Publications by authors named "McDevitt T"

During development, early regionalization segregates lineages and directs diverse cell fates. Sometimes, however, distinct progenitors produce analogous cell types. For example, V2a neurons, are excitatory interneurons that emerge from different anteroposterior progenitors.

View Article and Find Full Text PDF

Purpose: Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene as though having equivalent penetrance, despite increasing evidence of intervariant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants in which reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance. We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network.

View Article and Find Full Text PDF

Background: The 2015 American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) variant classification framework specifies that case-control observations can be scored as 'strong' evidence (PS4) towards pathogenicity.

Methods: We developed the PS4-likelihood ratio calculator (PS4-LRCalc) for quantitative evidence assignment based on the observed variant frequencies in cases and controls. Binomial likelihoods are computed for two models, each defined by prespecified OR thresholds.

View Article and Find Full Text PDF

Loss of Cdx2 in vivo leads to stunted development of the allantois, an extraembryonic mesoderm-derived structure critical for nutrient delivery and waste removal in the early embryo. Here, we investigate how CDX2 dose-dependently influences the gene regulatory network underlying extraembryonic mesoderm development. By engineering human induced pluripotent stem cells (hiPSCs) consisting of wild-type (WT), heterozygous (CDX2-Het), and homozygous null CDX2 (CDX2-KO) genotypes, differentiating these cells in a 2D gastruloid model, and subjecting these cells to single-nucleus RNA and ATAC sequencing, we identify several pathways that are dose-dependently regulated by CDX2 including VEGF and non-canonical WNT.

View Article and Find Full Text PDF

Hereditary Breast and Ovarian Cancer (HBOC) is a genetic condition associated with increased risk of cancers. The past decade has brought about significant changes to hereditary breast and ovarian cancer (HBOC) diagnostic testing with new treatments, testing methods and strategies, and evolving information on genetic associations. These best practice guidelines have been produced to assist clinical laboratories in effectively addressing the complexities of HBOC testing, while taking into account advancements since the last guidelines were published in 2007.

View Article and Find Full Text PDF

In the nascent mesoderm, TBXT expression must be precisely regulated to ensure that cells exit the primitive streak and pattern the anterior-posterior axis, but how varying dosage informs morphogenesis is not well understood. In this study, we define the transcriptional consequences of TBXT dosage reduction during early human gastrulation using human induced pluripotent stem cell models of gastrulation and mesoderm differentiation. Multi-omic single-nucleus RNA and single-nucleus ATAC sequencing of 2D gastruloids comprising wild-type, TBXT heterozygous or TBXT null human induced pluripotent stem cells reveal that varying TBXT dosage does not compromise the ability of a cell to differentiate into nascent mesoderm, but instead directly influences the temporal progression of the epithelial-to-mesenchymal transition with wild type transitioning first, followed by TBXT heterozygous and then TBXT null.

View Article and Find Full Text PDF

Proper regulation of gene dosage is critical for the development of the early embryo and the extraembryonic tissues that support it. Specifically, loss of leads to stunted development of the allantois, an extraembryonic mesoderm-derived structure critical for nutrient delivery and waste removal in the early embryo. In this study, we investigate how CDX2 dose-dependently influences the gene regulatory network underlying extraembryonic mesoderm development.

View Article and Find Full Text PDF

Advances in cell therapy offer promise for some of the most devastating neural injuries, including spinal cord injury (SCI). Endogenous VSX2-expressing spinal V2a interneurons have been implicated as a key component in plasticity and therapeutically driven recovery post-SCI. While transplantation of generic V2a neurons may have therapeutic value, generation of human spinal V2a neurons with rostro-caudal specificity and assessment of their functional synaptic integration with the injured spinal cord has been elusive.

View Article and Find Full Text PDF
Article Synopsis
  • The study examines the integration of genomic data across NHS laboratories in England and Wales, highlighting variations in data structure, quality, and ease of local assembly for cancer susceptibility gene testing.
  • A survey of 51 clinical scientists revealed significant differences in how variant data is transferred, formatted, and classified within Laboratory Information Management Systems (LIMS) across the participating labs.
  • The findings indicate that current workflows are often inefficient and prone to errors due to their manual nature, suggesting that implementing recommended improvements could streamline data submission processes for better national and international collaboration.
View Article and Find Full Text PDF

In the nascent mesoderm, levels of Brachyury (TBXT) expression must be precisely regulated to ensure cells exit the primitive streak and pattern the anterior-posterior axis, but how this varying dosage informs morphogenesis is not well understood. In this study, we define the transcriptional consequences of TBXT dose reduction during early human gastrulation using human induced pluripotent stem cell (hiPSC)-based models of gastrulation and mesoderm differentiation. Multiomic single-nucleus RNA and single-nucleus ATAC sequencing of 2D gastruloids comprised of WT, TBXT heterozygous (TBXT-Het), or TBXT null (TBXT-KO) hiPSCs reveal that varying TBXT dosage does not compromise a cell's ability to differentiate into nascent mesoderm, but that the loss of TBXT significantly delays the temporal progression of the epithelial to mesenchymal transition (EMT).

View Article and Find Full Text PDF

The hepatitis C virus (HCV) causes liver disease, affecting millions. Even though we have effective antivirals that cure HCV, they cannot stop terminal liver disease. We used an adult stem cell-derived liver organoid system to understand how HCV infection leads to the progression of terminal liver disease.

View Article and Find Full Text PDF

Biological patterning events that occur early in development establish proper tissue morphogenesis. Identifying the mechanisms that guide these patterning events is necessary in order to understand the molecular drivers of development and disease and to build tissues in vitro. In this study, we use an in vitro model of gastrulation to study the role of tight junctions and apical/basolateral polarity in modulating bone morphogenic protein-4 (BMP4) signaling and gastrulation-associated patterning in colonies of human pluripotent stem cells (hPSCs).

View Article and Find Full Text PDF

Introduction: Predictive testing for BRCA1 or BRCA2 allows at-risk individuals to engage with appropriate screening and treatment services if a pathogenic mutation is identified. Previous studies have shown uptake of predictive testing to most commonly range between 20% and 40% (Table 2). This represents a missed cancer prevention opportunity.

View Article and Find Full Text PDF

The rapidly growing field of cellular engineering is enabling scientists to more effectively create models of disease and develop specific cell types that can be used to repair damaged tissue. In particular, the engineering of neurons and other components of the nervous system is at the forefront of this field. The methods used to engineer neural cells can be largely divided into systems that undergo directed differentiation through exogenous stimulation (i.

View Article and Find Full Text PDF

The ability to engineer complex multicellular systems has enormous potential to inform our understanding of biological processes and disease and alter the drug development process. Engineering living systems to emulate natural processes or to incorporate new functions relies on a detailed understanding of the biochemical, mechanical, and other cues between cells and between cells and their environment that result in the coordinated action of multicellular systems. On April 3-6, 2022, experts in the field met at the Keystone symposium "Engineering Multicellular Living Systems" to discuss recent advances in understanding how cells cooperate within a multicellular system, as well as recent efforts to engineer systems like organ-on-a-chip models, biological robots, and organoids.

View Article and Find Full Text PDF

Engineered cardiac tissue models aim to recapitulate the multicellular composition of the native myocardium by incorporating multiple tissue-relevant cell populations. Here, we describe the process of generating self-assembled cardiac microtissue spheroids comprised of heterotypic cardiac cell types. The absence of exogenous extracellular matrix (ECM) or scaffolding makes microtissue assembly dependent upon intercellular adhesion interactions over cell-ECM interactions, analogous to early development.

View Article and Find Full Text PDF

Neurotrophic keratopathy (NK), or neurotrophic keratitis, is a degenerative condition that results from decreased innervation to the cornea. The cornea is innervated by the ophthalmic branch of the trigeminal nerve. Neurotrophic keratopathy is most commonly caused by herpes keratitis however, any condition that disrupts the normal corneal innervation can cause NK.

View Article and Find Full Text PDF

Hepatitis C virus (HCV) remains a global public health challenge with an estimated 71 million people chronically infected, with surges in new cases and no effective vaccine. New methods are needed to study the human immune response to HCV since animal models are limited and cancer cell models often show dysregulated immune and proliferative responses. Here, we developed a CD8 T cell and adult stem cell liver organoid system using a microfluidic chip to coculture 3D human liver organoids embedded in extracellular matrix with HLA-matched primary human T cells in suspension.

View Article and Find Full Text PDF

Quantum information theorists have created axiomatic reconstructions of quantum mechanics (QM) that are very successful at identifying precisely what distinguishes quantum probability theory from classical and more general probability theories in terms of information-theoretic principles. Herein, we show how one such principle, Information Invariance and Continuity, at the foundation of those axiomatic reconstructions, maps to "no preferred reference frame" (NPRF, aka "the relativity principle") as it pertains to the invariant measurement of Planck's constant for Stern-Gerlach (SG) spin measurements. This is in exact analogy to the relativity principle as it pertains to the invariant measurement of the speed of light at the foundation of special relativity (SR).

View Article and Find Full Text PDF

During embryogenesis, paracrine signaling between tissues in close proximity contributes to the determination of their respective cell fate(s) and development into functional organs. Organoids are in vitro models that mimic organ formation and cellular heterogeneity, but lack the paracrine input of surrounding tissues. Here, we describe a human multilineage iPSC-derived organoid that recapitulates cooperative cardiac and gut development and maturation, with extensive cellular and structural complexity in both tissues.

View Article and Find Full Text PDF

Many neuromuscular disorders are caused by dominant missense mutations that lead to dominant-negative or gain-of-function pathology. This category of disease is challenging to address via drug treatment or gene augmentation therapy because these strategies may not eliminate the effects of the mutant protein or RNA. Thus, effective treatments are severely lacking for these dominant diseases, which often cause severe disability or death.

View Article and Find Full Text PDF

The spinal cord contains a diverse array of sensory and motor circuits that are essential for normal function. Spinal cord injury (SCI) permanently disrupts neural circuits through initial mechanical damage, as well as a cascade of secondary injury events that further expand the spinal cord lesion, resulting in permanent paralysis. Tissue clearing and 3D imaging have recently emerged as promising techniques to improve our understanding of the complex neural circuitry of the spinal cord and the changes that result from damage due to SCI.

View Article and Find Full Text PDF

Functional human tissues engineered from patient-specific induced pluripotent stem cells (hiPSCs) hold great promise for investigating the progression, mechanisms, and treatment of musculoskeletal diseases in a controlled and systematic manner. For example, bioengineered models of innervated human skeletal muscle could be used to identify novel therapeutic targets and treatments for patients with complex central and peripheral nervous system disorders. There is a need to develop standardized and objective quantitative methods for engineering and using these complex tissues, in order increase their robustness, reproducibility, and predictiveness across users.

View Article and Find Full Text PDF