Prognostic value of FGFR2 alterations in patients with iCCA undergoing surgery or systemic treatments: A meta-analysis.

BACKGROUND: Over recent years, there has been a notable rise in the incidence of intrahepatic cholangiocarcinoma (iCCA), which presents a significant challenge in treatment due to its complex disease characteristics and prognosis. Notably, the identification of fibroblast growth factor receptor 2 (FGFR2) fusion/rearrangement, a potential oncogenic driver primarily observed in iCCA, raises questions about its impact on the prognostic outcomes of patients undergoing surgical intervention or other therapeutic approaches. METHODS: A comprehensive search from inception to July 2023 was conducted across PubMed, Embase, Web of Science, and the Cochrane Library databases. The objective was to identify relevant publications comparing the prognosis of FGFR2 alterations and no FGFR2 alterations groups among patients with iCCA undergoing surgical resection or other systemic therapies. The primary outcome indicators, specifically Overall Survival (OS) and Disease-Free Survival (DFS), were estimated using Hazard Ratios (HRs) with 95% confidence intervals (CIs), and statistical significance was defined as p < .05. Study quality was assessed using the Newcastle-Ottawa Quality Assessment Scale. Statistical analyses were performed using Review Manager 5.4 software and Stata, version 12.0. RESULTS: Six studies, involving 1314 patients (FGFR2 alterations group n = 173 and no FGFR2 alterations group n = 1141), were included in the meta-analysis. The analysis revealed that the FGFR2 alterations group exhibited a significantly better OS prognosis compared to the no FGFR2 alterations group, with a fixed-effects combined effect size HR = 1.31, 95%CI = 1.001-1.715, p = .049. Furthermore, meta-regression and subgroup analysis showed that the length of the follow-up period did not introduce heterogeneity into the results. This finding indicates the stability and reliability of the study outcomes. CONCLUSION: The current study provides compelling evidence that FGFR2 alterations are frequently associated with improved survival outcomes for patients with iCCA undergoing surgical resection or other systemic treatments. Additionally, the study suggests that FGFR2 holds promise as a safe and dependable therapeutic target for managing metastatic, locally advanced or unresectable iCCA. This study offers a novel perspective in the realm of targeted therapy for iCCA, presenting a new and innovative approach to its treatment.

Aqueous Graphene Dispersion and Biofunctionalization via Enzymatic Oxidation of Tripeptides.

Graphene, a 2D carbon material, possesses extraordinary mechanical, electrical, and thermal properties, making it highly attractive for various biological applications such as biosensing, biotherapeutics, and tissue engineering. However, the tendency of graphene sheets to aggregate and restack hinders its dispersion in water, limiting these applications. Peptides, with their defined amino acid sequences and versatile functionalities, are compelling molecules with which to modify graphene-aromatic amino acids can strengthen interactions through π-stacking and charged groups can be chosen to make the sheets dispersible and stable in water. Here, a facile and green method for covalently functionalizing and dispersing graphene using amphiphilic tripeptides, facilitated by a tyrosine phenol side chain, through an aqueous enzymatic oxidation process is demonstrated. The presence of a second aromatic side chain group enhances this interaction through non-covalent support via π-π stacking with the graphene surface. Futhermore, the addition of charged moieties originating from either ionizable amino acids or terminal groups facilitates profound interactions with water, resulting in the dispersion of the newly functionalized graphene in aqueous solutions. This biofunctionalization method resulted in ≈56% peptide loading on the graphene surface, leading to graphene dispersions that remain stable for months in aqueous solutions outperforming currently used surfactants.

Comparison for the diagnostic performance of early diagnostic methods for biliary atresia: a systematic review and network meta-analysis.

BACKGROUND: Biliary atresia (BA), a progressive condition affecting canalicular-bile duct function/anatomy, requires prompt surgical intervention for favorable outcomes. Therefore, we conducted a network meta-analysis of common diagnostic methods to assess their performance and provide evidence-based support for clinical decision-making. METHODS: We reviewed literature in PubMed, EMBASE, and Cochrane for BA diagnostics. The search included gamma-glutamyl transferase (GGT), direct/combined bilirubin, matrix metalloproteinase 7 (MMP-7), ultrasonic triangular cord sign (TCS), hepatic scintigraphy (HS), and percutaneous cholangiocholangiography/percutaneous transhepatic cholecysto-cholangiography (PCC/PTCC). QUADAS-2 assessed study quality. Heterogeneity and threshold effect were evaluated using I2 and Spearman's correlation. We combined effect estimates, constructed SROC models, and conducted a network meta-analysis based on the ANOVA model, along with meta-regression and subgroup analysis, to obtain precise diagnostic performance assessments for BA. RESULTS: A total of 40 studies were included in our analysis. GGT demonstrated high diagnostic accuracy for BA with a sensitivity of 81.5% (95% CI 0.792-0.836) and specificity of 72.1% (95% CI 0.693-0.748). Direct bilirubin/conjugated bilirubin showed a sensitivity of 87.6% (95% CI 0.833-0.911) but lower specificity of 59.4% (95% CI 0.549-0.638). MMP-7 exhibited a total sensitivity of 91.5% (95% CI 0.893-0.934) and a specificity of 84.3% (95% CI 0.820-0.863). TCS exhibited a sensitivity of 58.1% (95% CI 0.549-0.613) and high specificity of 92.9% (95% CI 0.911-0.944). HS had a high sensitivity of 98.4% (95% CI 0.968-0.994) and moderate specificity of 79.0% (95% CI 0.762-0.816). PCC/PTCC exhibited excellent diagnostic performance with a sensitivity of 100% (95% CI 0.900-1.000) and specificity of 87.0% (95% CI 0.767-0.939). Based on the ANOVA model, the network meta-analysis revealed that MMP-7 ranked second overall, with PCC/PTCC ranking first, both exhibiting superior diagnostic accuracy compared to other techniques. Our analysis showed no significant bias in most methodologies, but MMP-7 and hepatobiliary scintigraphy exhibited biases, with p values of 0.023 and 0.002, respectively. CONCLUSION: MMP-7 and ultrasound-guided PCC/PTCC show diagnostic potential in the early diagnosis of BA, but their clinical application is restricted due to practical limitations. Currently, the cutoff value of MMP-7 is unclear, and further evidence-based medical research is needed to firmly establish its diagnostic value. Until more evidence is available, MMP-7 is not suitable for widespread diagnostic use. Therefore, considering cost and operational simplicity, liver function tests combined with ultrasound remain the most clinically valuable non-invasive diagnostic methods for BA.

Quercetin on the properties of rice bran oil body: Focused surface charge, oxidative stability and digestive properties.

To further enhance the stability of rice bran oil body (RBOB) emulsions, this study examined the impact of various concentrations of quercetin (QU) on the microstructure, rheological properties, oxidative stability, and digestive properties of RBOB emulsions. The results indicated that by incorporating QU concentration, the particle size of RBOB emulsions could be significantly reduced to 300 nm; QU could improve the surface hydrophobicity, the emulsifying activity index and emulsification stability index of RBOB emulsions of 550, 0.078 m2/g and 50.78 min, respectively; the storage stability of RBOB emulsions was further improved; the higher concentration of QU could delay the oxidation of RBOB emulsions, among which, the 500 µmol/L concentration inhibited the strongest effect of oil oxidation. It also improved the thermal stability of RBOB emulsions. After gastrointestinal digestion, the free fatty acids release rate of RBOB emulsions with QU addition decreased to 14.68%, and RBOB emulsions were slowly hydrolyzed. Therefore, adding QU to RBOB helps to improve its stability and delay digestion.

TFEB/LAMP2 contributes to PM0.2-induced autophagy-lysosome dysfunction and alpha-synuclein dysregulation in astrocytes.

Atmospheric particulate matter (PM) exacerbates the risk factor for Alzheimer's and Parkinson's diseases (PD) by promoting the alpha-synuclein (α-syn) pathology in the brain. However, the molecular mechanisms of astrocytes involvement in α-syn pathology underlying the process remain unclear. This study investigated PM with particle size <200 nm (PM0.2) exposure-induced α-syn pathology in ICR mice and primary astrocytes, then assessed the effects of mammalian target of rapamycin inhibitor (PP242) in vitro studies. We observed the α-syn pathology in the brains of exposed mice. Meanwhile, PM0.2-exposed mice also exhibited the activation of glial cell and the inhibition of autophagy. In vitro study, PM0.2 (3, 10 and 30 µg/mL) induced inflammatory response and the disorders of α-syn degradation in primary astrocytes, and lysosomal-associated membrane protein 2 (LAMP2)-mediated autophagy underlies α-syn pathology. The abnormal function of autophagy-lysosome was specifically manifested as the expression of microtubule-associated protein light chain 3 (LC3II), cathepsin B (CTSB) and lysosomal abundance increased first and then decreased, which might both be a compensatory mechanism to toxic α-syn accumulation induced by PM0.2. Moreover, with the transcription factor EB (TFEB) subcellular localization and the increase in LC3II, LAMP2, CTSB, and cathepsin D proteins were identified, leading to the restoration of the degradation of α-syn after the intervention of PP242. Our results identified that PM0.2 exposure could promote the α-syn pathological dysregulation in astrocytes, providing mechanistic insights into how PM0.2 increases the risk of developing PD and highlighting TFEB/LAMP2 as a promising therapeutic target for antagonizing PM0.2 toxicity.

Repeated trans-spinal magnetic stimulation promotes microglial phagocytosis of myelin debris after spinal cord injury through LRP-1.

Spinal cord injury (SCI) is a serious trauma of the central nervous system. The clearance of myelin debris is a critical step in the functional recovery following spinal cord injury (SCI). Recent studies have begun to reveal critical roles for professional phagocytes in the central nervous system, microglia, and their receptors in the control of myelin debris in neurodegenerative disease. Repeated trans-spinal magnetic stimulation (rTSMS) has been demonstrated as a noninvasive SCI treatment that enhances tissue repair and functional recovery. In this study, we investigated the role and molecular mechanism of rTSMS on microglial phagocytosis of myelin debris in a rat SCI model. In our studies, we found that rTSMS significantly promoted the motor function recovery of SCI rats associated with the inhibition the neuroinflammation and glia scar formation. Immunofluorescence results further showed that the rTSMS promotes the clearance of myelin debris by microglia in vivo and in vitro. Additionally, receptor-associated protein (RAP), a Low-density lipoprotein receptor-related protein-1 (LRP-1) inhibitor, could cancel the accelerated microglial phagocytosis of myelin debris after rTSMS in vitro experiments. Simultaneously, Elisa's results and western blotting respectively showed that rTSMS significantly decreased the levels of soluble LRP-1(sLRP-1) and the LRP-1 splicing enzyme of ADAM17. In conclusion, rTSMS could promote the clearance of myelin debris by microglia through LRP-1 to improve the functional recovery of SCI rats.

Network analysis reveals context-dependent structural complexity of social calls in serrate-legged small treefrogs.

Vocal communication plays an important role in survival, reproduction, and animal social association. Birds and mammals produce complex vocal sequence to convey context-dependent information. Vocalizations are conspicuous features of the behavior of most anuran species (frogs and toads), and males usually alter their calling strategies according to ecological context to improve the attractiveness/competitiveness. However, very few studies have focused on the variation of vocal sequence in anurans. In the present study, we used both conventional method and network analysis to investigate the context-dependent vocal repertoire, vocal sequence, and call network structure in serrate-legged small treefrogs Kurixalus odontotarsus. We found that male K. odontotarsus modified their vocal sequence by switching to different call types and increasing repertoire size in the presence of a competitive rival. Specifically, compared with before and after the playback of advertisement calls, males emitted fewer advertisement calls, but more aggressive calls, encounter calls, and compound calls during the playback period. Network analysis revealed that the mean degree, mean closeness, and mean betweenness of the call networks significantly decreased during the playback period, which resulted in lower connectivity. In addition, the increased proportion of one-way motifs and average path length also indicated that the connectivity of the call network decreased in competitive context. However, the vocal sequence of K. odontotarsus did not display a clear small-world network structure, regardless of context. Our study presents a paradigm to apply network analysis to vocal sequence in anurans and has important implications for understanding the evolution and function of sequence patterns.

The impact of monotherapies for male androgenetic alopecia: A network meta-analysis study.

BACKGROUND: The evidence base pertaining to the efficacy of monotherapies for androgenetic alopecia (AGA), the most common form of hair loss, is ever expanding-and this warrants a formal comparison therapies' effect on a frequent basis. AIMS: The objective of the current study was to determine the comparative effect of relevant monotherapies for male AGA. PATIENTS/METHODS: Our aim was achieved by conducting Bayesian network meta-analysis (NMA), under a random effects model, for two outcomes: 6-month change in (1) total and (2) terminal hair density in adult (i.e., aged 18 years and above) men with AGA; these analyses were preceded by a systematic search of the peer-reviewed literature for suitable data. Interventions' surface under the cumulative ranking curve (SUCRA) and pairwise relative effects (quantified as mean differences) were estimated through the NMAs. RESULTS: We determined the comparative effect of 20 active comparators and a control (i.e., placebo/vehicle). "Dutasteride 0.5 mg once daily for 24 weeks" was ranked the most effective in terms of 6-month change in (1) total hair density (SUCRA = 87%) and terminal hair density (SUCRA = 98%). Our results showed that interventions' effectiveness can be dose dependent. CONCLUSIONS: Our updated analyses of the up-to-date evidence regarding monotherapies for male AGA showed that the oral form of 5-alpha reductase inhibitors are more effective than oral minoxidil and other newer agents like Botox, microneedling, and photobiomodulation. Our findings can better inform clinical decision making and design of future research studies.

Identification of CD5/SOX11 double-negative pleomorphic mantle cell lymphoma.

Cyclin D1 protein-positive diffuse large B cell lymphoma (DLBCL) has an immunophenotype of CD5(-) cyclin D1(+) SOX11(-), and most cases lack a CCND1 rearrangement and have a gene expression profile of DLBCL. Rarely, cyclin D1 protein-positive DLBCL harbors a CCND1 rearrangement, and some genetic copy number features typical of mantle cell lymphoma (MCL) have been detected. Since gene expression studies have not been performed, whether such CCND1-rearranged cases represent cyclin D1 protein-positive DLBCL or CD5/SOX11 double-negative pleomorphic MCL remains unclear. To date, no cases of CD5/SOX11 double-negative MCL have been reported. In this study, we collected eight cases initially diagnosed as cyclin D1 protein-positive DLBCL, including four with a CCND1 rearrangement and four without. Immunohistochemically, all four CCND1-rearranged cases had >50% of tumor cells positive for cyclin D1 protein, whereas only one (25%) non-rearranged case had >50% positive tumor cells. Analysis of genome-wide copy number, mutational, and gene expression profiles revealed that CCND1-rearranged cases were similar to MCL, whereas CCND1-non-rearranged cases resembled DLBCL. Despite the SOX11 negativity by immunohistochemistry, CCND1-rearranged cases had a notable trend (P = 0.064) of higher SOX11 mRNA levels compared to non-rearranged cases. Here, we show for the first time that CCND1 rearrangement could be useful for identifying CD5/SOX11 double-negative pleomorphic MCL in cases diagnosed as cyclin D1 protein-positive DLBCL. Cases with >50% cyclin D1 protein-positive tumor cells immunohistochemically and higher SOX11 mRNA levels are more likely to have a CCND1 rearrangement, and fluorescence in situ hybridization can be used to detect the rearrangement.

Actomyosin-II protects axons from degeneration induced by mild mechanical stress.

Whether, to what extent, and how the axons in the central nervous system (CNS) can withstand sudden mechanical impacts remain unclear. By using a microfluidic device to apply controlled transverse mechanical stress to axons, we determined the stress levels that most axons can withstand and explored their instant responses at nanoscale resolution. We found mild stress triggers a highly reversible, rapid axon beading response, driven by actomyosin-II-dependent dynamic diameter modulations. This mechanism contributes to hindering the long-range spread of stress-induced Ca2+ elevations into non-stressed neuronal regions. Through pharmacological and molecular manipulations in vitro, we found that actomyosin-II inactivation diminishes the reversible beading process, fostering progressive Ca2+ spreading and thereby increasing acute axonal degeneration in stressed axons. Conversely, upregulating actomyosin-II activity prevents the progression of initial injury, protecting stressed axons from acute degeneration both in vitro and in vivo. Our study unveils the periodic actomyosin-II in axon shafts cortex as a novel protective mechanism, shielding neurons from detrimental effects caused by mechanical stress.

The impact of sunlight exposure on brain structural markers in the UK Biobank.

Sunlight is closely intertwined with daily life. It remains unclear whether there are associations between sunlight exposure and brain structural markers. General linear regression analysis was used to compare the differences in brain structural markers among different sunlight exposure time groups. Stratification analyses were performed based on sex, age, and diseases (hypertension, stroke, diabetes). Restricted cubic spline was performed to examine the dose-response relationship between natural sunlight exposure and brain structural markers, with further stratification by season. A negative association of sunlight exposure time with brain structural markers was found in the upper tertile compared to the lower tertile. Prolonged natural sunlight exposure was associated with the volumes of total brain (ß: - 0.051, P < 0.001), white matter (ß: - 0.031, P = 0.023), gray matter (ß: - 0.067, P < 0.001), and white matter hyperintensities (ß: 0.059, P < 0.001). These associations were more pronounced in males and individuals under the age of 60. The results of the restricted cubic spline analysis showed a nonlinear relationship between sunlight exposure and brain structural markers, with the direction changing around 2 h of sunlight exposure. This study demonstrates that prolonged exposure to natural sunlight is associated with brain structural markers change.

A review of common statistical methods for dealing with multiple pollutant mixtures and multiple exposures.

Traditional environmental epidemiology has consistently focused on studying the impact of single exposures on specific health outcomes, considering concurrent exposures as variables to be controlled. However, with the continuous changes in environment, humans are increasingly facing more complex exposures to multi-pollutant mixtures. In this context, accurately assessing the impact of multi-pollutant mixtures on health has become a central concern in current environmental research. Simultaneously, the continuous development and optimization of statistical methods offer robust support for handling large datasets, strengthening the capability to conduct in-depth research on the effects of multiple exposures on health. In order to examine complicated exposure mixtures, we introduce commonly used statistical methods and their developments, such as weighted quantile sum, bayesian kernel machine regression, toxic equivalency analysis, and others. Delineating their applications, advantages, weaknesses, and interpretability of results. It also provides guidance for researchers involved in studying multi-pollutant mixtures, aiding them in selecting appropriate statistical methods and utilizing R software for more accurate and comprehensive assessments of the impact of multi-pollutant mixtures on human health.

Preparation and Performance Study of HTPB-g-(PNIPAM/PEG) Thermoresponsive Polymer Brush.

In recent years, a great deal of work has been devoted to the development of thermoresponsive polymers that can be made into new types of smart materials. In this paper, a branched polymer, HTPB-g-(PNIPAM/PEG), with polyolefin chain segments as the backbone and having polyethylene glycol (PEG) and poly(N-isopropylacrylamide) (PNIPAM) as side chains was synthesized by ATRP and click reactions using N3-HTPB-Br as the macroinitiator. This initiator was designed and synthesized using hydroxyl-terminated polybutadiene (HTPB) as the substrate. The temperature-responsive behavior of the branched polymer was investigated. The lower critical solution temperature (LCST) of the branched polymer was determined by ultraviolet and visible spectrophotometry (UV-vis) and was found to be 35.2 °C. The relationship between the diameter size of micelles and temperature was determined by dynamic light scattering (DLS). It was found that the diameter size changed at 36 °C, which was nearly consistent with the result obtained by UV-vis. The results of the study indicate that HTPB-g-(PNIPAM/PEG) is a temperature-responsive polymer. At room temperature, the polymer can self-assemble into composite micelles, with the main chain as the core and the branched chain as the shell. When the temperature was increased beyond LCST, the polyolefin main chain along with the PNIPAM branched chain assembled to form the nucleus, and the PEG branched chain constituted the shell.

Association between plasma long-chain polyunsaturated n-3 fatty acids concentrations and cognitive function: findings from NHANES III.

Background: With increased life expectancy, cognitive decline has emerged as a prevalent neurodegenerative disorder. Objective: This study aimed to examine the correlation between concentrations of Plasma long-chain n-3 polyunsaturated fatty acids (LCPUFAs) and cognitive performance in elderly Americans. Methods: Data were analyzed from older adults enrolled in two NHANES cycles. Participants completed four cognitive assessments, including the Immediate Recall Test (IRT), Delayed Recall Test (DRT), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). Linear regression and restricted cubic spline modeling examined associations between plasma LCPUFAs levels and cognitive test outcomes. Results: The cohort included 610 adults aged 69 years on average, 300 (49.2%) males and 310 (50.8%) females. The median LCPUFAs concentration was 309.4 µmol/L, with an interquartile range of 244.7-418.9 µmol/L. In unadjusted and adjusted generalized linear regression model analyses, circulating LCPUFAs exhibited significant positive correlations with DRT performance. No relationships were detected among those with chronic conditions (chronic heart failure, stroke, diabetes). A significant association between LCPUFAs levels and DRT scores was evident in males but not females. Conclusion: Plasma LCPUFAs concentrations were significantly associated with DRT performance in males free of chronic illnesses, including heart failure, stroke, and diabetes.

Polygenic risk-stratified screening for nasopharyngeal carcinoma in high-risk endemic areas of China: a cost-effectiveness study.

Background: Nasopharyngeal carcinoma (NPC) has an extremely high incidence rate in Southern China, resulting in a severe disease burden for the local population. Current EBV serologic screening is limited by false positives, and there is opportunity to integrate polygenic risk scores for personalized screening which may enhance cost-effectiveness and resource utilization. Methods: A Markov model was developed based on epidemiological and genetic data specific to endemic areas of China, and further compared polygenic risk-stratified screening [subjects with a 10-year absolute risk (AR) greater than a threshold risk underwent EBV serological screening] to age-based screening (EBV serological screening for all subjects). For each initial screening age (30-34, 35-39, 40-44, 45-49, 50-54, 55-59, 60-64, and 65-69 years), a modeled cohort of 100,000 participants was screened until age 69, and then followed until age 79. Results: Among subjects aged 30 to 54 years, polygenic risk-stratified screening strategies were more cost-effective than age-based screening strategies, and almost comprised the cost-effectiveness efficiency frontier. For men, screening strategies with a 1-year frequency and a 10-year absolute risk (AR) threshold of 0.7% or higher were cost-effective, with an incremental cost-effectiveness ratio (ICER) below the willingness to pay (¥203,810, twice the local per capita GDP). Specifically, the strategies with a 10-year AR threshold of 0.7% or 0.8% are the most cost-effective strategies, with an ICER ranging from ¥159,752 to ¥201,738 compared to lower-cost non-dominated strategies on the cost-effectiveness frontiers. The optimal strategies have a higher probability (29.4-35.8%) of being cost-effective compared to other strategies on the frontier. Additionally, they reduce the need for nasopharyngoscopies by 5.1-27.7% compared to optimal age-based strategies. Likewise, for women aged 30-54 years, the optimal strategy with a 0.3% threshold showed similar results. Among subjects aged 55 to 69 years, age-based screening strategies were more cost-effective for men, while no screening may be preferred for women. Conclusion: Our economic evaluation found that the polygenic risk-stratified screening could improve the cost-effectiveness among individuals aged 30-54, providing valuable guidance for NPC prevention and control policies in endemic areas of China.

Protective Mechanisms of SGLTi in Ischemic Heart Disease.

Ischemic heart disease (IHD) is a common clinical cardiovascular disease with high morbidity and mortality. Sodium glucose cotransporter protein inhibitor (SGLTi) is a novel hypoglycemic drug. To date, both clinical trials and animal experiments have shown that SGLTi play a protective role in IHD, including myocardial infarction (MI) and ischemia/reperfusion (I/R). The protective effects may be involved in mechanisms of energy metabolic conversion, anti-inflammation, anti-fibrosis, ionic homeostasis improvement, immune cell development, angiogenesis and functional regulation, gut microbiota regulation, and epicardial lipids. Thus, this review summarizes the above mechanisms and aims to provide theoretical evidence for therapeutic strategies for IHD.

Molecular transmission network and drug resistance in treatment-naïve HIV-1 infected patients in the Liangshan District, China.

Objective This study aimed to investigate the molecular transmission network and drug resistance in treatment-naïve HIV-1 infected patients in the Liangshan District, China. Methods The research subjects for this study were HIV-1 infected patients who did not receive any anti-retroviral therapy (ART) in the Liangshan District between January 2022 and July 2023. Peripheral venous whole blood samples were collected from the research subjects. 2 mL blood was used for CD4+ T lymphocyte counting detection. 10 mL blood was centrifuged to separate the plasma and blood cells for quantitative detection of HIV-1 RNA and DNA and drug resistance testing of HIV-1. Results A total of 156 participants were included in this study (88 males and 68 females). The median age of the participants was 37 years old. The findings revealed a positive correlation between the HIV-1 DNA and the HIV-1 RNA levels (r=0.478, P<0.001). However, a negative correlation was observed between HIV-1 DNA levels and CD4+ T lymphocyte counts (r=-0.186, P=0.020). Of the 156 participants, 148 were successfully tested for drug resistance of HIV-1 RNA and HIV-1 DNA simultaneously. Four cases failed the HIV-1 RNA drug resistance testing, and another four failed the HIV-1 DNA drug resistance testing. The most common HIV-1 subtype was the CRF07_BC recombinant. In this study, the overall incidence of transmitted drug resistance (TDR) was 8.33%. The resistance rates of non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI) were 7.69% and 0.64%, respectively. Additionally, 32 participants were found to have drug-resistant mutations. The primary drug-resistant mutations were K103N, V179D, E157Q, and A128T, mainly against efavirenz (EFV) and nevirapine (NVP) resistance. Conclusion The drug resistance of HIV-1 infected ART-naïve patients in the Liangshan District cannot be ignored. HIV-1 drug resistance testing is recommended before initiating ART.

Pairing metagenomics and metaproteomics to characterize ecological niches and metabolic essentiality of gut microbiomes.

The genome of a microorganism encodes its potential functions that can be implemented through expressed proteins. It remains elusive how a protein's selective expression depends on its metabolic essentiality to microbial growth or its ability to claim resources as ecological niches. To reveal a protein's metabolic or ecological role, we developed a computational pipeline, which pairs metagenomics and metaproteomics data to quantify each protein's gene-level and protein-level functional redundancy simultaneously. We first illustrated the idea behind the pipeline using simulated data of a consumer-resource model. We then validated it using real data from human and mouse gut microbiome samples. In particular, we analyzed ABC-type transporters and ribosomal proteins, confirming that the metabolic and ecological roles predicted by our pipeline agree well with prior knowledge. Finally, we performed in vitro cultures of a human gut microbiome sample and investigated how oversupplying various sugars involved in ecological niches influences the community structure and protein abundance. The presented results demonstrate the performance of our pipeline in identifying proteins' metabolic and ecological roles, as well as its potential to help us design nutrient interventions to modulate the human microbiome.

Sources, trigger points, and effect size of associations between PM2.5-bound polycyclic aromatic hydrocarbons (PAHs) and fractional exhaled nitric oxide (FeNO): A panel study with 16 follow-up visits over 4 years.

Exposure to fine particulate matter (PM2.5) is a significant concern for respiratory health. However, the sources, trigger points, and effect size of specific associations between PM2.5 components, particularly polycyclic aromatic hydrocarbons (PAHs) and the airway inflammatory marker fractional exhaled nitric oxide (FeNO) have not been fully explored. In this study, 69 healthy college students were enrolled and followed up 16 times from 2014 to 2018. Individual FeNO was measured and ambient air PM2.5 samples were collected for 7 consecutive days before each follow-up. PAHs were quantified using Gas Chromatography-Mass Spectrometry. Linear mixed-effect regression models were employed to evaluate the associations between PM2.5-bound PAHs and FeNO. Additionally, PMF (Positive Matrix Factorization) was utilized to identify sources of PM2.5-bound PAHs and assess their impact on FeNO. Throughout the study, the average (SD) of ΣPAHs concentrations was 78.50 (128.9) ng/m3. PM2.5 and PM2.5-bound PAHs were significantly associated with FeNO at various lag days. Single-day lag analyses revealed maximum effects of PM2.5 on FeNO, with an increase of 7.71% (95% CI: 4.67%, 10.83%) per interquartile range (IQR) (48.10 µg/m3) increase of PM2.5 at lag2, and ΣPAHs showed a maximum elevation in FeNO of 6.40% (95% CI: 2.33%, 10.63%) at lag4 per IQR (57.39 ng/m3) increase. Individual PAHs exhibited diversity peak effects on FeNO at lag3 (6 of 17), lag4 (9 of 17) in the single-day model, and lag0-5 (8 of 17) (from lag0-1 to lag0-6) in the cumulative model. Source apportionment indicated coal combustion as the primary contributor (accounting for 30.7%). However, a maximum effect on FeNO (an increase of 21.57% (95% CI: 13.58%, 30.13%) per IQR increase) was observed with traffic emissions at lag4. The findings imply that strategic regulation of particular sources of PAHs, like traffic emissions, during specific periods could significantly contribute to safeguarding public health.

Nicotinamide phosphoribosyltransferase prompts bleomycin-induced pulmonary fibrosis by driving macrophage M2 polarization in mice.

Rationale: Idiopathic pulmonary fibrosis (IPF) is an irreversible, fatal interstitial lung disease lacking specific therapeutics. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the nicotinamide adenine dinucleotide (NAD) salvage biosynthesis pathway and a cytokine, has been previously reported as a biomarker for lung diseases; however, the role of NAMPT in pulmonary fibrosis has not been elucidated. Methods: We identified the NAMPT level changes in pulmonary fibrosis by analyzing public RNA-Seq databases, verified in collected clinical samples and mice pulmonary fibrosis model by Western blotting, qRT-PCR, ELISA and Immunohistochemical staining. We investigated the role and mechanism of NAMPT in lung fibrosis by using pharmacological inhibition on NAMPT and Nampt transgenic mice. In vivo macrophage depletion by clodronate liposomes and reinfusion of IL-4-induced M2 bone marrow-derived macrophages (BMDMs) from wild-type mice, combined with in vitro cell experiments, were performed to further validate the mechanism underlying NAMPT involving lung fibrosis. Results: We found that NAMPT increased in the lungs of patients with IPF and mice with bleomycin (BLM)-induced pulmonary fibrosis. NAMPT inhibitor FK866 alleviated BLM-induced pulmonary fibrosis in mice and significantly reduced NAMPT levels in bronchoalveolar lavage fluid (BALF). The lung single-cell RNA sequencing showed that NAMPT expression in monocytes/macrophages of IPF patients was much higher than in other lung cells. Knocking out NAMPT in mouse monocytes/macrophages (Namptfl/fl;Cx3cr1CreER) significantly alleviated BLM-induced pulmonary fibrosis in mice, decreased NAMPT levels in BALF, reduced the infiltration of M2 macrophages in the lungs and improved mice survival. Depleting monocytes/macrophages in Namptfl/fl;Cx3cr1CreER mice by clodronate liposomes and subsequent pulmonary reinfusion of IL-4-induced M2 BMDMs from wild-type mice, reversed the protective effect of monocyte/macrophage NAMPT-deletion on lung fibrosis. In vitro experiments confirmed that the mechanism of NAMPT engaged in pulmonary fibrosis is related to the released NAMPT by macrophages promoting M2 polarization in a non-enzyme-dependent manner by activating the STAT6 signal pathway. Conclusions: NAMPT prompts bleomycin-induced pulmonary fibrosis by driving macrophage M2 polarization in mice. Targeting the NAMPT of monocytes/macrophages is a promising strategy for treating pulmonary fibrosis.