Biology subjects

Noorani, A.

Publications and source records attributed to Noorani, A..

7 recordsLinked to original sources

bioRxiv2023

Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes

Alzheimers disease is characterized pathologically by cerebral deposition of 42-residue amyloid {beta}-peptide (A{beta}42), proteolytically produced from amyloid precursor protein (APP) by {beta}- and {gamma}-secretases.1 Although mutations in APP and presenilin, the catalytic component of {gamma}-secretase, cause familial Alzheimers disease (FAD), a role for A{beta}42 as the primary disease driver has not been clearly established and remains controversial.2,3 Here we show through comprehensive analysis of the multi-step proteolysis of APP substrate C99 by {gamma}-secretase that FAD mutations are consistently deficient in early proteolytic events, not later events that produce secreted A{beta} peptides. Cryo-electron microscopy revealed that a substrate mimetic traps {gamma}-secretase at the transition state for intramembrane proteolysis, and this structure closely aligns with activated enzyme-substrate complex captured by molecular dynamics simulations. In silico simulations and fluorescence lifetime imaging microscopy in cultured cells support stabilization by FAD mutations of enzyme-substrate and/or enzyme-intermediate complexes. Neuronal expression of C99 and/or presenilin-1 in Caenorabditis elegans led to age-dependent synaptic loss only when one of the transgenes carried an FAD mutation. Designed mutations that stabilize the enzyme-substrate complex and block proteolysis likewise led to synaptic loss. Collectively, these findings implicate the stalled process--not the released products--of {gamma}-secretase cleavage of substrates in FAD pathogenesis.

neuroscience↗

bioRxiv2020

Extensive phylogenies of human development reveal variable embryonic patterns

Starting from the zygote, all cells in the developing and adult human body continuously acquire mutations. A mutation shared between two different cells implies a shared progenitor cell and can thus be used as a naturally occurring marker for lineage tracing. Here, we reconstruct extensive phylogenies of normal tissues from three adult individuals using whole-genome sequencing of 511 laser capture microdissected samples from multiple organs. Early embryonic progenitor cells inferred from the phylogenies often contribute in different proportions to the adult body and the extent of this asymmetry is variable between individuals, with ratios between the first two reconstructed cells ranging from 56:44 to 92:8. Asymmetries also pervade subsequent cell generations and can differ between tissues in the same individual. The phylogenies also resolve the spatial embryonic origins and patterning of tissues, revealing a spatial effect in the development of the human brain. Supplemented by data on eleven men, we timed the split between soma and germline, with the earliest observed segregation occurring at the first cell divisions. This research demonstrates that, despite reaching the same ultimate tissue patterns, early bottlenecks and lineage commitments lead to substantial variation in embryonic patterns both within and between individuals.

genomics↗

bioRxiv2020

The mutational landscape of human somatic and germline cells

During the course of a lifetime normal human cells accumulate mutations. Here, using multiple samples from the same individuals we compared the mutational landscape in 29 anatomical structures from soma and the germline. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types but their absolute and relative contributions varied substantially. SBS18, potentially reflecting oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The mutation rate was lowest in spermatogonia, the stem cell from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutation processes and may be partially attributable to a low cell division rate of basal spermatogonia. The results provide important insights into how mutational processes affect the soma and germline.

genomics↗

bioRxiv2020

CRIMSON: An Open-Source Software Framework for Cardiovascular Integrated Modelling and Simulation

In this work, we describe the CRIMSON (CardiovasculaR Integrated Modelling and SimulatiON) software environment. CRIMSON provides a powerful, customizable and user-friendly system for performing three-dimensional and reduced-order computational haemodynamics studies via a pipeline which involves: 1) segmenting vascular structures from medical images; 2) constructing analytic arterial and venous geometric models; 3) performing finite element mesh generation; 4) designing, and 5) applying boundary conditions; 6) running incompressible Navier-Stokes simulations of blood flow with fluid-structure interaction capabilities; and 7) post-processing and visualizing the results, including velocity, pressure and wall shear stress fields. A key aim of CRIMSON is to create a software environment that makes powerful computational haemodynamics tools accessible to a wide audience, including clinicians and students, both within our research laboratories and throughout the community. The overall philosophy is to leverage best-in-class open source standards for medical image processing, parallel flow computation, geometric solid modelling, data assimilation, and mesh generation. It is actively used by researchers in Europe, North and South America, Asia, and Australia. It has been applied to numerous clinical problems; we illustrate applications of CRIMSON to real-world problems using examples ranging from pre-operative surgical planning to medical device design optimization. CRIMSON binaries for Microsoft Windows 10, documentation and example input files are freely available for download from www.crimson.software, and the source code with compilation instructions is available on GitHub https://github.com/carthurs/CRIMSONFlowsolver (CRIMSON Flowsolver) under the GPL v3.0 license, and https://github.com/carthurs/CRIMSONGUI (CRIMSON GUI), under the AGPL v3.0 license. Support is available on the CRIMSON Google Groups forum, located at https://groups.google.com/forum/#!forum/crimson-users.

bioengineering↗

bioRxiv2018

Genomic evidence supports a clonal diaspora model for metastases of esophageal adenocarcinoma

Continual evolution of cancer makes it challenging to predict clinical outcomes. Highly varied and unpredictable patient outcomes in esophageal adenocarcinoma (EAC) prompted us to question the pattern and timing of metastatic spread. Whole genome sequencing and phylogenetic analysis of 396 samples across 18 EAC cases demonstrated a stellate pattern on the phylogenetic trees in 90% cases. The age-dependent trinucleotide signature, which can serve as a molecular clock, was absent or reduced in the stellate branches beyond the trunk in most cases (p<0.0001). Clustering of lymph nodes and distant metastases (n=250) demonstrated samples sharing a common clonal origin were widely dispersed anatomically. Metastatic subclones at autopsy were present in tissue and blood samples from earlier time-points. We infer that metastasis occurs rapidly across multiple sites, constituting a model of metastatic spread we term clonal diaspora. This has implications for understanding metastatic progression, clinical staging and patient management.

genomics↗

bioRxiv2018

The landscape of somatic mutation in normal colorectal epithelial cells

The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions leading to cancer. As for most cancer types, however, understanding of the earliest phases of colorectal neoplastic change, which may occur in morphologically normal tissue, is comparatively limited because of the difficulty of detecting somatic mutations in normal cells. Each colorectal crypt is a small clone of cells derived from a single recently-existing stem cell. Here, we whole genome sequenced hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed, some ubiquitous and continuous, others only found in some individuals, in some crypts or during some phases of the cell lineage from zygote to adult cell. Likely driver mutations were present in [~]1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium.

cancer biology↗

bioRxiv2018

Low-cost and clinically applicable copy number profiling using repeat DNA

Large-scale cancer genome studies suggest that tumors are driven by somatic copy number alterations (SCNAs) or single-nucleotide variants (SNVs). Due to the low-cost, the clinical use of genomics assays is biased towards targeted gene panels, which identify SNVs. There is a need for a comparably low-cost and simple assay for high-resolution SCNA profiling. Here we present our method, conliga, which infers SCNA profiles from a low-cost and simple assay.

genomics↗