Search

Background The genetic architecture of JIA remains only partially comprehended. There is a clear imperative for continued endeavours to uncover insights into the underlying causes of JIA. Methods This study encompassed a comprehensive spectrum of endeavours, including conducting a JIA genome-wide association study (GWAS) meta-analysis that incorporated data from 4550 JIA cases and 18 446 controls. We employed in silico and genome-editing approaches to prioritizing target genes. To investigate pleiotropic effects, we conducted phenome-wide association studies. Cell-type enrichment analyses were performed by integrating bulk and single-cell sequencing data. Finally, we delved into potential druggable targets for JIA. Results Fourteen genome-wide significant non-HLA loci were identified, including four novel loci, each exhibiting pleiotropic associations with other autoimmune diseases or musculoskeletal traits. We uncovered strong genetic correlation between JIA and BMD traits at 52 genomic regions, including three GWAS loci for JIA. Candidate genes with immune functions were captured by in silico analyses at each novel locus, with additional findings identified through our experimental approach. Cell-type enrichment analysis revealed 21 specific immune cell types crucial for the affected organs in JIA, indicating their potential contribution to the disease. Finally, 24 known or candidate druggable target genes were prioritized. Conclusions Our identification of four novel JIA-associated genes, CD247 , RHOH , COLEC10 and IRF8 , broadens the novel potential drug repositioning opportunities. We established a new genetic link between COLEC10 , TNFRSF11B and JIA/BMD. Additionally, the identification of RHOH underscores its role in positive thymocyte selection, thereby illuminating a critical facet of JIA's underlying biological mechanisms. [ABSTRACT FROM AUTHOR]

Clinical neurosciences, and psychiatry specifically, have been challenged by the lack of a comprehensive and practical framework that explains the core mechanistic processes of variable psychiatric presentations. Current conceptualization and classification of psychiatric presentations are primarily centered on a non-biologically based clinical descriptive approach. Despite various attempts, advances in neuroscience research have not led to an improved conceptualization or mechanistic classification of psychiatric disorders. This perspective article proposes a new--work-in-progress--framework for conceptualizing psychiatric presentations based on neural network components (NNC). This framework could guide the development of mechanistic disease classification, improve understanding of underpinning pathology, and provide specific intervention targets. This model also has the potential to dissolve artificial barriers between the fields of psychiatry and neurology. [ABSTRACT FROM AUTHOR]

Cerebrovascular diseases (CVDs) are a major threat to global health. Elucidation of the molecular mechanisms underlying the pathology of CVDs is critical for the development of efficacious preventative and therapeutic approaches. Accumulating studies have highlighted the significance of ubiquitin‐modifying enzymes (UMEs) in the regulation of CVDs. UMEs are a group of enzymes that orchestrate ubiquitination, a post‐translational modification tightly involved in CVDs. Functionally, UMEs regulate multiple pathological processes in ischemic and hemorrhagic stroke, moyamoya disease, and atherosclerosis. Considering the important roles of UMEs in CVDs, they may become novel druggable targets for these diseases. Besides, techniques applying UMEs, such as proteolysis‐targeting chimera and deubiquitinase‐targeting chimera, may also revolutionize the therapy of CVDs in the future. [ABSTRACT FROM AUTHOR]

Abstract Cerebrovascular diseases (CVDs) are a major threat to global health. Elucidation of the molecular mechanisms underlying the pathology of CVDs is critical for the development of efficacious preventative and therapeutic approaches. Accumulating studies have highlighted the significance of ubiquitin‐modifying enzymes (UMEs) in the regulation of CVDs. UMEs are a group of enzymes that orchestrate ubiquitination, a post‐translational modification tightly involved in CVDs. Functionally, UMEs regulate multiple pathological processes in ischemic and hemorrhagic stroke, moyamoya disease, and atherosclerosis. Considering the important roles of UMEs in CVDs, they may become novel druggable targets for these diseases. Besides, techniques applying UMEs, such as proteolysis‐targeting chimera and deubiquitinase‐targeting chimera, may also revolutionize the therapy of CVDs in the future.

Abstract Pathway Figure OCR (PFOCR) is a novel kind of pathway database approaching the breadth and depth of Gene Ontology while providing rich, mechanistic diagrams and direct literature support. Here, we highlight the utility of PFOCR in disease research in comparison with popular pathway databases through an assessment of disease coverage and analytical applications. In addition to common pathway analysis use cases, we present two advanced case studies demonstrating unique advantages of PFOCR in terms of cancer subtype and grade prediction analyses.

Abstract Background As the availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including secondary findings. Methods We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering. Results For 36/65 gene-disease pairs, loss of function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using the CardiacG2P dataset as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches. Conclusions Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is a pre-requisite for scalable genomic testing.

Pathway Figure OCR (PFOCR) is a novel kind of pathway database approaching the breadth and depth of Gene Ontology while providing rich, mechanistic diagrams and direct literature support. Here, we highlight the utility of PFOCR in disease research in comparison with popular pathway databases through an assessment of disease coverage and analytical applications. In addition to common pathway analysis use cases, we present two advanced case studies demonstrating unique advantages of PFOCR in terms of cancer subtype and grade prediction analyses. [ABSTRACT FROM AUTHOR]

Background: As the availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including secondary findings. Methods: We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering. Results: For 36/65 gene-disease pairs, loss of function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using the CardiacG2P dataset as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches. Conclusions: Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is a pre-requisite for scalable genomic testing. [ABSTRACT FROM AUTHOR]

Parasites such as schistosome, liver fluke, and echinococcus mainly parasitize or cause diseases in the liver, and liver fibrosis is the main pathological feature and primary cause of morbidity and mortality of hosts after infection. The liver fibrosis caused by these parasites still has a heavy disease burden in the world, and due to its unique disease characteristics, the animal model of liver fibrosis caused by parasites has a unique position in the study of liver fibrosis. The essential distinguishing feature of parasitic infection-induced hepatic fibrosis from other types of hepatic fibrosis is the variety of parasitic-secreted molecules initiating fibrosis, including proteins, nucleic acids, lipids, metabolic small molecules and other types. These molecules induce the formation of type 2 immunity or inflammatory microenvironment in the host liver. Although in-depth research has been conducted on the initiation, maintenance, and regression of type 2 immunity in the liver after parasitic infection, many core mechanisms remain unclear. Chronic inflammation ultimately activates stellate cells and other types of cells to differentiate into myofibroblasts (MF), thus promoting the formation of liver fibrosis. After clearing parasites, MF may undergo reverse differentiation, apoptosis or senescence, and liver fibers may undergo reversal. Deep research on the activation and regression of MF is the foundation for effective prevention and treatment of liver fibrosis. This article reviews the disease burden and pathological characteristics of liver fibrosis caused by parasite infection. [ABSTRACT FROM AUTHOR]

The heterogeneity of Parkinson's disease (PD), i.e. the various clinical phenotypes, pathological findings, genetic predispositions and probably also the various implicated pathophysiological pathways pose a major challenge for future research projects and therapeutic trail design. We outline several pathophysiological concepts, pathways and mechanisms, including the presumed roles of α-synuclein misfolding and aggregation, Lewy bodies, oxidative stress, iron and melanin, deficient autophagy processes, insulin and incretin signaling, T-cell autoimmunity, the gut–brain axis and the evidence that microbial (viral) agents may induce molecular hallmarks of neurodegeneration. The hypothesis is discussed, whether PD might indeed be triggered by exogenous (infectious) agents in susceptible individuals upon entry via the olfactory bulb (brain first) or the gut (body-first), which would support the idea that disease mechanisms may change over time. The unresolved heterogeneity of PD may have contributed to the failure of past clinical trials, which attempted to slow the course of PD. We thus conclude that PD patients need personalized therapeutic approaches tailored to specific phenomenological and etiologic subtypes of disease. [ABSTRACT FROM AUTHOR]

Rice production is severely hampered by the bakanae disease (Fusarium fujikuroi), formerly recognized as Fusarium moniliforme. F. moniliforme was called the F. fujikuroi species complex (FFSC) because it was later discovered that it had some separate species. The FFSC's constituents are also well recognized for producing phytohormones, which include auxins, cytokinin, and gibberellins (GAs). The normal symptoms of bakanae disease in rice are exacerbated by GAs. The members of the FFSC are responsible for the production of fumonisin (FUM), fusarins, fusaric acid, moniliformin, and beauvericin. These are harmful to both human and animal health. This disease is common around the world and causes significant yield losses. Numerous secondary metabolites, including the plant hormone gibberellin, which causes classic bakanae symptoms, are produced by F. fujikuroi. The strategies for managing bakanae, including the utilization of host resistance, chemical compounds, biocontrol agents, natural goods, and physical approaches, have been reviewed in this study. Bakanae disease is still not entirely preventable, despite the adoption of many different tactics that have been used to manage it. The benefits and drawbacks of these diverse approaches are discussed by the authors. The mechanisms of action of the main fungicides as well as the strategies for resistance to them are outlined. The information compiled in this study will contribute to a better understanding of the bakanae disease and the development of a more effective management plan for it. [ABSTRACT FROM AUTHOR]

More reliable and cheaper sequencing technologies have revealed the vast mutational landscapes characteristic of many phenotypes. The analysis of such genetic variants has led to successful identification of altered proteins underlying many Mendelian disorders. Nevertheless the simple one-variant one-phenotype model valid for many monogenic diseases does not capture the complexity of polygenic traits and disorders. Although experimental and computational approaches have improved detection of functionally deleterious variants and important interactions between gene products, the development of comprehensive models relating genotype and phenotypes remains a challenge in the field of genomic medicine. In this context, a new view of the pathologic state as significant perturbation of the network of interactions between biomolecules is crucial for the identification of biochemical pathways associated with complex phenotypes. Seminal studies in systems biology combined the analysis of genetic variation with protein-protein interaction networks to demonstrate that even as biological systems evolve to be robust to genetic variation, their topologies create disease vulnerabilities. More recent analyses model the impact of genetic variants as changes to the "wiring" of the interactome to better capture heterogeneity in genotype-phenotype relationships. These studies lay the foundation for using networks to predict variant effects at scale using machine-learning or algorithmic approaches. A wealth of databases and resources for the annotation of genotype-phenotype relationships have been developed to support developments in this area. This overview describes how study of the molecular interactome has generated insights linking the organization of biological systems to disease mechanism, and how this information can enable precision medicine. This article is categorized under: Translational, Genomic, and Systems Medicine > Translational Medicine Biological Mechanisms > Cell Signaling Models of Systems Properties and Processes > Mechanistic Models Analytical and Computational Methods > Computational Methods.

Rice production is severely hampered by the bakanae disease (Fusarium fujikuroi), formerly recognized as Fusarium moniliforme. F. moniliforme was called the F. fujikuroi species complex (FFSC) because it was later discovered that it had some separate species. The FFSC's constituents are also well recognized for producing phytohormones, which include auxins, cytokinin, and gibberellins (GAs). The normal symptoms of bakanae disease in rice are exacerbated by GAs. The members of the FFSC are responsible for the production of fumonisin (FUM), fusarins, fusaric acid, moniliformin, and beauvericin. These are harmful to both human and animal health. This disease is common around the world and causes significant yield losses. Numerous secondary metabolites, including the plant hormone gibberellin, which causes classic bakanae symptoms, are produced by F. fujikuroi. The strategies for managing bakanae, including the utilization of host resistance, chemical compounds, biocontrol agents, natural goods, and physical approaches, have been reviewed in this study. Bakanae disease is still not entirely preventable, despite the adoption of many different tactics that have been used to manage it. The benefits and drawbacks of these diverse approaches are discussed by the authors. The mechanisms of action of the main fungicides as well as the strategies for resistance to them are outlined. The information compiled in this study will contribute to a better understanding of the bakanae disease and the development of a more effective management plan for it.

Over a third of the human genome is comprised of repetitive sequences, including more than a million short tandem repeats (STRs). While studies of the pathologic consequences of repeat expansions that cause syndromic human diseases are extensive, the potential native functions of STRs are often ignored. Here, we summarize a growing body of research into the normal biological functions for repetitive elements across the genome, with a particular focus on the roles of STRs in regulating gene expression. We propose reconceptualizing the pathogenic consequences of repeat expansions as aberrancies in normal gene regulation. From this altered viewpoint, we predict that future work will reveal broader roles for STRs in neuronal function and as risk alleles for more common human neurological diseases.

Background: Migraine is considered a multifactorial genetic disorder. Different platforms and methods are used to unravel the genetic basis of migraine. Initially, linkage analysis in multigenerational families followed by Sanger sequencing of protein-coding parts (exons) of genes in the genomic region shared by affected family members identified high-effect risk DNA mutations for rare Mendelian forms of migraine, foremost hemiplegic migraine. More recently, genome-wide association studies testing millions of DNA variants in large groups of patients and controls have proven successful in identifying many dozens of low-effect risk DNA variants for the more common forms of migraine with the number of associated DNA variants increasing steadily with larger sample sizes. Currently, next-generation sequencing, utilising whole exome and whole genome sequence data, and other omics data are being used to facilitate their functional interpretation and the discovery of additional risk factors. Various methods and analysis tools, such as genetic correlation and causality analysis, are used to further characterise genetic risk factors. Findings: We describe recent findings in genome-wide association studies and next-generation sequencing analysis in migraine. We show that the combined results of the two most recent and most powerful migraine genome-wide association studies have identified a total of 178 LD-independent (r 2 < 0.1) genome-wide significant single nucleotide polymorphisms (SNPs), of which 99 were unique to Hautakangas et al., 11 were unique to Choquet et al., and 68 were identified by both studies. When considering that Choquet et al. also identified three SNPs in a female-specific genome-wide association studies then these two recent studies identified 181 independent SNPs robustly associated with migraine. Cross-trait and causal analyses are beginning to identify and characterise specific biological factors that contribute to migraine risk and its comorbid conditions. Conclusion: This review provides a timely update and overview of recent genetic findings in migraine. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is an enigmatic and deadly vascular disease with no known cure. Recent years have seen rapid advances in our understanding of the molecular underpinnings of PAH, with an expanding knowledge of the molecular, cellular, and systems-level drivers of disease that are being translated into novel therapeutic modalities. Simultaneous advances in clinical technology have led to a growing list of tools with potential application to diagnosis and phenotyping. Guided by fundamental biology, these developments hold the potential to usher in a new era of personalized medicine in PAH with broad implications for patient management and great promise for improved outcomes. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a multifaceted neurodegenerative condition marked by gradual cognitive deterioration and the loss of neurons. While conventional bulk RNA sequencing techniques have shed light on AD pathology, they frequently obscure the cellular diversity within brain tissues. The advent of single-cell RNA sequencing (scRNA-seq) has transformed our capability to analyze the cellular composition of AD, allowing for the detection of unique cell populations, rare cell types, and gene expression alterations at an individual cell level. This review examines the use of scRNA-seq in AD research, focusing on its contributions to understanding cellular diversity, disease progression, and potential therapeutic targets. We discuss key technological innovations, data analysis techniques, and challenges associated with scRNA-seq in studying AD. Furthermore, we highlight recent studies that have utilized scRNA-seq to identify novel biomarkers, uncover disease-associated pathways, and elucidate the role of non-neuronal cells, such as microglia and astrocytes, in AD pathogenesis. By providing a comprehensive overview of advancements in scRNA-seq for unraveling cellular heterogeneity in AD, this review highlights the transformative impact of scRNA-seq on our comprehension of disease mechanisms and the creation of targeted treatments. [Display omitted] [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults, causing progressive degeneration of motor neurons, which results in muscle atrophy, respiratory failure and ultimately death of the patients. The pathogenesis of ALS is complex, and extensive efforts have focused on unravelling the underlying molecular mechanisms with a large emphasis on the dying motor neurons. However, a recent shift in focus towards the supporting glial population has revealed a large contribution and influence in ALS, which stresses the need to explore this area in more detail. Especially studies into astrocytes, the residential homeostatic supporter cells of neurons, have revealed a remarkable astrocytic dysfunction in ALS, and therefore could present a target for new and promising therapeutic entry points. In this review, we provide an overview of general astrocyte function and summarize the current literature on the role of astrocytes in ALS by categorizing the potentially underlying molecular mechanisms. We discuss the current efforts in astrocyte-targeted therapy, and highlight the potential and shortcomings of available models.

Cardiovascular disease is the largest single cause of disease-related mortality worldwide and the major underlying pathology is atherosclerosis. Atherosclerosis develops as a complex process of vascular lipid deposition and retention by modified proteoglycans, endothelial dysfunction and unresolved chronic inflammation. There are a multitude of current therapeutic agents, most based on lowering plasma lipid levels, but, overall, they have a lower than optimum level of efficacy and many deaths continue to arise from cardiovascular disease world-wide. To identify and evaluate potential novel cardiovascular drugs, suitable animal models that reproduce human atherosclerosis with a high degree of fidelity are required as essential pre-clinical research tools. Commonly used animal models of atherosclerosis include mice (ApoE−/−, LDLR−/− mice and others), rabbits (WHHL rabbits and others), rats, pigs, hamster, zebrafish and non-human primates. Models based on various wild-type and genetically modified mice have been extensively reviewed but mice may not always be appropriate. Thus, here, we provide an overview of the advantages and shortcomings of various non-mouse animal models of atherosclerotic plaque formation, and plaque rupture, as well as commonly used interventional strategies. Taken together, the combinatorial selection of suitable animal models readily facilitates reproducible and rigorous translational research in discovering and validating novel anti-atherosclerotic drugs. [ABSTRACT FROM AUTHOR]

Erosion diseases often appear on the upper part of the Great Wall of China. Low precipitation, intense solar radiation, and severe soil salinization occur in northwest China, and the migration of salt and damage can be described with respect to the rainfall-radiation cycle. Rainfall and radiation conditions were simulated in the laboratory, and reproduced samples were subjected to cyclic experiments to determine salt migration and the damage progress. Surface hardness and ultrasonic velocity were used to measure the surface damage, and the microstructure damage was determined by computed tomography and scanning electronic microscopy. The results show that under the rainfall-radiation cycle, most of the salt in the upper part, including sulfate, migrates to an area 2–3 cm from, while a small part of the salt, including chloride, moves down into the lower half of the sample. In areas where salt is concentrated, the soil density decreases, cracks develop, and a vulnerable zone appears, reducing the surface hardness and ultrasonic velocity. The concentration of salt causing destruction of the soil structure is the main factor leading to erosion of the upper walls of earthen sites. Infiltration of rainwater is required for the migration of soluble sulfate and the damage to soil on the upper wall. Increasing radiation intensity would greatly accelerate the migration of soluble sulfate and damage to the soil structure. [ABSTRACT FROM AUTHOR]

This review outlines the role of electrostatics in computational molecular biophysics and its implication in altering wild-type characteristics of biological macromolecules, and thus the contribution of electrostatics to disease mechanisms. The work is not intended to review existing computational approaches or to propose further developments. Instead, it summarizes the outcomes of relevant studies and provides a generalized classification of major mechanisms that involve electrostatic effects in both wild-type and mutant biological macromolecules. It emphasizes the complex role of electrostatics in molecular biophysics, such that the long range of electrostatic interactions causes them to dominate all other forces at distances larger than several Angstroms, while at the same time, the alteration of short-range wild-type electrostatic pairwise interactions can have pronounced effects as well. Because of this dual nature of electrostatic interactions, being dominant at long-range and being very specific at short-range, their implications for wild-type structure and function are quite pronounced. Therefore, any disruption of the complex electrostatic network of interactions may abolish wild-type functionality and could be the dominant factor contributing to pathogenicity. However, we also outline that due to the plasticity of biological macromolecules, the effect of amino acid mutation may be reduced, and thus a charge deletion or insertion may not necessarily be deleterious. [ABSTRACT FROM AUTHOR]

Background: During the last 2 years of the coronavirus disease 2019 (COVID-19) pandemic, knowledge about the long-term effects of the disease, the so-called long COVID, has rapidly grown; however, many questions remain unanswered, especially regarding the causes of persistent symptoms and their prognosis. Cognitive disorders and sleep disturbances are among the most frequent complaints. Both are associated with severe suffering and significant impairment in everyday functioning. Objective: What is known about the occurrence of cognitive disorders and sleep disturbances in long COVID? What are the influencing factors and what is known about the course over time and possible underlying mechanisms? What treatment options are available? Material and method: In a narrative review, the most important findings on cognitive disorders and sleep disturbances in long COVID are presented. An overview of cohort studies with data on the prevalence and influencing factors of both symptom complexes is given. Current knowledge and hypotheses on pathophysiological mechanisms are presented and an outlook on treatment approaches is given. Results: About one in five of those affected report cognitive impairment more than 3 months after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and about one third report sleep disturbances. The latter comprise symptoms of insomnia as well as hypersomnia. Cognitive impairment and sleep disturbances occur in patients with all levels of initial disease severity. There are indications of an improvement of cognitive deficits over time but further longitudinal studies are needed. Conclusion: In addition to the prognosis, the underlying disease mechanisms are still insufficiently understood. Furthermore, there is a great need for research on the efficacy and specific effective factors of therapeutic interventions. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a complex neurodegenerative disorder. The relative contribution of the numerous underlying functional mechanisms is poorly understood. To comprehensively understand the context and distribution of pathways that contribute to AD, we performed text-mining to generate an exhaustive, systematic assessment of the breadth and diversity of biological pathways within a corpus of 206,324 dementia publication abstracts. A total of 91% (325/335) of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways have publications containing an association via at least 5 studies, while 63% of pathway terms have at least 50 studies providing a clear association with AD. Despite major technological advances, the same set of top-ranked pathways have been consistently related to AD for 30 years, including AD , immune system , metabolic pathways , cholinergic synapse , long-term depression , proteasome , diabetes , cancer , and chemokine signaling. AD pathways studied appear biased: animal model and human subject studies prioritize different AD pathways. Surprisingly, human genetic discoveries and drug targeting are not enriched in the most frequently studied pathways. Our findings suggest that not only is this disorder incredibly complex, but that its functional reach is also nearly global. As a consequence of our study, research results can now be assessed in the context of the wider AD literature, supporting the design of drug therapies that target a broader range of mechanisms. The results of this study can be explored at www.adpathways.org. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. VIDEO ABSTRACT.

Alzheimer’s disease (AD) is a complex neurodegenerative disorder. The relative contribution of the numerous underlying functional mechanisms is poorly understood. To comprehensively understand the context and distribution of pathways that contribute to AD, we performed text-mining to generate an exhaustive, systematic assessment of the breadth and diversity of biological pathways within a corpus of 206,324 dementia publication abstracts. A total of 91% (325/335) of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways have publications containing an association via at least 5 studies, while 63% of pathway terms have at least 50 studies providing a clear association with AD. Despite major technological advances, the same set of top-ranked pathways have been consistently related to AD for 30 years, including AD, immune system, metabolic pathways, cholinergic synapse, long-term depression, proteasome, diabetes, cancer, and chemokine signaling. AD pathways studied appear biased: animal model and human subject studies prioritize different AD pathways. Surprisingly, human genetic discoveries and drug targeting are not enriched in the most frequently studied pathways. Our findings suggest that not only is this disorder incredibly complex, but that its functional reach is also nearly global. As a consequence of our study, research results can now be assessed in the context of the wider AD literature, supporting the design of drug therapies that target a broader range of mechanisms. The results of this study can be explored at www.adpathways.org.

Genetic cardiomyopathies are disorders of the cardiac muscle, most often explained by pathogenic mutations in genes encoding sarcomere, cytoskeleton, or ion channel proteins. Clinical phenotypes such as heart failure and arrhythmia are classically treated with generic drugs, but aetiology‐specific and targeted treatments are lacking. As a result, cardiomyopathies still present a major burden to society, and affect many young and older patients. The Translational Committee of the Heart Failure Association (HFA) and the Working Group of Myocardial Function of the European Society of Cardiology (ESC) organized a workshop to discuss recent advances in molecular and physiological studies of various forms of cardiomyopathies. The study of cardiomyopathies has intensified after several new study setups became available, such as induced pluripotent stem cells, three‐dimensional printing of cells, use of scaffolds and engineered heart tissue, with convincing human validation studies. Furthermore, our knowledge on the consequences of mutated proteins has deepened, with relevance for cellular homeostasis, protein quality control and toxicity, often specific to particular cardiomyopathies, with precise effects explaining the aberrations. This has opened up new avenues to treat cardiomyopathies, using contemporary techniques from the molecular toolbox, such as gene editing and repair using CRISPR‐Cas9 techniques, antisense therapies, novel designer drugs, and RNA therapies. In this article, we discuss the connection between biology and diverse clinical presentation, as well as promising new medications and therapeutic avenues, which may be instrumental to come to precision medicine of genetic cardiomyopathies. [ABSTRACT FROM AUTHOR]

The new SARS-CoV-2 virus is a great danger for the worldwide population since there is no known pre-immunity, no specific treatment, and no vaccine. Still, the testing and tracing are the best tools to isolate the infected and prevent the spread of COVID-19. The major goals are to save lives, reduce the mortality rate, increase the survival rate of those are in severe or critical conditions, reduce the hospital stay and accelera­te the recovery. This review summarizes the findings on the novel coronavirus that causes COVID-19 and outlines information about symptoms, testing, disease mechanism, vascular dysfunction, immune responses, treatments, and vaccination. At this time no vaccine is available to prevent COVID-19. A literature review reveals that more research is necessary to investigate the interactions between respiratory viruses, human coronaviruses, and the new SARS-CoV-2 virus in the infected population to guide the design of COVID-19 specific therapeutics and vaccines. Almost every government on earth has realized that daily life cannot return to normal until citizens have built up antibodies to safeguard them from the virus. Scientists and manufacturers worldwide are accelerating COVID-19 vaccine research, and pharmaceutical companies are already investing in the large-scale production of vaccines. A synopsis of the most recent sources presented in this review was the starting point for several COVID-19 research projects in the Regional Cooperation for Health, Science and Technology (RECOOP HST) Association managed by Cedars – Sinai Medical Center to gain a better understanding of the COVID-19 disease.

Cone photoreceptors are responsible for the visual acuity and color vision of the human eye. Red/green cone opsin missense mutations N94K, W177R, P307L, R330Q, and G338E have been identified in subjects with congenital blue cone monochromacy or color‐vision deficiency. Studies on disease mechanisms due to these cone opsin mutations have been previously carried out exclusively in vitro, and the reported impairments were not always consistent. Here we expressed these mutants via AAV specifically in vivo in M‐opsin knockout mouse cones to investigate their subcellular localization, the pathogenic effects on cone structure, function, and cone viability. We show that these mutations alter the M‐opsin structure, function, and localization. N94K and W177R mutants appeared to be misfolded since they localized exclusively in cone inner segments and endoplasmic reticulum. In contrast, P307L, R330Q, and G338E mutants were detected predominately in cone outer segments. Expression of R330Q and G338E, but not P307L opsins, also partially restored expression and correct localization of cone PDE6α’ and cone transducin γ and resulted in partial rescue of M‐cone‐mediated light responses. Expression of W177R and P307L mutants significantly reduced cone viability, whereas N94K, R330Q, and G338E were only modestly toxic. We propose that although the underlying biochemical and cellular defects caused by these mutants are distinct, they all seem to exhibit a dominant phenotype, resembling autosomal dominant retinitis pigmentosa associated with the majority of rhodopsin missense mutations. The understanding of the molecular mechanisms associated with these cone opsin mutants is fundamental to developing targeted therapies for cone dystrophy/dysfunction. [ABSTRACT FROM AUTHOR]

The U2AF heterodimer is generally accepted to play a vital role in defining functional 3' splice sites in pre-mRNA splicing. Given prevalent mutations in U2AF, particularly in the U2AF1 gene (which encodes for the U2AF35 subunit) in blood disorders and other human cancers, there are renewed interests in these classic splicing factors to further understand their regulatory functions in RNA metabolism in both physiological and disease settings. We recently reported that U2AF has a maximal capacity to directly bind ˜88% of functional 3' splice sites in the human genome and that numerous U2AF binding events also occur in various exonic and intronic locations, thus providing additional mechanisms for the regulation of alternative splicing besides their traditional role in titrating weak splice sites in the cell. These findings, coupled with the existence of multiple related proteins to both U2AF65 and U2AF35, beg a series of questions on the universal role of U2AF in functional 3' splice site definition, their binding specificities in vivo, potential mechanisms to bypass their requirement for certain intron removal events, contribution of splicing-independent functions of U2AF to important cellular functions, and the mechanism for U2AF mutations to invoke specific diseases in humans.

Pulmonary arterial hypertension (PAH) is an enigmatic and deadly vascular disease with no known cure. Recent years have seen rapid advances in our understanding of the molecular underpinnings of PAH, with an expanding knowledge of the molecular, cellular, and systems-level drivers of disease that are being translated into novel therapeutic modalities. Simultaneous advances in clinical technology have led to a growing list of tools with potential application to diagnosis and phenotyping. Guided by fundamental biology, these developments hold the potential to usher in a new era of personalized medicine in PAH with broad implications for patient management and great promise for improved outcomes.

Cardiovascular disease is the largest single cause of disease-related mortality worldwide and the major underlying pathology is atherosclerosis. Atherosclerosis develops as a complex process of vascular lipid deposition and retention by modified proteoglycans, endothelial dysfunction and unresolved chronic inflammation. There are a multitude of current therapeutic agents, most based on lowering plasma lipid levels, but, overall, they have a lower than optimum level of efficacy and many deaths continue to arise from cardiovascular disease world-wide. To identify and evaluate potential novel cardiovascular drugs, suitable animal models that reproduce human atherosclerosis with a high degree of fidelity are required as essential pre-clinical research tools. Commonly used animal models of atherosclerosis include mice (ApoE−/−, LDLR−/− mice and others), rabbits (WHHL rabbits and others), rats, pigs, hamster, zebrafish and non-human primates. Models based on various wild-type and genetically modified mice have been extensively reviewed but mice may not always be appropriate. Thus, here, we provide an overview of the advantages and shortcomings of various non-mouse animal models of atherosclerotic plaque formation, and plaque rupture, as well as commonly used interventional strategies. Taken together, the combinatorial selection of suitable animal models readily facilitates reproducible and rigorous translational research in discovering and validating novel anti-atherosclerotic drugs.

Objective: The environmental crisis we are experiencing is becoming a more popular topic of expert discussion and analysis. Human activity and expansion on the planet are exacerbating climate change and global warming, this, together with the increase in plastic production, and general pollution, posing a threat to our resources, supplies, and survival. This research aims to review what is known about the association between pollution and pregnancy and sensitize experts to women’s education towards healthier behaviors. Mechanism: We chose to focus on the effects of the environment on fetal development and maternal health, considering various studies that highlight the potential consequences of exposure to certain environmental stressors. The paper briefly illustrates the probable mechanisms that, starting from cellular and intracellular damage, determined above all by plastics, lead to chronic activation of the immune system in response to danger and, therefore, to epigenetic modifications at the base of diseases in adulthood. Findings in Brief: We describe the effects of the main pollutants on pregnancy, with particular attention to the role of plastic. Finally, we briefly outline some individual possible solutions to this complex problem. Conclusions: In the era of environmental crisis, becoming aware of the mechanisms behind biological damage resulting from exposure to certain pollutants and plastics, especially in a period as sensitive as pregnancy, should be the driving force behind a change of direction. As physicians, this means educating our patients and recommending individual solutions to reduce the impact of contaminants to provide the best possible environment for women’s and children’s health, especially during the delicate period of pregnancy; but the ultimate solution is to drastically reduce global plastic production and pollution, and to recycle the plastic that is needed anyway.

This review outlines the role of electrostatics in computational molecular biophysics and its implication in altering wild-type characteristics of biological macromolecules, and thus the contribution of electrostatics to disease mechanisms. The work is not intended to review existing computational approaches or to propose further developments. Instead, it summarizes the outcomes of relevant studies and provides a generalized classification of major mechanisms that involve electrostatic effects in both wild-type and mutant biological macromolecules. It emphasizes the complex role of electrostatics in molecular biophysics, such that the long range of electrostatic interactions causes them to dominate all other forces at distances larger than several Angstroms, while at the same time, the alteration of short-range wild-type electrostatic pairwise interactions can have pronounced effects as well. Because of this dual nature of electrostatic interactions, being dominant at long-range and being very specific at short-range, their implications for wild-type structure and function are quite pronounced. Therefore, any disruption of the complex electrostatic network of interactions may abolish wild-type functionality and could be the dominant factor contributing to pathogenicity. However, we also outline that due to the plasticity of biological macromolecules, the effect of amino acid mutation may be reduced, and thus a charge deletion or insertion may not necessarily be deleterious.

Aim: To demonstrate the little‐known metabolic changes and pathways in patients with colorectal cancer (CRC). Methods: We used gas chromatography time‐of‐flight mass spectrometry (GC‐TOF/MS) to perform metabolic profiling of urine samples from 163 consecutive patients with CRC and 111 healthy controls without history of gastrointestinal tumors. The metabolic profiles were assayed using multivariate statistical analysis and one‐way analysis of variance, and further analyzed to identify potential marker metabolites related to CRC. The GC‐TOF/MS‐derived models showed clear discriminations in metabolic profiles between the CRC group and healthy control group. Results: We demonstrated that 15 metabolites contributed to the differences. Among them, eleven metabolites were significantly upregulated, while other four metabolites were downregulated in the urine samples of CRC patients compared with healthy controls. Pathway analysis revealed changes in energy metabolism of patients with CRC, which are reflected in the upregulation of glycolysis and amino acid metabolism and the downregulation of lipid metabolism. Our study revealed the metabolic profile of urine from CRC patients and indicated that GC‐TOF/MS‐based methods can distinguish CRC from healthy controls. Conclusion: GC‐TOF/MS‐based metabolomics has the potential to be developed into a novel, non‐invasive, and painless clinical tool for CRC diagnosis, and may contribute to an improved understanding of disease mechanisms. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review discusses the mechanisms, clinical implications, and treatments of left atrial (LA) myopathy in comorbid atrial fibrillation (AF) and heart failure (HF) across the spectrum of ejection fraction. Recent Findings: AF and HF are highly comorbid conditions. Left atrial (LA) myopathy, characterized by impairments in LA structure, function, or electrical conduction, plays a fundamental role in the development of both AF and HF with preserved ejection fraction (AF-HFpEF) along with AF and HF with reduced ejection fraction (AF-HFrEF). While the nature of LA myopathy in AF-HFpEF is unique from that of AF-HFrEF, LA myopathy also leads to progression of both of these conditions. Summary: There may be a vulnerable cohort of AF-HF patients who have a disproportionate degree of LA myopathy compared with left ventricular (LV) dysfunction. Further investigations are required to identify therapies to improve LA function in this cohort. [ABSTRACT FROM AUTHOR]

Keywords: high-throughput sequencing; biomarker development; chronic disease; disease mechanism; omics study; prognosis prediction EN high-throughput sequencing biomarker development chronic disease disease mechanism omics study prognosis prediction 1 3 3 06/23/22 20220621 NES 220621 This "High-throughput sequencing-based investigation of chronic disease markers and mechanisms" issue focuses on the genomics studies on cancer and chronic diseases. Using high-throughput sequencing, various markers of chronic diseases have been developed at all omics levels, which have been used for diagnosis and classification of diseases, prediction of treatment effects, and prevention of diseases ([9]; [3]). High-throughput sequencing, biomarker development, chronic disease, disease mechanism, omics study, prognosis prediction This Research Topic aimed at 1) developing new chronic disease markers at four levels (i.e., genome, epigenome, transcriptome, and translatome) with the help of high-throughput sequencing, and 2) delineating potential marker-related mechanisms for chronic disease occurrence or development. [Extracted from the article]

Four areas deserve increased attention during the next decade: Disease Modification The biggest challenge for the reduction of the global health burden of neurological conditions is a paradigm shift from symptomatic to disease modifying treatments. Keywords: disease burden; disease mechanism; disease modification; network pharmacology; epigenetics; global approaches; neurological disorders; CNS disorders EN disease burden disease mechanism disease modification network pharmacology epigenetics global approaches neurological disorders CNS disorders N.PAG N.PAG 5 05/13/21 20210510 NES 210510 Global Burden of CNS Disorders The global burden of CNS diseases is expected to increase dramatically within the next decades. Therefore, there is a major unmet need to identify treatment options, which are disease modifying and thereby affect fundamental mechanisms implicated in pathogenic processes leading to disease and its progression. Disease burden, disease mechanism, disease modification, network pharmacology, epigenetics, global approaches, neurological disorders, CNS disorders. [Extracted from the article]

Aims  The cardiac ryanodine receptor (RyR2), which mediates intracellular Ca2+ release to trigger cardiomyocyte contraction, participates in development of acquired and inherited arrhythmogenic cardiac disease. This study was undertaken to characterize the network of inter- and intra-subunit interactions regulating the activity of the RyR2 homotetramer. Methods and results  We use mutational investigations combined with biochemical assays to identify the peptide sequence bridging the β8 with β9 strand as the primary determinant mediating RyR2 N-terminus self-association. The negatively charged side chains of two aspartate residues (D179 and D180) within the β8–β9 loop are crucial for the N-terminal inter-subunit interaction. We also show that the RyR2 N-terminus domain interacts with the C-terminal channel pore region in a Ca2+-independent manner. The β8–β9 loop is required for efficient RyR2 subunit oligomerization but it is dispensable for N-terminus interaction with C-terminus. Deletion of the β8–β9 sequence produces unstable tetrameric channels with subdued intracellular Ca2+ mobilization implicating a role for this domain in channel opening. The arrhythmia-linked R176Q mutation within the β8–β9 loop decreases N-terminus tetramerization but does not affect RyR2 subunit tetramerization or the N-terminus interaction with C-terminus. RyR2R176Q is a characteristic hypersensitive channel displaying enhanced intracellular Ca2+ mobilization suggesting an additional role for the β8–β9 domain in channel closing. Conclusion  These results suggest that efficient N-terminus inter-subunit communication mediated by the β8–β9 loop may constitute a primary regulatory mechanism for both RyR2 channel activation and suppression. [ABSTRACT FROM AUTHOR]

Cardiovascular disease plays a central role in the electrical and structural remodeling of the right atrium, predisposing to arrhythmias, heart failure, and sudden death. Here, we dissect with single-nuclei RNA sequencing (snRNA-seq) and spatial transcriptomics the gene expression changes in the human ex vivo right atrial tissue and pericardial fluid in ischemic heart disease, myocardial infarction, and ischemic and non-ischemic heart failure using asymptomatic patients with valvular disease who undergo preventive surgery as the control group. We reveal substantial differences in disease-associated gene expression in all cell types, collectively suggesting inflammatory microvascular dysfunction and changes in the right atrial tissue composition as the valvular and vascular diseases progress into heart failure. The data collectively suggest that investigation of human cardiovascular disease should expand to all functionally important parts of the heart, which may help us to identify mechanisms promoting more severe types of the disease., Competing Interests: Declaration of interests Authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The phospholamban (PLN) pathogenic gene variant, p.Arg14del (PLN-R14del), can lead to dilated and arrhythmogenic cardiomyopathy, resulting in heart failure. PLN-R14del cardiomyopathy has been conceptualized as a disease caused by sarco/endoplasmic reticulum calcium adenosine triphosphatase 2a (SERCA2a) superinhibition. However, recent studies raised controversy regarding the effect of PLN-R14del on SERCA activity and revealed a prominent role for abnormal PLN protein distribution and sarco/endoplasmic reticulum disorganization as underlying disease mechanism. Strategies targeting sarco/endoplasmic reticulum malformation may, therefore, prove more effective than SERCA activity modulation. This review reassesses the disease mechanisms of PLN-R14del cardiomyopathy and emphasizes the importance of dissecting the underlying molecular mechanisms to uncover targets for innovative treatments., Competing Interests: This work was supported by grants from the Netherlands Heart Foundation (CVON PREDICT2, grant 2018-30; CARMA, grant 01-003-2022-0358); the Leducq Foundation (Cure-PLaN), EU Horizon grant Geremy, the Netherlands Heart Institute, the PLN Foundation. It was also supported by National Institutes of Health grant HL171221 to Dr Makarewich. Dr de Boer has received grant support from the Netherlands Heart Foundation (grants 2017-21; 2017-11; 2018-30; 2020B005; 01-003-2022-0358) and the European Research Council (ERC CoG 818715); has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Novo Nordisk, and Roche; has had speaker engagements with and/or received fees from and/or served on an advisory board for Abbott, AstraZeneca, Cardior Pharmaceuticals GmbH, Novo Nordisk, and Roche; and received travel support from Abbott, Cardior Pharmaceuticals GmbH, and Novo Nordisk. Dr van der Meer has received grant support from the European Research Council (ERC CoG 101045236, DISSECT-HF); has received consulting fees and/or grants from Novartis, Pharmacosmos, Vifor Pharma, AstraZeneca, Pfizer, Pharma Nord, BridgeBio, Novo Nordisk, Daiichi Sankyo, Boehringer Ingelheim, and Ionis. Dr Silljé has received research grants from AstraZeneca, Novo Nordisk and Ionis Pharmaceuticals. Dr Stege has reported that she has no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Abstract Loss of memory during Alzheimer's disease (AD), a fatal neurodegenerative disorder, is associated with neuronal loss and the aggregation of amyloid proteins into neurotoxic β‐sheet enriched structures. However, the mechanism of amyloid protein aggregation is still not well understood due to many challenges when studying the endogenous amyloid structures in neurons or in brain tissue. Available methods either require chemical processing of the sample or may affect the amyloid protein structure itself. Therefore, new approaches, which allow studying molecular structures directly in neurons, are urgently needed. A novel approach is tested, based on label‐free optical photothermal infrared super‐resolution microspectroscopy, to study AD‐related amyloid protein aggregation directly in the neuron at sub‐micrometer resolution. Using this approach, amyloid protein aggregates are detected at the subcellular level, along the neurites and strikingly, in dendritic spines, which has not been possible until now. Here, a polymorphic nature of amyloid structures that exist in AD transgenic neurons is reported. Based on the findings of this work, it is suggested that structural polymorphism of amyloid proteins that occur already in neurons may trigger different mechanisms of AD progression.

The Special Issue on “Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches” has published interesting and useful review articles and original experimental articles on fibrodysplasia ossificans progressiva (FOP), a very rare genetic disorder for which much effort is being devoted to search for a cure. In this editorial, I briefly cite the essential content of all the published articles.

Emphysematous cystitis is a relatively rare disease entity characterized by intramural and/or intraluminal bladder gas best depicted by cross-sectional imaging. Its disease mechanism is not well understood. A case of a diabetic patient with emphysematous cystitis is presented and is notable for the rare finding of extraperitoneal gas in the pelvis based on a review of 114 case reports. Herein we propose a distension-based mechanism with intramural bacterial seeding as the pathogenesis of emphysematous cystitis based on the patient's imaging and the disease's established associations with diabetes and E. coli. The ability to recognize extraperitoneal pelvic gas as a feature of emphysematous cystitis allowed prompt diagnosis. This facilitated early commencement of successful treatment in a diabetic patient in whom the diagnosis was not suspected clinically. • Extraperitoneal gas can be seen in emphysematous cystitis. • This finding suggests a distension-based mechanism like that of emphysematous cholecystitis and pneumatosis intestinalis. • Distension aids bacterial seeding of the bladder wall, leading to gas formation. [ABSTRACT FROM AUTHOR]

Loss of memory during Alzheimer's disease (AD), a fatal neurodegenerative disorder, is associated with neuronal loss and the aggregation of amyloid proteins into neurotoxic β‐sheet enriched structures. However, the mechanism of amyloid protein aggregation is still not well understood due to many challenges when studying the endogenous amyloid structures in neurons or in brain tissue. Available methods either require chemical processing of the sample or may affect the amyloid protein structure itself. Therefore, new approaches, which allow studying molecular structures directly in neurons, are urgently needed. A novel approach is tested, based on label‐free optical photothermal infrared super‐resolution microspectroscopy, to study AD‐related amyloid protein aggregation directly in the neuron at sub‐micrometer resolution. Using this approach, amyloid protein aggregates are detected at the subcellular level, along the neurites and strikingly, in dendritic spines, which has not been possible until now. Here, a polymorphic nature of amyloid structures that exist in AD transgenic neurons is reported. Based on the findings of this work, it is suggested that structural polymorphism of amyloid proteins that occur already in neurons may trigger different mechanisms of AD progression. [ABSTRACT FROM AUTHOR]