Role of N6-methyladenosine RNA modification in cancer.

N6-methyladenosine (m6A) is the most abundant modification of RNA in eukaryotic cells. Previous studies have shown that m6A is pivotal in diverse diseases especially cancer. m6A corelates with the initiation, progression, resistance, invasion, and metastasis of cancer. However, despite these insights, a comprehensive understanding of its specific roles and mechanisms within the complex landscape of cancer is still elusive. This review begins by outlining the key regulatory proteins of m6A modification and their posttranslational modifications (PTMs), as well as the role in chromatin accessibility and transcriptional activity within cancer cells. Additionally, it highlights that m6A modifications impact cancer progression by modulating programmed cell death mechanisms and affecting the tumor microenvironment through various cancer-associated immune cells. Furthermore, the review discusses how microorganisms can induce enduring epigenetic changes and oncogenic effect in microorganism-associated cancers by altering m6A modifications. Last, it delves into the role of m6A modification in cancer immunotherapy, encompassing RNA therapy, immune checkpoint blockade, cytokine therapy, adoptive cell transfer therapy, and direct targeting of m6A regulators. Overall, this review clarifies the multifaceted role of m6A modification in cancer and explores targeted therapies aimed at manipulating m6A modification, aiming to advance cancer research and improve patient outcomes.

Sodium aescinate alleviates neuropathic pain through suppressing OGT-mediated O-GlcNAc modification of TLR3 to inactivate MAPK signaling pathway.

Neuropathic pain results from damage to nerves or the brain, and is characterized by symptoms such as allodynia, spontaneous pain, and hyperalgesia. The causes of this type of pain are intricate, which can make it difficult to treat. Sodium aescinate (SA), a natural extract from horse chestnut tree seeds, has been shown to act as a neuroprotector by inhibiting microglia activation. This study aims to explore the therapeutic potential of SA for neuropathic pain and the molecular mechanisms regulated by SA treatment. Through in vivo animal models and experiments, we found that SA treatment significantly reduced mechanical allodynia and heat hyperalgesia in neuropathic pain models. Additionally, SA inhibited O-GlcNAc-transferase (OGT)-induced O-GlcNAcylation (O-GlcNAc) modification in neuropathic pain mice. OGT overexpression could impede the therapeutic effects of SA on neuropathic pain. Further investigation revealed that Toll-like receptor 3 (TLR3), stabilized by OGT-induced O-GlcNAc modification, could activate the Mitogen activated protein kinase (MAPK) signaling pathway. Further in vivo experiments demonstrated that TLR3-mediated p38 mitogen-activated protein kinase (p38MAPK) activation is involved in SA-mediated relief of neuropathic pain. In conclusion, this study uncovers a novel molecular pathway deactivated by SA treatment in neuropathic pain.

Plastic film from the source of anaerobic digestion: Surface degradation, biofilm and UV response characteristics.

This study simulates a major environmental scenario involving "organic fertilizer source" plastics, by exploring the key factors influencing the changes in plastic-films during anaerobic digestion (AD), as well as the responses of the anaerobically digested plastics to ultraviolet (UV) radiation exposure. The results demonstrate that the degradation effect of AD on plastics is reflected by their yellowish and ruptured appearance, slightly worn surfaces, hardening and opacity, and fragmentation. AD significantly increases the content of oxygen-containing functional groups and the degree of unsaturation in plastic films, with thermophilic temperature processes proving more effective than those conducted at mesophilic temperatures. Exposure to UV light has been found to amplify the degradative effects, suggesting the potential cumulative impact of AD and UV. Both AD and UV irradiation reduced the hydrophilicity of plastics. In particular, the hydrophobicity of polylactic acid films was completely disrupted under overlay-exposure. Furthermore, microbial populations on plastic surfaces were mainly bacterial. These bacterial populations were primarily influenced by temperature, and moderately by the plastic types. In contrast, archaea were predominantly affected by both temperature and digested substrate. This study offers a theoretical foundation for strategies aimed at preventing and controlling plastic pollution derived from organic fertilizers.

A comprehensive assessment of heavy metals, VOCs and petroleum hydrocarbon in different soil layers and groundwater at an abandoned Al/Cu industrial site.

Compound pollution at industrial sites impedes urban development, especially when there is a lack of understanding about the spatial variations of internal pollution in industrial areas producing light-weight materials. In this study, spatial distribution and ecological risks of potentially toxic elements (PTEs), volatile organic compounds (VOCs), and petroleum hydrocarbons (C10-40) in the soil and groundwater of an Al/Cu (aluminum/copper) industrial site have been analyzed comprehensively. Results revealed the progressive clustering of pollutants in different soil layers, which indicated varying levels of penetration and migration of pollutants from the surface downward. Furthermore, severity of pollution varied according to pollutant type, with Cu (5-10,228 mg kg-1) often exceeding the background levels significantly (>40). Cd (0.03-2.60 mg kg-1) and Hg (0.01-3.73 mg kg-1) were found at elevated concentrations in deeper soil layers, suggesting distinct variations of PTEs across different soil depths. Among the more hazardous VOCS, polychlorinated biphenyls (1.80-234 µg kg-1) were particularly prevalent in the deeper layers of soil. Petroleum hydrocarbons (C10-40) were widely detected (6-582 mg kg-1), showing significant migration potential from surface to deep soil. These findings suggest that prolonged industrial activities lead to deep-seated accumulation of pollutants, which also impacts the groundwater, contributing to long-term dispersion of contaminants. Furthermore, multivariate statistical analysis indicated certain positive correlations among the distribution of Cu, Pb and petroleum hydrocarbons, indicating possible coupling of these pollutants. Severe Cu pollution caused an ecological risk in the surface soil layer (covering >20 % area of high pollution site, contributing >40 % ecological risk). While the Hg and Cd posed significant risks in the deeper soil layers, showing higher risk coefficients and mobility. The study provides crucial insights into the transformation of urban areas with a history of industrial uses into community spaces and highlights the risks posed by the remaining pollutants.

Black phosphorus quantum dots prevent atherosclerosis in high-fat diet-fed apolipoprotein E knockout mice.

Atherosclerosis (AS) is the main pathological basis of cardiovascular diseases such as coronary heart disease. Black phosphorus quantum dots (BPQDs) are a novel nanomaterial with good optical properties and biocompatibility, which was applied in the treatment of AS in mice, with good results shown in our previous study. In this study, BPQDs were injected into high-fat diet-fed apolipoprotein E knockout mice as a preventive drug for 12 weeks. Simvastatin, a classic preventive drug for AS, was used as a control to verify the preventive effect of BPQDs. The results showed that after preventive treatment with BPQDs, the plaque area in mice was significantly reduced, the vascular elasticity was increased, and serum lipid levels were significantly lower than those in the model group. To explore the mechanism, macrophages were induced to become foam cells using oxidized low-density lipoprotein. We found that BPQDs treatment could increase cell autophagy, thereby regulating intracellular lipid metabolism. Taken together, these data revealed that BPQDs may serve as a functional drug in preventing the development of AS.

Narrative review of stereotactic body radiation therapy combined with tyrosine kinase inhibitors for oligometastatic EGFR-mutated non-small cell lung cancer: present and future developments.

Background and Objective: A significant number of individuals diagnosed with non-small cell lung cancer (NSCLC) have distant metastases, and the concept of oligometastatic NSCLC has shown promise in achieving a cure. Stereotactic body radiation therapy (SBRT) is currently considered a viable treatment option for a limited number of tumor metastases. It has also been demonstrated that third-generation tyrosine kinase inhibitors (TKIs) are effective in extending the survival of patients with epidermal growth factor receptor (EGFR)-mutated NSCLC. Hence, the combination of SBRT with third-generation TKIs holds the potential to enhance treatment efficacy in patients with oligometastatic EGFR-mutated NSCLC. This review aimed to assess the possibility of combining SBRT with TKIs as an optimum treatment option for patients with oligometastatic EGFR-mutated NSCLC. Methods: We performed a narrative review by searching the PubMed, Web of Science, Elsevier and ClinicalTrials.gov databases for articles published in the English language from January 2009 to February 2024 and by reviewing the bibliographies of key references to identify important literature related to combining SBRT with third-generation TKIs in oligometastatic EGFR-mutated NSCLC. Key Content and Findings: This review aimed to assess the viability of combining SBRT and EGFR-TKIs in oligometastatic EGFR-mutated NSCLC. Current clinical trials suggest that the combined therapies have better progression free survival (PFS) when using SBRT as either concurrent with EGFR-TKIs or consolidated with EGFR-TKIs. Furthermore, research with third-generation EGFR-TKIs and SBRT combinations has demonstrated tolerable toxicity levels without significant additional adverse effects as compared to prior therapies. However, further clinical trials are required to establish its effectiveness. Conclusions: The combined approach of SBRT and TKIs can effectively impede the progression of oligometastatic NSCLC in patients harboring EGFR mutations and, most notably, can prolong progression-free survival rates. However, the feasibility of combining SBRT with third-generation TKIs in clinical trials remains unclear.

Dynamic immune status analysis of peripheral blood mononuclear cells in patients with Klebsiella pneumoniae bloodstream infection sepsis using single-cell RNA sequencing.

Background: Klebsiella pneumoniae is a common Gram-negative bacterium. Blood infection caused by K. pneumoniae is one of the most common causes of human sepsis, which seriously threatens the life of patients. The immune status of peripheral blood mononuclear cells (PBMCs) based on single-cell RNA sequencing (scRNA-seq) in acute stage and recovery stage of sepsis caused by K. pneumoniae bloodstream infection has not been studied. Methods: A total of 13 subjects were included in this study, 3 healthy controls, 7 patients with K. pneumoniae bloodstream infection in the acute stage (4 patients died), and 3 patients in the recovery stage. Peripheral blood of all patients was collected and PBMCs were isolated for scRNA-seq analysis. We studied the changes of PBMCs components, signaling pathways, differential genes, and cytokines in acute and recovery stages. Results: During K. pneumoniae acute infection we observed a decrease in the proportion of T cells, most probably due to apoptosis and the function of T cell subtypes was disorder. The proportion of monocytes increased in acute stage. Although genes related to their phagocytosis function were upregulated, their antigen presentation capacity-associated genes were downregulated. The expression of IL-1ß, IL-18, IFNGR1 and IFNGR2 genes was also increased in monocytes. The proportion of DCs was depleted during the acute stage and did not recover during sepsis recovery. DCs antigen presentation was weakened during the acute stage but recovered fast during the recovery stage. pDCs response to MCP-1 chemokine was weakened, they recovered it quickly during the recovery stage. B cells showed apoptosis both in the acute stage and recovery stage. Their response to complement was weakened, but their antigen presentation function was enhanced. The proportion of NK cells stable during all disease's stages, and the expression of IFN-γ gene was upregulated. Conclusion: The proportion of PBMCs and their immune functions undergo variations throughout the course of the disease, spanning from the acute stage to recovery. These findings provide new insights into the mechanism of PBMCs immune function during K. pneumoniae bloodstream infection sepsis and recovery and sets the basis for further understanding and treatment.

Recent progress of electrospun nanofibers as burning dressings.

Burns are a global public health problem, which brings great challenges to public health and the economy. Severe burns often lead to systemic infection, shock, multiple organ failure, and even death. With the increasing demand for the therapeutic effect of burn wounds, traditional dressings have been unable to meet people's needs due to their single function and many side effects. In this context, electrospinning shows a great prospect on the way to open up advanced wound dressings that promote wound repairing and prevent infection. With its large specific surface area, high porosity, and similar to natural extracellular matrix (ECM), electrospun nanofibers can load drugs and accelerate wound healing. It provides a promising solution for the treatment and management of burn wounds. This review article introduces the concept of burn and the types of electrospun nanofibers, then summarizes the polymers used in electrospun nanofiber dressings. Finally, the drugs (plant extracts, small molecule drugs and nanoparticles) loaded with electrospun burn dressings are summarized. Some promising aspects for developing commercial electrospun burn dressings are proposed.

Photoregulatory protein kinases fine-tune plant photomorphogenesis by directing a bifunctional phospho-code on HY5 in Arabidopsis.

Photomorphogenesis is a light-dependent plant growth and development program. As the core regulator of photomorphogenesis, ELONGATED HYPOCOTYL 5 (HY5) is affected by dynamic changes in its transcriptional activity and protein stability; however, little is known about the mediators of these processes. Here, we identified PHOTOREGULATORY PROTEIN KINASE 1 (PPK1), which interacts with and phosphorylates HY5 in Arabidopsis, as one such mediator. The phosphorylation of HY5 by PPK1 is essential to establish high-affinity binding with B-BOX PROTEIN 24 (BBX24) and CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1), which inhibit the transcriptional activity and promote the degradation of HY5, respectively. As such, PPKs regulate not only the binding of HY5 to its target genes under light conditions but also HY5 degradation when plants are transferred from light to dark. Our data identify a PPK-mediated phospho-code on HY5 that integrates the molecular mechanisms underlying the regulation of HY5 to precisely control plant photomorphogenesis.

Boosting Efficiency in Piezo-Photocatalysis Process Using Poled Ba0.7Sr0.3TiO3 Nanorod Arrays for Pollutant Degradation and Hydrogen Production.

Recently, the combination of the piezoelectric effect in the photocatalytic process, referred to as piezo-photocatalysis, has gained considerable attention as a promising approach for enhancing the degradation of organic pollutants. In this investigation, we studied the piezo-photocatalysis by fabricating arrays of barium strontium titanate (Ba0.7Sr0.3TiO3) nanorods (BST NRs) on a glass substrate as recoverable catalysts. We found that the degradation rate constant k of the rhodamine B solution achieved 0.0447 min-1 using poled BST NRs in the piezo-photocatalytic process, indicating a 2-fold increase in efficiency compared to the photocatalytic process (0.00183 min-1) utilizing the same material. This is mainly ascribed to the generation of the piezopotential in the poled BST NRs under ultrasonic vibration. Moreover, the BST NR array demonstrated a hydrogen (H2) production rate of 411.5 µmol g-1 h-1. In the photoelectrochemical process, the photocurrent density of poled BST NRs achieved 1.97 mA cm-2 at an applied potential of 1.23 V (ERHE (reversible hydrogen electrode)) under ultrasonic vibrations, representing a 1.7-fold increase compared with the poled BST NRs without ultrasonic vibrations. The measurement results from the liquid chromatograph mass spectrometer (LC-MS) demonstrated the formulation of a degradation pathway for rhodamine B molecules. Moreover, ab initio molecular dynamics (AIMD) simulation results demonstrate the dominance of hydroxyl radicals (•OH) rather than superoxide radicals (•O2-) in the degradation process. This study not only benefits the understanding of the principle of the piezo-photocatalytic process but also provides a new perspective for improving the catalytic efficiency for organic pollutants degradation.

Experimental and numerical study of the mixed lubrication under the action of magnetic ionic liquid additives.

In this paper, the tribological characteristics of an oil-soluble magnetic fluid additive under mixed lubrication are studied by experiments and numerical simulation. [bmim][FeCl4] is dissolved in CF10W-40 lubricating oil as a magnetic liquid additive, and its friction coefficient is tested by a point contact friction tester at different temperatures, rotational speeds and magnetic field intensities. The transition condition of lubrication state is obtained through analyzing the Stribeck curves based on the experiments, and the strength model of boundary film is established accordingly. A mixed lubrication model is established by substituting the boundary film strength model and the surface roughness model into the hydrodynamic lubrication model based on Reynolds equation. The results show that the magnetic solution as an additive can obviously reduce friction and wear, and the effect is more obvious under the condition of magnetic field. The boundary film strength model can accurately reflect the transition characteristics of lubrication state in the presence of boundary film, and the mixed lubrication model based on boundary film strength model can more precisely reflect the tribological characteristics of friction pairs, so this study provides a new theoretical method for the related research on the influence of boundary film on lubrication characteristics.

Exploring correlations between microplastics, microorganisms, and water quality in an urban drinking water source.

The microplastic pollution in freshwater system is gradually becoming more severe, which has led to increasing attention on the distribution and potential harmful effects of microplastics. Moreover, microplastics may have an impact on river ecology and pose risks to ecosystems. Therefore, it is important to reveal this process. This study aimed to explore correlations between microplastics and free-living microorganisms in an urban drinking water source of Xiangjiang River by using multivariate statistical analysis. The results indicated that the abundance of microplastics (size 50 µm to 5 mm) in surface water and sediments ranged from 0.72 to 18.6 (mean ± SD: 7.32 ± 2.36) items L-1 and 26.3-302 (150 ± 75.6) items kg-1 dry weight (dw), respectively, suggesting potential microplastic pollution despite the protected status as a drinking water source. Higher microplastic abundances were observed in urban areas and the downstream of wastewater plants, with mostly granular shape, transparent and black color as well as 50-100 µm in size. The multivariate statistical analysis presented that the abundance of microplastics is not significantly correlated with water indicators, due to the complexity of the abundance data. The water indicators showed an obvious correlation with microplastics in colors of transparent and black, and smaller sizes of 50-100 µm. This is also true for microplastics and microorganisms in water and sediment. Proteobacteria was the main prokaryote in water and sediments, being positively correlated with 50-100 µm microplastics; while Chloroplastida was the dominated eukaryotes, presenting a weak correlation with smaller-size microplastics. Overall, when considering the properties of microplastics such as shape, color and size, the potential correlations with water indicators and microorganisms were more evident than abundance. This study provides new insights into the multivariate statistical analysis, explaining the potential correlations among microplastic properties, microorganisms and environmental factors in a river system.

Establishment of a hybrid model of atherosclerosis and acute colitis in ApoE-/- mice.

Inflammatory bowel disease (IBD) and atherosclerosis (AS) are both common chronic inflammatory diseases with similar pathophysiological mechanisms. Some studies have shown that IBD patients are at increased risk for early atherosclerosis, myocardial infarction and venous thrombosis. Here we set up a hybrid mouse model associated with atherosclerosis and acute colitis in order to investigate the interplay of the two diseases. We fed ApoE-/- mice with high fat diet to establish atherosclerosis model, and used animal ultrasound machine to detect the artery of mice noninvasively. Then a new hybrid model of atherosclerosis and acute colitis was prepared by drinking water for 7 days. At the end of the experiment, the hybrid model mice showed typically pathological and intuitionistic changes of atherosclerosis and acute colitis. We found the shortened colon length, high histopathological scores of the colon with mucosal erosion and necrosis, hyperlipidemia, a plaque-covered mouse aorta and plaque with foam cells and lipid deposition in the hybrid model group, which proved that the hybrid model was successfully established. At the same time, ultrasonic detection showed that the end-diastolic blood flow velocity and the relative dilation value were decreased, while systolic time / diastolic time, the wall thickness, systolic diameters as well as diastolic diameters were gradually increased, and statistical significance appeared as early as 8 weeks. We clearly described the process of establishing a hybrid model of atherosclerosis and acute colitis, which might provide a repeatable platform for the interaction mechanism exploring and drug screening of atherosclerosis and inflammatory bowel disease in preclinical study.

Identification of sources and analysis of spatial distribution of soil heavy metals in northern China coal mining areas.

The mining and utilization of coal resources has not only promoted rapid economic development but also poses a potential threat to the ecological environment. The purpose of this study is to clarify the effects both of mining and land use types on the spatial distribution and particular sources of heavy metals in soil, using inverse distance weighted (IDW) and the Positive Matrix Factorization (PMF) model. A total of 99 topsoil and profile soil samples across different land use types and mining conditions were collected. The contamination of soil with Cd, Pb, and Hg in the research area was most severe, with the coefficient of variation (CV) of Hg being the largest, while also being heavily influenced by human activities. Severely polluted regions were mainly distributed in the center of the coal mining area, as well as near the highway. The contents of heavy metals for various land use patterns were ranked as follows: forestland > farmland > bare land > grassland > building land. Hg, Cd, Pb, Cr, and Zn had showed migration in the 0-60 cm depth range, and the enrichment factors (EFs) of Cd, Pb, Hg, and As in the soil profile were the most significant. The PMF demonstrated that the contributions of industrial activities and atmospheric deposition, transportation and mining activities, agricultural activities, and natural sources accounted for 31.25%, 28.13%, 22.24%, and 18.38%, respectively. The migration and deposition of atmospheric particulate matter from coal mining, transportation, and coal combustion under winds triggered heavy metal contamination in semi-arid areas of northern China. This phenomenon has important implications for the prevention and reduction of heavy metal pollution through various effective measures in coal-mining cities in northern China.

From organic fertilizer to the soils: What happens to the microplastics? A critical review.

In recent, soil microplastic pollution arising from organic fertilizers has been of a great increasing concern. In response to this concern, this review presents a comprehensive analysis of the occurrence and evolution of microplastics in organic fertilizers, their ingress into the soil, and the subsequent impacts. Organic fertilizers are primarily derived from solid organic waste generated by anthropocentric activities including urban (daily-life, municipal wastes and sludge), agricultural (manure, straw), and industrial (like food industrial waste etc.) processes. In order to produce organic fertilizer, the organic solid wastes are generally treated by aerobic composting or anaerobic digestion. Currently, microplastics have been widely detected in the raw materials and products of organic fertilizer. During the process of converting organic solid waste materials into fertilizer, intense oxidation, hydrolysis, and microbial actions significantly alter the physical, chemical, and surface biofilm properties of the plastics. After the organic fertilizer application, the abundances of microplastics significantly increased in the soil. Additionally, the degradation of these microplastics often promotes the adsorption of organic pollutants and affects their retention time in the soil. These microplastics, covered by biofilms, also significantly alter soil ecology due to the unique properties of the biofilm. Furthermore, the biofilms also play a role in the degradation of microplastics in the soil environment. This review offers a new perspective on the soil environmental processes involving microplastics from organic fertilizer sources and highlights the challenges associated with further research on organic fertilizers and microplastics.

Spatial distribution and risk assessment of pyrethroid insecticides in surface waters of East China Sea estuaries.

Pyrethroid insecticides are the most commonly used household insecticides and pose substantial risks to marine aquatic organisms. many studies have detected pyrethroid insecticides in the waters and estuaries of the western United States, but their distributions within western Pacific estuaries have not been reported. Accordingly, we used high-throughput organic analyses combined with high volume solid-phase extraction to comprehensively assess 13 pyrethroid insecticides in East China Sea estuaries and the Huangpu River. The results demonstrated the presence of various ∑13pyrethroid insecticides in East China Sea estuaries (mean and median values of 8.45 ± 5.57 and 7.78 ng L-1, respectively), among which cypermethrin was the primary contaminant. The concentrations of ∑12pyrethroid insecticide detected in the surface waters at the Huangpu River (mean 6.7 ng L-1, outlet 16.4 ng L-1) were higher than those in the Shanghai estuary (4.7 ng L-1), suggesting that runoff from inland areas is a notable source of insecticides. Wetlands reduced the amount of runoff containing pyrethroid insecticides that reached the ocean. Several factors influenced pesticide distributions in East China Sea estuaries, and higher proportions were derived from agricultural sources than from urban sources, with a higher proportion of agricultural sources than urban sources, influenced by anthropogenic use in the region. Permethrin and cypermethrin were the main compounds contributing to the high ecological risk in the estuaries. Consequently, to prevent risks to marine aquatic life, policymakers should aim to reduce insecticide contaminants derived from urban and agricultural sources.

Impact of time-lagging and time-preceding environmental variables on top layer soil moisture in semiarid grasslands.

Top soil moisture (SM) is an important medium connecting the exchange of matter and energy between the ground and the atmosphere. Previous studies of the relationship between SM and environmental factors, especially aerodynamics, have lacked analysis of the variability in the timing of effects. In this study, we analyzed how environmental factors affect SM, as well as soil moisture memory, by observing precipitation, radiation, and wind speed during the 2019 to 2021 growing seasons in grazing prohibited and grazed areas of a semiarid grassland. The results show that there is a clear threshold (7 mm) for the effect of precipitation on SM, that changes in SM across time scales were influenced by preceding precipitation and net radiation in addition to lagging vegetation greening characteristics (NDVI) and wind speed, and that the role of albedo was related to grazing management. The inhibitory effect of albedo on SM and the depletion of SM by NDVI were more pronounced in comparison to other meteorological factors. Wind speed, precipitation, and radiation directly or indirectly influenced SM duration, and these relationships varied with grazing management and annual variation. These results help to clarify the influence of environmental factors on SM, and provide insight for minimizing the degradation of grassland ecosystems in the process of climate change.

Clinical evaluation of metagenomic next-generation sequencing in unbiased pathogen diagnosis of urinary tract infection.

BACKGROUND: Early availability of pathogen identification in urinary tract infections (UTIs) has critical importance in disease management. Metagenomic next-generation sequencing (mNGS) has the potential to transform how acute and serious infections are diagnosed by offering unbiased and culture-free pathogen detection. However, clinical experience with application of the mNGS test is relatively limited. METHODS: We therefore established a MinION-based mNGS pathogens diagnostic platform and evaluated its potential for clinical implementation in UTIs with clinical samples. 213 urine samples from patients with suspected UTIs were included and subjected to mNGS testing using the MinION platform. mNGS results were compared to the gold standard of clinical culture and composite standard of combining clinical testing, confirmatory qPCR testing, and clinical adjudication by doctors. RESULTS: The mNGS exhibited a sensitivity of 81.4% and a specificity of 92.3%, along with a positive predictive value of 96.6%, a negative predictive value of 64.9%, and an overall accuracy of 84.4%, all of which were determined based on the gold standard of routine culture results. When assessed against the composite standard, the sensitivity and specificity both increased to 89.9% and 100%, respectively, while the accuracy rose to 92.4%. Notably, the positive predictive value and negative predictive value also saw improvements, reaching 100% and 76.8%, respectively. Moreover, this diagnostic platform successfully identified dsDNA viruses. Among the 65 culture-negative samples, the viral detection rate reached 33.8% (22/65) and was subsequently validated through qPCR. Furthermore, the automatic bioinformatics pipeline we developed enabled one-click analysis from data to results, leading to a significant reduction in diagnosis time. CONCLUSION: These results demonstrate that the pathogen detection performance of mNGS is sufficient for diagnostic testing in clinical settings. As the method is generally unbiased, it can improve diagnostic testing of UTIs and other microbial infections.

Volumetric brain correlates of gait associated with cognitive decline in community-dwelling older adults.

Objective: To determine the extent to which the regional brain volumes associated with slow gait speed can inform subsequent cognitive decline in older adults from the Rush Memory and Aging Project. Approach: We utilized deformation-based morphometry (DBM) in a whole-brain exploratory approach to identify the regional brain volumes associated with gait speed assessed over a short distance during an in-home assessment. We created deformation scores to summarize the gait-associated regions and entered the scores into a series of longitudinal mixed effects models to determine the extent to which deformation predicted change in cognition over time, controlling for associations between gait and cognition. Results: In 438 older adults (81 ± 7; 76% female), DBM revealed that slower gait speed was associated with smaller volumes across frontal white matter, temporal grey matter, and subcortical areas and larger volumes in the ventricles during the same testing cycle. When a subset was followed over multiple (5 ± 2) years, slower gait speed was also associated with annual declines in global cognition, executive functioning, and memory abilities. Several of the gait-related brain structures were associated with these declines in cognition; however, larger ventricles and smaller medial temporal lobe volumes proved most robust and attenuated the association between slow gait and cognitive decline. Conclusion: Regional brain volumes in the ventricles and temporal lobe associated with both slow gait speed and faster cognitive decline have potential to improve risk stratification for cognitive decline in older adults.