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Results for “Physiology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 307 records · Page 17Linked to original sources

bioRxiv2022

Serine-129 phosphorylation of α-synuclein is a trigger for physiologic protein-protein interactions and synaptic function

Phosphorylation of -synuclein at the Serine-129 site (-syn Ser129P) is an established pathologic hallmark of synucleinopathies, and also a therapeutic target. In physiologic states, only a small fraction of total -syn is phosphorylated at this site, and consequently, almost all studies to date have focused on putative pathologic roles of this post-translational modification. We noticed that unlike native (total) -syn that is widely expressed throughout the brain, the overall pattern of -syn Ser129P is restricted, suggesting intrinsic regulation and putative physiologic roles. Surprisingly, preventing phosphorylation at the Ser-129 site blocked the ability of -syn to attenuate activity-dependent synaptic vesicle (SV) recycling - widely thought to reflect its normal function. Exploring mechanisms, we found that neuronal activity augments -syn Ser-129P, and this phosphorylation is required for -syn binding to VAMP2 and synapsin - two functional binding-partners that are necessary for -syn function. AlphaFold2-driven modeling suggests a scenario where Ser129P induces conformational changes in the C-terminus that stabilizes this region and facilitates protein-protein interactions. Our experiments indicate that the pathology-associated Ser129P is an unexpected physiologic trigger of -syn function, which has broad implications for pathophysiology and drug-development.

neuroscience↗

bioRxiv2023

Bioen-OSMOSE: A bioenergetic marine ecosystem model with physiological response to temperature and oxygen

O_LIMarine ecosystem models have been used to project the impacts of climate-induced changes in temperature and oxygen on biodiversity mainly through changes in species spatial distributions and primary production. However, fish populations may also respond to climatic pressures via physiological changes, leading to modifications in their life history that could either mitigate or worsen the consequences of climate change. C_LIO_LIBuilding on the individual-based multispecies ecosystem model OSMOSE, Bioen-OSMOSE has been developed to account for high trophic levels physiological responses to temperature and oxygen in future climate projections. This paper presents an overview of the Bioen-OSMOSE model, mainly detailing the new developments. These consist in the implementation of a bioenergetic sub-model that mechanistically describes somatic growth, sexual maturation and reproduction as they emerge from the energy fluxes sustained by food intake under the hypotheses of a biphasic growth model and plastic maturation age and size represented by a maturation reaction norm. These fluxes depend on temperature and oxygen concentration, thus allowing plastic physiological responses to climate change. C_LIO_LITo illustrate the capabilities of Bioen-OSMOSE to represent realistic ecosystem dynamics, the model is applied to the North Sea ecosystem. The model outputs are confronted with population biomass, catch, maturity ogive, mean size-at-age and diet data of each species of the fish community. A first exploration of current species spatial variability in response to temperature or oxygen is presented in this paper. The model succeeds in reproducing observations, with good performances for all indicators. C_LIO_LIThis new model development opens the scope for new fields of research such as the exploration of seasonal or spatial variation in life history in response to biotic and abiotic factors at the individual, population and community levels. Understanding such variability is crucial to improve our knowledge on potential climate change impacts on marine ecosystems and to make more reliable projections under climate change scenarios. C_LI

ecology↗

bioRxiv2023

Cooperation between physiological defenses and immune resistance produces asymptomatic carriage of a lethal bacterial pathogen

Animals have evolved two defense strategies to survive infections. Antagonistic strategies include mechanisms of immune resistance that operate to sense and kill invading pathogens. Cooperative or physiological defenses mediate host adaptation to the infected state, limiting physiological damage and disease, without killing the pathogen, and have been shown to cause asymptomatic carriage and transmission of lethal pathogens. Here we demonstrate that physiological defenses cooperate with the adaptive immune response to generate long-term asymptomatic carriage of the lethal enteric murine pathogen, Citrobacter rodentium. Asymptomatic carriage of genetically virulent C. rodentium provided immune resistance against subsequent infections. Host immune protection was dependent on systemic antibody responses and pathogen virulence behavior, rather than the recognition of specific virulent factor antigens. Finally, we demonstrate that an avirulent strain of C. rodentium in the field has background mutations in two genes that are important for LPS structure. Our work reveals novel insight into how asymptomatic infections can arise mechanistically with immune resistance, mediating exclusion of phenotypically virulent enteric pathogen to promote asymptomatic carriage.

immunology↗

bioRxiv2023

Investigating the roles of reflexes and central pattern generators in the control and modulation of human locomotion using a physiologically plausible neuromechanical model

Studying the neural components regulating movement in human locomotion is obstructed by the inability to perform invasive experimental recording. Neuromechanical simulations can provide insights by modeling the locomotor circuits. Past neuromechanical models proposed control of locomotion either driven by central pattern generators (CPGs) with simple sensory commands or by a purely reflex-based network regulated by state-machine mechanisms. However, the physiological interpretation of these state-machines remains unclear. Here, we present a physiologically plausible model to investigate spinal control and modulation of human locomotion. We propose a bio-inspired controller composed of two coupled central pattern generators (CPGs) that produce the rhythm and pattern and a reflex-based network simulating low-level reflex pathways and Renshaw cells. This reflex network is based on leaky-integration neurons, and the whole system does not rely on changing reflex gains according to the gait cycle state. The only component of the controller that maintains a state-machine mechanism is the balance controller of the trunk. The musculoskeletal model is composed of a skeletal structure and 9 muscles per leg generating movement in sagittal plane. After optimizing the open parameters, human locomotion replicating kinematics and muscle activation naturally emerged. Furthermore, when CPGs were not activated, no stable and physiologically plausible gaits could be achieved through optimization, suggesting the necessity of this component to generate rhythmic behavior without a state machine mechanism regulating reflex activation. The controller could reproduce a wide range of speeds from 0.3 to 1.9 m/s. The results also showed that the net influence of feedback on motoneurons during perturbed locomotion is predominantly inhibitory and that the CPG network provides the timing of motoneurons activation by exciting or inhibiting muscles in specific gait phases. The proposed bio-inspired controller could contribute to our understanding of locomotor circuits of the intact spinal cord and could be used to study neuromotor disorders.

neuroscience↗

bioRxiv2023

Housing conditions affect adult zebrafish (Danio rerio) behavior but not their physiological status

Zebrafish is a valuable model for neuroscience research, but the housing conditions to which it is daily exposed may be impairing its welfare status. The use of environmental enrichment and the refinement of methodology for cortisol measurement could reduce stress, improving its welfare and its suitability as an animal model used in stress research. Thus, this study aimed to evaluate (I) the influence of different housing conditions on zebrafish physiology and behavior and (II) skin mucus potential for cortisol measurement in adult zebrafish. For this, AB zebrafish were raised under barren or enriched (PVC pipes and gravel image) environmental conditions. After 6 months, the behavior was assessed by different behavioral paradigms (shoaling, white-black box test, and novel tank). The physiological response was also evaluated through cortisol levels (whole-body homogenates and skin mucus) and brain oxidative stress markers. Results revealed that enriched-housed fish had an increased nearest neighbors distance and reduced activity. However, no effect on body length or stress biomarkers was observed; whole-body and skin mucus cortisol levels had the same profile between groups. In conclusion, this study highlights the skin mucus potential as a matrix for cortisol quantification and how environmental enrichment could influence the data in future studies. Simple SummaryThe delivery of proper housing conditions may translate into good fish welfare. As zebrafish housing is usually poorly enriched, the fish could be unable to express some natural behaviors, leading to distress and/ or stress mechanisms dysregulation. This work focused on the examination of zebrafish welfare raised under different housing conditions (barren or environmentally enriched) and the testing of a low-invasive technique (skin mucus collection) to measure the main stress hormone (cortisol). The data was processed to assess body length, behavior, and physiological status. Results revealed that enrichment induced minor alterations on zebrafish behavior. Thus, the influence of housing conditions should be considered in future research, depending on the purpose of the study. Also, skin mucus appears to be a promising matrix to replace whole-body to measure cortisol in zebrafish, since its collection is nonlethal and showed similar results to the traditional method.

animal behavior and cognition↗

bioRxiv2023

Efflux pumps mediate changes to fundamental bacterial physiology via membrane potential

Efflux pumps are well known to be an important mechanism for removing noxious substances such as antibiotics from bacteria. Given that many antibiotics function by accumulating inside bacteria, efflux pumps contribute to resistance. Efflux pump inactivation is a potential strategy to combat antimicrobial resistance, as bacteria would not be able to pump out antibiotics. We recently discovered that the impact of loss of efflux function is only apparent in actively growing cells. We demonstrated that the global transcriptome of Salmonella Typhimurium is drastically altered during slower growth leading to stationary phase cells having a re-modelled, less permeable, envelope that prevents antibiotics entering the cell. Here, we investigated the effects of deleting the major efflux pump of Salmonella Typhimurium, AcrB, on global gene transcription across growth. We revealed that an acrB knockout entered stationary phase later than the wild type strain SL1344, and displayed increased and prolonged expression of genes responsible for anaerobic energy metabolism. We devised a model linking efflux and membrane potential, whereby deactivation of AcrB prevents influx of protons across the inner membrane and thereby hyperpolarisation. Knockout or deactivation of AcrB was demonstrated to increase membrane potential. We propose that the global transcription regulator ArcBA senses changes to the redox state of the quinol pool (linked to the membrane potential of the bacterium) and coordinates the shift from exponential to stationary phase via the key master regulators RpoS, Rsd, and Rmf. Inactivation of efflux pumps therefore influences the fundamental physiology of Salmonella, with likely impacts on multiple phenotypes. ImportanceWe demonstrate for the first time that deactivation of efflux pumps brings about changes to gross bacterial physiology and metabolism. Rather than simply being a response to noxious substances, efflux pumps appear to play a key role in maintenance of membrane potential and thereby energy metabolism. This discovery suggests that efflux pump inhibition or inactivation might have unforeseen positive consequences on antibiotic activity. Given that stationary phase bacteria are more resistant to antibiotic uptake, late entry into stationary phase would prolong antibiotic accumulation by bacteria. Furthermore, membrane hyperpolarisation could result in increased generation of reactive species proposed to be important for the activity of some antibiotics. Finally, changes in gross physiology could also explain the decreased virulence of efflux mutants.

microbiology↗

bioRxiv2023

The action of physiological and synthetic steroids on the calcium channel CatSper in human sperm

The sperm-specific channel CatSper (cation channel of sperm) controls the intracellular Ca2+ concentration ([Ca2+]i) and plays an essential role in sperm function. It is mainly activated by the steroid progesterone (P4) but is also promiscuously activated by a wide range of synthetic and physiological compounds. These compounds include diverse steroids whose action on the channel is so far still controversial. To investigate the effect of these compounds on CatSper and sperm function, we developed a high-throughput-screening (HTS) assay to measure changes in [Ca2+]i in human sperm and screened 1,280 approved and off-patent drugs including 90 steroids from the Prestwick chemical library. More than half of the steroids tested (53%) induced an increase in [Ca2+]i and reduced the P4-induced Ca2+ influx in human sperm in a dose-dependent manner. Ten of the most potent steroids (activating and inhibiting) were selected for a detailed analysis of their action on CatSper and their ability to act on sperm motility, acrosomal exocytosis (AR), and penetration in viscous media. We found that these steroids show an inhibitory effect on P4 but not on prostaglandin E1-induced CatSper activation, suggesting that they compete for the same binding site as P4. Pregnenolone, dydrogesterone, epiandrosterone, nandrolone, and dehydroepiandrosterone acetate (DHEA) were found to activate CatSper at physiological concentrations. Stanozolol, epiandrosterone, and pregnenolone induced AR similarly to P4, whereas stanozolol and estropipate induced an increase in sperm penetration into viscous medium. Furthermore, using a hybrid approach integrating pharmacophore analysis and statistical modelling, we were able to screen in silico for steroids that can activate the channel and define the physicochemical and structural properties required for a steroid to exhibit agonist activity against CatSper. Overall, our results indicate that not only physiological but also synthetic steroids can modulate the activity of CatSper with varying potency and affect human sperm functions in vitro.

cell biology↗

bioRxiv2023

The marine natural microbiome mediates physiological outcomes in host nematodes

Nematodes are the most abundant metazoans in marine sediments, many of which are bacterivores, however how habitat bacteria effects physiological outcomes in marine nematodes remains largely unknown. Here, we used a Litoditis marina inbred line to assess how native bacteria modulates host nematode physiology. We characterized seasonal dynamic bacterial compositions in L. marina habitats, and examined the impacts of 448 habitat bacteria isolates on L. marina development, then focused on HQbiome with 73 native bacteria, of which we generated 72 whole genomes sequences. Unexpectedly, we found that the effects of marine native bacteria on the development of L. marina and its terrestrial relative Caenorhabditis elegans were significantly positively correlated. Next, we reconstructed bacterial metabolic networks and identified several bacterial metabolic pathways positively correlated with L. marina development (e.g., ubiquinol and heme b biosynthesis), while pyridoxal 5-phosphate biosynthesis pathway was negatively associated. Through single metabolite supplementation, we verified CoQ10, heme b, Acetyl-CoA, and acetaldehyde promoted L. marina development, while vitamin B6 attenuated growth. Notably, we found that only four development correlated metabolic pathways were shared between L. marina and C. elegans. Furthermore, we identified two bacterial metabolic pathways correlated with L. marina lifespan, while a distinct one in C. elegans. Strikingly, we found that glycerol supplementation significantly extended L. marina but not C. elegans longevity. Moreover, we comparatively demonstrated the distinct gut microbiota characteristics and their effects on L. marina and C. elegans physiology. Our integrative approach will provide a microbe-nematodes framework for microbiome mediated effects on host animal fitness.

microbiology↗

bioRxiv2023

Physiological Responses of The Leaves of a High-Altitude Plant Picrorhiza kurroa to Cold Stress

There are various plants that grow in high elevations and experience various environmental stresses, cold stress being the most prevalent one. Plants undergo biochemical, metabolic, molecular, and physiological changes under cold stress hence, they adopt various mechanisms to tolerate it. The antioxidant defense system, osmotic regulators and photosynthetic pigments in the plant provide them stress tolerance. The present study is conducted on a high-altitude plant, Picrorhiza kurroa which grows in such environmental conditions, to study the physiological parameters that provides it the coping mechanism against the cold stress. For this study, the leaves were collected from Pothivasa (2200 m asl) and Tungnath (3600 m asl) in Rudraprayag, Uttarakhand, India. The photosynthetic pigments, lipid peroxidation, antioxidant enzymes, and osmoprotectants present in the leaves were determined to visualize the impact of cold stress. It was revealed that the concentration of chlorophyll a, chlorophyll b, and carotenoids increased with increase in elevation. The activity of SOD, CAT, POD, APOX and GR were analyzed and they were observed to decrease with altitude. The MDA concentration which is an indicator of lipid peroxidation is higher in Pothivasa (2.214 mol L-1) and lower in Tungnath (1.697 mol L-1). There is a significant increase in the total protein content, total soluble sugar content and total proline content along the altitudinal gradient. Therefore, the leaves from both the sampling locations revealed the physiological changes occurred in them to adapt to the cold stress conditions.

plant biology↗

bioRxiv2023

Prospecting is physiologically costly in a resident cooperative breeder, the Florida scrub-jay

Prospecting is an understudied yet pivotal information-gathering process often preceding natal dispersal. While prospecting may enable individuals to optimise dispersal outcomes and obtain high quality territories, it is also likely to incur costs stemming from energy expenditure and predation risks. This trade-off may drive individual differences in prospecting effort. We tested for evidence of costs of prospecting behaviour in a wild population of Florida scrub-jays, Aphelocoma coerulescens, which prospect as nonbreeding helpers. Using random sampling across all helpers, we compared prospecting effort--approximated by frequency, distance, and activity level--with body mass changes and oxidative stress levels. We tested if prospecting incurred costs and if early-life body condition predicted subsequent prospecting effort. Prospecting frequency was positively linked to oxidative damage but not to any loss in body mass during the breeding season, suggesting that extra-territorial movement costs manifest unevenly. Early-stage body condition did not affect subsequent prospecting effort across a large set of helpers, but early-stage body condition and morphometric measures did correlate with subsequent oxidative status of those sampled. Our results suggest that prospecting movement carries some physiological costs, perhaps contributing to individual differences in prospecting. This research highlights how body condition plays a role in trade-offs between information gathering movement and physiological costs of movement itself, ultimately providing insight on the evolution of prospecting in social species. HIGHLIGHTSO_LIProspecting prior to breeding enables informed dispersal but incurs cost C_LIO_LIWe tested whether prospecting by nonbreeding Florida scrub-jays results in physiological costs or varies with initial condition C_LIO_LIWe measured oxidative status using assays testing antioxidant capacity and oxidative damage C_LIO_LIFrequent prospecting was linked to subsequent oxidative damage C_LIO_LIEarly-stage body condition and wing length affected subsequent oxidative status C_LI

ecology↗

bioRxiv2023

Systems Age: A single blood methylation test to quantify aging heterogeneity across 11 physiological systems

Individuals, organs, tissues, and cells age in diverse ways throughout the lifespan. Epigenetic clocks attempt to quantify differential aging between individuals, but they typically summarize aging as a single measure, ignoring within-person heterogeneity. Our aim was to develop novel systems-based methylation clocks that, when assessed in blood, capture aging in distinct physiological systems. We combined supervised and unsupervised machine learning methods to link DNA methylation, system-specific clinical chemistry and functional measures, and mortality risk. This yielded a panel of 11 system-specific scores- Heart, Lung, Kidney, Liver, Brain, Immune, Inflammatory, Blood, Musculoskeletal, Hormone, and Metabolic. Each system score predicted a wide variety of outcomes, aging phenotypes, and conditions specific to the respective system. We also combined the system scores into a composite Systems Age clock that is predictive of aging across physiological systems in an unbiased manner. Finally, we showed that the system scores clustered individuals into unique aging subtypes that had different patterns of age-related disease and decline. Overall, our biological systems based epigenetic framework captures aging in multiple physiological systems using a single blood draw and assay and may inform the development of more personalized clinical approaches for improving age-related quality of life.

systems biology↗

bioRxiv2023

Bacterial communities in residential wastewater treatment plants are physiologically adapted to high concentrations of quaternary ammonium compounds

Benzalkonium chloride (BAC) is a quaternary ammonium compound (QAC) widely used as the active ingredient of disinfectants. Its excessive discharge in wastewater is constant and in high concentrations, likely affecting the physiology of microbial communities. We compared the community physiological profile of activated sludge bacteria with and without in vitro previous exposure to a high concentration of BAC (10 mg/L). We measured the community functional diversity (FD), carbon substrate multifunctionality (MF), and the median effective concentration that inhibits carbon respiration (EC50) using Biolog(R) EcoPlatesTM supplemented with a gradient of 0 to 50 mg/L of BAC. Surprisingly, we did not find significant differences in the physiological parameters between treatments. Certain abundant bacteria, including Pseudomonas, could explain the communitys tolerance to high concentrations of BAC. We suggest that bacterial communities in wastewater treatment facilities activated sludge (AS) are "naturally" adapted to BAC due to frequent and high-dose exposure. We highlight the need to understand better the effects of QACs in wastewater, their impact on the selection of tolerant groups, and the alteration in community metabolic profiles.

microbiology↗

bioRxiv2023

UPRER-immunity axis acts as physiological food evaluation system that promotes aversion behavior in sensing low-quality food

To survive in challenging environments, animals must develop a system to assess food quality and adjust their feeding behavior accordingly. However, the mechanisms that regulate this chronic physiological food evaluation system, which monitors specific nutrients from ingested food and influences food-response behavior, are still not fully understood. Here, we established a low-quality food evaluation assay system and found that heat-killed E. coli (HK-E. coli), a low sugar food, triggers cellular UPRER and immune response. This encourages animals to avoid low-quality food. The physiological system for evaluating low-quality food depends on the UPRER (IRE-1/XBP-1) - Innate immunity (PMK-1/p38 MAPK) axis, particularly its neuronal function, which subsequently regulates feeding behaviors. Moreover, animals can adapt to a low-quality food environment through sugar supplementation, which inhibits the UPRER -PMK-1 regulated stress response by increasing vitamin C biosynthesis. This study reveals the role of the cellular stress response pathway as physiological food evaluation system for assessing nutritional deficiencies in food, thereby enhancing survival in natural environments.

developmental biology↗

bioRxiv2023

The physiological costs of spatial positioning and leadership in collective movements

Individuals can gain substantial benefits from collective actions1-7. However, collective behaviours introduce new challenges, like coordinating actions, maintaining cohesion, and meeting the needs of different individuals. When making collective movements, leaders are typically thought to gain disproportionate benefits through the choice of more beneficial resources3 and/or earlier access to resources8. However, reaping these benefits can also have costs. Being at the front of a group can increase physical exertion4,9,10 and predation risk11,12. Moreover, ending up in a leadership position (i.e., at the front), is a process of negotiation in many animal groups. Within-group differences in directional preferences are typically resolved by some individuals initiating directional movements, after which they are either followed (if they are successful in leading) or return to the group (if they fail)13-30. By combining data on movement initiations (using whole-group GPS tracking31 and individual heart rate from implanted ECG loggers) in wild vulturine guineafowl, we found significant increases in heart rate (and decreases in heart rate variability) during collective movements. We found that attempting--and failing--to initiate directional movement was particularly costly, with the highest costs when consensus among group members was low and when individuals acted against the majority. Increases in heart rate and decreases in its variability can indicate physiological stress, entailing increased energy expenditure and long-term physiological damage. These results suggest that behaviours often thought beneficial to individuals (by influencing group behaviours) are also physiologically costly, representing a constraint on group-living and explaining why sometimes individuals opt out of contributing to leadership.

ecology↗

bioRxiv2023

Novel rapid high-throughput method of NETosis Induction and Inhibition with physiological triggers and inhibitors

Neutrophils, the most abundant white blood cells in humans, play pivotal roles in innate immunity, rapidly migrating to sites of infection and inflammation to phagocytose, neutralize, and eliminate invading pathogens. Neutrophil Extracellular Trap (NET) formation in response to pathogens is increasingly recognized as an essential rapid innate immune response, but when dysregulated contributes to pathogenesis of sepsis and immunothrombotic disease. Current models of NETosis are limited, routinely employing non-physiological triggers that can bypass natural NET regulatory pathways. Models utilizing isolated neutrophils and immortalized cell lines, do not reflect the complex biology underlying neutrophil activation and NETosis, that occurs in whole-blood. Here we describe a novel, high-throughput ex-vivo whole blood induced NETosis model using combinatorial pooling of native NETosis inducing factors in a more biologically relevant Synthetic-Sepsis model. We found different combinations of factors evoked distinct neutrophil responses in the rate of NET generation and/or magnitude of NETosis. Despite inter-donor variability, similar sets of pro-inflammatory molecules induced consistent responses across donors. We found at least three biological triggers were necessary to induce NETosis in our system including either TNF- or LT-. To our knowledge, we report the first human ex-vivo model utilizing naturally occurring molecules to induce NETosis in whole blood. This approach could be used for drug screening and, importantly, inadvertent activators of NETosis. These findings emphasize the importance of investigating neutrophil physiology in a biologically relevant context to enable a better understanding of disease pathology, risk factors, and therapeutic targets, potentially, providing novel strategies for disease intervention and treatment. EssentialsO_LINETosis is a vital immune response, but dysregulation leads to disastrous health outcomes. C_LIO_LICurrent NETosis models dont reflect the complex endogenous signaling that occurs in whole blood C_LIO_LINetosis induction stimuli differs between isolated neutrophils and whole blood. C_LIO_LIA minimum of three physiological factors are required to induce NETosis in whole blood. C_LI

immunology↗

bioRxiv2023

Physiological constraints limiting the growth of Drosophila larvae

The phenotype of organisms is the result of complex interactions between physiology, developmental conditions, and intra-organismic processes, such as metabolism and genetic adaptation. Organisms pursue various developmental strategies that depend on factors such as available resources. How organisms regulate and control critical developmental principles is not fully understood. In this study, we investigated the dynamic development of Drosophila melanogaster larvae through in vitro and in silico experiments. First, we enhanced the larval metabolic network FlySilico and its parameters using growth and metabolite measurements. Subsequently, we established a dynamic flux balance analysis approach and incorporated spatial physiological information from the larval gut to improve the prediction results. We successfully predicted larval growth on different media and developmental critical processes, such as the emergence of larval metamorphosis. This expands the ability to investigate and understand the process of the larval critical weight and, furthermore, the influence of critical developmental processes of multicellular organisms on metabolism. Thus, we present an approach to understand the development, metabolism, and the role of physiology in the development of multicellular organisms. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=177 HEIGHT=200 SRC="FIGDIR/small/572459v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@ad726corg.highwire.dtl.DTLVardef@1334d52org.highwire.dtl.DTLVardef@1197e9aorg.highwire.dtl.DTLVardef@c6ef99_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

Single-cell RNA-seq analysis profiling characterizes differences in cell composition and physiology between normal tissue, treatment-naive, and cisplatin-treated ovarian cancer

BackgroundIntense efforts have focused on identifying heterogeneity of the cellular composition in ovarian cancer. However, tissue composition and physiological conditions of cancer cells in cisplatin-sensitive ovarian cancer remains largely unknown. Moreover, comparisons of different cellular states in normal tissue, in treatment naive ovarian cancer, and in cisplatin-treated tissue after adjuvant therapy of cisplatin-sensitive ovarian cancer at the single-cell level might offer clues for ovarian cancer treatment and prevention of cisplatin-resistance formation. MethodsSingle-cell transcriptome sequencing of a cisplatin-treated ovarian cancer was performed. Data sets of non-tumorous ovarian tissues and treatment-naive ovarian cancer were downloaded from the European Genome-phenome Archive (accession number EGAS00001004987). Quality control, batch effect correction, integration, and clustering analysis of the integrated single-cell transcriptome data was done. Cell subsets were annotated based on surface marker phenotypes. Finally, the proportions of subclusters, the immune cell population, and the potential biological processes among different cellular states were compared. ResultsSixteen distinct cell subsets were identified from the integrated single-cell transcriptome sequencing data of a pool of all tissues. The composition of the three different tissue types was characterized. The proportion of fibroblasts in cisplatin-treated ovarian tumor was remarkably lower than in treatment-naive ovarian tumor (1.33% vs. 13.53%, p < 0.05). Moreover, each subjects sample had differing relative proportions of the identified cell types. In primary untreated ovarian cancer, the prevalent immune cells were B cells and myeloid-related immunosuppressive M2 macrophages. However, there were less B cells and myeloid-related immunosuppressive M2 macrophages after cisplatin-treatment, while significantly more T cells were found. The physiological cellular state in primary untreated ovarian tumors was associated with dysfunctional gene expression and modulation of cellular homeostasis, while cells from cisplatin-treated tumor showed more activation of immune and inflammatory genes as compared to healthy ovarian tissue. ConclusionOur molecular gene expression analysis allowed for the separation and identification of differences in normal ovarian tissues, treatment-naive, and cisplatin-sensitive ovarian cancer cell populations at single-cell resolution. We identified different cell type composition and discriminative marker expression concerning specific cell subsets and identified differences among their physiological cell states. This knowledge may open new possibilities for elucidating important pathogenetic features and therapeutic strategies for treating ovarian cancer.

cancer biology↗

bioRxiv2024

Molecular, physiological and functional features underlying cortical thinning related to antipsychotic medication use

Use of antipsychotic medication is related to thinning of the cerebral cortex, but the underlying mechanisms of this effect remain largely unknown. Here, we investigated potential mechanisms across multiple levels of description, from molecular and physiological factors to whole-brain functional patterns. We first analyzed a single site discovery sample of patients (N=131) with early psychosis for whom antipsychotic related cortical thinning was estimated based on lifetime exposure to antipsychotics. Findings were replicated using data from a large (N[≥]2168) ENIGMA meta-analysis. We discovered that antipsychotic related cortical thinning is associated with a number of neurotransmitter systems, most notably the serotonin system, physiological measures, and functional networks and neural oscillatory power distributions typical for regions subserving higher cognition. At the functional level, antipsychotic related cortical thinning affects regions involved in executive function and motivation, but not perception. These results show how molecular, physiological, and large-scale functional patterns underlie antipsychotic related cortical thinning.

neuroscience↗