Patient-specific induced pluripotent stem cells as“disease-in-adish”models for inherited cardiomyopathies and channelopathies–15 years of research

Among inherited cardiac conditions,a special place is kept by cardiomyopathies(CMPs)and channelopathies(CNPs),which pose a substantial healthcare burden due to the complexity of the therapeutic management and cause early mortality.Like other inherited cardiac conditions,genetic CMPs and CNPs exhibit incomplete penetrance and variable expressivity even within carriers of the same pathogenic deoxyribonucleic acid variant,challenging our understanding of the underlying pathogenic mechanisms.Until recently,the lack of accurate physiological preclinical models hindered the investigation of fundamental cellular and molecular mechanisms.The advent of induced pluripotent stem cell(iPSC)technology,along with advances in gene editing,offered unprecedented opportunities to explore hereditary CMPs and CNPs.Hallmark features of iPSCs include the ability to differentiate into unlimited numbers of cells from any of the three germ layers,genetic identity with the subject from whom they were derived,and ease of gene editing,all of which were used to generate“disease-in-a-dish”models of monogenic cardiac conditions.Functionally,iPSC-derived cardiomyocytes that faithfully recapitulate the patient-specific phenotype,allowed the study of disease mechanisms in an individual-/allele-specific manner,as well as the customization of therapeutic regimen.This review provides a synopsis of the most important iPSC-based models of CMPs and CNPs and the potential use for modeling disease mechanisms,personalized therapy and deoxyribonucleic acid variant functional annotation.     

Chromatin dynamics after DNA damage: The legacy of the access–repair–restore model

Eukaryotic genomes are packaged into chromatin, which is the physiological substrate for all DNA transactions, including DNA damage and repair. Chromatin organization imposes major constraints on DNA damage repair and thus undergoes critical rearrangements during the repair process. These rearrangements have been integrated into the “access–repair–restore” (ARR) model, which provides a molecular framework for chromatin dynamics in response to DNA damage. Here, we take a historical perspective on the elaboration of this model and describe the molecular players involved in damaged chromatin reorganization in human cells. In particular, we present our current knowledge of chromatin assembly coupled to DNA damage repair, focusing on the role of histone variants and their dedicated chaperones. Finally, we discuss the impact of chromatin rearrangements after DNA damage on chromatin function and epigenome maintenance.     

Variant TREM2 Signaling in Alzheimer's Disease

Alzheimer's disease is the most common form of dementia, accounting for as much as three-quarters of cases globally with individuals in low- and middle-income countries being worst affected. Numerous risk factors for the disease have been identified and our understanding of gene-environment interactions have shed light on several gene variants that contribute to the most common, sporadic form of Alzheimer’s disease. Triggering Receptor Expressed on Myeloid cells 2 (TREM2) is an important receptor that is crucial to the functioning of microglial cells, and variants of this protein have been found to be associated with a significantly increased risk of Alzheimer's disease. Several studies have elucidated the signaling processes involved in the normal functioning of the TREM2 receptor. However, current knowledge of the idiosyncrasies of the signaling processes triggered by stimulation of the variants of this receptor is limited.In this review, we examine the existing literature and highlight the effects that various receptor variants have on downstream signaling processes and discuss how these perturbations may affect physiologic processes in Alzheimer's disease. Despite the fact that this is a territory yet to be fully explored, the studies that currently exist report mostly quantitative effects on signaling. More mechanistic studies with the aim of providing qualitative results in terms of downstream signaling among these receptor variants are warranted. Such studies will provide better opportunities of identifying therapeutic targets that may be exploited in designing new drugs for the management of Alzheimer's disease.     

Genomic monitoring of SARS-CoV-2 uncovers an Nsp1 deletion variant that modulates type I interferon response

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Strong humoral immune responses against SARS-CoV-2 Spike after BNT162b2 mRNA vaccination with a 16-week interval between doses

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SARS-CoV-2 Omicron triggers cross-reactive neutralization and Fc effector functions in previously vaccinated,but not unvaccinated,individuals

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Identification of regulatory variants of carboxylesterase 1 (CES1): A proof-of-concept study for the application of the Allele-Specific Protein Expression (ASPE) assay in identifying cis-acting regulatory genetic polymorphisms

It is challenging to study regulatory genetic variants as gene expression is affected by both genetic polymorphisms and non-genetic regulators. The mRNA allele-specific expression (ASE) assay has been increasingly used for the study of cis-acting regulatory variants because cis-acting variants affect gene expression in an allele-specific manner. However, poor correlations between mRNA and protein expressions were observed for many genes, highlighting the importance of studying gene expression regulation at the protein level. In the present study, we conducted a proof-of-concept study to utilize a recently developed allele-specific protein expression (ASPE) assay to identify the cis-acting regulatory variants of CES1 using a large set of human liver samples. The CES1 gene encodes for carboxylesterase 1 (CES1), the most abundant hepatic hydrolase in humans. Two cis-acting regulatory variants were found to be significantly associated with CES1 ASPE, CES1 protein expression, and its catalytic activity on enalapril hydrolysis in human livers. Compared to conventional gene expression-based approaches, ASPE demonstrated an improved statistical power to detect regulatory variants with small effect sizes since allelic protein expression ratios are less prone to the influence of non-genetic regulators (e.g., diseases and inducers). This study suggests that the ASPE approach is a powerful tool for identifying cis-regulatory variants.     

Evaluation of T cell responses to naturally processed variant SARS-CoV-2 spike antigens in individuals following infection or vaccination

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