average viral clearance time was 19.40±9.03 days. Adjusted linear regression result showed peripheral lymphocyte count was associated with viral clearance time negatively after adjusting confounders (ß, -2.79; 95% CI, -5.21 to -0.36). The trend of peripheral lymphocyte count treated as a categorical variable in linear regression was also consistent with the result when peripheral lymphocyte count was treated as a continuous variable. There was a negative association between peripheral lymphocyte count and viral clearance time of SARS-CoV-2 in Chinese patients with COVID-19. Key Words: Peripheral lymphocyte count, Viral clearance, COVID-19.

Clinical features and effectiveness of Chinese medicine in patients with COVID-19 from overseas: A retrospective study in Xiamen, China.

COVID-19, referred to as new coronary pneumonia, is an acute infectious disease caused by a new type of coronavirus SARS-CoV-2. To evaluate the effect of integrated Chinese medicine and Western medicine in patients with COVID-19 from overseas. Data were collected from 178 COVID-19 patients overseas at First Affiliated Hospital of Xiamen University from April 1, 2021 to July 31, 2021. These patients received therapy of integrated Chinese medicine and western medicine. Demographic data and clinical characteristics were extracted and analyzed. In addition, the prescription which induced less length of PCR positive days and hospitalization days than the median value was obtained. The top 4 frequently used Chinese medicine and virus-related genes were analyzed by network pharmacology and bioinformatics analysis. According to the chest computed tomography (CT) measurement, abnormal lung findings were observed in 145 subjects. The median length of positive PCR/hospitalization days was 7/7 days for asymptomatic subjects, 14/24 days for mild subjects, 10/15 days for moderate subjects, and 14/20 days for severe subjects. The most frequently used Chinese medicine were Scutellaria baicalensis (Huangqin), Glycyrrhiza uralensis (Gancao), Bupleurum chinense (Chaihu), and Pinellia ternata (Banxia). The putative active ingredients were baicalin, stigmasterol, sigmoidin-B, cubebin, and troxerutin. ACE, SARS-CoV-2 3CL, SARS-CoV-2 Spike, SARS-CoV-2 ORF7a, and caspase-6 showed good binding properties to active ingredients. In conclusion, the clinical results showed that integrated Chinese medicine and Western medicine are effective in treating COVID-19 patients from overseas. Based on the clinical outcomes, the putative ingredients from Chinese medicine and the potential targets of SARS-CoV-2 were provided, which could provide a reference for the clinical application of Chinese medicine in treating COVID-19 worldwide.

Biomass-Based N-Rich Porous Carbon Materials for CO2 Capture and in-situ Conversion.

Capturing CO2 and subsequently converting into valuable chemicals has attracted extensive attention. Herein, a series of biomass-based N-rich porous carbon materials with high specific surface area and pore volume were prepared using biomass waste soybean dregs as precursors. The nitrogen content was up to 4 % with different forms in the carbon skeleton such as pyridine-N, pyrrole-N. The synergistic effect of ultra-micropore (pore size <0.7 nm) and N-containing groups endowed the materials with a high CO2 adsorption capacity, reaching 6.3 and 3.6 mmol g-1 at 0 and 25 °C under atmospheric pressure, respectively. In addition, the sufficient interaction between N-containing groups and CO2 was demonstrated by solid-state nuclear magnetic resonance spectroscopy, and the captured CO2 was possibly activated in the form of carbamate, which is conducive to subsequent conversion. Therefore, the supported catalyst with the as-synthetic porous carbon material as the carrier and ZnII as catalytic sites was prepared and successfully applied for carboxylative cyclization of propargylic amine with CO2 to afford the 3-benzyl-5-methyleneoxazolidin-2-one. The results showed that CO2 capture and in-situ conversion work effectively to produce highly value-added chemicals. In this process, the captured CO2 could be activated and fixed into chemicals in mild conditions. More importantly, the energy consumption in CO2 desorption and adsorbent regeneration could be avoided. The valorization of both solid waste and CO2 to valuable chemicals provides an elegant strategy of killing three birds with one stone.

Cell-based reporter assays for measurements of antibody-mediated cellular cytotoxicity and phagocytosis against SARS-CoV-2 spike protein.

The COVID-19 pandemic caused by SARS-CoV-2 infections has led to excess deaths worldwide. Neutralizing antibodies (nAbs) against viral spike protein acquired from natural infections or vaccinations contribute to protection against new- and re-infections. Besides neutralization, antibody-mediated cellular cytotoxicity (ADCC) and phagocytosis (ADCP) are also important for viral clearance. However, due to the lack of convenient methods, the ADCC and ADCP responses elicited by viral infections or vaccinations remain to be explored. Here, we developed cell-based assays using target cells stably expressing SARS-CoV-2 spikes and Jurkat-NFAT-CD16a/CD32a effector cells for ADCC/ADCP measurements of monoclonal antibodies and human convalescent COVID-19 plasmas (HCPs). In control samples (n = 190), the specificity was 99.5% (95%CI: 98.4-100%) and 97.4% (95%CI: 95.1-99.6%) for the ADCC and ADCP assays, respectively. Among 87 COVID-19 HCPs, 83 (sensitivity: 95.4%, 95%CI: 91.0-99.8%) and 81 (sensitivity: 93.1%, 95%CI: 87.8-98.4%) showed detectable ADCC (titer range: 7.4-1721.6) and ADCP activities (titer range: 4-523.2). Notably, both ADCC and ADCP antibody titers positively correlated with the nAb titers in HCPs. In summary, we developed new tools for quantitative ADCC and ADCP analysis against SARS-CoV-2, which may facilitate further evaluations of Fc-mediated effector functions in preventing and treating against SARS-CoV-2.

Identification of serum metabolites enhancing inflammatory responses in COVID-19.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by a strong production of inflammatory cytokines such as TNF and IL-6, which underlie the severity of the disease. However, the molecular mechanisms responsible for such a strong immune response remains unclear. Here, utilizing targeted tandem mass spectrometry to analyze serum metabolome and lipidome in COVID-19 patients at different temporal stages, we identified that 611 metabolites (of 1,039) were significantly altered in COVID-19 patients. Among them, two metabolites, agmatine and putrescine, were prominently elevated in the serum of patients; and 2-quinolinecarboxylate was changed in a biphasic manner, elevated during early COVID-19 infection but levelled off. When tested in mouse embryonic fibroblasts (MEFs) and macrophages, these 3 metabolites were found to activate the NF-κB pathway that plays a pivotal role in governing cytokine production. Importantly, these metabolites were each able to cause strong increase of TNF and IL-6 levels when administered to wildtype mice, but not in the mice lacking NF-κB. Intriguingly, these metabolites have little effects on the activation of interferon regulatory factors (IRFs) for the production of type I interferons (IFNs) for antiviral defenses. These data suggest that circulating metabolites resulting from COVID-19 infection may act as effectors to elicit the peculiar systemic inflammatory responses, exhibiting severely strong proinflammatory cytokine production with limited induction of the interferons. Our study may provide a rationale for development of drugs to alleviate inflammation in COVID-19 patients.

Highly Robust Rhenium(I) Bipyridyl Complexes Containing Dipyrromethene-BF2 Chromophores for Visible Light-Driven CO2 Reduction.

New rhenium bipyridyl complexes with dipyrromethene-BF2 chromophores (A-ReBDP-CZ, A-ReBDP2 , ReBDP-CZ, and ReBDP2 ) were developed for highly efficient photocatalytic carbon dioxide (CO2 ) reduction to carbon monoxide (CO). These catalysts consisted of two moderate electron-deficient groups (dipyrromethene-BF2 , BDP) as the visible-light-harvesting antenna as well as both electron donor (N-phenylcarbazole, CZ) and acceptor (BDP) on Re bipyridyl framework. Among ReBDP-CZ and ReBDP2 complexes, the ReBDP2 incorporating two electron-deficient BDP chromophores had a longer-lived photoexcited state (182.4 µs) and a twofold enhanced molar absorption coefficient (ϵ=157000 m-1 cm-1 ) compared with ReBDP-CZ. Thus, ReBDP2 achieved the superior photocatalytic reactivity and stability with a CO turnover number (TONCO ) value as high as 1323 and quantum yield (ΦCO ) up to 55 %, which was the most excellent photocatalysis efficiency among the single-active-site Re catalysts without additional photosensitizer. Furthermore, the acetylene-bridged linker was detrimental to the photoactivity and durability of the catalyst. In brief, two BDP-based Re bipyridyl systems with outstanding catalytic performance and significant visible-light-harvesting capabilities in the solar spectrum offer a promising strategy for solar-to-fuel conversion schemes.

Visible light-driven carbamoyloxylation of the α-C(sp3)-H bond of arylacetones via radical-initiated hydrogen atom transfer.

Photocatalytic synthesis has emerged as an efficient route to transform CO2 into functionalized organic carbamates by photocatalysis. Herein, a catalyst-free carbamoyloxylation of arylacetones with CO2 and amines under visible light was developed for the synthesis of O-ß-oxoalkyl carbamates in yields up to 93%. This protocol proceeded smoothly with the assistance of inexpensive carbon tetrabromide at room temperature under atmospheric CO2 pressure, leading to simultaneous construction of C-O and C-N bonds. Mechanism studies suggested the photoinduced hydrogen atom transfer (HAT) pathway followed by radical addition or single electron transfer (SET).

Whole blood GBP5 protein levels in patients with and without active tuberculosis.

BACKGROUND: The host blood transcriptional levels of several genes, such as guanylate binding protein 5 (GBP5), have been reported as potential biomarkers for active tuberculosis (aTB) diagnosis. The aim of this study was to investigate whole blood GBP5 protein levels in aTB and non-tuberculosis patients. METHODS: An in-house immunoassay for testing GBP5 protein levels in whole blood was developed, and suspected aTB patients were recruited. Whole blood samples were collected and tested at enrolment using interferon-gamma release assay (IGRA) and the GBP5 assay. RESULTS: A total of 470 participants were enrolled, and 232 and 238 patients were finally diagnosed with aTB and non-TB, respectively. The GBP5 protein levels of aTB patients were significantly higher than those of non-tuberculosis patients (p < 0.001), and the area under the ROC curve of the GBP5 assay for aTB diagnosis was 0.76. The reactivity of the GBP5 assay between pulmonary and extrapulmonary tuberculosis patients was comparable (p = 0.661). With the optimal cut-off value, the sensitivity and specificity of the GBP5 assay for diagnosing aTB were 78.02 and 66.81%, respectively, while those of IGRA were 77.59 and 76.47%. The combination of the GBP5 assay and IGRA results in 88.52% accuracy for diagnosing aTB in 63.83% of suspected patients with a positive predictive value of 89.57% and a negative predictive value of 87.59%. CONCLUSIONS: Whole blood GBP5 protein is a valuable biomarker for diagnosing of aTB. This study provides an important idea for realizing the clinical application of whole blood transcriptomics findings by immunological methods.

OncoSplicing: an updated database for clinically relevant alternative splicing in 33 human cancers.

Alternative splicing (AS) represents a crucial method in mRNA level to regulate gene expression and contributes to the protein complexity. Abnormal splicing has been reported to play roles in several diseases, including cancers. We developed the OncoSplicing database for visualization of survival-associated and differential alternative splicing in 2019. Here, we provide an updated version of OncoSplicing for an integrative view of clinically relevant alternative splicing based on 122 423 AS events across 33 cancers in the TCGA SpliceSeq project and 238 558 AS events across 32 cancers in the TCGA SplAdder project. The new version of the database contains several useful features, such as annotation of alternative splicing-associated transcripts, survival analysis based on median and optimal cut-offs, differential analysis between TCGA tumour samples and adjacent normal samples or GTEx normal samples, pan-cancer views of alternative splicing, splicing differences and results of Cox'PH regression, identification of clinical indicator-relevant and cancer-specific splicing events, and downloadable splicing data in the SplAdder project. Overall, the substantially updated version of OncoSplicing (www.oncosplicing.com) is a user-friendly and registration-free database for browsing and searching clinically relevant alternative splicing in human cancers.