Asymptomatic Phase Research Articles

A LysM Effector Mediates Adhesion and Plant Immunity Suppression in the Necrotrophic Fungus Botrytis cinerea.

LysM effectors are suppressors of chitin-triggered plant immunity in biotrophic and hemibiotrophic fungi. In necrotrophic fungi, LysM effectors might induce a mechanism to suppress host immunity during the short asymptomatic phase they establish before these fungi activate plant defenses and induce host cell death leading to necrosis. Here, we characterize a secreted LysM protein from a major necrotrophic fungus, Botrytis cinerea, called BcLysM1. Transcriptional induction of BcLysM1 gene was observed in multicellular appressoria, called infection cushions, in unicellular appressoria and in the early phase of infection on bean leaves. We confirmed that BcLysM1 protein binds chitin in the fungus cell wall and protects hyphae against degradation by external chitinases. This effector is also able to suppress the chitin-induced ROS burst in Arabidopsis thaliana, suggesting sequestration of chitooligosaccharides in apoplast during infection. Moreover, contribution of BcLysM1 in infection initiation and in adhesion to bean leaf surfaces were demonstrated. Our data show for the first time that a LysM effector can play a dual role in mycelial adhesion and suppression of chitin-triggered host immunity, both of which occur during the early asymptomatic phase of infection by necrotrophic fungi.

Epigenomic and clinical analyses of striatal DAT binding in healthy individuals reveal well-known loci of Parkinson's disease

BackgroundStriatal dopamine transporter (DAT) binding is a sensitive and specific endophenotype for detecting dopaminergic deficits across Parkinson's disease (PD) spectrum. Molecular and clinical signatures of PD in asymptomatic phases help understand the earliest pathophysiological mechanisms underlying the disease. We aimed to investigate whether blood epigenetic markers are associated with inter-individual variation of striatal DAT binding among healthy elderly individuals. We also investigated whether this potential inter-individual variation can manifest as dysfunction of particular cognitive domains. Omics studies conducted on endophenotypes of PD among healthy asymptomatic individuals can provide invaluable insights into early detection, disease mechanisms, and potential therapeutic targets for PD. MethodWe conducted a blood epigenome-wide association study of striatal DAT binding on 96 healthy individuals using the Illumina EPIC array. For functional annotation of our top results, we employed the enhancer-gene mapping strategy using a midbrain single-nucleus multimodal dataset. Finally, we conducted several investigative regression analyses on several neuropsychological tests across five cognitive domains to assess their association with striatal DAT binding among 250 healthy subjects. ResultsWe identified seven suggestive (P-value<10−5) CpG probes. Specifically, three probes were colocalized with three risk loci previously identified in PD's largest Genome-Wide Association Study (GWAS). UCN5A and APOE loci were identified as suggestive DMRs associated with striatal DAT binding. Functional analyses prioritized the FDFT1 gene as the potential target gene in the previously reported CTSB GWAS locus. We also showed that delayed recall memory impairment was correlated with reduced striatal DAT binding, irrespective of age. ConclusionOur study suggested epigenetic and cognitive signatures of striatal DAT binding among healthy individuals, providing valuable insights for future experimental and clinical studies of early PD.

Prediction, prognosis and monitoring of neurodegeneration at biobank-scale via machine learning and imaging.

Alzheimer's disease and related dementias (ADRD) and Parkinson's disease (PD) are the most common neurodegenerative conditions. These central nervous system disorders impact both the structure and function of the brain and may lead to imaging changes that precede symptoms. Patients with ADRD or PD have long asymptomatic phases that exhibit significant heterogeneity. Hence, quantitative measures that can provide early disease indicators are necessary to improve patient stratification, clinical care, and clinical trial design. This work uses machine learning techniques to derive such a quantitative marker from T1-weighted (T1w) brain Magnetic resonance imaging (MRI). In this retrospective study, we developed machine learning (ML) based disease-specific scores based on T1w brain MRI utilizing Parkinson's Disease Progression Marker Initiative (PPMI) and Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts. We evaluated the potential of ML-based scores for early diagnosis, prognosis, and monitoring of ADRD and PD in an independent large-scale population-based longitudinal cohort, UK Biobank. 1,826 dementia images from 731 participants, 3,161 healthy control images from 925 participants from the ADNI cohort, 684 PD images from 319 participants, and 232 healthy control images from 145 participants from the PPMI cohort were used to train machine learning models. The classification performance is 0.94 [95% CI: 0.93-0.96] area under the ROC Curve (AUC) for ADRD detection and 0.63 [95% CI: 0.57-0.71] for PD detection using 790 extracted structural brain features. The most predictive regions include the hippocampus and temporal brain regions in ADRD and the substantia nigra in PD. The normalized ML model's probabilistic output (ADRD and PD imaging scores) was evaluated on 42,835 participants with imaging data from the UK Biobank. There are 66 cases for ADRD and 40 PD cases whose T1 brain MRI is available during pre-diagnostic phases. For diagnosis occurrence events within 5 years, the integrated survival model achieves a time-dependent AUC of 0.86 [95% CI: 0.80-0.92] for dementia and 0.89 [95% CI: 0.85-0.94] for PD. ADRD imaging score is strongly associated with dementia-free survival (hazard ratio (HR) 1.76 [95% CI: 1.50-2.05] per S.D. of imaging score), and PD imaging score shows association with PD-free survival (hazard ratio 2.33 [95% CI: 1.55-3.50]) in our integrated model. HR and prevalence increased stepwise over imaging score quartiles for PD, demonstrating heterogeneity. As a proxy for diagnosis, we validated AD/PD polygenic risk scores of 42,835 subjects against the imaging scores, showing a highly significant association after adjusting for covariates. In both the PPMI and ADNI cohorts, the scores are associated with clinical assessments, including the Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog), and pathological markers, which include amyloid and tau. Finally, imaging scores are associated with polygenic risk scores for multiple diseases. Our results suggest that we can use imaging scores to assess the genetic architecture of such disorders in the future. Our study demonstrates the use of quantitative markers generated using machine learning techniques for ADRD and PD. We show that disease probability scores obtained from brain structural features are useful for early detection, prognosis prediction, and monitoring disease progression. To facilitate community engagement and external tests of model utility, an interactive app to explore summary level data from this study and dive into external data can be found here https://ndds-brainimaging-ml.streamlit.app. As far as we know, this is the first publicly available cloud-based MRI prediction application. US National Institute on Aging, and US National Institutes of Health.

Analysis of the expression characteristics and clinical value of immune function indicators in patients with human immunodeficiency virus infection.

To explore the expression characteristics and clinical value of immune function indicators in patients with human immunodeficiency virus (HIV) infection. In this retrospective study, clinical data of 196 patients with HIV infection (observation group) and 196 health examinees (control group) admitted to our hospital from November 2021 to March 2023 were retrospectively analyzed. Patients in the observation group were further classified based on the staging as acute phase (n=53), asymptomatic phase (n=65), and acquired immunodeficiency (AIDS) phase (n=78). Levels of immune function indicators in the observation group and the control group were compared, and the correlation between immune function index levels and disease staging was analyzed. Levels of CD3+, CD4+, CD4+/CD8+, B cells, and NK cells were lower in the observation group (P<0.05), were significantly lower in asymptomatic patients compared with patients in the acute phase (P<0.05), and were significantly lower in patients with AIDS than those in asymptomatic patients (P<0.05). The results for CD8+ were in contrast to the above(P<0.05). Spearman analysis confirmed that levels of CD3+, CD4+, CD4+/CD8+, B cells and NK cells significantly negatively correlated, and levels of CD8+ significantly positively correlated with the stages of HIV (P<0.05). The immune function indicators of patients with HIV infection are markedly abnormal, which is mainly manifested by the decreased levels of CD3+, CD4+, CD4+/CD8+, B cells and NK cells, and the increased levels of CD8+. The profile of the immune function indicators correlates with the progressive severity of the disease.

Progressive T1 high-intensity plaques in carotid stenosis: Comparative MRI analyses in asymptomatic and symptomatic phases of low-grade stenosis

Background and PurposeCarotid artery stenosis, particularly the progression from asymptomatic to symptomatic lesions, is a key factor in cerebrovascular events. This study identifies predictors of symptom development in low-grade carotid stenosis (<50%), focusing on intraplaque hemorrhage (IPH) and dynamic plaque changes. Materials and MethodsWe conducted a retrospective study analyzing 30 cases of symptomatic low-grade carotid stenosis, using carotid MRI before and after symptom onset. Key measures included relative plaque signal intensity (rSI) and high-intensity plaque (HI plaque) volume. Stepwise regression analysis examined the influence of these factors on Symptomatic rSI, Symptomatic plaque volume, and NIHSS scores. ResultsSignificant increases were observed in rSI (1.32 ± 0.32 to 1.69 ± 0.25, p < 0.001) and HI plaque volume (296.4 ± 362.7 mm³ to 717.5 ± 554.9 mm³, p < 0.001) from asymptomatic to symptomatic phases. Past smoking (p = 0.008) and statin use (p = 0.04) were associated with higher Symptomatic rSI, while poor risk factor control (p = 0.03) was negatively associated. Female sex (p = 0.007) and current smoking (p = 0.009) were linked to smaller Symptomatic plaque volumes, while ischemic heart disease (p = 0.0002) and poor risk factor control (p = 0.002) predicted larger plaque volumes. Larger plaques were correlated with higher NIHSS scores (p = 0.002). ConclusionsIPH and plaque volume are key markers of progression in low-grade carotid stenosis. Poor control of cardiovascular risk factors and a history of ischemic heart disease contribute to plaque burden and stroke severity. Continuous monitoring and strict risk management are essential in reducing stroke severity in these patients.

Energy demanding RNA and protein metabolism drive dysfunctionality of HIV-specific T cell changes during chronic HIV infection.

Antiretroviral treatment of HIV infected individuals cannot eliminate the HIV reservoir and immune control of HIV is rarely seen upon treatment interruption. In long-term non-progressors (LTNP), an effective CD8 T cell response is thought to contribute to be immune control of HIV. Here we studied the transcriptional profile of virus specific CD8 T cells during the asymptomatic phase of disease, to gain molecular insights in CD8 T cell functionality in HIV progressors and different groups of LTNP: HLA-B*57 LTNP, non-HLA-B*57 LTNP and individuals carrying the MAVS minor genotype (rs7262903/rs7269320). Principal component analysis revealed distinct overall transcriptional profiles between the groups. The transcription profile of HIV-specific CD8 T cells of LTNP groups was associated with increased cytokine/IL-12 signaling and protein/RNA metabolism pathways, indicating an increased CD8 T cell functionality. Although the transcription profile of CMV-specific CD8 T cells differed from that of HIV-specific CD8 T cells, with mainly an upregulation of gene expression in progressors, similar affected pathways were identified. Moreover, CMV-specific CD8 T cells from progressors showed increased expression of genes related to effector functions and suggests recent antigen exposure. Our data shows that changes in cytokine signaling and the energy demanding RNA and protein metabolism are related to CD8 T cell dysfunction, which may indicate that mitochondrial dysfunction is an important driver of T cell dysfunctionality during chronic HIV infection. Indeed, improvement of mitochondrial function by IL-12 and mitoTempo treatment, enhanced in vitro IFNγ release by PBMC from PWH upon HIV gag and CMV pp65 peptide stimulation. Our study provides new insights into the molecular pathways associated with CD8 T cell mediated immune control of chronic HIV infection which is important for the design of novel treatment strategies to restore or improve the HIV-specific immune response.

Effects of Transjugular Intrahepatic Portosystemic Shunt on Renal and Pulmonary Function in Hepatic Decompensation with and without Hepatorenal and Hepatopulmonary Syndromes: A Review.

Cirrhosis is often characterized by decreased liver function, ranging from a compensated, typically asymptomatic phase to a decompensated phase characterized by the appearance of ascites or variceal bleeding, and ultimately hepatorenal syndrome (HRS) or hepatopulmonary syndrome (HPS). The latter two complications are associated with a poor prognosis and limited treatment efficacy. In cases of ascites or variceal bleeding resistant to medical therapy, transjugular intrahepatic portosystemic shunt (TIPS) is effective and safe. Shunting blood by TIPS diverts portal blood to the systemic circulation, potentially increasing systemic blood volume and benefiting renal function. However, TIPS could also divert nitric oxide to the systemic circulation, potentially worsening systemic hypotension and perfusion, which could be detrimental to renal function. Available evidence indicates that TIPS often improves renal function in patients with portal hypertension, with or without HRS. No studies have shown persistently decreased renal function after TIPS. However, these data are insufficient to support a recommendation for the use of TIPS specifically for HRS. In patients without pre-existing HPS, TIPS does not appear to significantly affect pulmonary gas exchange. Results of TIPS in HPS have been inconsistent; some studies have shown improvement, but effects were transient. No studies have shown a persistent decline in pulmonary function after TIPS. The evidence supports the need for large randomized controlled trials to investigate the beneficial effects of TIPS for HRS. Similar pulmonary function data are less clear regarding TIPS for HPS. The aim of the current report was to review the literature regarding the effects of TIPS on renal and pulmonary function in hepatic decompensation, with or without the development of HRS or HPS.

Kinetics of Viral Shedding for Outbreak Surveillance of Emerging Infectious Diseases: Modeling Approach to SARS-CoV-2 Alpha and Omicron Infection.

Previous studies have highlighted the importance of viral shedding using cycle threshold (Ct) values obtained via reverse transcription polymerase chain reaction to understand the epidemic trajectories of SARS-CoV-2 infections. However, it is rare to elucidate the transition kinetics of Ct values from the asymptomatic or presymptomatic phase to the symptomatic phase before recovery using individual repeated Ct values. This study proposes a novel Ct-enshrined compartment model to provide a series of quantitative measures for delineating the full trajectories of the dynamics of viral load from infection until recovery. This Ct-enshrined compartment model was constructed by leveraging Ct-classified states within and between presymptomatic and symptomatic compartments before recovery or death among people with infections. A series of recovery indices were developed to assess the net kinetic movement of Ct-up toward and Ct-down off recovery. The model was applied to (1) a small-scale community-acquired Alpha variant outbreak under the "zero-COVID-19" policy without vaccines in May 2021 and (2) a large-scale community-acquired Omicron variant outbreak with high booster vaccination rates following the lifting of the "zero-COVID-19" policy in April 2022 in Taiwan. The model used Bayesian Markov chain Monte Carlo methods with the Metropolis-Hastings algorithm for parameter estimation. Sensitivity analyses were conducted by varying Ct cutoff values to assess the robustness of the model. The kinetic indicators revealed a marked difference in viral shedding dynamics between the Alpha and Omicron variants. The Alpha variant exhibited slower viral shedding and lower recovery rates, but the Omicron variant demonstrated swifter viral shedding and higher recovery rates. Specifically, the Alpha variant showed gradual Ct-up transitions and moderate recovery rates, yielding a presymptomatic recovery index slightly higher than 1 (1.10), whereas the Omicron variant had remarkable Ct-up transitions and significantly higher asymptomatic recovery rates, resulting in a presymptomatic recovery index much higher than 1 (152.5). Sensitivity analysis confirmed the robustness of the chosen Ct values of 18 and 25 across different recovery phases. Regarding the impact of vaccination, individuals without booster vaccination had a 19% higher presymptomatic incidence rate compared to those with booster vaccination. Breakthrough infections in boosted individuals initially showed similar Ct-up transition rates but higher rates in later stages compared to nonboosted individuals. Overall, booster vaccination improved recovery rates, particularly during the symptomatic phase, although recovery rates for persistent asymptomatic infection were similar regardless of vaccination status once the Ct level exceeded 25. The study provides new insights into dynamic Ct transitions, with the notable finding that Ct-up transitions toward recovery outpaced Ct-down and symptom-surfacing transitions during the presymptomatic phase. The Ct-up against Ct-down transition varies with variants and vaccination status. The proposed Ct-enshrined compartment model is useful for the surveillance of emerging infectious diseases in the future to prevent community-acquired outbreaks.

'Knock down the brain': a nonlinear analysis of electroencephalography to study the effects of sub-concussion in boxers.

Boxing is associated with a high risk of head injuries and increases the likelihood of chronic traumatic encephalopathy. This study explores the effects of sub-concussive impacts on boxers by applying both linear and nonlinear analysis methods to electroencephalogram (EEG) data. Twenty-one boxers were selected (mean ± SD, age 28.38 ± 5.5 years; weight 67.55 ± 8.90 kg; years of activity 6.76 ± 5.45; education 14.19 ± 3.08 years) and divided into 'beginner' and 'advanced' groups. The Montreal Cognitive Assessment and the Frontal Assessment Battery were administered; EEG data were collected in both eyes-open (EO) and eyes-closed (EC) conditions during resting states. Analyses of EEG data included normalized power spectral density (nPSD), power law exponent (PLE), detrended fluctuation analysis and multiscale entropy. Statistical analyses were used to compare the groups. Significant differences in nPSD and PLE were observed between the beginner and advanced boxers, with advanced boxers showing decreased mean nPSD and PLE (nPSD 4-7 Hz, p = 0.013; 8-13 Hz, p = 0.003; PLE frontal lobe F3 EC, p = 0.010). Multiscale entropy analysis indicated increased entropy at lower frequencies and decreased entropy at higher frequencies in advanced boxers (F3 EC, p = 0.024; occipital lobe O1 EO, p = 0.029; occipital lobe O2 EO, p = 0.036). These changes are similar to those seen in Alzheimer's disease. Nonlinear analysis of EEG data shows potential as a neurophysiological biomarker for detecting the asymptomatic phase of chronic traumatic encephalopathy in boxers. This methodology could help monitor athletes' health and reduce the risk of future neurological injuries in sports.

Light gradient boost tree classifier predictions on appendicitis with periodontal disease from biochemical and clinical parameters.

Untreated periodontitis significantly increases the risk of tooth loss, often delaying treatment due to asymptomatic phases. Recent studies have increasingly associated poor dental health with conditions such as rheumatoid arthritis, diabetes, obesity, pneumonia, cardiovascular disease, and renal illness. Despite these connections, limited research has investigated the relationship between appendicitis and periodontal disease. This study aims to predict appendicitis in patients with periodontal disease using biochemical and clinical parameters through the application of a light gradient boost tree classifier. Data from 125 patient records at Saveetha Institute of Dental College and Medical College were pre-processed and analyzed. We utilized data preprocessing techniques, feature selection methods, and model development approaches to estimate the risk of appendicitis in patients with periodontitis. Both Random Forest and Light Gradient Boosting algorithms were evaluated for accuracy using confusion matrices to assess their predictive performance. The Random Forest model achieved an accuracy of 94%, demonstrating robust predictive capability in this context. In contrast, the Light Gradient Boost algorithms achieved a significantly higher accuracy of 98%, underscoring their superior predictive efficiency. This substantial difference highlights the importance of algorithm selection and optimization in developing reliable predictive models. The higher accuracy of Light Gradient Boost algorithms suggests effective minimization of prediction errors and improved differentiation between appendicitis with periodontitis and healthy states. Our study identifies age, white blood cell count, and symptom duration as pivotal predictors for detecting concurrent periodontitis in acute appendicitis cases. The newly developed prediction model introduces a novel and promising approach, providing valuable insights into distinguishing between periodontitis and acute appendicitis. These findings highlight the potential to improve diagnostic accuracy and support informed clinical decision-making in patients presenting with both conditions, offering new avenues for optimizing patient care strategies.

CCR5-mediated homing of regulatory T cells and monocytic-myeloid derived suppressor cells to dysfunctional endothelium contributes to early atherosclerosis.

A disbalance between immune regulatory cells and inflammatory cells is known to drive atherosclerosis. However, the exact mechanism is not clear. Here, we investigated the homing of immune regulatory cells, mainly, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) subsets in asymptomatic coronary artery disease (CAD) risk factor-exposed young individuals (dyslipidemia [DLP] group) and stable CAD patients (CAD group). Compared with healthy controls (HCs), Tregs frequency was reduced in both DLP and CAD groups but expressed high levels of CCR5 in both groups. The frequency of monocytic-myeloid-derived suppressor cells (M-MDSCs) was increased while polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were decreased in CAD patients only. Interestingly, although unchanged in frequency, M-MDSCs of the DLP group expressed high levels of CCR5. Serum levels of chemokines (CCL5, CX3CL1, CCL26) and inflammatory cytokines (IL-6, IL-1β, IFN-γ, TNF-α) were higher in the DLP group. Stimulation with inflammatory cytokines augmented CCR5 expression in Tregs and M-MDSCs isolated from HCs. Activated endothelial cells showed elevated levels of CX3CL1 and CCL5 in vitro. Blocking CCR5 with D-Ala-peptide T-amide (DAPTA) increased Treg and M-MDSC frequency in C57Bl6 mice fed a high-fat diet. In accelerated atherosclerosis model, DAPTA treatment led to the formation of smooth muscle-rich plaque with less macrophages. Thus, we show that CCR5-CCL5 axis is instrumental in recruiting Tregs and M-MDSCs to dysfunctional endothelium in the asymptomatic phase of atherosclerosis contributing to atherosclerosis progression. Drugs targeting CCR5 in asymptomatic and CAD risk-factor/s-exposed individuals might be a novel therapeutic regime to diminish atherogenesis.

Novel Biomarkers: Soluble Urokinase-Type Plasminogen Activator Receptor and Procalcitonin- and Histological Chorioamnionitis after Preterm Premature Rupture of Membranes

Fetal inflammatory response syndrome or infection after preterm premature rupture of membranes (PPROM) increases neonatal morbidity in preterm deliveries. Biochemical markers from the amniotic fluid (AF) have been used to evaluate possible intra-amniotic infection during the asymptomatic phase after PPROM. This study aimed to describe whether soluble urokinase-type plasminogen activator receptor (suPAR) or procalcitonin (PCT) from AF or maternal sera could reveal fetal inflammatory response or infection after PPROM. AF and maternal serum samples were collected weekly after PPROM (23+ 0 − 34+ 6 gestational weeks) until delivery from twenty women and two women with possible chorioamnionitis with intact membranes. Levels of suPAR, PCT, interleukin-6 (IL-6), glucose, lactate dehydrogenase (LDH), and bacterial PCR were determined from AF and suPAR and PCT and IL-6 from maternal sera. Fetal infection or inflammation response were determined by the histology of the placenta after delivery. AF glucose was significantly lower and AF LDH higher in the fetal site histologic chorioamnionitis (HCA) group, while AF suPAR concentrations tended to be higher in this group. AF suPAR correlated significantly with AF glucose and LDH. Based on receiver operating characteristic (ROC) analysis, AF glucose had the best predictability for fetal site histological chorioamnionitis. The findings of AF PCT were insignificant considering HCA. AF glucose had the highest accuracy in predicting fetal site histologic chorioamnionitis. AF suPAR may be a promising marker; however, our findings were limited by a small study population.

Unraveling the Missing Pieces: Exploring the Gaps in Understanding Chagas Cardiomyopathy.

Chagas cardiomyopathy affects a considerable number of patients infected with the protozoan Trypanosoma cruzi (T. cruzi) and remains one of the mostneglected tropical diseases despite being a significant contributor to morbidity and mortality in both endemic regions of Latin America and non-endemic countries like the United States. Since its discovery almost a century ago, knowledge gaps still exist in the mechanisms involved in the pathogenesis of Chagas cardiomyopathy, and numerous challenges exist in its diagnosis and treatment. This article reviews the main pathogenetic mechanisms involved in the progression of Chagas cardiomyopathy, which has been proposed as a result of years of research. It also emphasizes the challenges involved in the diagnosis of the asymptomatic indeterminate phase and has focused on several diagnostic techniques, including echocardiography, electrocardiogram (ECG), magnetic resonance imaging (MRI), and nuclear imaging in diagnosing symptomatic Chagas cardiomyopathy. In this article, we have also provided a brief overview of the current treatment of Chagas cardiomyopathy, which is not etiology-specific but insteadderived from the knowledge acquired from the treatment of other cardiomyopathies.

Biocontrol efficacy of Pseudomonas mediterranea PVCT 3C against Plenodomus tracheiphilus: In vitro and in planta mechanisms at early disease stages

In this study, we investigated the biocontrol activity of the P. mediterranea strain PVCT 3C against Mal secco, a severe disease of citrus caused by the vascular fungus Plenodomus tracheiphilus. In vitro, bacterial diffusible compounds, volatile organic compounds and culture filtrates produced by PVCT 3C reduced the mycelial growth and conidial germination of P. tracheiphilus, also affecting the mycelial pigmentation. The application of bacterial suspensions by leaf-spraying before the inoculation with the pathogen on plants of the highly susceptible species sour orange and lemon led to an overall reduction in incidence and disease index, above all during the early disease stage. PVCT 3C genome was subjected to whole-genome shotgun sequencing to study the molecular mechanisms of action of this strain. In silico annotation of biosynthetic gene clusters for secondary metabolites revealed the presence of numerous clusters encoding antimicrobial compounds (e.g. cyclic lipopeptides, hydrogen cyanide, siderophores) and candidate novel products. During the asymptomatic disease phase (seven days post-inoculation), bacterial treatments interfered with the expression of different fungal genes, as assessed with an NGS and de novo assembly RNA-seq approach. These results suggest that P. mediterranea PVCT 3C or its secondary metabolites may offer a potential effective and sustainable alternative to contain P. tracheiphilus infections via integrated management.

The Long Noncoding RNA PANDAR as a Prognostic and Diagnostic Biomarker in Panceratic Cancer ‏‏.

Pancreatic cancer (PC) is a lethal complication in the world, affecting around half a million individuals each year. The treatment of PC is relatively difficult due to the difficulty in making an early diagnosis. Most PC patients are confronted with locally metastatic or advanced diseases in the asymptomatic phase, and about 80% have late diagnosis with metastasis. Recently, long noncoding RNAs (lncRNAs) have drawn attention as a novel biological regulation layer. They take part in the regulation of mRNA and can be used as a prognostic factor or drug target. Based on their functions as regulators of PC initiation and progress, the lncRNAs can be categorized as tumor suppressors or oncogenic. They can be considered as a target for finding new biomarkers for prognosis, diagnosis, monitoring, and treating drug response in PC. Therefore, the present study summarizes the lncRNAs role in PC and the probable strategies to deal with their expression and controlling tumorigenesis and detection of the prognosis of PC.

Screening for Hepatocellular Carcinoma and Survival in Patients With Cirrhosis After Hepatitis C Virus Cure

The risk of hepatocellular carcinoma (HCC) declines over time after hepatitis C virus (HCV) cure by direct-acting antiviral (DAA) therapies. Liver society guidelines recommend continuing HCC screening for these patients, but data on screening outcomes are lacking. To evaluate the association of HCC screening after HCV cure with overall survival. This cohort study evaluated patients with HCV cirrhosis who achieved DAA-induced HCV cure in the Veterans Affairs health care system between January 2014 and December 2022. Data analysis occurred from October 2023 to January 2024. The percentage of time spent up to date with recommended HCC screening was calculated by year of follow-up and during the 4 years preceding HCC diagnosis (the detectable asymptomatic phase). The primary outcome was overall survival after HCC diagnosis and was compared by percentage of time spent up to date with screening using Kaplan-Meier analyses and Cox proportional hazards regression. Early-stage HCC at diagnosis and curative treatment were secondary outcomes assessed using logistic regression. A total of 16 902 individuals were included (median [IQR] age, 64.0 [60.5-67.4] years; 16 426 male [97.2%]), of whom 1622 developed HCC. The cumulative incidence of HCC declined from 2.4% (409 of 16 902 individuals) to 1.0% (27 of 2833 individuals) from year 1 to year 7 of follow-up. Being up to date with screening for at least 50% of time during the 4 years preceding HCC diagnosis was associated with improved overall survival (log-rank test of equality over strata P = .002). In multivariate analysis, each 10% increase in follow-up spent up to date with screening was associated with a 3.2% decrease in the hazard of death (hazard ratio, 0.97; 95% CI, 0.95-0.99). There was a statistically significant interaction between time since HCV cure and screening, with no association observed among those who received a diagnosis of HCC more than 5 years after HCV cure. Each 10% of time spent up to date with screening was associated with a 10.1% increased likelihood of diagnosis with early-stage HCC (95% CI, 6.3%-14.0%) and a 6.8% increased likelihood of curative treatment (95% CI, 2.8%-11.0%). In this cohort study of persons with HCV-related cirrhosis who achieved HCV cure and subsequently developed HCC, remaining up to date with screening was associated with improved overall survival, supporting the screening of eligible individuals.

Role of Serum Vitamin D Level in the Progression of Dengue Viral Illness: A Potential Immunomodulator?: A Literature Review

This is a literature review on the role of serum vitamin D levels in dengue viral illness as a potential immunomodulator. The dengue virus is an RNA virus that causes many symptoms, from asymptomatic phases to severe forms like dengue hemorrhagic fever and dengue shock syndrome. The review methodology was based on evidence-based rapid review, and the review's objectives are to scrutinize all the available articles on dengue virus and vitamin D from standard databases and literature searches. It was found that there are no specific antivirals for the definitive management of the dengue virus, and vitamin D, with its potential antiviral and immunomodulatory effects, can play a significant role against the dengue viral illness. It was also found that there are limited reviews on the association between dengue virus and vitamin D. The review concludes that there is a possible association between supplementing with vitamin D and lowering the risk of progression to severe dengue viral illness and that regular testing of serum vitamin D levels is highly encouraged during the illness as vitamin D levels get depleted with the progression of the illness.

Systemic inflammatory cytokine profiles in patients with gout during flare, intercritical and treat-to-target phases: TNFSF14 as new biomarker

IntroductionUntreated gout is characterised by monosodium urate (MSU) crystal accumulation responsible for recurrent flares that are commonly separated by asymptomatic phases. Both phases are inflammatory conditions of variable intensity. Gout...

Unraveling the genetic architecture of blood unfolded p-53 among non-demented elderlies: novel candidate genes for early Alzheimer's disease

BackgroundAlzheimer's disease (AD) is a heritable neurodegenerative disease whose long asymptomatic phase makes the early diagnosis of it pivotal. Blood U-p53 has recently emerged as a superior predictive biomarker for AD in the early stages. We hypothesized that genetic variants associated with blood U-p53 could reveal novel loci and pathways involved in the early stages of AD.ResultsWe performed a blood U-p53 Genome-wide association study (GWAS) on 484 healthy and mild cognitively impaired subjects from the ADNI cohort using 612,843 Single nucleotide polymorphisms (SNPs). We performed a pathway analysis and prioritized candidate genes using an AD single-cell gene program. We fine-mapped the intergenic SNPs by leveraging a cell-type-specific enhancer-to-gene linking strategy using a brain single-cell multimodal dataset. We validated the candidate genes in an independent brain single-cell RNA-seq and the ADNI blood transcriptome datasets. The rs279686 between AASS and FEZF1 genes was the most significant SNP (p-value = 4.82 × 10–7). Suggestive pathways were related to the immune and nervous systems. Twenty-three candidate genes were prioritized at 27 suggestive loci. Fine-mapping of 5 intergenic loci yielded nine cell-specific candidate genes. Finally, 15 genes were validated in the independent single-cell RNA-seq dataset, and five were validated in the ADNI blood transcriptome dataset.ConclusionsWe underlined the importance of performing a GWAS on an early-stage biomarker of AD and leveraging functional omics datasets for pinpointing causal genes in AD. Our study prioritized nine genes (SORCS1, KIF5C, TMEFF2, TMEM63C, HLA-E, ATAT1, TUBB, ARID1B, and RUNX1) strongly implicated in the early stages of AD.

A Pilot Study of the Role of Selected Biomarkers of Kidney Injury in Dogs with Dilated Cardiomyopathy.

Heart and kidney diseases are among the most frequent medical conditions diagnosed in small animals. Due to the functional interconnection between these organs, the concept of the cardio-renal axis has been developed. In this context, renal disease or dysfunction often occurs secondary to heart diseases, such as dilated cardiomyopathy (DCM). DCM is the most common cardiomyopathy and a leading cause of mortality in large-breed dogs. Traditional biomarkers like creatinine or symmetric dimethylarginine concentration are not always effective, especially in the early stages of the disease, underscoring the need for more sensitive markers of renal impairment during heart failure (HF). This study aimed to evaluate the efficacy of selected biomarkers as indicators for early kidney damage in dogs with stage B2 DCM. We measured serum concentrations of cystatin C, KIM-1 (kidney injury molecule-1), and NGAL (neutrophil gelatinase-associated lipocalin) and their ratios to creatinine, analyzing their diagnostic values. Cystatin C was quantified using a sandwich enzyme immunoassay, while KIM-1 and NGAL were measured with enzyme-linked immunosorbent assay kits designed for canine diagnostics. The concentrations were indexed against serum creatinine. The study included 26 dogs: 9 with HF and 17 healthy controls. The mean ± standard deviation for healthy dogs for cystatin C, cystatin C/creatinine ratio, KIM-1, KIM-1/creatinine ratio, NGAL, and NGAL/creatinine ratio were 0.24 ± 0.04, 0.26 ± 0.07, 0.61 ± 0.07, 0.67 ± 0.13, 2.76 ± 1.8, and 2.79 ± 1.81, respectively. For DCM dogs, these values were 0.27 ± 0.1, 0.32 ± 0.12, 0.61 ± 0.08, 0.69 ± 0.17, 6.46 ± 5.22 (p = 0.02), and 7.99 ± 6.53 (p = 0.04). This study's findings suggest that during the asymptomatic phase of DCM, only NGAL concentration and the NGAL/creatinine ratio may serve as diagnostic markers for early-stage kidney injury.