Neuronal-enriched small extracellular vesicles trigger a PD-L1-mediated broad suppression of T cells in Parkinson's disease.

Many clinical studies indicate a significant decrease of peripheral T cells in Parkinson's disease (PD). There is currently no mechanistic explanation for this important observation. Here, we found that small extracellular vesicles (sEVs) derived from in vitro and in vivo PD models suppressed IL-4 and INF-γ production from both purified CD4+ and CD8+ T cells and inhibited their activation and proliferation. Furthermore, neuronal-enriched sEVs (NEEVs) isolated from plasma of A53T-syn mice and culture media of human dopaminergic neurons carrying A53T-syn mutation also suppressed Th1 and Th2 differentiation of naive CD4+ T cells. Mechanistically, the suppressed phenotype induced by NEEVs was associated with altered programmed death ligand 1 (PD-L1) level in T cells. Blocking PD-L1 with an anti-PD-L1 antibody or a small molecule inhibitor BMS-1166 reversed T cell suppression. Our study provides the basis for exploring peripheral T cells in PD pathogenesis and as biomarkers or therapeutic targets for the disease.

Sex-specific associations of urinary mixed-metal concentrations with femoral bone mineral density among older people: an NHANES (2017-2020) analysis.

Background: Heavy metal exposure is an important cause of reduced bone mineral density (BMD). Epidemiological studies focusing on the effects of mixed heavy metal exposure on BMD in middle-aged and older people are scarce. In single-metal studies, men and women have shown distinct responses of BMD to environmental metal exposure. This study therefore aimed to elucidate the association between mixed heavy metal exposure and BMD and to investigate whether it is sex-specific. Methods: Data from the 2017-2020 National Health and Nutrition Examination Survey were selected for this cross-sectional study. The study used three statistical methods, i.e., linear regression, Bayesian kernel machine regression (BKMR) modeling, and weighted quartiles (WQS) regression, to explore the association between the urinary concentrations of 11 metals (barium, cadmium, cobalt, cesium, manganese, molybdenum, lead, antimony, tin, thallium, and Tungsten), either individually or as a mixture, and total femoral BMD. Results: A total of 1,031 participants were included in this study. Femoral BMD was found to be higher in men than women. A significant negative correlation between the urinary concentrations of the 10 metals and femoral BMD was found in the overall cohort. Further gender sub-stratified analyses showed that in men, urinary metal concentrations were negatively correlated with femoral BMD, with cobalt and barium playing a significant and non-linear role in this effect. In women, although urinary metal concentrations negatively modulated femoral BMD, none of the correlations was statistically significant. Antimony showed sex-specific differences in its effect. Conclusion: The urinary concentrations of 10 mixed heavy metals were negatively correlated with femoral BMD in middle-aged and older participants, and this effect showed gender differences. These findings emphasize the differing role of mixed metal exposure in the process of BMD reduction between the sexes but require further validation by prospective studies.

Brucellosis-induced peritonitis and abdominal aortitis in a non-endemic area patient on peritoneal dialysis: a case report and literature review.

Background: Brucella infection is uncommon among peritoneal dialysis (PD) patients in non-endemic areas, and the occurrence of both peritonitis and abdominal aortitis is rare. Case presentation: In December 2023, a 63-year-old male patient undergoing PD was admitted to Shaoxing Second Hospital due to fever, abdominal pain, and cloudy dialysate. Upon physical examination, diffuse mild abdominal pain and tenderness were observed. Subsequent investigation into the patient's medical history revealed consumption of freshly slaughtered lamb from local farmers 3 days prior to the onset of symptoms. Various diagnostic tests, including routine blood tests, procalcitonin levels, and PD fluid analysis, indicated the presence of infection. Abdominal computed tomography (CT) imaging revealed localized lumen widening of the abdominal aorta with surrounding exudative changes. On the sixth day in the hospital, blood and PD fluid cultures confirmed Brucella melitensis infection. The patient was diagnosed with brucella-associated peritonitis and aortitis. Treatment was adjusted to include rifampin and doxycycline for 6 weeks, and the decision was made to keep the PD catheter. Remarkably, the patient exhibited resolution of peritonitis and abdominal aortitis within the initial week of the adjusted treatment. Currently, the patient continues to receive ongoing clinical monitoring. Conclusion: Brucella is rare but can cause PD-associated peritonitis and arteritis. Prompt diagnosis and treatment can lead to a good outcome in PD patients. Dual therapy is effective, but the need for catheter removal is unclear. Consider international guidelines and patient factors when deciding on catheter removal.

Function of hemocyanin-mediated succinate dehydrogenase in glucose metabolism and immunity of Penaeus vannamei.

Succinate dehydrogenase (SDH) is a crucial enzyme in the tricarboxylic acid cycle (TCA) and has established roles in immune function. However, the understanding of SDH in Penaeus vannamei, particularly its involvement in immune responses, is currently limited. Through affinity proteomics, a potential interaction between hemocyanin (HMC) and SDH in shrimp has been identified. The successful cloning of PvSDH in this study has revealed a high degree of evolutionary conservation. Additionally, it has been found that hemocyanin regulates SDH not only at the transcriptional and enzymatic levels but also through confirmed protein-protein interactions observed via Co-immunoprecipitation (CoIP) assay. Moreover, by combining PvHMC knockdown and Vibrio parahaemolyticus challenge, it was demonstrated that fumaric acid, a product of SDH, enhances the host's immune resistance to pathogen infection by modulating the expression of antimicrobial peptides. This research provides new insights into HMC as a crucial regulator of SDH, potentially impacting glycometabolism and the dynamics of immune responses.

Computer Vision-Based Biomass Estimation for Invasive Plants.

We report on the detailed steps of a method to estimate the biomass of invasive plants based on UAV remote sensing and computer vision. To collect samples from the study area, we prepared a sample square assembly to randomize the sampling points. An unmanned aerial camera system was constructed using a drone and camera to acquire continuous RGB images of the study area through automated navigation. After completing the shooting, the aboveground biomass in the sample frame was collected, and all correspondences were labeled and packaged. The sample data was processed, and the aerial images were segmented into small images of 280 x 280 pixels to create an image dataset. A deep convolutional neural network was used to map the distribution of Mikania micrantha in the study area, and its vegetation index was obtained. The organisms collected were dried, and the dry weight was recorded as the ground truth biomass. The invasive plant biomass regression model was constructed using the K-nearest neighbor regression (KNNR) by extracting the vegetation index from the sample images as an independent variable and integrating it with the ground truth biomass as a dependent variable. The results showed that it was possible to predict the biomass of invasive plants accurately. An accurate spatial distribution map of invasive plant biomass was generated by image traversal, allowing precise identification of high-risk areas affected by invasive plants. In summary, this study demonstrates the potential of combining unmanned aerial vehicle remote sensing with machine learning techniques to estimate invasive plant biomass. It contributes significantly to the research of new technologies and methods for real-time monitoring of invasive plants and provides technical support for intelligent monitoring and hazard assessment at the regional scale.

The association between homocysteine and bacterial vaginosis: results from NHANES 2001-2004.

Although no study has directly shown the relationship between bacterial vaginosis (BV) and homocysteine (HCY), we still found some association between these two through extensive literature and data analysis. BV score was calculated by Nugent's method, less than equal to 6 is negative and greater than equal to 7 is positive. This article describes interrelationships we mined from data extracted by NHANES regarding BV and HCY under multiple covariates. We used two cycles of NHANES 2001-2002 and 2003-2004 in our study. We included 2398 participants in our study who recently completed the interview and the MEC tests. By investigating the relationship between BV and HCY under multivariate conditions, multiple linear regression analysis was performed. These factors may have influenced the results, such as ethnicity, age, education level, body mass index (BMI), etc. Serum vitamin B12, ferritin, percentage of segmented centrioles, and number of segmented centrioles were selected as potential covariates in our study. We observed that both the coarse model and the two adjusted models showed a high correlation between HCY and BV, and the correlation was positive. In the coarse model, OR = 1.26, 95% confidence interval (CI) 1.10, 1.44, P = 0.0018); HCY was positively correlated with BV (OR = 1.19, 95% confidence interval (CI) 1.05, 1.34, P = 0.0121). Multiple linear regression analysis was used to investigate the connection between BV and HCY under multivariate settings. The results of this study indicate that HCY is positively associated with the prevalence of BV and may play an important role in the prevention and management of BV.

Mechanism of synergistic removal of NO and SO2 by sodium bicarbonate.

Sodium bicarbonate (NaHCO3) is considered to be an effective alkaline adsorbent for SO2 removal and surprisingly, the concentration of NO is significantly reduced along with the generation of NO2 during its desulfurization. Unfortunately, the mechanism of NO interaction with NaHCO3, SO2 and O2 is ambiguous. In this work, the effects of absorption gas and absorber composition on SO2/NO absorption performance were explored, the absorption products were characterized using XPS and SEM, and the Gibbs free energy of the inferred reaction path was calculated based on density functional theory (DFT). The results showed that SO2 and O2 synergistically promoted the absorption and removal of NO by NaHCO3, which could completely remove SO2 and absorb 90% of NO at 160 °C. Sodium metabisulfite (Na2S2O5) and sodium dithionate (Na2S2O6) were identified as the active substances responsible for efficient NO absorption, and the oxidation of Na2S2O5 to Na2S2O6 is the controlling step of the NO removal reaction. Specifically, Na2S2O5 is an intermediate produced by the reaction of NaHCO3 with SO2, and subsequently reacts with O2 to produce Na2S2O6, which releases reactive oxygen species to oxidize NO to NO2. In addition, when the S/N ratio is greater than 1 and the O2 content is greater than 5%, both SO2 and NO can maintain removal efficiency higher than 90%, indicating that the absorption reaction of SO2 and NO by NaHCO3 is highly adaptable to the flue gas composition.

Systematic P2Y receptor survey identifies P2Y11 as modulator of immune responses and virus replication in macrophages.

The immune system is in place to assist in ensuring tissue homeostasis, which can be easily perturbed by invading pathogens or nonpathogenic stressors causing tissue damage. Extracellular nucleotides are well known to contribute to innate immune signaling specificity and strength, but how their signaling is relayed downstream of cell surface receptors and how this translates into antiviral immunity is only partially understood. Here, we systematically investigated the responses of human macrophages to extracellular nucleotides, focusing on the nucleotide-sensing GPRC receptors of the P2Y family. Time-resolved transcriptomic analysis showed that adenine- and uridine-based nucleotides induce a specific, immediate, and transient cytokine response through the MAPK signaling pathway that regulates transcriptional activation by AP-1. Using receptor trans-complementation, we identified a subset of P2Ys (P2Y1, P2Y2, P2Y6, and P2Y11) that govern inflammatory responses via cytokine induction, while others (P2Y4, P2Y11, P2Y12, P2Y13, and P2Y14) directly induce antiviral responses. Notably, P2Y11 combined both activities, and depletion or inhibition of this receptor in macrophages impaired both inflammatory and antiviral responses. Collectively, these results highlight the underappreciated functions of P2Y receptors in innate immune processes.

SpotLight Proteomics Identifies Variable Sequences of Blood Antibodies Specific Against Deamidated Human Serum Albumin.

Spontaneous deamidation of asparaginyl residues in proteins, if not repaired or cleared, can set in motion a cascade that leads to deteriorated health. Previously, we have discovered that deamidated human serum albumin (HSA) is elevated in the blood of patients with Alzheimer's disease and other neurodegenerative diseases, while the level of endogenous antibodies against deamidated HSA is significantly diminished, creating an imbalance between the risk factor and the defense against it. Endogenous antibodies against deamidated proteins are still unexplored. In the current study, we employed the SpotLight proteomics approach to identify novel amino acid sequences in antibodies specific to deamidated HSA. The results provide new insights into the clearance mechanism of deamidated proteins, a possible avenue for prevention of neurodegeneration.

Urine metabolomic characteristics of female patients with occupational chronic cadmium poisoning after 15 years of treatment.

Occupational chronic cadmium poisoning (OCCP) can cause irreversible organ damage. Currently, no effective treatment is available for OCCP, and effective and sensitive biomarkers for treatment evaluation are still lacking. In this study, metabolomics techniques were used to analyze changes in endogenous metabolites in the urine of patients with OCCP after 15 years of treatment. Thirty urine samples from female patients with OCCP and healthy female controls (n = 15 per group) were assessed using gas chromatography-time-of-flight mass spectrometry and ultra-high-performance liquid chromatography-Q-Exactive mass spectrometry. The OCCP group had higher concentrations of blood urea nitrogen and urinary cadmium but near-normal urinary concentrations of ß2 -microglobulin and retinol-binding protein. Compared with the control group, the OCCP group had 66 significantly different metabolites with a variable importance in projection score >1 and p < 0.05. These differential metabolites were involved in various metabolic pathways, such as creatine metabolism, nicotinate and nicotinamide metabolism, the pentose phosphate pathway, d-glutamine and d-glutamate metabolism, and amino acid metabolism. Compared with the control group, the OCCP group had significantly higher urinary concentrations of creatine, glutamic acid, quinolinic acid and nicotinic acid. In a receiver operator characteristic analysis, the area under the curve of creatine was higher than those for glutamic acid, quinolinic acid and nicotinic acid, indicating that urinary concentrations of creatine could be used as a sensitive biomarker for the diagnosis and prognosis of OCCP and for monitoring its treatment.

A case report: Infection-related glomerulonephritis and mantle cell lymphoma due to mycobacterium avium complex infection.

RATIONALE: Mycobacterium avium complex (MAC) infection is common in lung, liver and skin. However, MAC presenting with peritonitis is uncommon and is particularly rare in immunocompetent patients. We report a case of infection-associated glomerulonephritis and mantle cell lymphoma caused by peritonitis due to MAC. PATIENT CONCERNS: We report a case of a 73-year-old elderly man with fever and abdominal pain for 2 days and gradually developed anuria, ascites, and abdominal lymphadenopathy. DIAGNOSES: The initial diagnosis was peritonitis and acute renal failure. There was no significant relief of symptoms after empirical anti-infective therapy and hemodialysis. infection-associated glomerulonephritis, mantle cell lymphoma, and peritonitis due to MAC were diagnosed by renal biopsy, abdominal lymph node biopsy, and metagenomics next-generation sequencing. INTERVENTIONS: The patient received empirical antibiotic therapy, hemodialysis, and anti-MAC therapy. OUTCOMES: Unfortunately, the patient eventually died of septic shock after the 21st day of admissiom. LESSONS: Early diagnosis of MAC infection is essential. When the cause of fever is unknown, metagenomics next-generation sequencing can be considered.

Attenuation of SARS-CoV-2 replication and associated inflammation by concomitant targeting of viral and host cap 2'-O-ribose methyltransferases.

The SARS-CoV-2 infection cycle is a multistage process that relies on functional interactions between the host and the pathogen. Here, we repurposed antiviral drugs against both viral and host enzymes to pharmaceutically block methylation of the viral RNA 2'-O-ribose cap needed for viral immune escape. We find that the host cap 2'-O-ribose methyltransferase MTr1 can compensate for loss of viral NSP16 methyltransferase in facilitating virus replication. Concomitant inhibition of MTr1 and NSP16 efficiently suppresses SARS-CoV-2 replication. Using in silico target-based drug screening, we identify a bispecific MTr1/NSP16 inhibitor with anti-SARS-CoV-2 activity in vitro and in vivo but with unfavorable side effects. We further show antiviral activity of inhibitors that target independent stages of the host SAM cycle providing the methyltransferase co-substrate. In particular, the adenosylhomocysteinase (AHCY) inhibitor DZNep is antiviral in in vitro, in ex vivo, and in a mouse infection model and synergizes with existing COVID-19 treatments. Moreover, DZNep exhibits a strong immunomodulatory effect curbing infection-induced hyperinflammation and reduces lung fibrosis markers ex vivo. Thus, multispecific and metabolic MTase inhibitors constitute yet unexplored treatment options against COVID-19.

Antimicrobial abietane-type diterpenoids from Torreya grandis.

Twelve undescribed abietane-type diterpenoids, along with ten known analogues were isolated from the twigs and leaves of Torreya grandis var. merrillii Hu. Their structures were characterized by spectroscopic data analyses, single-crystal X-ray diffraction, and ECD spectra. Torgranols A-C possess three different architectures shaped via a common 6,7-seco-procedure and subsequent ring formations. In particular, torgranol A represents the first example of a 6,7-seco-abietane diterpenoid featuring a unique oxygen bridge between C-3 and C-6. The biosynthetic pathways for torgranols A-C were proposed. Some compounds displayed antimicrobial activities against Mycobacterium tuberculosis and/or Staphylococcus aureus.