Biology subjects

Cohen, A. A.

Publications and source records attributed to Cohen, A. A..

27 records · Page 2Linked to original sources

bioRxiv2020

Newfound coding potential of transcripts unveils missing members of human protein communities

Recent proteogenomic approaches have led to the discovery that regions of the transcriptome previously annotated as non-coding regions (i.e. UTRs, open reading frames overlapping annotated coding sequences in a different reading frame, and non-coding RNAs) frequently encode proteins (termed alternative proteins). This suggests that previously identified protein-protein interaction networks are partially incomplete since alternative proteins are not present in conventional protein databases. Here we used the proteogenomic resource OpenProt and a combined spectrum- and peptide-centric analysis for the re-analysis of a high throughput human network proteomics dataset thereby revealing the presence of 280 alternative proteins in the network. We found 19 genes encoding both an annotated (reference) and an alternative protein interacting with each other. Of the 136 alternative proteins encoded by pseudogenes, 38 are direct interactors of reference proteins encoded by their respective parental gene. Finally, we experimentally validate several interactions involving alternative proteins. These data improve the blueprints of the human protein-protein interaction network and suggest functional roles for hundreds of alternative proteins.

systems biology↗

bioRxiv2020

Mosaic RBD nanoparticles elicit neutralizing antibodies against SARS-CoV-2 and zoonotic coronaviruses

Protection against SARS-CoV-2 and SARS-related emergent zoonotic coronaviruses is urgently needed. We made homotypic nanoparticles displaying the receptor-binding domain (RBD) of SARS-CoV-2 or co-displaying SARS-CoV-2 RBD along with RBDs from animal betacoronaviruses that represent threats to humans (mosaic nanoparticles; 4-8 distinct RBDs). Mice immunized with RBD-nanoparticles, but not soluble antigen, elicited cross-reactive binding and neutralization responses. Mosaic-RBD-nanoparticles elicited antibodies with superior cross-reactive recognition of heterologous RBDs compared to sera from immunizations with homotypic SARS-CoV-2-RBD-nanoparticles or COVID-19 convalescent human plasmas. Moreover, sera from mosaic-RBD-immunized mice neutralized heterologous pseudotyped coronaviruses equivalently or better after priming than sera from homotypic SARS-CoV-2-RBD-nanoparticle immunizations, demonstrating no immunogenicity loss against particular RBDs resulting from co-display. A single immunization with mosaic-RBD-nanoparticles provides a potential strategy to simultaneously protect against SARS-CoV-2 and emerging zoonotic coronaviruses. One sentence summaryNanoparticle strategy for pan-sarbecovirus vaccine 125-character summary for online ToCImmunizing with nanoparticles displaying diverse coronavirus RBDs elicits cross-reactive and neutralizing antibody responses.

immunology↗

bioRxiv2020

Physiological System Dysregulation in Gene Expression Correlates Negatively with Age

We attempted to identify gene expression systems that dysregulate with age in human peripheral blood samples across five public datasets. Dysregulation of gene ontology (GO)-defined systems was measured using the Mahalanobis distance (DM), a measure of multivariant aberrance. We expected many weak positive DM-age correlations, indicating loss of homeostatic control. Out of the 5180 GO terms tested, we found 230 systems that replicated in at least three datasets. Surprisingly, all 230 systems showed negative DM-age correlations, in contrast to findings with clinical biomarkers. These systems were mostly metabolic functions related to small molecules and nitrogen compounds, transport functions, biosynthetic processes and response to stress functions. These results suggest a loss of responsiveness in these gene expression systems during the aging process, and contrast to some previous literature showing increased gene expression heterogeneity with age.

cell biology↗

bioRxiv2020

The frailty syndrome as an emergent state of parallel dysregulation in multiple physiological systems

Frailty is a clinical syndrome often present in older adults and characterized by a heightened vulnerability to stressors. The biological antecedents and etiology of frailty are unclear despite decades of research: frailty is associated with dysregulation in a wide range of physiological systems, but no specific cause has been identified. Here, we test predictions stemming from the hypothesis that there is no specific cause: that frailty is an emergent property arising from the complex systems dynamics of the broad loss of organismal homeostasis. Specifically, we use dysregulation of six physiological systems using the Mahalanobis distance approach in two cohorts of older adults to test the breadth, diffuseness, and nonlinearity of associations between frailty and system-specific dysregulation. We find clear support for the breadth of associations between frailty and physiological dysregulation: positive associations of all systems with frailty in at least some analyses. We find partial support for diffuseness: the number of systems or total amount of dysregulation is more important than the identity of the systems dysregulated, but results only partially replicate across cohorts. We find partial support for nonlinearity: trends are exponential but not always significantly so, and power is limited for groups with very high levels of dysregulation. Overall, results are consistent with - but not definitive proof of - frailty as an emergent property of complex systems dynamics. Substantial work remains to understand how frailty relates to underlying physiological dynamics across systems.

systems biology↗

bioRxiv2020

Construction, characterization, and immunization of nanoparticles that display a diverse array of influenza HA trimers

Current influenza vaccines do not elicit broadly protective immune responses against multiple strains. New strategies to focus the humoral immune response to conserved regions on influenza antigens are therefore required for recognition by broadly neutralizing antibodies. It has been suggested that B-cells with receptors that recognize conserved epitopes would be preferentially stimulated through avidity effects by mosaic particles presenting multiple forms of a variable antigen. We adapted SpyCatcher-based platforms, AP205 virus-like particles (VLPs) and mi3 nanoparticles (NPs), to covalently co-display SpyTagged hemagglutinin (HA) trimers from group 1 and group 2 influenza A strains. Here we show successful homotypic and heterotypic conjugation of up to 8 different HA trimers to both VLPs and NPs. We characterized the HA-VLPs and HA-NPs by cryo-electron tomography to derive the average number of conjugated HAs and their separation distances on particles, and compared immunizations of mosaic and homotypic particles in wild-type mice. Both types of HA particles elicited strong antibody responses, but the mosaic particles did not consistently elicit broader immune responses than mixtures of homotypic particles. We conclude that covalent attachment of HAs from currently-circulating influenza strains represents a viable alternative to current annual influenza vaccine strategies, but in the absence of further modifications, is unlikely to represent a method for making a universal influenza vaccine.

immunology↗

bioRxiv2018

Healthspan pathway maps in C. elegans and humans highlight transcription, prolifera-tion/biosynthesis and lipids

The molecular basis of aging and of aging-associated diseases is being unraveled at an increasing pace. An extended healthspan, and not merely an extension of lifespan, has become the aim of medical practice. However, a precise definition of health and healthspan is not straightforward, and the causal molecular basis of health \"per se\" is largely unknown. Here, we define health based on the absence of diseases and dysfunctions. Based on an extensive review of the literature, in particular for humans and C. elegans, we compile a list of features of health and of the genes associated with them. Clusters of these genes based on molecular interaction data give rise to maps of healthspan pathways for humans, featuring the themes transcription initiation, proliferation and cholesterol/lipid processing, and for C. elegans, featuring the themes immune response, mitochondrion and biosynthesis based on genetic and compound intervention data, and lipids, biosynthesis and transcription based on WormBase compound intervention data. Overlaying healthspan-related gene expression data (describing effects of metabolic intervention associated with improvements in health) onto the aforementioned healthspan pathway maps, we observe the downregulation of Notch signalling in humans and of proliferation/cell-cycle in C. elegans. The former reflects the proinflammatory role of the Notch pathway. We identify transcription, proliferation/biosynthesis and lipids as a common theme on the annotation level, and proliferation-related kinases on the gene/protein level. Our literature-based data corpus, including visualization, is available as a reference for future investigations, at http://www.h2020awe.eu/index.php/pathways/.

bioinformatics↗

bioRxiv2018

Physiological predictors of reproductive performance in the European Starling (Sturnus vulgaris): II. Multivariate Analysis

Physiological variation is generally thought or supposed to underlie variation in fitness related traits in wild animals, including reproductive effort, reproductive success, and survival. However, physiological markers of individual quality have proven elusive. In this paper and its companion, we use data on 14 physiological parameters measured in 152 observations of 93 individual European starlings (Sturnus vulgaris) over 2 years in an attempt to understand how physiological variation relates to variation in current breeding productivity, future fecundity, and survival. The companion paper, focusing on univariate analysis, showed that individual physiological parameters have little relationship with these performance measures. Here, we used more sophisticated statistical approaches in an attempt to extract a multivariate signal from the biomarkers - physiological dysregulation as calculated via statistical distance, and a number of principal components analysis approaches. Broadly speaking, there was a surprising lack of association between physiology and performance: while some physiological summary measures were associated with some performance measures, the associations were not particularly strong or robust given the large number of statistical tests conducted. This implies either that there are relatively few links between physiology and performance, or, more likely, that the complexity of these relationships exceeds our ability to measure and model it, even using state-of-the-art statistical approaches. This is likely particularly true because our population was quite heterogeneous; we nonetheless urge caution regarding the over-interpretation of isolated significant findings in the literature.

ecology↗

bioRxiv2018

Physiological predictors of reproductive performance in the European Starling (Sturnus vulgaris): I. Univariate analysis

Costs of reproduction are assumed to be widespread, and to have a physiological basis, but the mechanisms driving decreased survival and future fecundity remain elusive. Our overall goals were to assess whether physiological variables are related to workload ability or immediate fitness consequences and if they mediate future survival or reproductive success. We investigated individual variation in physiological state at two breeding stages (incubation, chick-rearing) in female European starlings (Sturnus vulgaris), for first-and second-broods over two years. Specifically, we measured a suite of 13 physiological traits related to aerobic/metabolic capacity, oxidative stress and muscle damage, intermediary metabolism and energy supply, and immune function. We tested for relationships to traits for workload (e.g. nest visit rate) and fitness (current reproduction, survival and future reproduction).\n\nThere was little co-variation among the 13 physiological traits, either in incubating or chick-rearing birds. There were some systematic differences in incubation versus chick-rearing physiology. Chick-rearing birds had lower hematocrit and plasma creatine kinase but higher hemoglobin, triglyceride and uric acid levels. Only plasma corticosterone was repeatable between incubation and chick-rearing. We assessed relationships in a univariate manner, and found very few significant relationships between incubation or chick-rearing physiology and measures of workload, current productivity, future fecundity or survival. Variability in ecological context may complicate the relationship between physiology and behavior. Additionally, individuals may regulate different aspects of their physiology independently, making detection of physiological mediators of cost of reproduction difficult. In a companion paper (Cohen et al. submitted) we explore the utility of multivariate analysis (Principal Components Analysis, Mahalanobis distance) of the same data to account for potentially complex physiological integration.

ecology↗

bioRxiv2017

Deep transcriptome annotation suggests that small and large proteins encoded in the same genes often cooperate

Recent studies in eukaryotes have demonstrated the translation of alternative open reading frames (altORFs) in addition to annotated protein coding sequences (CDSs). We show that a large number of small proteins could in fact be coded by altORFs. The putative alternative proteins translated from altORFs have orthologs in many species and evolutionary patterns indicate that altORFs are particularly constrained in CDSs that evolve slowly. Thousands of predicted alternative proteins are detected in proteomic datasets by reanalysis with a database containing predicted alternative proteins. Protein domains and co-conservation analyses suggest potential functional cooperation or shared function between small and large proteins encoded in the same genes. This is illustrated with specific examples, including altMID51, a 70 amino acid mitochondrial fission-promoting protein encoded in MiD51/Mief1/SMCR7L, a gene encoding an annotated protein promoting mitochondrial fission. Our results suggest that many coding genes code for more than one protein that are often functionally related.

biochemistry↗