Biology subjects

Patel, J.

Publications and source records attributed to Patel, J..

78 records · Page 5Linked to original sources

bioRxiv2019

Deceptive combined effects of short allele dominance and stuttering: an example with Ixodes scapularis, the main vector of Lyme disease in the U.S.A.

Null alleles, short allele dominance (SAD), and stuttering increase the perceived relative inbreeding of individuals and subpopulations as measured by Wrights FIS and FST. Ascertainment bias, due to such amplifying problems are usually caused by inaccurate primer design (if developed from a different species or a distant population), poor DNA quality, low DNA concentration, or a combination of some or all these sources of inaccuracy. When combined, these issues can increase the correlation between polymorphism at concerned loci and, consequently, of linkage disequilibrium (LD) between those. In this note, we studied an original microsatellite data set generated by analyzing nine loci in Ixodes scapularis ticks from the eastern U.S.A. To detect null alleles and SAD we used correlation methods and variation measures. To detect stuttering, we evaluated heterozygote deficit between alleles displaying a single repeat difference. We demonstrated that an important proportion of loci affected by amplification problems (one with null alleles, two with SAD and three with stuttering) lead to highly significant heterozygote deficits (FIS=0.1, p-value<0.0001). This occurred together with an important proportion (22%) of pairs of loci in significant LD, two of which were still significant after a false discovery rate (FDR) correction, and some variation in the measurement of population subdivision across loci (Wrights FST). This suggested a strong Wahlund effect and/or selection at several loci. By finding small peaks corresponding to previously disregarded larger alleles in some homozygous profiles for loci with SAD and by pooling alleles close in size for loci with stuttering, we generated an amended dataset. Except for one locus with null alleles and another still displaying a modest SAD, the analyses of the corrected dataset revealed a significant excess of heterozygotes (FIS=-0.07 as expected in dioecious and strongly subdivided populations, with a more reasonable proportion (19%) of pairs of loci characterized by significant LD, none of which stayed significant after the FDR procedure. Strong subdivision was also confirmed by the standardized FST corrected for null alleles (FST=0.19) and small effective subpopulation sizes (Ne=7).

evolutionary biology↗

bioRxiv2019

Thymosin β4 mediates vascular protection via regulation of Low Density Lipoprotein Related Protein 1 (LRP1)

Vascular stability and tone are maintained by contractile smooth muscle cells (VSMCs). However, injury-induced growth factors stimulate a contractile-synthetic phenotypic switch which promotes atherosclerosis and susceptibility to abdominal aortic aneurysm (AAA). As a regulator of embryonic VSMC differentiation, we hypothesised that Thymosin {beta}4 (T{beta}4) may additionally function to maintain healthy vasculature and protect against disease throughout postnatal life. This was supported by identification of an interaction with Low density lipoprotein receptor related protein 1 (LRP1), an endocytic regulator of PDGF-BB signalling and VSMC proliferation. LRP1 variants have been identified by GWAS as major risk loci for AAA and coronary artery disease. T{beta}4-null mice display aortic VSMC and elastin defects, phenocopying LRP1 mutants and suggesting compromised vascular integrity. We confirmed predisposition to disease in models of atherosclerosis and AAA. Diseased vessels and plaques were characterised by accelerated contractile-synthetic VSMC switching and augmented PDGFR{beta} signalling. In vitro, enhanced sensitivity to PDGF-BB, upon loss of T{beta}4, coincided with dysregulated endocytosis, leading to increased recycling of LRP1-PDGFR{beta} and reduced lysosomal targeting. Our study identifies T{beta}4 as a key regulator of LRP1 for maintaining vascular health, providing insight which may reveal useful therapeutic targets for modulation of VSMC phenotypic switching and disease progression.

cell biology↗

bioRxiv2018

Diffeomorphic registration with intensity transformation and missing data: Application to 3D digital pathology of Alzheimer’s disease

This paper examines the problem of diffeomorphic image mapping in the presence of differing image intensity profiles and missing data. Our motivation comes from the problem of aligning 3D brain MRI with 100 micron isotropic resolution, to histology sections with 1 micron in plane resolution. Multiple stains, as well as damaged, folded, or missing tissue are common in this situation. We overcome these challenges by introducing two new concepts. Cross modality image matching is achieved by jointly estimating polynomial transformations of the atlas intensity, together with pose and deformation parameters. Missing data is accommodated via a multiple atlas selection procedure where several atlases may be of homogeneous intensity and correspond to \"background\" or \"artifact\". The two concepts are combined within an Expectation Maximization algorithm, where atlas selection posteriors and deformation parameters are updated iteratively, and polynomial coefficients are computed in closed form. We show results for 3D reconstruction of digital pathology and MRI in standard atlas coordinates. In conjunction with convolutional neural networks, we quantify the 3D density distribution of tauopathy throughout the medial temporal lobe of an Alzheimers disease postmortem specimen.\n\nAuthor summaryOur work in Alzheimers disease (AD) is attempting to connect histopathology at autopsy and longitudinal clinical magnetic resonance imaging (MRI), combining the strengths of each modality in a common coordinate system. We are bridging this gap by using post mortem high resolution MRI to reconstruct digital pathology in 3D. This image registration problem is challenging because it combines images from different modalities in the presence of missing tissue and artifacts. We overcome this challenge by developing a new registration technique that simultaneously classifies each pixel as \"good data\" / \"missing tissue\" / \"artifact\", learns a contrast transformation between modalities, and computes deformation parameters. We name this technique \"(D)eformable (R)egistration and (I)ntensity (T)ransformation with (M)issing (D)ata\", pronounced as \"Dr. It, M.D.\". In conjunction with convolutional neural networks, we use this technique to map the three dimensional distribution of tau tangles in the medial temporal lobe of an AD postmortem specimen.

neuroscience↗

bioRxiv2018

Inhibition of the 60S ribosome biogenesis GTPase LSG1 causes endoplasmic reticular disruption and cellular senescence

Cellular senescence is triggered by diverse stimuli and is characterised by long-term growth arrest and secretion of cytokines and chemokines (termed the SASP - senescence-associated secretory phenotype). Senescence can be organismally beneficial as it can prevent the propagation of damaged or mutated clones and stimulate their clearance by immune cells. However, it has recently become clear that senescence also contributes to the pathophysiology of aging through the accumulation of damaged cells within tissues. Here we describe that inhibition of the reaction catalysed by LSG1, a GTPase involved in the biogenesis of the 60S ribosomal subunit, leads to a robust induction of cellular senescence. Perhaps surprisingly, this was not due to ribosome depletion or translational insufficiency, but rather through perturbation of endoplasmic reticulum (ER) homeostasis and a dramatic upregulation of the cholesterol biosynthesis pathway. This cholesterol/ER signature is shared with several other forms of senescence and contributes to the cell cycle arrest in oncogene-induced senescence (OIS). Furthermore, targetting of LSG1 resulted in amplification of the cholesterol/ER signature and restoration of a robust cellular senescence response in transformed cells, suggesting potential therapeutic uses of LSG1 inhibition.

cancer biology↗

bioRxiv2018

Mutant lamins cause mechanically-induced nuclear envelope rupture, DNA damage, and DNA-PK activation in muscle

Mutations in the human LMNA gene, which encodes the nuclear envelope (NE) proteins lamins A and C, cause autosomal dominant Emery-Dreifuss muscular dystrophy, congenital muscular dystrophy, limb-girdle muscular dystrophy, and other diseases collectively known as laminopathies. The molecular mechanisms responsible for these diseases remain incompletely understood, but the muscle-specific defects suggest that mutations may render nuclei more susceptible to mechanical stress. Using three mouse models of muscle laminopathies, we found that Lmna mutations caused extensive NE abnormalities, consisting of chromatin protrusions into the cytoplasm and transient rupture of the NE in skeletal muscle cells. NE damage was associated with DNA damage, activation of DNA damage response pathways, and reduced viability. Intriguingly, NE damage resulted from nuclear migration in maturing skeletal muscle cells, rather than actomyosin contractility. NE damage and DNA damage was reduced by either depletion of kinesin-1 or disruption of the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. LINC complex disruption rescued myofiber function and viability in Lmna mutant myofibers, indicating that the myofiber dysfunction is the result of mechanically induced NE damage. The extent of NE damage and DNA damage in Lmna mouse models correlated with the disease onset and severity in vivo. Moreover, inducing DNA damage in wild-type muscle cells was sufficient to phenocopy the reduced cell viability of lamin A/C-deficient muscle cells, suggesting a causative role of DNA damage in disease pathogenesis. Corroborating the mouse model data, muscle biopsies from patients with LMNA muscular dystrophy revealed significant DNA damage compared to age-matched controls, particularly in severe cases of the disease. Taken together, these findings point to a new and important role of DNA damage as a pathogenic contributor for LMNA skeletal muscle diseases.

cell biology↗

bioRxiv2017

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations

Though the added value of proteomic measurements to gene expression profiling has been demonstrated, profiling of gene expression on its own remains the dominant means of understanding cellular responses to perturbation. Direct protein measurements are typically limited due to issues of cost and scale; however, the recent development of high-throughput, targeted sentinel mass spectrometry assays provides an opportunity for proteomics to contribute at a meaningful scale in high-value areas for drug development. To demonstrate the feasibility of a systematic and comprehensive library of perturbational proteomic signatures, we profiled 90 drugs (in triplicate) in six cell lines using two different proteomic assays -- one measuring global changes of epigenetic marks on histone proteins and another measuring a set of peptides reporting on the phosphoproteome -- for a total of more than 3,400 samples. This effort represents a first-of-its-kind resource for proteomics. The majority of tested drugs generated reproducible responses in both phosphosignaling and chromatin states, but we observed differences in the responses that were cell line-and assay-specific. We formalized the process of comparing response signatures within the data using a concept called connectivity, which enabled us to integrate data across cell types and assays. Furthermore, it facilitated incorporation of transcriptional signatures. Consistent connectivity among cell types revealed cellular responses that transcended cell-specific effects, while consistent connectivity among assays revealed unexpected associations between drugs that were confirmed by experimental follow-up. We further demonstrated how the resource could be leveraged against public domain external datasets to recognize therapeutic hypotheses that are consistent with ongoing clinical trials for the treatment of multiple myeloma and acute lymphocytic leukemia (ALL). These data are available for download via the Gene Expression Omnibus (accession GSE101406), and web apps for interacting with this resource are available at https://clue.io/proteomics.\n\nHighlightsO_LIFirst-of-its-kind public resource of proteomic responses to systematically administered perturbagens\nC_LIO_LIDirect proteomic profiling of phosphosignaling and chromatin states in cells for 90 drugs in six different cell lines\nC_LIO_LIExtends Connectivity Map concept to proteomic data for integration with transcriptional data\nC_LIO_LIEnables recognition of unexpected, cell type-specific activities and potential translational therapeutic opportunities\nC_LI

systems biology↗