Exploring the Correlation Between Fibrosis Biomarkers and Clinical Disease Severity in PLN p.Arg14del Patients

Background: Pathogenic variants in phospholamban (PLN, like p. Arg14del), are found in patients diagnosed with arrhythmogenic (ACM) and dilated cardiomyopathy (DCM). Fibrosis formation in the heart is one of the hallmarks in PLN p.Arg14del carriers. During collagen synthesis and breakdown, propeptides are released into the circulation, such as procollagen type I carboxy-terminal propeptide (PICP) and C-terminal telopeptide collagen type I (ICTP).Aim: To investigate if PICP/ICTP levels in blood are correlative biomarkers for clinical disease severity and outcome in PLN p.Arg14del variant carriers.Methods: Serum and EDTA blood samples were collected from 72 PLN p.Arg14del carriers (age 50.5 years, 63% female) diagnosed with ACM (n = 12), DCM (n = 14), and preclinical variant carriers (n = 46). PICP levels were measured with an enzyme-linked immune sorbent assay and ICTP with a radio immuno-assay. Increased PICP/ICTP ratios suggest a higher collagen deposition. Clinical data including electrocardiographic, and imaging results were adjudicated from medical records.Results: No correlation between PICP/ICTP ratios and late gadolinium enhancement (LGE) was found. Moderate correlations were found between the PICP/ICTP ratio and end-diastolic/systolic volume (both rs = 0.40, n = 23, p = 0.06). PICP/ICTP ratio was significantly higher in patients with T wave inversion (TWI), especially in leads V4–V6, II, III, and aVF (p < 0.022) and in patients with premature ventricular contractions (PVCs) during an exercise tolerance test (p = 0.007).Conclusion: High PICP/ICTP ratios correlated with clinical parameters, such as TWI and PVCs. Given the limited size and heterogeneity of the patient group, additional studies are required to substantiate the incremental prognostic value of these fibrosis biomarkers in PLN p.Arg14del patients.

The dark and light sides of extra-tumor environment

The paradox in the pathobiological processes driving the incidence and progression across carcinomas unveil new opportunities for effective cancer treatment. The scattered evidence across the literature indicates that the insufficiencies/alterations in mesothelial cell migration, development, or function dramatically change the clinical disease course. We succinctly report in-general phenomena extensible across carcinomas predisposing to desmoplasia/reactive stroma, with due understanding of the limitations associated with such broader extrapolation. We further highlight the need for a comprehensive understanding of these purported pathways with an emphasis towards determining the tradeoffs between the risks associated with cancer susceptibility and disease progression.

Reduced Pathogenicity of the SARS-CoV-2 Omicron Variant in Hamsters

The SARS-CoV-2 Omicron (B.1.1.529) variant has proven highly transmissible and has outcompeted the Delta variant in many regions of the world. Early reports have also suggested that Omicron may result in less severe clinical disease in humans. Here we show that Omicron is less pathogenic than prior SARS-CoV-2 variants in Syrian golden hamsters. Infection of hamsters with the SARS-CoV-2 WA1/2020, Alpha, Beta, or Delta strains led to 4-10% weight loss by day 4 and 10-17% weight loss by day 6, as expected. In contrast, infection of hamsters with two different Omicron challenge stocks did not result in any detectable weight loss, even at high challenge doses. Omicron infection still led to substantial viral replication in both the upper and lower respiratory tracts and pulmonary pathology, but with a trend towards higher viral loads in nasal turbinates and lower viral loads in lung parenchyma compared with WA1/2020 infection. These data suggest that the SARS-CoV-2 Omicron variant may result in more robust upper respiratory tract infection but less severe lower respiratory tract clinical disease compared with prior SARS-CoV-2 variants.

Genome-wide association study of disease resilience traits from a natural polymicrobial disease challenge model in pigs identifies the importance of the major histocompatibility complex region

Infectious diseases cause tremendous financial losses in the pork industry, emphasizing the importance of disease resilience, which is the ability of an animal to maintain performance under disease. Previously, a natural polymicrobial disease challenge model was established, in which pigs were challenged in the late nursery phase by multiple pathogens to maximize expression of genetic differences in disease resilience. Genetic analysis found that performance traits in this model, including growth rate, feed and water intake, and carcass traits, as well as clinical disease phenotypes, were heritable and could be selected for to increase disease resilience of pigs. The objectives of the current study were to identify genomic regions that are associated with disease resilience in this model, using genome-wide association studies and fine mapping methods, and to use gene set enrichment analyses to determine whether genomic regions associated with disease resilience are enriched for previously published quantitative trait loci (QTL), functional pathways, and differentially expressed genes subject to physiological states. Multiple QTL were detected for all recorded performance and clinical disease traits. The major histocompatibility complex (MHC) region was found to explain substantial genetic variance for multiple traits, including for growth rate in the late nursery (12.8%) and finisher (2.7%), for several clinical disease traits (up to 2.7%), and for several feeding and drinking traits (up to 4%). Further fine mapping identified four QTL in the MHC region for growth rate in the late nursery that spanned the subregions for class I, II, and III, with one SNP in the MHC Class I subregion capturing the largest effects, explaining 0.8 to 27.1% of genetic variance for growth rate and for multiple clinical disease traits. This SNP was located in the enhancer of TRIM39 gene, which is involved in innate immune response. The MHC region was pleiotropic for growth rate in the late nursery and finisher, and for treatment and mortality rates. Growth rate in the late nursery showed strong negative genetic correlations in the MHC region with treatment or mortality rates (-0.62 to -0.85) and a strong positive genetic correlation with growth rate in the finisher (0.79). Gene set enrichment analyses found genomic regions associated with resilience phenotypes to be enriched for previously identified disease susceptibility and immune capacity QTL, for genes that were differentially expressed following bacterial or virus infection and immune response, and for gene ontology terms related to immune and inflammatory response. In conclusion, the MHC and other QTL that harbor immune related genes were identified to be associated with disease resilience traits in a large-scale natural polymicrobial disease challenge. The MHC region was pleiotropic for growth rate under challenge and for clinical disease traits. Four QTL were identified across the class I, II, and III subregions of the MHC for nursery growth rate under challenge, with one SNP in the MHC Class I subregion capturing the largest effects. The MHC and other QTL identified play an important role in host response to infectious diseases and can be incorporated in selection to improve disease resilience, in particular the identified SNP in the MHC Class I subregion.

Impaired Folate-Mediated One-Carbon Metabolism in Type 2 Diabetes, Late-Onset Alzheimer’s Disease and Long COVID

Impaired folate-mediated one-carbon metabolism (FOCM) is associated with many pathologies and developmental abnormalities. FOCM is a metabolic network of interdependent biosynthetic pathways that is known to be compartmentalized in the cytoplasm, mitochondria and nucleus. Currently, the biochemical mechanisms and causal metabolic pathways responsible for the initiation and/or progression of folate-associated pathologies have yet to be fully established. This review specifically examines the role of impaired FOCM in type 2 diabetes mellitus, Alzheimer’s disease and the emerging Long COVID/post-acute sequelae of SARS-CoV-2 (PASC). Importantly, elevated homocysteine may be considered a biomarker for impaired FOCM, which is known to result in increased oxidative–redox stress. Therefore, the incorporation of hyperhomocysteinemia will be discussed in relation to impaired FOCM in each of the previously listed clinical diseases. This review is intended to fill gaps in knowledge associated with these clinical diseases and impaired FOCM. Additionally, some of the therapeutics will be discussed at this early time point in studying impaired FOCM in each of the above clinical disease states. It is hoped that this review will allow the reader to better understand the role of FOCM in the development and treatment of clinical disease states that may be associated with impaired FOCM and how to restore a more normal functional role for FOCM through improved nutrition and/or restoring the essential water-soluble B vitamins through oral supplementation

Preclinical models of acute liver failure: a comprehensive review

Acute liver failure is marked by the rapid deterioration of liver function in a previously well patient over period of days to weeks. Though relatively rare, it is associated with high morbidity and mortality. This makes it a challenging disease to study clinically, necessitating reliance on preclinical models as means to explore pathophysiology and novel therapies. Preclinical models of acute liver failure are artificial by nature, and generally fall into one of three categories: surgical, pharmacologic or immunogenic. This article reviews preclinical models of acute liver failure and considers their relevance in modeling clinical disease.

Paradoxical sex-specific patterns of autoantibody response to SARS-CoV-2 infection

Background Pronounced sex differences in the susceptibility and response to SARS-CoV-2 infection remain poorly understood. Emerging evidence has highlighted the potential importance of autoimmune activation in modulating the acute response and recovery trajectories following SARS-CoV-2 exposure. Given that immune-inflammatory activity can be sex-biased in the setting of severe COVID-19 illness, the aim of the study was to examine sex-specific autoimmune reactivity to SARS-CoV-2 in the absence of extreme clinical disease. Methods In this study, we assessed autoantibody (AAB) reactivity to 91 autoantigens previously linked to a range of classic autoimmune diseases in a cohort of 177 participants (65% women, 35% men, mean age of 35) with confirmed evidence of prior SARS-CoV-2 infection based on presence of antibody to the nucleocapsid protein of SARS-CoV-2. Data were compared to 53 pre-pandemic healthy controls (49% women, 51% men). For each participant, socio-demographic data, serological analyses, SARS-CoV-2 infection status and COVID-19 related symptoms were collected by an electronic survey of questions. The symptoms burden score was constructed based on the total number of reported symptoms (N = 21) experienced within 6 months prior to the blood draw, wherein a greater number of symptoms corresponded to a higher score and assigned as more severe burden. Results In multivariable analyses, we observed sex-specific patterns of autoreactivity associated with the presence or absence (as well as timing and clustering of symptoms) associated with prior COVID-19 illness. Whereas the overall AAB response was more prominent in women following asymptomatic infection, the breadth and extent of AAB reactivity was more prominent in men following at least mildly symptomatic infection. Notably, the observed reactivity included distinct antigens with molecular homology with SARS-CoV-2. Conclusion Our results reveal that prior SARS-CoV-2 infection, even in the absence of severe clinical disease, can lead to a broad AAB response that exhibits sex-specific patterns of prevalence and antigen selectivity. Further understanding of the nature of triggered AAB activation among men and women exposed to SARS-CoV-2 will be essential for developing effective interventions against immune-mediated sequelae of COVID-19.