Interpretable feature extraction and dimensionality reduction in ESM2 for protein localization prediction.

As the application of large language models (LLMs) has broadened into the realm of biological predictions, leveraging their capacity for self-supervised learning to create feature representations of amino acid sequences, these models have set a new benchmark in tackling downstream challenges, such as subcellular localization. However, previous studies have primarily focused on either the structural design of models or differing strategies for fine-tuning, largely overlooking investigations into the nature of the features derived from LLMs. In this research, we propose different ESM2 representation extraction strategies, considering both the character type and position within the ESM2 input sequence. Using model dimensionality reduction, predictive analysis and interpretability techniques, we have illuminated potential associations between diverse feature types and specific subcellular localizations. Particularly, the prediction of Mitochondrion and Golgi apparatus prefer segments feature closer to the N-terminal, and phosphorylation site-based features could mirror phosphorylation properties. We also evaluate the prediction performance and interpretability robustness of Random Forest and Deep Neural Networks with varied feature inputs. This work offers novel insights into maximizing LLMs' utility, understanding their mechanisms, and extracting biological domain knowledge. Furthermore, we have made the code, feature extraction API, and all relevant materials available at https://github.com/yujuan-zhang/feature-representation-for-LLMs.

Mycoplasma glycine cleavage system key subunit GcvH is an apoptosis inhibitor targeting host endoplasmic reticulum.

Mycoplasmas are minimal but notorious bacteria that infect humans and animals. These genome-reduced organisms have evolved strategies to overcome host apoptotic defense and establish persistent infection. Here, using Mycoplasma bovis as a model, we demonstrate that mycoplasma glycine cleavage system (GCS) H protein (GcvH) targets the endoplasmic reticulum (ER) to hijack host apoptosis facilitating bacterial infection. Mechanically, GcvH interacts with the ER-resident kinase Brsk2 and stabilizes it by blocking its autophagic degradation. Brsk2 subsequently disturbs unfolded protein response (UPR) signaling, thereby inhibiting the key apoptotic molecule CHOP expression and ER-mediated intrinsic apoptotic pathway. CHOP mediates a cross-talk between ER- and mitochondria-mediated intrinsic apoptosis. The GcvH N-terminal amino acid 31-35 region is necessary for GcvH interaction with Brsk2, as well as for GcvH to exert anti-apoptotic and potentially pro-infective functions. Notably, targeting Brsk2 to dampen apoptosis may be a conserved strategy for GCS-containing mycoplasmas. Our study reveals a novel role for the conserved metabolic route protein GcvH in Mycoplasma species. It also sheds light on how genome-reduced bacteria exploit a limited number of genomic proteins to resist host cell apoptosis thereby facilitating pathogenesis.

Mycoplasma hyopneumoniae inhibits the unfolded protein response to prevent host macrophage apoptosis and M2 polarization.

Enzootic pneumonia caused by Mycoplasma hyopneumoniae (M. hyopneumoniae) has inflicted substantial economic losses on the global pig industry. The progression of M. hyopneumoniae induced-pneumonia is associated with lung immune cell infiltration and extensive proinflammatory cytokine secretion. Our previous study established that M. hyopneumoniae disrupts the host unfolded protein response (UPR), a process vital for the survival and immune function of macrophages. In this study, we demonstrated that M. hyopneumoniae targets the UPR- and caspase-12-mediated endoplasmic reticulum (ER)-associated classical intrinsic apoptotic pathway to interfere with host cell apoptosis signaling, thereby preserving the survival of host tracheal epithelial cells (PTECs) and alveolar macrophages (PAMs) during the early stages of infection. Even in the presence of apoptosis inducers, host cells infected with M. hyopneumoniae exhibited an anti-apoptotic potential. Further analyses revealed that M. hyopneumoniae suppresses the three UPR branches and their induced apoptosis. Interestingly, while UPR activation typically drives host macrophages toward an M2 polarization phenotype, M. hyopneumoniae specifically obstructs this process to maintain a proinflammatory phenotype in the host macrophages. Overall, our findings propose that M. hyopneumoniae inhibits the host UPR to sustain macrophage survival and a proinflammatory phenotype, which may be implicated in its pathogenesis in inducing host pneumonia.

Comparative transcriptome and coexpression network analysis revealed the regulatory mechanism of Astragalus cicer L. in response to salt stress.

BACKGROUND: Astragalus cicer L. is a perennial rhizomatous legume forage known for its quality, high biomass yield, and strong tolerance to saline-alkaline soils. Soil salinization is a widespread environmental pressure. To use A. cicer L. more scientifically and environmentally in agriculture and ecosystems, it is highly important to study the molecular response mechanism of A. cicer L. to salt stress. RESULTS: In this study, we used RNA-seq technology and weighted gene coexpression network analysis (WGCNA) were performed. The results showed 4 key modules were closely related to the physiological response of A. cicer. L. to salt stress. The differentially expressed genes (DEGs) of key modules were mapped into the KEGG database, and found that the most abundant pathways were the plant hormone signal transduction pathway and carbon metabolism pathway. The potential regulatory networks of the cytokinin signal transduction pathway, the ethylene signal transduction pathway, and carbon metabolism related pathways were constructed according to the expression pathways of the DEGs. Seven hub genes in the key modules were selected and distributed among these pathways. They may involved in the positive regulation of cytokinin signaling and carbon metabolism in plant leaves, but limited the positive expression of ethylene signaling. Thus endowing the plant with salt tolerance in the early stage of salt stress. CONCLUSIONS: Based on the phenotypic and physiological responses of A. cicer L. to salt stress, this study constructed the gene coexpression network of potential regulation to salt stress in key modules, which provided a new reference for exploring the response mechanism of legumes to abiotic stress.

Tumor Microenvironment Specific Regulation Ca-Fe-Nanospheres for Ferroptosis-Promoted Domino Synergistic Therapy and Tumor Immune Response.

Reactive oxygen species (ROS)-mediated emerging treatments exhibit unique advantages in cancer therapy in recent years. While the efficacy of ROS-involved tumor therapy is greatly restricted by complex tumor microenvironment (TME). Herein, a dual-metal CaO2@CDs-Fe (CCF) nanosphere, with TME response and regulation capabilities, are proposed to improve ROS lethal power by a multiple cascade synergistic therapeutic strategy with domino effect. In response to weak acidic TME, CCF will decompose, accompanied with intracellular Ca2+ upregulated and abundant H2O2 and O2 produced to reverse antitherapeutic TME. Then the exposed CF cores can act as both Fenton agent and sonosensitizer to generate excessive ROS in the regulated TME for enhanced synergistic CDT/SDT. In combination with calcium overloading, the augmented ROS induced oxidative stress will cause more severe mitochondrial damage and cellular apoptosis. Furthermore, CCF can also reduce GPX4 expression and enlarge the lipid peroxidation, causing ferroptosis and apoptosis in parallel. These signals of damage will finally initiate damage-associated molecular patterns to activate immune response and to realize excellent antitumor effect. This outstanding domino ROS/calcium loading synergistic effect endows CCF with excellent anticancer effect to efficiently eliminate tumor by apoptosis/ferroptosis/ICD both in vitro and in vivo.

Reducing Indoor Particulate Air Pollution Improves Student Test Scores: A Randomized Double-Blind Crossover Study.

Short-term exposure to air pollution is associated with a decline in cognitive function. Standardized test scores have been employed to evaluate the effects of air pollution exposure on cognitive performance. Few studies aimed to prove whether air pollution is responsible for reduced test scores; none have implemented a "gold-standard" method for assessing the association such as a randomized, double-blind intervention. This study used a "gold-standard" method─randomized, double-blind crossover─to assess whether reducing short-term indoor particle concentrations results in improved test scores in college students in Tianjin, China. Participants (n = 162) were randomly assigned to one of two similar classrooms and completed a standardized English test on two consecutive weekends. Air purifiers with active or sham (i.e., filter removed) particle filtration were placed in each classroom. The filtration mode was switched between the two test days. Linear mixed-effect models were used to evaluate the effect of the intervention mode on the test scores. The results show that air purification (i.e., reducing PM) was significantly associated with increases in the z score for combined (0.11 [95%CI: 0.02, 0.21]) and reading (0.11 [95%CI: 0.00, 0.22]) components. In conclusion, a short-term reduction in indoor particle concentration led to improved test scores in students, suggesting an improvement in cognitive function.

Characteristics of Trypsin genes and their roles in insecticide resistance based on omics and functional analyses in the malaria vector Anopheles sinensis.

Trypsin is one of the most diverse and widely studied protease hydrolases. However, the diversity and characteristics of the Trypsin superfamily of genes have not been well understood, and their role in insecticide resistance is yet to be investigated. In this study, a total of 342 Trypsin genes were identified and classified into seven families based on homology, characteristic domains and phylogenetics in Anopheles sinensis, and the LY-Domain and CLECT-Domain families are specific to the species. Four Trypsin genes, (Astry2b, Astry43a, Astry90, Astry113c) were identified to be associated with pyrethroid resistance based on transcriptome analyses of three field resistant populations and qRT-PCR validation, and the knock-down of these genes significantly decrease the pyrethroid resistance of Anopheles sinensis based on RNAi. The activity of Astry43a can be reduced by five selected insecticides (indoxacarb, DDT, temephos, imidacloprid and deltamethrin); and however, the Astry43a could not directly metabolize these five insecticides, like the trypsin NYD-Tr did in earlier reports. This study provides the overall information frame of Trypsin genes, and proposes the role of Trypsin genes to insecticide resistance. Further researches are necessary to investigate the metabolism function of these trypsins to insecticides.

Engineering of g-C3N4 for Photocatalytic Hydrogen Production: A Review.

Graphitic carbon nitride (g-C3N4)-based photocatalysts have garnered significant interest as a promising photocatalyst for hydrogen generation under visible light, to address energy and environmental challenges owing to their favorable electronic structure, affordability, and stability. In spite of that, issues such as high charge carrier recombination rates and low quantum efficiency impede its broader application. To overcome these limitations, structural and morphological modification of the g-C3N4-based photocatalysts is a novel frontline to improve the photocatalytic performance. Therefore, we briefly summarize the current preparation methods of g-C3N4. Importantly, this review highlights recent advancements in crafting high-performance g-C3N4-based photocatalysts, focusing on strategies like elemental doping, nanostructure design, bandgap engineering, and heterostructure construction. Notably, sophisticated doping techniques have propelled hydrogen production rates to a 104-fold increase. Ingenious nanostructure designs have expanded the surface area by a factor of 26, concurrently extending the fluorescence lifetime of charge carriers by 50%. Moreover, the strategic assembly of heterojunctions has not only elevated charge carrier separation efficiency but also preserved formidable redox properties, culminating in a dramatic hundredfold surge in hydrogen generation performance. This work provides a reliable and brief overview of the controlled modification engineering of g-C3N4-based photocatalyst systems, paving the way for more efficient hydrogen production.

Drug Repurposing for COVID-19 by Constructing a Comorbidity Network with Central Nervous System Disorders.

In the post-COVID-19 era, treatment options for potential SARS-CoV-2 outbreaks remain limited. An increased incidence of central nervous system (CNS) disorders has been observed in long-term COVID-19 patients. Understanding the shared molecular mechanisms between these conditions may provide new insights for developing effective therapies. This study developed an integrative drug-repurposing framework for COVID-19, leveraging comorbidity data with CNS disorders, network-based modular analysis, and dynamic perturbation analysis to identify potential drug targets and candidates against SARS-CoV-2. We constructed a comorbidity network based on the literature and data collection, including COVID-19-related proteins and genes associated with Alzheimer's disease, Parkinson's disease, multiple sclerosis, and autism spectrum disorder. Functional module detection and annotation identified a module primarily involved in protein synthesis as a key target module, utilizing connectivity map drug perturbation data. Through the construction of a weighted drug-target network and dynamic network-based drug-repurposing analysis, ubiquitin-carboxy-terminal hydrolase L1 emerged as a potential drug target. Molecular dynamics simulations suggested pregnenolone and BRD-K87426499 as two drug candidates for COVID-19. This study introduces a dynamic-perturbation-network-based drug-repurposing approach to identify COVID-19 drug targets and candidates by incorporating the comorbidity conditions of CNS disorders.

Asymmetric Synthesis of Three Alkenyl Epoxides: Crafting the Sex Pheromones of the Elm Spanworm and the Painted Apple Moth.

A concise synthesis of the sex pheromones of elm spanworm as well as painted apple moth has been achieved. The key steps were the alkylation of acetylide ion, Sharpless asymmetric epoxidation and Brown's P2-Ni reduction. This approach provided the sex pheromone of the elm spanworm (1) in 31% total yield and those of the painted apple moth (2, 3) in 26% and 32% total yields. The ee values of three final products were up to 99%. The synthesized pheromones hold promising potential for use in the management and control of these pests.

Mycoplasma hyopneumoniae membrane protein Mhp271 interacts with host UPR protein GRP78 to facilitate infection.

The unfolded protein response (UPR) plays a crucial role in Mycoplasma hyopneumoniae (M. hyopneumoniae) pathogenesis. We previously demonstrated that M. hyopneumoniae interferes with the host UPR to foster bacterial adhesion and infection. However, the underlying molecular mechanism of this UPR modulation is unclear. Here, we report that M. hyopneumoniae membrane protein Mhp271 interacts with host GRP78, a master regulator of UPR localized to the porcine tracheal epithelial cells (PTECs) surface. The interaction of Mhp271 with GRP78 reduces the porcine beta-defensin 2 (PBD-2) production, thereby facilitating M. hyopneumoniae adherence and infection. Furthermore, the R1-2 repeat region of Mhp271 is crucial for GRP78 binding and the regulation of PBD-2 expression. Intriguingly, a coimmunoprecipitation (Co-IP) assay and molecular docking prediction indicated that the ATP, rather than the substrate-binding domain of GRP78, is targeted by Mhp271 R1-2. Overall, our findings identify host GRP78 as a target for M. hyopneumoniae Mhp271 modulating the host UPR to facilitate M. hyopneumoniae adherence and infection.

Gut microbiota-induced microRNA-206-3p increases anxiety-like behaviors by inhibiting expression of Cited2 and STK39.

BACKGROUND: Anxiety disorder is highly prevalent worldwide and represents a chronic and functionally disabling condition, with high levels of psychological stress characterized by cognitive and physiological symptoms. The purpose of this study is to evaluate the clinical significance of gut microbiota regulating microRNA (miR)-206-3p as a biomarker in the anxiety-like behaviors. METHODS: Initially, bioinformatics analysis was performed to predict the related factors for gut microbiota affecting anxiety-like behaviors. Next, the anxiety-like behaviors in mice were measured by multiple experiments. Western blot analysis, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) were utilized to measure the levels of 5-hydroxytryptamine (5-HT), brain derived neurotrophic factor (BDNF), and neutrophil expressed (NE) in brain tissues and serum and cAMP responsive element binding protein 1 (CREB) phosphorylation in brain tissues of germ-free (GF) mice. Dual-luciferase reporter gene assay was employed to verify the relationship between miR-206-3p and Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 2 (Cited2)/serine/threonine kinase 39 (STK39). Ectopic expression and depletion experiments of miR-206-3p were conducted to determine the expression of miR-206-3p and mRNA and protein levels of Cited2, and STK39 in HT22 cells and brain tissues. Finally, transmission electron microscope (TEM) was used to observe the effects of miR-206-3p on hippocampal mitochondria and synapses. RESULTS: Gut microbiota could elevate miR-206-3p expression in brain tissues to increase the anxiety-like behaviors. GF mice displayed the increased levels of 5-HT, BDNF, and NE in brain tissues and serum and CREB phosphorylation in brain tissues. Cited2/STK39 was identified as the target genes of miR-206-3p. Upregulated miR-206-3p increased anxiety-like behaviors by promoting degeneration of mitochondria and synapses in hippocampus via downregulation of Cited2 and STK39. CONCLUSIONS: In conclusion, the key findings of the current study demonstrate that gut microbiota aggravated anxiety-like behaviors via the miR-206-3p/Cited2/STK39 axis.

Sex- and reproductive status-specific relationships between body composition and non-alcoholic fatty liver disease.

BACKGROUND: Sex and reproductive status differences exist in both non-alcoholic fatty liver disease (NAFLD) and body composition. Our purpose was to investigate the relationship between body composition and the severity of liver steatosis and fibrosis in NAFLD in different sex and reproductive status populations. METHODS: This cross-sectional study included 880 patients (355 men, 417 pre-menopausal women, 108 post-menopausal women). Liver steatosis and fibrosis and body composition data were measured using FibroScan and a bioelectrical impedance body composition analyzer (BIA), respectively, and the following parameters were obtained: liver stiffness measurement (LSM), controlled attenuation parameter (CAP), waist circumference (WC), body mass index (BMI), percent body fat (PBF), visceral fat area (VFA), appendicular skeletal muscle mass (ASM), appendicular skeletal muscle mass index (ASMI), fat mass (FM), fat free mass (FFM), and FFM to FM ratio (FFM/FM). Multiple ordinal logistic regression (MOLR) was used to analyze the independent correlation between body composition indicators and liver steatosis grade and fibrosis stage in different sex and menopausal status populations. RESULTS: Men had higher WC, ASM, ASMI, FFM, and FFM/FM than pre- or post-menopausal women, while pre-menopausal women had higher PBF, VFA, and FM than the other two groups (p < 0.001). Besides, men had greater CAP and LSM values (p < 0.001). For MOLR, after adjusting for confounding factors, WC (OR, 1.07; 95% CI, 1.02-1.12; P = 0.011) and FFM/FM (OR, 0.52; 95% CI, 0.31-0.89; P = 0.017) in men and visceral obesity (OR, 4.16; 95% CI, 1.09-15.90; P = 0.037) in post-menopausal women were independently associated with liver steatosis grade. WC and visceral obesity were independently associated with liver fibrosis stage in men (OR, 1.05; 95% CI, 1.01-1.09, P = 0.013; OR, 3.92; 95% CI, 1.97-7.81; P < 0.001, respectively). CONCLUSIONS: Increased WC and low FFM/FM in men and visceral obesity in post-menopausal women were independent correlates of more severe liver steatosis. In addition, increased WC and visceral obesity were independent correlates of worse liver fibrosis in men. These data support the sex- and reproductive status-specific management of NAFLD.

RNA modification-mediated translational control in immune cells.

RNA modifications play a vital role in multiple pathways of mRNA metabolism, and translational regulation is essential for immune cells to promptly respond to stimuli and adapt to the microenvironment. N6-methyladenosine (m6A) methylation, which is the most abundant mRNA modification in eukaryotes, primarily functions in the regulation of RNA splicing and degradation. However, the role of m6Amethylation in translational control and its underlying mechanism remain controversial. The role of m6A methylation in translation regulation in immune cells has received relatively limited attention. In this review, we aim to provide a comprehensive summary of current studies on the translational regulation of m6A modifications and recent advances in understanding the translational control regulated by RNA modifications during the immune response. Furthermore, we envision the possible pathways through which m6A modifications may be involved in the regulation of immune cell function via translational control.

Extended-spectrum beta-lactamase-producing Enterobacteriaceae related urinary tract infection in adult cancer patients: a multicenter retrospective study, 2015-2019.

BACKGROUND: The aim of this study was to investigate the prevalence and risk factors of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae related urinary tract infections (UTI) in adult cancer patients. METHODS: We conducted a retrospective study of three cancer hospitals centered on Cancer Hospital of Chinese Academy of Medical Sciences from 2015 to 2019. The clinical characters, risk factors and antimicrobial susceptibility of ESBL-producing Enterobacteriaceae UTI in adult cancer patients were described and analyzed. RESULTS: A total of 4967 specimens of UTI were evaluated, of which 909 were positive. After excluding multiple infection bacteria, non-conforming strains, inconsistent pathological information, no drug sensitivity test or medical records, 358 episodes remained. Among them, 160 episodes belonged to ESBL-producing Enterobacteriaceae, while 198 were classified into non-ESBL group. The prevalence of ESBL UTI circled around 39.73 to 53.03% for 5 years. Subgroup analysis by tumor type revealed that 62.5% of isolates from patients with urological tumors were ESBL positive. Multivariate analysis showed that tumor metastasis (OR 3.41, 95%CI 1.84-6.30), urological cancer (OR 2.96, 95%CI 1.34-6.53), indwelling catheter (OR 2.08, 95%CI 1.22-3.55) and surgery or invasive manipulation (OR 1.98, 95%CI 1.13-3.50) were the independent risk factors. According to antimicrobial sensitivity, meropenem, imipenem and piperacillin/tazobactam were the most commonly used antibiotics for ESBL-producing Enterobacteriaceae UTI. CONCLUSIONS: In view of the high prevalence, clinicians should be alert to the occurrence of ESBL UTI, especially for patients with urological cancer or metastatic tumors. Regular replacement of urinary catheters, reduction of unnecessary invasive operations and selection of appropriate antibiotics are the necessary conditions to deal with the occurrence of ESBL UTI in adult cancer patients.

Integrated analysis of the faecal metagenome and serum metabolome reveals the role of gut microbiome-associated metabolites in the detection of colorectal cancer and adenoma.

OBJECTIVE: To profile gut microbiome-associated metabolites in serum and investigate whether these metabolites could distinguish individuals with colorectal cancer (CRC) or adenoma from normal healthy individuals. DESIGN: Integrated analysis of untargeted serum metabolomics by liquid chromatography-mass spectrometry and metagenome sequencing of paired faecal samples was applied to identify gut microbiome-associated metabolites with significantly altered abundance in patients with CRC and adenoma. The ability of these metabolites to discriminate between CRC and colorectal adenoma was tested by targeted metabolomic analysis. A model based on gut microbiome-associated metabolites was established and evaluated in an independent validation cohort. RESULTS: In total, 885 serum metabolites were significantly altered in both CRC and adenoma, including eight gut microbiome-associated serum metabolites (GMSM panel) that were reproducibly detected by both targeted and untargeted metabolomics analysis and accurately discriminated CRC and adenoma from normal samples. A GMSM panel-based model to predict CRC and colorectal adenoma yielded an area under the curve (AUC) of 0.98 (95% CI 0.94 to 1.00) in the modelling cohort and an AUC of 0.92 (83.5% sensitivity, 84.9% specificity) in the validation cohort. The GMSM model was significantly superior to the clinical marker carcinoembryonic antigen among samples within the validation cohort (AUC 0.92 vs 0.72) and also showed promising diagnostic accuracy for adenomas (AUC=0.84) and early-stage CRC (AUC=0.93). CONCLUSION: Gut microbiome reprogramming in patients with CRC is associated with alterations of the serum metabolome, and GMSMs have potential applications for CRC and adenoma detection.

Comparative transcriptome analysis of resistant and susceptible Kentucky bluegrass varieties in response to powdery mildew infection.

BACKGROUND: Poa pratensis is one of the most common cold-season turfgrasses used for urban turf building, and it is also widely used in ecological environment management worldwide. Powdery mildew is a common disease of P. pratensis. To scientifically and ecologically control lawn powdery mildew, the molecular mechanism underlying the response of P. pratensis to powdery mildew infection must better understood. RESULTS: To explore molecular mechanism underlying the response of P. pratensis to powdery mildew infection, this study compared physiological changes and transcriptomic level differences between the highly resistant variety 'BlackJack' and the extremely susceptible variety 'EverGlade' under powdery mildew infection conditions. We analyzed DEGs using reference canonical pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, and the results showed that "starch and sucrose metabolism", "photosynthesis" and "fatty acid metabolism"pathways were only enriched in 'BlackJack', and the expression of DEGs such as HXK, INV, GS, SS, AGpase and ß-amylase in "starch and sucrose metabolism" pathway of 'BlackJack' were closely related to powdery mildew resistance. Meanwhile, compared with 'EverGlade', powdery mildew infection promoted synthesis of sucrose, expression of photosynthesis parameters and photosynthesis-related enzymes in leaves of 'BlackJack' and decreased accumulation of monosaccharides such as glucose and fructose. CONCLUSIONS: This study identified the key metabolic pathways of a P. pratensis variety with high resistance to powdery mildew infection and explored the differences in physiological characteristics and key genes related to sugar metabolism pathways under powdery mildew stress. These findings provide important insights for studying underlying molecular response mechanism.

Methamphetamine-mediated dissemination of ß-amyloid: Disturbances in endocytosis, transport and clearance of ß-amyloid in microglial BV2 cells.

Methamphetamine (Meth) abuse can cause neurodegenerative-like changes, such as those observed in Alzheimer's disease (AD), characterized by extracellular amyloid-ß (Aß) deposition. The "spreading hypothesis" suggests that pathological Aß spreads over the entire brain, which depends on Aß endocytosis, transport and clearance. However, whether Meth exposure impacts these effects remains poorly understood. Microglia play an important role in the clearance of Aß. Therefore, the effects of microglia on Aß ingestion, degradation, and efflux under Meth challenge were investigated. Meth significantly engulfed and elicited a massive accumulation of Aß42 when extracellular administration of FAM-Aß42, accompanied by an increase in endocytosis-associated mRNA and protein expression, including TREM2 and VSP35. Meanwhile, FAM-Aß42 degradation was obviously retarded, since the colocalization of Aß42 and LDL, Aß42 and lysosomes was decreased, and syntaxin 17 might be involved in this process. Intriguingly, Meth dramatically facilitated FAM-Aß42 dissemination in microglia, characterized by the massive overlap between FAM-Aß42 and transferrin, which is destined to be excreted out of the cells. The facilitation of FAM-Aß42 spreading was further validated by the increased colocalization of FAM-Aß42 and CD63. Mechanistically, Meth mediated Aß42 spreading through the exosomal pathway, since an exosomal inhibitor remarkably hindered this process. Therefore, the current study elucidated a novel mechanism of Meth-induced accelerated progression in neurodegenerative disease, and targeting the inhibition of Aß1-42 efflux in microglia might provide beneficial effects for Meth-induced neural damage.

Associations of Exposure to Fine Particulate Matter Mass and Constituents with Systemic Inflammation: A Cross-Sectional Study of Urban Older Adults in China.

Systemic inflammation is a key mechanism in the development of cardiovascular diseases induced by exposure to fine particles (particles with aerodynamic diameter ≤2.5 µm [PM2.5]). However, little is known about the effects of chemical constituents of PM2.5 on systemic inflammation. In this cross-sectional study, filter samples of personal exposure to PM2.5 were collected from community-dwelling older adults in Tianjin, China, and the chemical constituents of PM2.5 were analyzed. Blood samples were collected immediately after the PM2.5 sample collection. Seventeen cytokines were measured as targets. A linear regression model was applied to estimate the relative effects of PM2.5 and its chemical constituents on the measured cytokines. A positive matrix factorization model was employed to distinguish the sources of PM2.5. The calculated source contributions were used to estimate their effects on cytokines. After adjusting for other covariates, higher PM2.5-bound copper was significantly associated with increased levels of interleukin (IL)1ß, IL6, IL10, and IL17 levels. Source analysis showed that an increase in PM2.5 concentration that originated from tire/brake wear and cooking emissions was significantly associated with enhanced levels of IL1ß, IL6, tumor necrosis factor alpha (TNFα), and IL17. In summary, personal exposure to some PM2.5 constituents and specific sources could increase systemic inflammation in older adults. These findings may explain the cardiopulmonary effects of specific particulate chemical constituents of urban air pollution.

Short-term effects of the toxic component of traffic-related air pollution (TRAP) on lung function in healthy adults using a powered air purifying respirator (PAPR).

Short-term exposure to traffic-related air pollution (TRAP) are associated with reduced lung function. However, TRAP is a mixture of various gaseous pollutants and particulate matter (PM), and therefore it is unknown that which components of TRAP are responsible for the respiratory toxicity. Using a powered air-purifying respirator (PAPR), we conducted a randomized, double-blind, crossover trial in which 40 adults were exposed to TRAP for 2 h at the sidewalk of a busy road. During the exposure, the participants wore the PAPR fitted with a PM filter, a PM and volatile organic compounds (VOCs) filter, or a sham filter (no filtration, Sham mode). The participants were blinded to the type of filter in their PAPR, and experienced three exposures, once for each intervention mode in random order. We measured two lung function measures (forced expiratory volume in 1 s [FEV1] and forced vital capacity [FVC]) and an airway inflammation marker (fraction of exhaled nitric oxide [FENO]) before and immediately after each exposure, and further measured them at different time periods after exposure. We applied linear mixed effect models to estimate the effects of the interventions on the changes of lung function from baseline values after controlling for other covariates. Compared to baseline, exposing to TRAP decreased FEV1 and FVC, and increased FEV1/FVC and FENO in all three intervention modes. The mixed models showed that with the sham mode as reference, lung function and airway inflammation post exposure were significantly improved by filtering both PM and VOCs, but marginally affected by filtering only PM. In conclusion, the VOCs component of TRAP is responsible for the reduction in lung function caused by short-term exposure to TRAP. However, the result needs to be interpreted cautiously before further verified by laboratory experiment using purely isolated component(s) of TRAP.