Application and Quality of Model-Based Meta-Analysis in Pharmaceutical Research: A Systematic Cross-Sectional Analysis and Practical Considerations.

Model-based meta-analysis (MBMA) can be used in assisting drug development and optimizing treatment in clinical practice, potentially reducing costs and accelerating drug approval. We aimed to assess the application and quality of MBMA studies. We searched multiple databases to identify MBMA in pharmaceutical research. Eligible MBMA should incorporate pharmacological concepts to construct mathematical models and quantitatively examine and/or predict drug effects. Relevant information was summarized to provide an overview of the application of MBMA. We used AMSTAR-2 and PRISMA 2020 checklists to evaluate the methodological and reporting quality of included MBMA, respectively. A total of 143 MBMA studies were identified. MBMA was increasingly used over time for one or more areas: drug discovery and translational research (n = 8, 5.6%), drug development decision making (n = 42, 29.4%), optimization of clinical trial design (n = 46, 32.2%), medication in special populations (n = 15, 10.5%), and rationality and safety of drug use (n = 71, 49.7%). The included MBMA covered 17 disease areas, with the top three being nervous system diseases (n = 19, 13.2%), endocrine/nutritional/metabolic diseases (n = 17, 11.8%), and neoplasms (n = 16, 11.1%). Of these MBMA studies, 138 (96.5%) were rated as very low quality. The average rate of compliance with PRISMA was only 51.4%. Our findings suggested that MBMA was mainly used to evaluate the efficacy and safety of drugs, with a focus on chronic diseases. The methodological and reporting quality of MBMA should be further improved. Given AMSTAR-2 and PRISMA checklists were not specifically designed for MBMA, adapted assessment checklists for MBMA should be warranted.

Analysis of risk factors associated with pre-myopia among primary school students in the Mianyang Science City.

Objectives To find out the prevalence rate of pre-myopia among primary school students in the Mianyang Science City Area, analyze its related risk factors, and thus provide a reference for local authorities to formulate policies on the prevention and control of myopia for primary school students. Methods From September to October 2021, Cluster sampling was adopted by our research group to obtain the vision levels of primary school students employing a diopter test in the Science City Area. In addition, questionnaires were distributed to help us find the risk factors associated with pre-myopia. Through the statistical analysis, we identify the main risk factors for pre-myopia and propose appropriate interventions. Results The prevalence rate of pre-myopia among primary school students in the Science City Area was 45.27% (1020/2253), of which 43.82% were boys and 46.92% were girls, with no statistically significant difference in the prevalence rate of myopia between boys and girls (2 =2.171, P=0.141). The results of the linear trend test showed that the prevalence rate of pre-myopia tends to decrease with increasing age (Z=296.521, P=0.000). Logistic regression analysis demonstrated that the main risk factors for pre-myopia were having at least one parent with myopia, spending less than 2 hours a day outdoors, using the eyes continuously for more than 1 hour, looking at electronic screens for more than 2 hours, and having an improper reading and writing posture. Conclusion The Science City Area has a high prevalence rate of pre-myopia among primary school students. It is proposed that students, schools, families, and local authorities work together to increase the time spent outdoors, reduce digital screens and develop scientific use of eye habits.

Single-cell sequencing analysis confirms the association of ANRIL with the increased smooth muscle cell proliferation and migration gene signatures in pulmonary artery hypertension in silico.

PURPOSE: Smooth muscle cell (SMC) dysregulation is part of the pathological basis of pulmonary artery hypertension (PAH). We aimed to explore the heterogeneity of SMCs in PAH. METHODS: The profile GSE210248 was obtained from NCBI Gene Expression Omnibus, containing the scRNA-seq data of pulmonary arteries (PA) from three patients with PAH and three healthy donors. After quality control, normalization, and dimension reduction, cell clustering analysis was performed. Differential expression analysis and functional enrichment analysis were carried out successively in smooth muscle cells (SMCs). The enrichment scores of cell cycle and cell migration gene sets in SMCs were calculated. Then, the Spearman correlation coefficients between antisense non-coding RNA in the INK4 locus (ANRIL) expression and two gene sets were computed. RESULTS: Eight cell clusters were identified in PA from samples. The proportion of SMCs was increased in PAH samples. SMCs were divided into five subclusters with diverse biological functions. Muscle contraction-related SMC1 was decreased, while extracellular matrix organization-related SMC2, immune and inflammatory response-related SMC4 and SMC5 were increased in PAH samples compared with healthy donors. The enrichment scores of cell cycle and cell migration gene sets in SMCs were higher in PAH samples than in donors. ANRIL was down-regulated significantly in PAH samples and was negatively related to the scores of two gene sets. CONCLUSION: SMCs exhibited significant heterogeneity in PAH. The altered abilities of SMC proliferation and migration in PAH were associated with ANRIL expression.

Reconfigurable optoelectronic transistors for multimodal recognition.

Biological nervous system outperforms in both dynamic and static information perception due to their capability to integrate the sensing, memory and processing functions. Reconfigurable neuromorphic transistors, which can be used to emulate different types of biological analogues in a single device, are important for creating compact and efficient neuromorphic computing networks, but their design remains challenging due to the need for opposing physical mechanisms to achieve different functions. Here we report a neuromorphic electrolyte-gated transistor that can be reconfigured to perform physical reservoir and synaptic functions. The device exhibits dynamics with tunable time-scales under optical and electrical stimuli. The nonlinear volatile property is suitable for reservoir computing, which can be used for multimodal pre-processing. The nonvolatility and programmability of the device through ion insertion/extraction achieved via electrolyte gating, which are required to realize synaptic functions, are verified. The device's superior performance in mimicking human perception of dynamic and static multisensory information based on the reconfigurable neuromorphic functions is also demonstrated. The present study provides an exciting paradigm for the realization of multimodal reconfigurable devices and opens an avenue for mimicking biological multisensory fusion.

Stress-induced ordering evolution of 1D segmented heteronanostructures and their chemical post-transformations.

Investigations of one-dimensional segmented heteronanostructures (1D-SHs) have recently attracted much attention due to their potentials for applications resulting from their structure and synergistic effects between compositions and interfaces. Unfortunately, developing a simple, versatile and controlled synthetic method to fabricate 1D-SHs is still a challenge. Here we demonstrate a stress-induced axial ordering mechanism to describe the synthesis of 1D-SHs by a general under-stoichiometric reaction strategy. Using the continuum phase-field simulations, we elaborate a three-stage evolution process of the regular segment alternations. This strategy, accompanied by easy chemical post-transformations, enables to synthesize 25 1D-SHs, including 17 nanowire-nanowire and 8 nanowire-nanotube nanostructures with 13 elements (Ag, Te, Cu, Pt, Pb, Cd, Sb, Se, Bi, Rh, Ir, Ru, Zn) involved. This ordering evolution-driven synthesis will help to investigate the ordering reconstruction and potential applications of 1D-SHs.

A prognostic signature established based on genes related to tumor microenvironment for patients with hepatocellular carcinoma.

BACKGROUND: Complex cellular signaling network in the tumor microenvironment (TME) could serve as an indicator for the prognostic classification of hepatocellular carcinoma (HCC) patients. METHODS: Univariate Cox regression analysis was performed to screen prognosis-related TME-related genes (TRGs), based on which HCC samples were clustered by running non-negative matrix factorization (NMF) algorithm. Furthermore, the correlation between different molecular HCC subtypes and immune cell infiltration level was analyzed. Finally, a risk score (RS) model was established by LASSO and Cox regression analyses (CRA) using these TRGs. Functional enrichment analysis was performed using gene set enrichment analysis (GSEA). RESULTS: HCC patients were divided into three molecular subtypes (C1, C2, and C3) based on 704 prognosis-related TRGs. HCC subtype C1 had significantly better OS than C2 and C3. We selected 13 TRGs to construct the RS model. Univariate and multivariate CRA showed that the RS could independently predict patients' prognosis. A nomogram integrating the RS and clinicopathologic features of the patients was further created. We also validated the reliability of the model according to the area under the receiver operating characteristic (ROC) curve value, concordance index (C-index), and decision curve analysis. The current findings demonstrated that the RS was significantly correlated with CD8+ T cells, monocytic lineage, and myeloid dendritic cells. CONCLUSION: This study provided TRGs to help classify patients with HCC and predict their prognoses, contributing to personalized treatments for patients with HCC.

A review of long non-coding RNAs in ankylosing spondylitis: pathogenesis, clinical assessment, and therapeutic targets.

Ankylosing spondylitis (AS) is a chronic immune-mediated type of inflammatory arthritis characterized by inflammation, bone erosion, and stiffness of the spine and sacroiliac joints. Despite great efforts put into the investigation of the disease, the pathogenesis of AS remains unclear, posing challenges in identifying ideal targets for diagnosis and treatment. To enhance our understanding of AS, an increasing number of studies have been conducted. Some of these studies reveal that long non-coding RNAs (lncRNAs) play crucial roles in the etiology of AS. Some certain lncRNAs influence the development of AS by regulating inflammatory responses, autophagy, apoptosis, and adipogenesis, as well as the proliferation and differentiation of cells. Additionally, some lncRNAs demonstrate potential as biomarkers, aiding in monitoring disease progression and predicting prognosis. In this review, we summarize recent studies concerning lncRNAs in AS to elucidate the underlying mechanisms in which lncRNAs are involved and their potential values as biomarkers for disease assessment and druggable targets for therapy.

Targeting the MCP-GPX4/HMGB1 Axis for Effectively Triggering Immunogenic Ferroptosis in Pancreatic Ductal Adenocarcinoma.

Induction of ferroptosis can inhibit cancer cells in vitro, however, the role of ferroptosis in treatment in vivo is controversial. The immunosuppressive cells activated by the ferroptotic tumor cells can promote the growth of residual tumor cells, hindering the application of ferroptosis stimulation in tumor treatment. In this study, a new strategy is aimed to be identified for effectively triggering immunogenic ferroptosis in pancreatic ductal adenocarcinoma (PDAC) and simultaneously stimulating antitumor immune responses. Toward this, several molecular and biochemical experiments are performed using patient-derived organoid models and a KPC mouse model (LSL-KrasG12D /+, LSL-Trp53R172H/+, Pdx-1-Cre). It is observed that the inhibition of macrophage-capping protein (MCP) suppressed the ubiquitin fold modifier (UFM)ylation of pirin (PIR), a newly identified substrate of UFM1, thereby decreasing the transcription of GPX4, a marker of ferroptosis, and promoting the cytoplasmic transportation of HMGB1, a damage-associated molecular pattern. GPX4 deficiency triggered ferroptosis, and the pre-accumulated cytosolic HMGB1 is released rapidly. This altered release pattern of HMGB1 facilitated the pro-inflammatory M1-like polarization of macrophages. Thus, therapeutic inhibition of MCP yielded dual antitumor effects by stimulating ferroptosis and activating antitumor pro-inflammatory M1-like macrophages. The nanosystem developed for specifically silencing MCP is a promising tool for treating PDAC.

Reduced Volume Expansion of Micron-Sized SiOx via Closed-Nanopore Structure Constructed by Mg-Induced Elemental Segregation.

The inherently huge volume expansion during Li uptake has hindered the use of Si-based anodes in high-energy lithium-ion batteries. While some pore-forming and nano-architecting strategies show promises to effectively buffer the volume change, other parameters essential for practical electrode fabrication, such as compaction density, are often compromised. Here we propose a new in situ Mg doping strategy to form closed-nanopore structure into a micron-sized SiOx particle at a high bulk density. The doped Mg atoms promote the segregation of O, so that high-density magnesium silicates form to generate closed nanopores. By altering the mass content of Mg dopant, the average radii (ranged from 5.4 to 9.7 nm) and porosities (ranged from 1.4 % to 15.9 %) of the closed pores are precisely adjustable, which accounts for volume expansion of SiOx from 77.8 % to 22.2 % at the minimum. Benefited from the small volume variation, the Mg-doped micron-SiOx anode demonstrates improved Li storage performance towards realization of a 700-(dis)charge-cycle, 11-Ah-pouch-type cell at a capacity retention of >80 %. This work offers insights into reasonable design of the internal structure of micron-sized SiOx and other materials that undergo conversion or alloying reactions with drastic volume change, to enable high-energy batteries with stable electrochemistry.

Machine Learning-Assistant Colorimetric Sensor Arrays for Intelligent and Rapid Diagnosis of Urinary Tract Infection.

Urinary tract infections (UTIs), which can lead to pyelonephritis, urosepsis, and even death, are among the most prevalent infectious diseases worldwide, with a notable increase in treatment costs due to the emergence of drug-resistant pathogens. Current diagnostic strategies for UTIs, such as urine culture and flow cytometry, require time-consuming protocols and expensive equipment. We present here a machine learning-assisted colorimetric sensor array based on recognition of ligand-functionalized Fe single-atom nanozymes (SANs) for the identification of microorganisms at the order, genus, and species levels. Colorimetric sensor arrays are built from the SAN Fe1-NC functionalized with four types of recognition ligands, generating unique microbial identification fingerprints. By integrating the colorimetric sensor arrays with a trained computational classification model, the platform can identify more than 10 microorganisms in UTI urine samples within 1 h. Diagnostic accuracy of up to 97% was achieved in 60 UTI clinical samples, holding great potential for translation into clinical practice applications.

Short-term effects of ambient gaseous air pollution on blood platelet mitochondrial DNA methylation and myocardial ischemia.

BACKGROUND: The potential effects of short-term exposure to major ambient gaseous pollutants (ozone: O3, carbon monoxide: CO, and sulfur dioxide: SO2) on platelet mitochondrial DNA (mtDNA) methylation have been uncertain and no studies have examined whether platelet mtDNA methylation levels could modify the associations between ambient gaseous pollutants and the risks of ST-segment depression (STDE) and T-wave inversion events (TIE), two indicators of myocardial ischemia. METHODS: This study used data from a randomized, double-blind, placebo-controlled intervention study with a standardized 24-hour exposure protocol among 110 participants in Beijing. Absolute changes in platelet mtDNA methylation (ACmtDNAm) levels were determined by two repeated measurements on platelet mtDNA methylation levels in blood samples collected before and after the 24-hour exposure period. A multivariable linear regression model and a generalized linear model with a Poisson link function were used to investigate the associations of ambient gaseous pollutants with platelet mtDNA methylation levels, STDE, and TIE, respectively. RESULTS: Short-term O3 exposure was significantly associated with decreased ACmtDNAm at ATP6_P1 but increased ACmtDNAm at mt12sRNA, MT-COX1, and MT-COX1_P2; short-term CO and SO2 exposures were significantly associated with decreased ACmtDNAm at D-loop, MT-COX3- and ATP-related genes. Moreover, short-term O3 exposure was significantly associated with increased risks of STDE and TIE, and ACmtDNAm at MT-COX1 and MT-COX1_P2 modified the association between short-term O3 exposure and STDE events. L-Arg supplementation attenuated the effects of ambient gaseous pollutants, particularly O3, on ACmtDNAm and STDE. CONCLUSIONS: Platelet mtDNA methylation levels are promising biomarkers of short-term exposure to ambient gaseous air pollution, and are likely implicated in the mechanism behind the association of ambient O3 pollution with adverse cardiovascular effects. L-Arg supplementation showed the potential to mitigate the adverse effects of ambient O3 pollution.

Genetic regulatory effects in response to a high-cholesterol, high-fat diet in baboons.

Steady-state expression quantitative trait loci (eQTLs) explain only a fraction of disease-associated loci identified through genome-wide association studies (GWASs), while eQTLs involved in gene-by-environment (GxE) interactions have rarely been characterized in humans due to experimental challenges. Using a baboon model, we found hundreds of eQTLs that emerge in adipose, liver, and muscle after prolonged exposure to high dietary fat and cholesterol. Diet-responsive eQTLs exhibit genomic localization and genic features that are distinct from steady-state eQTLs. Furthermore, the human orthologs associated with diet-responsive eQTLs are enriched for GWAS genes associated with human metabolic traits, suggesting that context-responsive eQTLs with more complex regulatory effects are likely to explain GWAS hits that do not seem to overlap with standard eQTLs. Our results highlight the complexity of genetic regulatory effects and the potential of eQTLs with disease-relevant GxE interactions in enhancing the understanding of GWAS signals for human complex disease using non-human primate models.

Hierarchical Prior-Based Super Resolution for Point Cloud Geometry Compression.

The Geometry-based Point Cloud Compression (G-PCC) has been developed by the Moving Picture Experts Group to compress point clouds efficiently. Nevertheless, in its lossy mode, the reconstructed point cloud by G-PCC often suffers from noticeable distortions due to naïve geometry quantization (i.e., grid downsampling). This paper proposes a hierarchical prior-based super resolution method for point cloud geometry compression. The content-dependent hierarchical prior is constructed at the encoder side, which enables coarse-to-fine super resolution of the point cloud geometry at the decoder side. A more accurate prior generally yields improved reconstruction performance, albeit at the cost of increased bits required to encode this piece of side information. Our experiments on the MPEG Cat1A dataset demonstrate substantial Bjøntegaard-delta bitrate savings, surpassing the performance of the octree-based and trisoup-based G-PCC v14. We provide our implementations for reproducible research at https://github.com/lidq92/mpeg-pcc-tmc13.

5-HT7R enhances neuroimmune resilience and alleviates meningitis by promoting CCR5 ubiquitination.

INTRODUCTION: Excessive immune activation induces tissue damage during infection. Compared to external strategies to reconstruct immune homeostasis, host balancing ways remain largely unclear. OBJECTIVES: Here we found a neuroimmune way that prevents infection-induced tissue damage. METHODS: By FACS and histopathology analysis of brain Streptococcus pneumonia meningitis infection model and behavioral testing. Western blot, co-immunoprecipitation, and ubiquitination analyze the Fluoxetine initiate 5-HT7R-STUB1-CCR5 K48-linked ubiquitination degradation. RESULTS: Fluoxetine, a selective serotonin reuptake inhibitor, or the agonist of serotonin receptor 5-HT7R, protects mice from meningitis by inhibiting CCR5-mediated excessive immune response and tissue damage. Mechanistically, the Fluoxetine-5-HT7R axis induces proteasome-dependent degradation of CCR5 via mTOR signaling, and then recruits STUB1, an E3 ubiquitin ligase, to initiate K48-linked polyubiquitination of CCR5 at K138 and K322, promotes its proteasomal degradation. STUB1 deficiency blocks 5-HT7R-mediated CCR5 degradation. CONCLUSION: Our results reveal a neuroimmune pathway that balances anti-infection immunity via happiness neurotransmitter receptor and suggest the 5-HT7R-CCR5 axis as a potential target to promote neuroimmune resilience.

Comprehensive Assessment of Ischemic Stroke in Nonhuman Primates: Neuroimaging, Behavioral, and Serum Proteomic Analysis.

Ischemic strokes, prevalence and impactful, underscore the necessity of advanced research models closely resembling human physiology. Our study utilizes nonhuman primates (NHPs) to provide a detailed exploration of ischemic stroke, integrating neuroimaging data, behavioral outcomes, and serum proteomics to elucidate the complex interplay of factors involved in stroke pathophysiology. We observed a consistent pattern in infarct volume, peaking at 1-month postmiddle cerebral artery occlusion (MCAO) and then stabilized. This pattern was strongly correlated to notable changes in motor function and working memory performance. Using diffusion tensor imaging (DTI), we detected significant alterations in fractional anisotropy (FA) and mean diffusivity (MD) values, signaling microstructural changes in the brain. These alterations closely correlated with the neurological and cognitive deficits that we observed, highlighting the sensitivity of DTI metrics in stroke assessment. Behaviorally, the monkeys exhibited a reliance on their unaffected limb for compensatory movements, a common response to stroke impairment. This adaptation, along with consistent DTI findings, suggests a significant impact of stroke on motor function and spatial perception. Proteomic analysis through MS/MS functional enrichment identified two distinct groups of proteins with significant changes post-MCAO. Notably, MMP9, THBS1, MB, PFN1, and YWHAZ were identified as potential biomarkers and therapeutic targets for ischemic stroke. Our results underscore the complex nature of stroke and advocate for an integrated approach, combining neuroimaging, behavioral studies, and proteomics, for advancing our understanding and treatment of this condition.

[Mitigative Effect of Rare Earth Element Cerium on the Growth of Zinc-stressed Wheat （Triticum aestivum L.）Seedlings].

This research aimed to clarify the mitigative effect of exogenously applied rare earth element cerium （Ce） on the growth， zinc （Zn） accumulation， and physiological characteristics of wheat （Triticum aestivum L.） seedlings under Zn stress. The wheat variety studied was Bainong307 （BN307）， and Zn stress was achieved by growing seedlings in a hydroponic culture experiment with 500 µmol·L-1 Zn2 + added to the culture solution. It was found that Zn stress at 500 µmol·L-1 significantly inhibited the chlorophyll content， photosynthesis， and biomass accumulation of wheat seedlings. Seedling roots became shorter and thicker， and the lateral roots decreased under Zn stress. The Zn stress also increased MDA accumulation and the degree of cell membrane lipid peroxidation and reduced soluble protein contents and the activities of antioxidant enzymes such as superoxide dismutase （SOD）， catalase （CAT）， and ascorbate peroxidase （APX）. On the contrary， exogenous Ce decreased the adsorption and transport of Zn by the root system and alleviated the damage of Zn stress to wheat seedlings. Specifically， the increase in chlorophyll content （chlorophyll a， chlorophyll b， and total chlorophyll） and photosynthetic parameters， the enhancement of antioxidant enzymes activities and soluble protein levels， and the reduction in MDA content and the damage of lipid peroxidation to the cell membrane were all driven by exogenous Ce， which ultimately led to the increase in dry matter biomass of the root system and shoot. In summary， these results provide basic data for the application of exogenous Ce to alleviate Zn toxicity to plants.

[Effects of Exogenous Zinc on Growth and Root Architecture Classification of Maize Seedlings Under Cadmium Stress].

To explore the effects of different concentrations of zinc （Zn） on the growth and root architecture classification of maize seedlings under cadmium （Cd） stress， a hydroponic experiment was conducted to study the effects of different concentrations of Zn （0， 10， 25， 50， 100， 200， and 400 µmol·L-1） on the growth， root architecture and classification characteristics， Cd content， root Cd uptake capacity， and photosynthetic system of maize seedlings under Cd stress （50 µmol·L-1） by using Zhengdan 958 as the experimental material. Principal component analysis and the membership function method were used for comprehensive evaluation. The results showed that the 50 µmol·L-1 Cd stress had a significant toxic effect on maize seedlings， which significantly reduced chlorophyll content and photosynthetic parameters. The main root length， plant height， biomass， root forks， and root tips， including the root length and root surface area of the grade Ⅰ-Ⅲ diameter range and the root volume of the grade Ⅰ-Ⅱ diameter range， decreased significantly， which hindered the normal growth and development of maize seedlings. Compared with that under no Zn application， 100 µmol·L-1 and 200 µmol·L-1 Zn application reduced the uptake of Cd by maize seedlings， significantly reduced the Cd content in shoots and roots and the Cd uptake efficiency. The toxic effect on maize seedlings was alleviated， and the fresh weight， dry weight， tolerance index， and root forks of shoots and roots were significantly increased. The photosynthesis of maize seedlings was significantly enhanced， and the photosynthetic rate and the total chlorophyll content was significantly increased. The RL， SA， and RV in the Ⅰ-Ⅱ diameter range reached the maximum at 100 µmol·L-1 Zn， and the RL， SA， and RV in the Ⅲ diameter range reached the maximum at 200 µmol·L-1 Zn， which were significantly higher than those without Zn treatment. The comprehensive evaluation of the growth tolerance of maize seedlings showed that 100 µmol·L-1 and 200 µmol·L-1 Zn had better effects on alleviating Cd toxicity. Comprehensive analysis showed that the application of appropriate concentration of Zn could reduce the Cd content in maize seedlings， the Cd uptake capacity， and Cd uptake efficiency of roots； increase the biomass accumulation of maize seedlings； reduce the effect of Cd toxicity on root architecture； reduce the effect on the light and system； and improve the tolerance of maize seedlings to Cd.

Chlojaponilactone B Attenuates THP-1 Macrophage Pyroptosis by Inhibiting the TLR/MyD88/NF-κB Pathway.

Pyroptosis, an innate immune response, plays a crucial role in the pathological process of inflammatory diseases. Although pyroptosis blockade is considered a potential therapeutic strategy, no ideal candidate drug has been identified. The natural product Chojaponilactone B (CJB) has demonstrated anti-inflammatory effects, but its role in macrophage pyroptosis has not been studied. This study aimed to investigate the effect and mechanism of CJB in inhibiting macrophage pyroptosis. Using an LPS/ATP-induced THP-1 macrophage pyroptosis model, we found that CJB significantly inhibited pyroptosis and reduced the levels of NLRP3, caspase 1, N-GSDMD, and inflammatory cytokines IL-1ß and IL-18. RNA sequencing analysis revealed that CJB interfered with LPS/ATP-induced THP-1 macrophage gene expression, suggesting involvement in anti-inflammatory and anti-pyroptotic signaling pathways. Additionally, CJB suppressed LPS/ATP-induced elevations in TLRs, MyD88, pro-IL-1ß, and NF-κB and blocked NF-κB p65 nuclear translocation. In summary, CJB inhibits NLRP3 activation and macrophage pyroptosis through the TLR/MyD88/NF-κB pathway, providing important evidence for its development as a potential drug for treating pyroptosis-related inflammatory diseases.

CSF ß-Amyloid and Tau Biomarker Changes in Veterans With Mild Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: Moderate-to-severe traumatic brain injuries (TBI) have been reported to increase the risk of Alzheimer disease (AD). Whether mild TBI (mTBI) in veterans confers a similar increased risk of AD is less known. This study investigated early AD changes using CSF biomarkers in veterans with blast mTBI. METHODS: This was a cross-sectional case-control study of veterans with mTBI and non-mTBI veterans and civilians from 2 study sources. Blast-mTBI veterans had at least 1 war zone blast or combined blast/impact mTBI meeting Veterans Affairs (VA) and Department of Defense (DoD) criteria for mTBI. Non-mTBI participants had no lifetime history of TBI. All participants underwent standardized clinical and neuropsychological assessments and lumbar puncture for collection of the CSF. CSF biomarkers were measured using MesoScale Discovery assays for Aß40 and Aß42 and INNOTEST ELISAs for phosphorylated tau181 (p-tau181) and total tau (t-tau). RESULTS: Our sample comprised 51 participants with mTBI and 85 non-mTBI participants with mean (SD) ages 34.0 (10.1) and 33.5 years (8.9), respectively. All participants but 1 (99%) were male. Differences in CSF AD biomarkers between mTBI and non-mTBI groups were age dependent and most pronounced at older ages (omnibus test p ≤ 0.08). At age 50 years, the mTBI group had lower mean [95% CI] CSF Aß42 and Aß40 than the non-mTBI group by 154 [-12 to 319] and 1864 [610-3,118] pg/mL, respectively. By contrast, CSF p-tau181 and t-tau mean levels remained relatively constant with age in participants with mTBI, while tending to be higher at older ages for the non-mTBI group. The mTBI group also demonstrated poorer cognitive performance at older ages (omnibus p < 0.08): at age 50 years, the mean TMT-B time was higher by 34 seconds [10-58] and the mean CVLT-II short-delay recall was lower by 4.2 points [1.9-6.6]. Poorer verbal memory and verbal fluency performance were associated with lower CSF Aß42 (p ≤ 0.05) in older participants. DISCUSSION: CSF Aß levels decreased in middle-aged veterans with blast-related mTBI. These data suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes known to portend AD onset, thus raising concern that veterans with blast-related mTBI may develop a dementing disorder later in life.