Biology subjects

Clark, C.

Publications and source records attributed to Clark, C..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Sequential unfolding mechanisms of monomeric caspases

Caspases are evolutionarily conserved cysteinyl proteases that are integral in cell development and apoptosis. All apoptotic caspases evolved from a common ancestor into two distinct subfamilies with either monomeric (initiators) or dimeric (effectors) oligomeric states. The regulation of apoptosis is influenced by the activation mechanism of the two subfamilies, but the evolution of the well-conserved caspase-hemoglobinase fold into the two subfamilies is not well understood. We examined the folding landscape of monomeric caspases from two coral species over a broad pH range of 3 to 10.5. On an evolutionary timescale, the two coral caspases diverged from each other approximately 300 million years ago, and they diverged from human caspases about 600 million years ago. Our results indicate that both proteins have overall high stability, [~] 15 kcal mol-1 near the physiological pH range (pH 6 to pH 8), and unfold via two partially folded intermediates, I1 and I2, that are in equilibrium with the native and the unfolded state. Like the dimeric caspases, the monomeric coral caspases undergo a pH-dependent conformational change resulting from the titration of an evolutionarily conserved site. Data from molecular dynamics simulations paired with limited proteolysis and MALDI-TOF mass spectrometry show that the small subunit of the monomeric caspases is unstable and unfolds prior to the large subunit. Overall, the data suggest that all caspases share a conserved folding landscape, that a conserved allosteric site can be fine-tuned for species-specific regulation, and that the subfamily of stable dimers may have evolved to stabilize the small subunit.

biophysics↗

bioRxiv2022

SCIP: A self-paced, community-based summer coding program creates community and increases coding confidence

In 2020, many students lost summer opportunities due to the COVID-19 pandemic. We wanted to offer students an opportunity to learn computational skills and be part of a community while they were stuck at home. Because the pandemic was very isolating, it was important to support students to learn and build community online. We used lessons learned from literature and our own experience to design, run and test an online program for students called the Science Coding Immersion Program (SCIP). In our program, students worked in small teams for 8 hours a week spread over the week, with one participant as the team leader and Zoom host. Teams worked on an online R or Python class at their own pace with support on Slack from the organizing team. For motivation and career advice, we hosted a weekly webinar with guest speakers. We used pre- and post-program surveys to determine how different aspects of the program impacted students. We were able to recruit a large and diverse group of participants who were happy with the program, found community in their team, and improved their coding confidence. We hope that our work will inspire others to start their own version of SCIP.

scientific communication and education↗

bioRxiv2022

Sequence type diversity amongst antibiotic-resistant bacterial strains is lower than amongst antibiotic-susceptible strains

The increasing number of antibiotic resistant bacterial infections is a global threat to human health. Antibiotic resistant bacterial strains generally evolve from susceptible strains by either horizontal gene transfer or chromosomal mutations. After evolving within a host, such resistant strains can be transmitted to other hosts and increase in frequency in the population at large. Population genetic theory postulates that the increase in frequency of an adaptive trait can lead to signatures of selective sweeps. One would thus expect to observe reduced genetic diversity amongst that part of the population that carries the adaptive trait. Specifically, if the evolution of new resistant strains is rare, it is expected that resistant strains represent only a subset of the diversity of susceptible strains. It is currently unknown if diversity of resistant strains is indeed lower than diversity of susceptible strains when considering antibiotic resistance. Here we show that in several bacterial species in several different datasets, sequence-type diversity amongst antibiotic-resistant bacterial strains is indeed lower than amongst antibiotic-susceptible strains in most cases. We re-analysed eight existing clinical datasets with Escherichia coli, Staphylococcus aureus and Enterococcus faecium samples. These datasets consisted of 53 - 1094 patient samples, with multi-locus sequence types and antibiotic resistance phenotypes for 3 - 19 different antibiotics. Out of 59 comparisons, we found that resistant strains were significantly less diverse than susceptible strains in 51 cases (86%). In addition, we show that sequence-type diversity of antibiotic-resistant strains is lower if resistance is rare, compared to when resistance is common, which is consistent with rare resistance being due to fewer evolutionary origins. Our results show that for several different bacterial species, we observe reduced diversity of resistant strains, which is consistent with the evolution of resistance driven by selective sweeps stemming from a limited number of evolutionary origins. In future studies, more detailed analysis of such sweep signatures is warranted.

evolutionary biology↗

bioRxiv2022

A multi-omics analysis of glioma chemoresistance using a hybrid microphysiological model of glioblastoma

Chemoresistance is a major clinical challenge in the management of glioblastoma (GBM) Temozolomide (TMZ) is the chemotherapeutic drug of choice for GBM; however, the therapeutic effect of TMZ is limited due to the development of resistance. Recapitulating GBM chemoresistance in a controlled environment is thus essential in understanding the mechanism of chemoresistance. Herein, we present a hybrid microphysiological model of chemoresistant GBM-on-a-chip (HGoC) by directly co-culturing TMZ-resistant GBM spheroids with healthy neurons to mimic the microenvironment of both the tumor and the surrounding healthy tissue. We characterized the model with proteomics, lipidomics, and secretome assays. The results showed that our artificial model recapitulated the molecular signatures of recurrent GBM in humans. Both showed alterations in vesicular transport and cholesterol pathways, mitotic quiescence, and a switch in metabolism to oxidative phosphorylation associated with a transition from mesenchymal to amoeboid. This is the first report to unravel the interplay of all these molecular changes as a mechanism of chemoresistance in glioblastoma. Moreover, we have shown that the acquisition of resistance increases invasiveness and the presence of neurons decreases this property.

bioengineering↗

bioRxiv2022

Modeling the biomechanics of cells on microcarriers in a stirred-tank bioreactor An ABM-CFD coupling approach

Highly productive and efficient growth of biomass in bioreactors is an essential bioprocess outcome in many industrial applications. In the nascent cultivated meat industry, large-scale biomass creation will be critical given the size of demand in the conventional meat and seafood sectors. However, there are many challenges that must be overcome before cultivated meat and seafood become commercially viable including cost reductions of cell culture media, bioprocess design innovation and optimization, and scaling up in the longer term. Computational modelling and simulation can help to address many of these challenges, and can be a far cheaper and faster alternative to performing physical experiments. Computer modelling can also help researchers pinpoint system interactions that matter, and guide researchers to identify those parameters that should be changed in later designs for eventual optimization. In this work, a computational model that combines agent-based modeling and computational fluid dynamics was developed to study biomass growth as a function of the operative conditions of stirred-tank bioreactors. The focus was to analyze how the mechanical stress induced by rotor speed can influence the growth of cells attached to spherical microcarriers. The computer simulation results reproduced observations from physical experiments that high rotor speeds reduce cell growth rates and induce cell death under the high mechanical stresses induced at these stir speeds. Moreover, the results suggest that modeling both cell death and cell quiescence are required to recapitulate these observations from physical experiments. These simulation outcomes are the first step towards more comprehensive models that, in combination with experimental observations, will improve our knowledge of biomass production in bioreactors for cultivated meat and other industries.

bioinformatics↗

bioRxiv2022

Comparing the folding landscapes of evolutionarily divergent procaspase-3

All caspases evolved from a common ancestor and subsequently developed into two general classes, inflammatory or apoptotic caspases. The caspase-hemoglobinase fold has been conserved throughout nearly one billion years of evolution and is utilized for both the monomeric and dimeric subfamilies of apoptotic caspases, called initiator and effector caspases, respectively. We compared the folding and assembly of procaspase-3b from zebrafish to that of human effector procaspases in order to examine the conservation of the folding landscape. Urea-induced equilibrium folding/unfolding of procaspase-3b showed a minimum three-state folding pathway, where the native dimer isomerizes to a partially folded dimeric intermediate, which then unfolds. A partially folded monomeric intermediate observed in the folding landscape of human procaspase-3 is not well-populated in zebrafish procaspase-3b. By comparing effector caspases from different species, we show that the effector procaspase dimer undergoes a pH-dependent conformational change, and that the conformational species in the folding landscape exhibit similar free energies. Together, the data show that the landscape for the caspase-hemoglobinase fold is conserved, yet it provides flexibility for species-specific stabilization or destabilization of folding intermediates resulting in changes in stability. The common pH-dependent conformational change in the native dimer, which yields an enzymatically inactive species, may provide an additional, albeit reversible, mechanism for controlling caspase activity in the cell.

biophysics↗

bioRxiv2021

Engineering a thixotropic and biochemically tunable hyaluronan and collagen bioink for biofabrication of multiple tissue construct types

The field of three-dimensional (3D) bioprinting has advanced rapidly in recent years. Significant reduction in the costs associated with obtaining functional 3D bioprinting hardware platforms is both a cause and a result of these advances. As such, there are more laboratories than ever integrating bioprinting methodologies into their research. However, there is a lack of standards in the field of biofabrication governing any requirements or characteristics to support cross-compatibility with biomaterial bioinks, hardware, and different tissue types. Here we describe a modular extracellular matrix (ECM) inspired bioink comprised of collagen and hyaluronic acid base components that: 1) employ reversible internal hydrogen bonding forces to generate thixotropic materials that dynamically reduce their elastic moduli in response to increased shear stress, thus enabling increased compatibility with printing hardware; and 2) modular addons in the form of chemically-modified fibronectin and laminin that when covalently bound within the bioink support a variety of tissue types, including liver, neural, muscle, pancreatic islet, and adipose tissue. These features aim to accelerate the deployment of such bioinks for tissue engineering of functional constructs in the hands of various end users.

bioengineering↗

bioRxiv2020

Genetic ablation of serotonin receptor 2B improves aortic valve hemodynamics in a high-cholesterol diet mouse model

Calcific aortic valve disease (CAVD) is a deadly disease that is rising in prevalence due to population aging. While the disease is complex and poorly understood, one well-documented driver of valvulopathy is serotonin agonism. Both serotonin overexpression, as seen with carcinoid tumors and drug-related agonism, such as with Fenfluramine use, are linked with various diseases of the valves. Thus, the objective of this study was to determine if genetic ablation or pharmacological antagonism of the 5-HT2B serotonin receptor (gene: Htr2b) could improve the hemodynamic and histological progression of calcific aortic valve disease. Htr2b mutant mice were crossed with Notch1+/- mice, an established small animal model of CAVD, to determine if genetic ablation affects CAVD progression. To assess the effect of pharmacological inhibition on CAVD progression, Notch1+/- mice were treated with the 5-HT2B receptor antagonist SB204741. Mice were analyzed using echocardiography, histology, immunofluorescence, and real-time quantitative polymerase chain reaction. Htr2b mutant mice showed lower aortic valve peak velocity and mean pressure gradient - classical hemodynamic indicators of aortic valve stenosis - without concurrent left ventricle change. 5-HT2B receptor antagonism, however, did not affect hemodynamic progression. Leaflet thickness, collagen density, and CAVD-associated transcriptional markers were not significantly different in any group. This study reveals that genetic ablation of Htr2b attenuates hemodynamic development of CAVD in the Notch1+/- mice, but pharmacological antagonism may require high doses or long-term treatment to slow progression.

pharmacology and toxicology↗

bioRxiv2020

Remodeling hydrogen bond interactions results in relaxed specificity of Caspase-3

Caspase enzymes play important roles in apoptosis and inflammation, and the non-identical but overlapping specificity profiles direct cells to different fates. Although all caspases prefer aspartate at the P1 position of the substrate, the caspase-6 subfamily shows preference for valine at the P4 position, while caspase-3 shows preference for aspartate. In comparison to human caspases, caspase-3a from zebrafish has relaxed specificity and demonstrates equal selection for either valine or aspartate at the P4 position. In the context of the caspase-3 conformational landscape, we show that changes in hydrogen bonding near the S3 subsite affect selection of the P4 amino acid. Swapping specificity with caspase-6 requires accessing new conformational space, where each landscape results in optimal binding of DxxD (caspase-3) or VxxD (caspase-6) substrate and simultaneously disfavors binding of the other substrate. Within the context of the caspase-3 conformational landscape, substitutions near the active site result in nearly equal activity against DxxD and VxxD by disrupting a hydrogen bonding network in the substrate binding pocket. The converse substitutions in zebrafish caspase-3a result in increased selection for P4 aspartate over valine. Overall, the data show that evolutionary neofunctionalization resulting in a dual function protease, as in zebrafish caspase-3a, requires fewer amino acid substitutions compared to those required to access new conformational space for swapping substrate specificity, such as between caspases-3 and -6.

biochemistry↗

bioRxiv2020

Sister chromatid repair maintains genomic integrity during meiosis in Caenorhabditis elegans

During meiosis, the maintenance of genome integrity is critical for generating viable haploid gametes [1]. In meiotic prophase I, double-strand DNA breaks (DSBs) are induced and a subset of these DSBs are repaired as interhomolog crossovers to ensure proper chromosome segregation. DSBs in excess of the permitted number of crossovers must be repaired by other pathways to ensure genome integrity [2]. To determine if the sister chromatid is engaged for meiotic DSB repair during oogenesis, we developed an assay to detect sister chromatid repair events at a defined DSB site during Caenorhabditis elegans meiosis. Using this assay, we directly demonstrate that the sister chromatid is available as a meiotic repair template for both crossover and noncrossover recombination, with noncrossovers being the predominant recombination outcome. We additionally find that the sister chromatid is the exclusive recombination partner for DSBs during late meiotic prophase I. Analysis of noncrossover conversion tract sequences reveals that DSBs are processed similarly throughout prophase I and recombination intermediates remain central around the DSB site. Further, we demonstrate that the SMC-5/6 complex is required for long conversion tracts in early prophase I and intersister crossovers during late meiotic prophase I; whereas, the XPF-1 nuclease is required only in late prophase to promote sister chromatid repair. In response to exogenous DNA damage at different stages of meiosis, we find that mutants for SMC-5/6 and XPF-1 have differential effects on progeny viability. Overall, we propose that SMC-5/6 both processes recombination intermediates and promotes sister chromatid repair within meiotic prophase I, while XPF-1 is required as an intersister resolvase only in late prophase I.

genetics↗

bioRxiv2020

TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels

BackgroundNeurofilament light (NF-L), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are utilized as biomarkers for Alzheimers disease (AD), to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Here we performed genome-wide association study (GWAS) analyses using all three biomarkers as outcome. MethodsDNA and cerebrospinal fluid (CSF) samples originated from the European Medical Information Framework AD Multimodal Biomarker Discovery (EMIF-AD MBD) study. Overlapping genotype/phenotype data were available for n=671 (NF-L), 677 (YKL-40), and 672 (Ng) individuals. GWAS analyses applied linear regression models adjusting for relevant covariates. FindingsWe identify novel genome-wide significant associations with markers in TMEM106B and CSF levels of NF-L. Additional novel signals were observed with DNA variants in CPOX and CSF levels of YKL-40. Lastly, we confirmed previous work suggesting that YKL-40 levels are regulated by cis protein quantitative trait loci (pQTL) in CHI3L1. InterpretationOur study provides important new insights into the genetic architecture underlying inter-individual variation in all three tested AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.

genomics↗

bioRxiv2020

Caspases from Scleractinian Coral Show Unique Regulatory Features

Diseases affecting coral have led to massive decline and altered the community structure of reefs. In response to immune challenges, cnidaria activate apoptotic or autophagic pathways, and the particular pathway correlates with disease sensitivity (apoptosis) or resistance (autophagy). Although cnidaria contain complex apoptotic signaling pathways, similar to those in vertebrates, the mechanisms leading to cell death are largely unexplored. We identified and characterized two caspases each from Orbicella faveolata, a disease-sensitive stony coral, and Porites astreoides, a disease-resistant stony coral. The four caspases are predicted homologs of human caspases-3 and -7, but OfCasp3a and PaCasp7a contain an amino-terminal caspase activation and recruitment domain (CARD) similar to human initiator/inflammatory caspases. In contrast, OfCasp3b and PaCasp3 have short pro-domains, like human effector caspases. We show that OfCasp3a and PaCasp7a are DxxDases, like human caspases-3 and -7, while OfCasp3b and PaCasp3 are more similar to human caspase-6, with VxxDase activity. Our biochemical analyses suggest a mechanism in coral in which the CARD-containing DxxDase is activated on death platforms, but the protease does not directly activate the VxxDase. We also report the first X-ray crystal structure of a coral caspase, that of PaCasp7a determined at 1.57[A] resolution. The structure reveals overall conservation of the caspase-hemoglobinase fold in coral as well as an N-terminal peptide bound near the active site that may serve as a regulatory exosite. The binding pocket has been observed in initiator caspases of other species, suggesting mechanisms for the evolution of substrate selection while maintaining common activation mechanisms of CARD-mediated dimerization.

biochemistry↗

bioRxiv2019

Corollary Discharge Promotes a Sustained Motor State in a Neural Circuit for Navigation

Animals exhibit behavioral and neural responses that persist on longer time scales than transient or fluctuating stimulus inputs. Here, we report that C. elegans uses feedback from the motor circuit to a sensory processing interneuron to sustain its motor state during thermotactic navigation. By imaging circuit activity in behaving animals, we show that a principal postsynaptic partner of the AFD thermosensory neuron, the AIY interneuron, encodes both temperature and motor state information. By optogenetic and genetic manipulation of this circuit, we demonstrate that the motor state representation in AIY is a corollary discharge signal. RIM, an interneuron that is connected with premotor interneurons, is required for this corollary discharge. Ablation of RIM eliminates the motor representation in AIY, allows thermosensory representations to reach downstream premotor interneurons, and reduces the animals ability to sustain forward movements during thermotaxis. We propose that feedback from the motor circuit to the sensory processing circuit underlies a positive feedback mechanism to generate persistent neural activity and sustained behavioral patterns in a sensorimotor transformation.

neuroscience↗

bioRxiv2019

A dormant sub-population expressing interleukin-1 receptor characterises anti-estrogen resistant ALDH+ breast cancer stem cells

Estrogen receptor-positive (ER+) breast tumours are often treated with anti-estrogen (AE) therapies but frequently develop resistance. Cancer Stem Cells (CSCs) with high aldehyde dehydrogenase (ALDH) activity (ALDH+ cells) are reported to be enriched following AE treatment. Here we perform in vitro and in vivo functional CSC assays and gene expression analysis to characterise the ALDH+ population in AE resistant metastatic patient samples and an ER+ cell line. We show that the IL1{beta} signalling pathway is activated in ALDH+ cells and data from single cells reveals that AE treatment selects for IL1R1-expressing ALDH+ cells. Importantly, we demonstrate that increased expression of IL1R1 is observed in the tumours of patients treated with AE therapy and predicts for treatment failure. Single-cell gene expression analysis revealed that at least 2 sub-populations exist within the ALDH+ population, one proliferative and one quiescent. Following AE therapy, the quiescent ALDH+IL1R1+ population is expanded, which suggests CSC dormancy as an adaptive strategy that facilitates treatment resistance. Supporting this, analysis of AE resistant dormant tumours reveals significantly increased expression of ALDH1A1, ALDH1A3 and IL1R1 genes. Thus, we propose that targeting of ALDH+IL1R1+ cells will reverse AE resistance, including in patients with minimal residual disease.

cancer biology↗

bioRxiv2019

CADHERIN-11 BLOCKADE REDUCES INFLAMMATION DRIVEN FIBROTIC REMODELING AND IMPROVES OUTCOMES AFTER MYOCARDIAL INFARCTION

BackgroundOver one million Americans experience myocardial infarction (MI) every year, and the resulting scar and subsequent cardiac fibrosis contribute to heart failure and death. A specialized cell-cell adhesion protein, cadherin-11 (CDH11), contributes to inflammation and fibrosis in rheumatoid arthritis, pulmonary fibrosis, and aortic valve calcification but has not yet been studied in the context of cardiac remodeling after MI. We hypothesized that targeting CDH11 function after MI would reduce inflammation-driven fibrotic remodeling and infarct expansion to improve functional outcomes in mice. MethodsMI was induced by ligation of the left anterior descending artery in transgenic mice with reduced or ablated CDH11, wild type mice receiving bone marrow transplants from Cdh11 transgenic animals, and wild type mice treated with a functional blocking antibody against CDH11 (SYN0012). Cardiac function was measured by echocardiography, expression of cell populations was quantified by flow cytometry, and tissue remodeling by altered histological assessment and transcription of inflammatory and pro-angiogenic genes by qPCR. Co-culture was used to assess interactions between cardiac fibroblasts and macrophages. ResultsMI increased transcription of Cdh11 in non-cardiomyocyte cells. Mice with deletion of Cdh11 and wild type mice receiving bone marrow transplants from Cdh11 transgenic animals had improved cardiac function and dimensions after MI. Animals given SYN0012 had improved cardiac function, reduced tissue remodeling, and altered transcription of inflammatory and proangiogenic genes. Targeting CDH11 also reduced the number of bone marrow-derived myeloid cells and increased pro-angiogenic cells in the heart three days after MI, consistent with a decrease in transcription and expression of IL-6 in the infarct region. Cardiac fibroblast and macrophage interactions led to an increase in IL-6 secretion that was reduced with SYN0012 treatment in vitro. ConclusionsOur findings suggest that CDH11-expressing cells contribute to inflammation-driven fibrotic remodeling after MI, and that targeting CDH11 with a blocking antibody improves cardiac function after MI. This improvement is likely mediated by altered recruitment of bone marrow-derived cells, thereby limiting the macrophage-induced expression of IL-6 by fibroblasts and promoting vascularization.

molecular biology↗

bioRxiv2019

Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development

Mutations in the thyroid hormone receptor 1 gene (THRA) have recently been identified as a cause of intellectual deficit in humans. Patients present with structural abnormalities including microcephaly, reduced cerebellar volume and decreased axonal density. Here, we show that directed differentiation of THRA mutant patient-derived iPSCs to forebrain neural progenitors is markedly reduced, but mutant progenitor cells can generate deep and upper cortical layer neurons and form functional neuronal networks. Quantitative lineage tracing shows that THRA mutation-containing progenitor cells exit the cell cycle prematurely, resulting in reduced clonal output. Using a novel micropatterned chip assay, we find that spatial self-organisation of mutation-containing progenitor cells is impaired, consistent with downregulated expression of cell-cell adhesion genes. These results reveal for the first time that thyroid hormone receptor 1 is required for normal neural progenitor cell proliferation and organisation in human cerebral cortical development. They also exemplify novel quantitative approaches for studying neurodevelopmental disorders using patient-derived cells in vitro.

developmental biology↗

bioRxiv2018

The relative influence of niche versus neutral processes on Ediacaran communities

A fundamental question in community ecology is the relative influence of niche versus neutral processes in determining ecosystem dynamics. The extent to which these processes structured early animal communities is yet to be explored. Here we use spatial point process analyses (SPPA) to determine the influence of niche versus neutral processes on early total-group metazoan paleocommunities from the Ediacaran Period [~]565 million years in age. Preservation of these sessile organisms in large in-situ populations on exposed bedding planes enables inference of the most likely underlying processes governing their spatial distributions by SPPA. We conducted comprehensive spatial mapping of six of the largest Ediacaran paleocommunities in Newfoundland, Canada and Charnwood Forest, UK using LiDAR, photogrammetry and a laser-line probe. For each paleocommunity we determined the best-fit spatial model for each univariate and bivariate species distribution, comparing four sets of spatial models (complete spatial randomness, dispersal, habitat, and combined dispersal with habitat) using goodness-of-fit tests. Random and dispersal models are considered neutral processes while habitat and combined models are considered niche processes. We find the dynamics of these paleocommunities to be dominated by neutral processes, with limited influence from niche processes. Our findings are consistent with community model predictions of when neutral dynamics dominate, but are in stark contrast to the niche-dominated communities of the modern marine realm. Thus, while the underlying processes determining metazoan community assembly appear to have been in place since the appearance of the first macroscopic, complex animals, the dynamics of these early metazoan communities were fundamentally different to those of extant communities.\n\nSignificance statementThe extent to which habitat and dispersal processes structure the earliest animal communities found during the Ediacaran Period [~]565 million years ago, is unknown. In this study we analyse six of the largest and most diverse fossil assemblages from Newfoundland, Canada and Charnwood Forest, UK, using spatial point processes analyses to determine the relative influence of habitat processes (niche) and dispersal processes (neutral) on the spatial distribution of taxa. The vast majority of Ediacaran taxon distributions were controlled by neutral processes, in striking contrast to niche-dominated modern marine ecosystems, but consistent with model predictions of when neutral dynamics dominate communities. Thus the underlying processes determining metazoan community assembly have been in place since the appearance of the first macroscopic, complex animals.

ecology↗

bioRxiv2018

Stability and sensitivity of structural connectomes: effect of thresholding and filtering and demonstration in neurodegeneration

Structural connectomes derived using diffusion tractography are increasingly used to investigate white matter connectivity in neurological diseases. However inherent biases in diffusion tractography algorithms may lead to both false negatives and false positives in connectome construction. A range of graph thresholding approaches and more recently several streamline filtering algorithms have been developed to address these issues. However there is no consensus in the literature regarding the best available approach. Using a cohort of Huntingtons disease patients and healthy controls we compared the effect of several graph thresholding strategies: proportional, absolute, consensus and consistency thresholding, with and without streamline filtering, using Spherical Deconvolution Informed Filtering of tractograms (SIFT2) algorithm. We examined the effect of thresholding strategies on the stability of graph theory metrics and the sensitivity of these measures in neurodegeneration. We show that while a number of graph thresholding procedures result in stable metrics across thresholds, the detection of group differences is highly variable. We also showed that the application of streamline filtering using SIFT2 resultes in better detection of group differences and stronger clinical correlations. We therefore conclude that the application of SIFT2 streamline filtering without graph thresholding may be sufficient for structural connectome construction.

neuroscience↗