scholarly journals Mosaicism in Human Health and Disease

2020 ◽  
Vol 54 (1) ◽  
pp. 487-510 ◽  
Author(s):  
Jeremy Thorpe ◽  
Ikeoluwa A. Osei-Owusu ◽  
Bracha Erlanger Avigdor ◽  
Rossella Tupler ◽  
Jonathan Pevsner
Keyword(s):  
Somatic Mosaicism ◽  
Base Pairs ◽  
Exogenous Dna ◽  
Germline Mosaicism ◽  
Dna Mutation ◽  
Developmental Context ◽  
Technological Advances ◽  
Body Location ◽  
Health And Disease ◽  
Mitochondrial Heteroplasmy

Mosaicism refers to the occurrence of two or more genomes in an individual derived from a single zygote. Germline mosaicism is a mutation that is limited to the gonads and can be transmitted to offspring. Somatic mosaicism is a postzygotic mutation that occurs in the soma, and it may occur at any developmental stage or in adult tissues. Mosaic variation may be classified in six ways: ( a) germline or somatic origin, ( b) class of DNA mutation (ranging in scale from single base pairs to multiple chromosomes), ( c) developmental context, ( d) body location(s), ( e) functional consequence (including deleterious, neutral, or advantageous), and ( f) additional sources of mosaicism, including mitochondrial heteroplasmy, exogenous DNA sources such as vectors, and epigenetic changes such as imprinting and X-chromosome inactivation. Technological advances, including single-cell and other next-generation sequencing, have facilitated improved sensitivity and specificity to detect mosaicism in a variety of biological contexts.

scholarly journals Role of Biological Sex in the Cardiovascular-Gut Microbiome Axis

2022 ◽  
Vol 8 ◽  
Author(s):  
Shuangyue Li ◽  
Georgios Kararigas
Keyword(s):  
Gut Microbiota ◽  
Gut Microbiome ◽  
Microbial Composition ◽  
Biological Sex ◽  
Technological Advances ◽  
Host Health ◽  
Health And Disease ◽  
And Function ◽  
Insight Into

There has been a recent, unprecedented interest in the role of gut microbiota in host health and disease. Technological advances have dramatically expanded our knowledge of the gut microbiome. Increasing evidence has indicated a strong link between gut microbiota and the development of cardiovascular diseases (CVD). In the present article, we discuss the contribution of gut microbiota in the development and progression of CVD. We further discuss how the gut microbiome may differ between the sexes and how it may be influenced by sex hormones. We put forward that regulation of microbial composition and function by sex might lead to sex-biased disease susceptibility, thereby offering a mechanistic insight into sex differences in CVD. A better understanding of this could identify novel targets, ultimately contributing to the development of innovative preventive, diagnostic and therapeutic strategies for men and women.

The Genetics and Genomics of Asthma

2018 ◽  
Vol 19 (1) ◽  
pp. 223-246 ◽  
Author(s):  
Saffron A.G. Willis-Owen ◽  
William O.C. Cookson ◽  
Miriam F. Moffatt
Keyword(s):  
Sequence Variation ◽  
Human Microbiome ◽  
Technological Advances ◽  
Genome Wide ◽  
A Genome ◽  
Wide Range ◽  
Health And Disease ◽  
Wide Scale ◽  
Genetics And Genomics ◽  
The Individual

Asthma is a common, clinically heterogeneous disease with strong evidence of heritability. Progress in defining the genetic underpinnings of asthma, however, has been slow and hampered by issues of inconsistency. Recent advances in the tools available for analysis—assaying transcription, sequence variation, and epigenetic marks on a genome-wide scale—have substantially altered this landscape. Applications of such approaches are consistent with heterogeneity at the level of causation and specify patterns of commonality with a wide range of alternative disease traits. Looking beyond the individual as the unit of study, advances in technology have also fostered comprehensive analysis of the human microbiome and its varied roles in health and disease. In this article, we consider the implications of these technological advances for our current understanding of the genetics and genomics of asthma.

scholarly journals Mass spectrometry and its evolving role in assessing tissue specific steroid metabolism

2016 ◽  
Vol 44 (2) ◽  
pp. 645-651 ◽  
Author(s):  
Ruth Andrew ◽  
Natalie Z.M. Homer
Keyword(s):  
Mass Spectrometry ◽  
Drug Targets ◽  
Tissue Sections ◽  
Ms Imaging ◽  
Technological Advances ◽  
Physiology And Biochemistry ◽  
Liquid Chromatography Tandem Mass ◽  
Health And Disease ◽  
Tracer Dilution

Glucocorticoid hormones play vital roles in regulating diverse biological processes in health and disease. Tissue levels are regulated by enzymes which activate and inactivate hormones. The enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), in particular, has been identified as a potential drug target; inhibiting this enzyme attenuates glucocorticoid action by lowering local levels of active hormone. A variety of mass spectrometric approaches have been developed to characterize this enzyme in vivo. Endogenous glucocorticoids and their metabolites can be profiled in urine by GC–MS and circulating steroids are now more commonly quantified by liquid chromatography tandem mass spectrometry. Tracer dilution studies have allowed rates of generation of glucocorticoids by the enzyme to be distinguished from hormone generated directly by the adrenal glands and, in combination with arterio-venous (AV) sampling, rates of production by specific tissues have been quantified. This has allowed the contribution of liver, adipose, muscle and brain to cortisol production in metabolic disease and hence prioritized drug targets. Most recently MS imaging in combination with on-tissue derivatization has been developed to profile oxo-steroids in tissue sections, allowing molecular maps to be generated across complex tissues, where regional functions are important. The review provides a synopsis of how measurement of steroids by MS has evolved with technological advances and this has provided insight into the dynamic turnover of glucocorticoids in vivo, highlighting the milestones that have advanced the field and identifying the remaining challenges for researchers, in terms of analytical chemistry and endocrine physiology and biochemistry.

scholarly journals Oxidative stress and Rho GTPases in the biogenesis of tunnelling nanotubes: implications in disease and therapy

2021 ◽  
Author(s):  
Abinaya Raghavan ◽  
Pooja Rao ◽  
Jiri Neuzil ◽  
Dean L. Pountney ◽  
Sangeeta Nath
Keyword(s):  
Oxidative Stress ◽  
Intercellular Communication ◽  
Rho Gtpases ◽  
Crucial Role ◽  
Oxygen Species ◽  
Health And Disease ◽  
Mitochondrial Heteroplasmy ◽  
Mediate Cell ◽  
Cellular Stresses ◽  
And Oxidative Stress

AbstractTunnelling nanotubes (TNTs) are an emerging route of long-range intercellular communication that mediate cell-to-cell exchange of cargo and organelles and contribute to maintaining cellular homeostasis by balancing diverse cellular stresses. Besides their role in intercellular communication, TNTs are implicated in several ways in health and disease. Transfer of pathogenic molecules or structures via TNTs can promote the progression of neurodegenerative diseases, cancer malignancy, and the spread of viral infection. Additionally, TNTs contribute to acquiring resistance to cancer therapy, probably via their ability to rescue cells by ameliorating various pathological stresses, such as oxidative stress, reactive oxygen species (ROS), mitochondrial dysfunction, and apoptotic stress. Moreover, mesenchymal stem cells play a crucial role in the rejuvenation of targeted cells with mitochondrial heteroplasmy and oxidative stress by transferring healthy mitochondria through TNTs. Recent research has focussed on uncovering the key regulatory molecules involved in the biogenesis of TNTs. However further work will be required to provide detailed understanding of TNT regulation. In this review, we discuss possible associations with Rho GTPases linked to oxidative stress and apoptotic signals in biogenesis pathways of TNTs and summarize how intercellular trafficking of cargo and organelles, including mitochondria, via TNTs plays a crucial role in disease progression and also in rejuvenation/therapy.

scholarly journals Germline and somatic mosaicism in a family with multiple endocrine neoplasia type 1 (MEN1) syndrome

2019 ◽  
Vol 180 (2) ◽  
pp. K15-K19 ◽  
Author(s):  
Hanneke J B H Beijers ◽  
Nike M L Stikkelbroeck ◽  
Arjen R Mensenkamp ◽  
Rolph Pfundt ◽  
Rob B van der Luijt ◽  
...  
Keyword(s):  
Multiple Endocrine Neoplasia ◽  
De Novo ◽  
Multiple Endocrine Neoplasia Type ◽  
Somatic Mosaicism ◽  
Suppressor Gene ◽  
Germline Mosaicism ◽  
Endocrine Neoplasia ◽  
Endocrine Neoplasia Type ◽  
Dominant Disease

Context Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease caused by mutations in the tumor suppressor gene MEN1 and can be diagnosed based on clinical, familial and/or genetic criteria. We present a family in which we found both germline and somatic mosaicism for MEN1. Family description In our proband, we diagnosed MEN1. The mutation was not detected in her parents (DNA extracted from leucocytes). When her brother was found to harbor the same MEN1 mutation as our proband and, around the same time, their father was diagnosed with a neuroendocrine carcinoma, this tumor was investigated for the MEN1 mutation as well. In the histologic biopsy of this tumor, the same MEN1 mutation was detected as previously found in his children. Re-analysis of his blood using multiplex ligation-dependent probe amplification (MLPA) showed a minimal, but consistently decreased signal for the MEN1-specific MLPA probes. The deletion was confirmed in his son by high-resolution array analysis. Based on the array data, we concluded that the deletion was limited to the MEN1 gene and that the father had both germline and somatic mosaicism for MEN1. Conclusions To our knowledge, this is the first reported family with combined germline and somatic mosaicism for MEN1. This study illustrates that germline mosaicism is important to consider in apparently sporadic de novo MEN1 mutations, because of its particular importance for genetic counseling, specifically when evaluating the risk for family members and when considering the possibility of somatic mosaicism in the parent with germline mosaicism.

scholarly journals Unbridle biomedical research from the laboratory cage

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Garet P Lahvis
Keyword(s):  
Human Health ◽  
Biomedical Research ◽  
Health Research ◽  
Animal Studies ◽  
Standard Laboratory ◽  
Negative Experiences ◽  
Technological Advances ◽  
In The Wild ◽  
Natural Range ◽  
Health And Disease

Many biomedical research studies use captive animals to model human health and disease. However, a surprising number of studies show that the biological systems of animals living in standard laboratory housing are abnormal. To make animal studies more relevant to human health, research animals should live in the wild or be able to roam free in captive environments that offer a natural range of both positive and negative experiences. Recent technological advances now allow us to study freely roaming animals and we should make use of them.

scholarly journals A Case-Based Approach to Understanding Complex Genetic Information in an Evolving Landscape

2021 ◽  
pp. 1-11
Author(s):  
Courtney D. DiNardo ◽  
Larissa A. Korde ◽  
Matthew B. Yurgelun
Keyword(s):  
Genetic Testing ◽  
Genetic Information ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Somatic Mosaicism ◽  
Inherited Cancer ◽  
Clonal Hematopoiesis ◽  
Pathogenic Variants ◽  
Technological Advances ◽  
Case Based

The rapid integration of highly sensitive next-generation sequencing technologies into clinical oncology care has led to unparalleled progress, and yet these technological advances have also made genetic information considerably more complex. For instance, accurate interpretation of genetic testing for germline/inherited cancer predisposition syndromes and somatic/acquired pathogenic variants now requires a more nuanced understanding of the presence and incidence of clonal hematopoiesis and circulating tumor cells, with careful evaluation of pathogenic variants occurring at low variant allele frequency required. The interplay between somatic and germline pathogenic variants and awareness of distinct genotype-phenotype manifestations in various inherited cancer syndromes are now increasingly appreciated and can impact patient management. Through a case-based approach, we focus on three areas of particular relevance to the treating clinician oncologist: (1) understanding clonal hematopoiesis and somatic mosaicism, which can be detected on germline sequencing and lead to considerable confusion in clinical interpretation; (2) implications of the detection of a potentially germline pathogenic variant in a high-penetrance cancer susceptibility gene during routine tumor testing; and (3) a review of gene-specific risks and surveillance recommendations in Lynch syndrome. A discussion on the availability and difficulties often associated with direct-to-consumer genetic testing is also provided.

scholarly journals Multiplexed Single-Cell in situ RNA Profiling

2021 ◽  
Vol 8 ◽  
Author(s):  
Yu-Sheng Wang ◽  
Jia Guo
Keyword(s):  
Single Cell ◽  
Single Cells ◽  
Disease Diagnosis ◽  
Tissue Architecture ◽  
Rna Profiling ◽  
Rna Analysis ◽  
Technological Advances ◽  
Health And Disease ◽  
Type Classification

The ability to quantify a large number of varied transcripts in single cells in their native spatial context is crucial to accelerate our understanding of health and disease. Bulk cell RNA analysis masks the heterogeneity in the cell population, while the conventional RNA imaging approaches suffer from low multiplexing capacity. Recent advances in multiplexed fluorescence in situ hybridization (FISH) methods enable comprehensive RNA profiling in individual cells in situ. These technologies will have wide applications in many biological and biomedical fields, including cell type classification, signaling network analysis, tissue architecture, disease diagnosis and patient stratification, etc. In this minireview, we will present the recent technological advances of multiplexed single-cell in situ RNA profiling assays, discuss their advantages and limitations, describe their biological applications, highlight the current challenges, and propose potential solutions.

Unraveling Disease Pathophysiology with Mathematical Modeling

2020 ◽  
Vol 15 (1) ◽  
pp. 371-394 ◽  
Author(s):  
Brody H. Foy ◽  
Bronner P. Gonçalves ◽  
John M. Higgins
Keyword(s):  
Mathematical Modeling ◽  
Cellular Tissue ◽  
Research Community ◽  
Response To Treatment ◽  
Technological Advances ◽  
Challenges And Opportunities ◽  
Health And Disease ◽  
Organ Level

Modeling has enabled fundamental advances in our understanding of the mechanisms of health and disease for centuries, since at least the time of William Harvey almost 500 years ago. Recent technological advances in molecular methods, computation, and imaging generate optimism that mathematical modeling will enable the biomedical research community to accelerate its efforts in unraveling the molecular, cellular, tissue-, and organ-level processes that maintain health, predispose to disease, and determine response to treatment. In this review, we discuss some of the roles of mathematical modeling in the study of human physiology and pathophysiology and some challenges and opportunities in general and in two specific areas: in vivo modeling of pulmonary function and in vitro modeling of blood cell populations.

scholarly journals The Exposome Approach in Allergies and Lung Diseases: Is It Time to Define a Preconception Exposome?

2021 ◽  
Vol 18 (23) ◽  
pp. 12684
Author(s):  
Juan Pablo López-Cervantes ◽  
Marianne Lønnebotn ◽  
Nils Oskar Jogi ◽  
Lucia Calciano ◽  
Ingrid Nordeide Kuiper ◽  
...  
Keyword(s):  
Lung Diseases ◽  
Current Knowledge ◽  
Respiratory Health ◽  
Environmental Exposures ◽  
Multiple Exposures ◽  
Biological Responses ◽  
Technological Advances ◽  
Human Reproductive ◽  
Health And Disease ◽  
External Exposures

Emerging research suggests environmental exposures before conception may adversely affect allergies and lung diseases in future generations. Most studies are limited as they have focused on single exposures, not considering that these diseases have a multifactorial origin in which environmental and lifestyle factors are likely to interact. Traditional exposure assessment methods fail to capture the interactions among environmental exposures and their impact on fundamental biological processes, as well as individual and temporal factors. A valid estimation of exposure preconception is difficult since the human reproductive cycle spans decades and the access to germ cells is limited. The exposome is defined as the cumulative measure of external exposures on an organism (external exposome), and the associated biological responses (endogenous exposome) throughout the lifespan, from conception and onwards. An exposome approach implies a targeted or agnostic analysis of the concurrent and temporal multiple exposures, and may, together with recent technological advances, improve the assessment of the environmental contributors to health and disease. This review describes the current knowledge on preconception environmental exposures as related to respiratory health outcomes in offspring. We discuss the usefulness and feasibility of using an exposome approach in this research, advocating for the preconception exposure window to become included in the exposome concept.

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