Biology subjects

Murphy, C.

Publications and source records attributed to Murphy, C..

At least 19 recordsLinked to original sources

bioRxiv2026

Inflammasome Activation and IL-1β Release in Alveolar Macrophages Infected with Pseudomonas aeruginosa is Reduced in Hypoxia

Pseudomonas aeruginosa is an important agent of acute or chronic airway infections. A complex set of genetic and environmental factors determine the outcome of a P. aeruginosa airway infection. P. aeruginosa can undergo genetic adaptation to fine tune the expression of a type III secretion system (T3SS) and other virulence factors in response to selective pressures encountered during infection. Genetic and environmental factors predispose many patient groups for P. aeruginosa infections, including people with cystic fibrosis (pwCF). CF is a genetic disorder resulting in areas of hypoxia and thick mucus that fosters P. aeruginosa airway infection. Resident alveolar macrophages (AMs) help coordinate immune responses to P. aeruginosa in airways by producing proinflammatory cytokines such as IL-1{beta}, which can be important for infection resistance. AMs infected with laboratory strains of P. aeruginosa detect the T3SS and activate the NLRC4 inflammasome, resulting in IL-1{beta} release. Studies of inflammasome responses in AMs to a clinical CF isolate of P. aeruginosa have not been reported. Here, we characterized the CF clinical isolate DH1137 and found that it has a downregulated but functional T3SS, is adapted to grow in hypoxia, and induces significant production of the inflammasome cytokines IL-1{beta} and IL-1 during lung infection in a CF mouse model. Inflammasome gene expression was primed in AMs by LPS stimulation, and upon DH1137 infection these cells released IL-1[beta]. Intriguingly, we found that infection of AMs with DH1137 in hypoxia resulted in significantly dampened inflammasome activation compared to normoxia. These data describe a new mechanism that P. aeruginosa may exploit to evade immune detection by tissue-resident lung macrophages in the context of CF.

immunology↗

bioRxiv2026

Computationally guided design of a metastasis-on-a-chip platform for quantitative evaluation of chemotactic cues in developmental cancers

Metastatic dissemination is initiated by tumor cells interpreting spatially organized biochemical and biophysical cues that remain difficult to reproduce using conventional migration assays. Here, we developed a computationally guided metastasis-on-a-chip (MET-on-a-chip) platform based on the concept of the Minimally Functional Unit (MFU), in which only the biological components required to answer a defined experimental question are incorporated. The platform consists of two independent culture chambers connected through an array of confined microchannels that permits diffusion of soluble factors while constraining tumor cell migration. Rather than relying on empirical optimization, finite-element COMSOL simulations were first used to predict molecular transport, define growth factor loading conditions, identify biologically relevant exposure regions, and guide the rational design of the microfluidic assay. Computational predictions were experimentally validated using 70-kDa FITC-dextran diffusion and VEGF release studies, confirming the formation of stable spatial concentration gradients across the microfluidic platform. The simulations further demonstrated that both growth factor loading and cell positioning relative to the predicted gradients critically influenced assay performance, leading to the optimization of the platform through spatial reconfiguration of the tumor compartment. Using the optimized configuration, we compared the migratory responses of neuroblastoma, Ewing sarcoma, and osteosarcoma cells to vascular (VEGF-A165) and lymphatic (VEGF-C) chemotactic cues. VEGF-C significantly increased migration through the microchannel array in Ewing sarcoma and osteosarcoma cells, whereas VEGF-A165 produced no significant effect. In contrast, neuroblastoma cells exhibited minimal migration under either condition, revealing tumor-specific differences in responsiveness to VEGF signaling. Together, these findings establish a computationally guided workflow for the rational design of metastasis-on-a-chip assays, in which predictive modeling informs experimental design before biological validation. By substantially reducing empirical trial-and-error while enabling quantitative control over growth factor exposure, this strategy provides a robust framework for developing minimally functional microphysiological systems capable of dissecting individual steps of the metastatic cascade under experimentally defined conditions. Translational Impact StatementMetastatic dissemination remains one of the greatest clinical challenges in pediatric oncology, yet experimental models capable of quantitatively evaluating early migratory events remain limited. The computationally guided MET-on-a-Chip workflow presented here provides a human-relevant platform in which soluble microenvironmental cues can be systematically investigated under controlled and predictive conditions. Although demonstrated here using VEGF-A165 and VEGF-C, the platform can be readily adapted to study virtually any chemotactic factor, cytokine, extracellular vesicle population, or therapeutic candidate involved in metastatic dissemination. The modular MFU design allows biological complexity to be incorporated progressively as dictated by the scientific question, providing a flexible framework for future applications. In the longer term, this workflow could be combined with patient-derived tumor cells, organoids, or biopsy material to investigate patient-specific metastatic behavior and evaluate anti-metastatic therapeutic strategies in a personalized setting. Beyond identifying pro-migratory signaling pathways, the platform may serve as a preclinical tool to prioritize compounds capable of preventing tumor cell dissemination before evaluation in more complex animal models or clinical studies.

bioengineering↗

bioRxiv2026

Acute Paternal Immune Activation Shapes Embryonic Development and Protects Offspring from Viral Infection

The evolutionary arms race between host and pathogen is traditionally framed as a multigenerational paradigm, where beneficial host immune adaptations accrue in a population over time through DNA sequence variation. If pathogens exposure alters epigenetic information inherited by offspring through paternal gametes, advantageous immune traits could emerge within a single generation. We show that acute paternal immune activation (PIA) induces immune signaling in the male reproductive tract and remodels the sperm small RNA profile. Using IVF, we show that altered sperm small RNAs from immune-activated males reprograms gene expression in preimplantation embryos, eliciting sex-specific transcriptional responses. This transcriptional program is reflected in a striking inherited phenotype, as male offspring sired by PIA males exhibit enhanced survival following lethal viral challenge. These findings identify sperm small RNAs as a molecular mechanism that links PIA to embryonic development and offspring immunity, providing a comprehensive framework for how PIA shapes inherited pathogen protection.

immunology↗

bioRxiv2025

Human non-canonical inflammasomes activate CASP3 to limit intracellular Salmonella replication in macrophages.

Inflammasomes are multiprotein signaling platforms that activate inflammatory caspases to initiate innate immune signaling. In humans, canonical inflammasomes activate CASP1, which cleaves the pore-forming protein gasdermin D (GSDMD) and the cytokines IL-1{beta} and IL-18. In contrast, the non-canonical inflammasome detects bacterial lipopolysaccharide (LPS) through CASP4/5, which cleave GSDMD to drive pyroptosis. While CASP1 substrates are well characterized, CASP4/5 substrates remain less defined. Here, we show that in response to intracellular LPS and gram-negative bacterial infection, CASP4/5 directly cleave and activate the executioner caspases CASP3/7. CASP3 in turn cleaves and activates gasdermin E (GSDME). Surprisingly, CASP3, but not GSDME, was required for restricting intracellular Salmonella replication, suggesting that CASP4/5-induced apoptosis contributes to host defense. We further show that most GSDMD cleavage during non-canonical inflammasome activation is mediated by CASP1, and that GSDMD is the primary driver of pyroptosis. Finally, we confirm that CASP4/5 activate CASP3/7 and GSDME in human primary macrophages. These findings establish CASP4/5 as dual apoptotic initiator and inflammatory caspases and reveal a central role for the apoptotic signaling cascade in non-canonical inflammasome-mediated immunity.

cell biology↗

bioRxiv2025

Neuronal SET1/COMPASS-mediated epigenetic regulation of de novo transcription drives accelerated forgetting with age

Forgetting is a critical component of memory, but its molecular regulation - particularly with age - is not well understood. Epigenetic modifications are a candidate for this regulation and may further drive age-related behavioral decline, as they are dramatically altered in the aging brain. We found that multiple components of the SET1/COMPASS complex, a conserved histone methyltransferase complex associated with active gene transcription, are upregulated with age in the C. elegans nervous system. Neuronal knockdown of the SET1/COMPASS components improves memory in young adult animals and slows memory decline in old animals. By pharmacological and genetic inhibition, optogenetics, and neuronal mRNA and chromatin profiling, we demonstrate that SET1/COMPASS-mediated active transcription promotes forgetting. SET1/COMPASS regulates the de novo activity-dependent transcription and release of a neuropeptidergic signal from the AWC olfactory sensory neuron, which erases the associative memory trace in downstream motor neurons, resulting in forgetting. We further found that increased SET1/COMPASS-dependent chromatin accessibility at these gene loci with age primes these loci for transcription, resulting in accelerated forgetting. Our results reveal the role of active gene transcription in the regulation of forgetting and altered SET1/COMPASS-mediated gene transcription as a mechanism of cognitive decline, implicating increased expression of COMPASS components as a driver of increased forgetting in the aging brain. This mechanism may offer a new target for slowing loss of cognitive function with age.

neuroscience↗

bioRxiv2024

Single-Nucleus Neuronal Transcriptional Profiling of Male C. elegans Uncovers Regulators of Sex-Specific and Sex-Shared Behaviors

Sexual differentiation of the nervous system drives profound neurobiological and behavioral differences between the sexes across various organisms, including Caenorhabditis elegans. Using single-nucleus RNA sequencing, we profiled and compared adult male and hermaphrodite C. elegans neurons, generating an atlas of adult male-specific and sex-shared neurons. We expanded the molecular map of male-specific neurons, and identified highly dimorphic expression of GPCRs, neuropeptides, and ion channels. Our data demonstrate sex-shared neurons exhibit substantial heterogeneity between the sexes, while sex-specific neurons repurpose conserved molecular pathways to regulate dimorphic behaviors. We show that the PHD neurons display remarkable similarity to sex-shared AWA neurons, suggesting partial repurposing of conserved pathways, and that they and the GPCR SRT-18 may play a role in pheromone sensing. We further demonstrate that the ubiquitously expressed MAPK phosphatase vhp-1 regulates both sex-specific and sex-shared behaviors. Our data provide a rich resource for discovering sex-specific transcriptomic differences and the molecular basis of sex-specific behaviors.

neuroscience↗

bioRxiv2024

Absence of Evidence is Not Evidence of Absence: The many flaws in the case against transgenerational epigenetic inheritance of pathogen avoidance in C. elegans

After examining the data and methods presented in Gainey, et al., bioRxiv, 20241 we conclude that the authors did not use an experimental paradigm that would have allowed them to replicate our results on transgenerational epigenetic inheritance (TEI) of learned avoidance that we regularly observe2-5. That is, we agree with the authors that their experiments show no evidence of TEI. However, there are substantial differences in their execution of every step of the work that also make it impossible for the authors to claim that they are replicating our experiments or protocols. Based on these differences, we do not believe there is an issue of "robustness" and "reliability" in our TEI findings, but rather that Hunter and colleagues have in fact not tested the central condition of TEI - that is, small RNA production by bacteria and subsequent uptake by C. elegans - nor have they carried out proper behavioral and imaging assays to assess this behavior. Our subsequent work shows that indeed this example of transgenerational epigenetic inheritance is not just observed in laboratory settings with PA14, but is also induced by wild strains of Pseudomonas, exhibiting its robustness. Just as we offered advice and training to Hunter and colleagues, we are happy to advise anyone who wishes to learn this assay. We have now performed the experiments in the absence of azide, a deviation from our protocol that Hunter and colleagues deliberately made, and found that this omission may account for most if not all of the differences from our results. It is disingenuous for the authors to have presented their work as if they have used our protocol, given the fact that they chose to not use the same conditions for the most basic assay used in the work, the chemotaxis assay, which would have been necessary to replicate in order to reproduce our work. Therefore, Gainey et al.s claims that our protocol or results are "irreproducible" are not supported by their evidence.

genetics↗

bioRxiv2024

Pseudomonas fluorescens 15 small RNA Pfs1 mediates transgenerational epigenetic inheritance of pathogen avoidance in C. elegans through the Ephrin receptor VAB-1

C. elegans are exposed to a variety of pathogenic and non-pathogenic bacteria species in their natural environment. Correspondingly, C. elegans has evolved an ability to discern between nutritive and infectious bacterial food sources. Here we show that C. elegans can learn to avoid the pathogenic bacteria Pseudomonas fluorescens 15 (PF15), and that this learned avoidance behavior is passed on to progeny for four generations, as we previously demonstrated for Pseudomonas aeruginosa (PA14) and Pseudomonas vranovensis, using similar mechanisms, including the involvement of both the TGF-{beta} ligand DAF-7 and Cer1 retrotransposon-encoded virus-like particles. PF15 small RNAs are both necessary and sufficient to induce this transgenerational avoidance behavior. Unlike PA14 or P. vranovensis, PF15 does not use P11, Pv1, or a small RNA with maco-1 homology for this avoidance; instead, an unrelated PF15 small RNA, Pfs1, that targets the C. elegans vab-1 Ephrin receptor gene is necessary and sufficient for learned avoidance, suggesting the evolution of yet another bacterial sRNA/C. elegans gene target pair involved in transgenerational inheritance of pathogen avoidance. As VAB-2 Ephrin receptor ligand and MACO-1 knockdown also induce PF15 avoidance, we have begun to understand the genetic pathway involved in small RNA targeted pathogenic avoidance. Moreover, these data show that axon guidance pathway genes (VAB-1 and VAB-2) have previously unknown adult roles in regulating neuronal function. C. elegans may have evolved multiple bacterial specificity-encoded small RNA-dependent mechanisms to avoid different pathogenic bacteria species, thereby providing progeny with a survival advantage in a dynamic environment.

genetics↗

bioRxiv2024

Completion of the DrugMatrix Toxicogenomics Database using ToxCompl

The DrugMatrix Database contains systematically generated toxicogenomics data from short-term in vivo studies for over 600 chemicals. However, most of the potential endpoints in the database are missing due to a lack of experimental measurements. We present our study on leveraging matrix factorization and machine learning methods to predict the missing values in the DrugMatrix, which includes gene expression across eight tissues on two expression platforms along with paired clinical chemistry, hematology, and histopathology measurements. One major challenge we encounter is the skewed distribution of the available measured data, in terms of both tissue sources and values. We propose a method, ToxiCompl, that applies systematic hybrid sampling guided by Bayesian optimization in conjunction with low-rank matrix factorization to recover the missing values. ToxiCompl achieves good training and validation performance from a machine learning perspective. We further conduct an in-depth validation of the predicted data from biological and toxicological perspectives with a series of analyses. These include examining the connectivity pattern of predicted gene expression responses, characterizing molecular pathway-level responses from sets of differentially expressed genes, evaluating known transcriptional biomarkers of tissue toxicity, and characterizing pre-dicted apical endpoints. Our analysis shows that the predicted differential gene expression, broadly speaking, aligns with what would be anticipated. For example, in most instances, our predicted differentially expressed gene lists offer a connectivity level comparable to that of measured data in connectivity analysis. Using Havcr1, a known transcriptional biomarker of kidney injury, we identify treatments that, based on the predicted expression data, manifest kidney toxicity in a manner that is mechanistically plausible and supported by the literature. Characterization of the predicted clinical chemistry data suggests that strong effects are relatively reliably predicted, while more subtle effects pose a greater challenge. In the case of histopathological prediction, we find a significant overprediction due to positivity bias in the measured data. Developing methods to deal with this bias is one of the areas we plan to target for future improvement. The main advantage of the ToxiCompl approach is that, in the absence of additional experimental data, it drastically extends the toxicogenomic landscape into a number of data-poor tissues, thereby allowing researchers to formulate mechanistic hypotheses about effects in tissues that have been underrepresented in the literature. All measured and predicted DrugMatrix data (i.e., gene expression, clinical chemistry, hematology, and histopathology) are available to the public through an intuitive GUI interface that allows for data retrieval, gene set analysis and high dimensional visualization of gene expression similarity (https://rstudio.niehs.nih.gov/complete_drugmatrix/).

genomics↗

bioRxiv2024

Adult Single-nucleus Neuronal Transcriptomes of Insulin Signaling Mutants Reveal Regulators of Behavior and Learning

The insulin/insulin-like signaling (IIS) pathway regulates many of C. elegans adult functions, including learning and memory1. While whole-worm and tissue-specific transcriptomic analyses have identified IIS targets2,3, a higher-resolution single-cell approach is required to identify changes that confer neuron-specific improvements in the long-lived insulin receptor mutant, daf-2. To understand how behaviors that are controlled by a small number of neurons change in daf-2 mutants, we used the deep resolution of single-nucleus RNA sequencing to define each neuron types transcriptome in adult wild-type and daf-2 mutants. First, we found surprising differences between wild-type L4 larval neurons and young adult neurons in chemoreceptor expression, synaptic genes, and learning and memory genes. These Day 1 adult neuron transcriptomes allowed us to identify adult AWC-specific regulators of chemosensory function and to predict neuron-to-neuron peptide/receptor pairs. We then identified gene expression changes that correlate with daf-2s improved cognitive functions, particularly in the AWC sensory neuron that controls learning and associative memory4, and used behavioral assays to test their roles in cognitive function. Combining deep single-neuron transcriptomics, genetic manipulation, and behavioral analyses enabled us to identify genes that may function in a single adult neuron to control behavior, including conserved genes that function in learning and memory. One-Sentence SummarySingle-nucleus sequencing of adult wild-type and daf-2 C. elegans neurons reveals functionally relevant transcriptional changes, including regulators of chemosensation, learning, and memory.

neuroscience↗

bioRxiv2023

P. aeruginosa controls both C. elegans attraction and pathogenesis by regulating nitrogen assimilation

Detecting chemical signals is important for identifying food sources and avoiding harmful agents. Like most animals, C. elegans use olfaction to chemotax towards their main food source, bacteria. However, little is known about the bacterial compounds governing C. elegans attraction to bacteria and the physiological importance of these compounds to bacteria. Here, we address these questions by investigating the function of a small RNA, P11, in the pathogen, Pseudomonas aeruginosa, that was previously shown to mediate learned pathogen avoidance. We discovered that this RNA also affects the attraction of untrained C. elegans to P. aeruginosa and does so by controlling production of ammonia, a volatile odorant produced during nitrogen assimilation. We untangle the complex regulation of P. aeruginosa nitrogen assimilation, which is mediated by a partner-switching mechanism involving environmental nitrates, sensor proteins, and P11. In addition to mediating C. elegans attraction, nitrogen assimilation is important for bacterial fitness and pathogenesis during C. elegans infection by P. aeruginosa. These studies define ammonia as a major mediator of trans-kingdom signaling, reveal the physiological importance of nitrogen assimilation for both bacteria and host organisms, and highlight how a bacterial metabolic pathway can either benefit or harm a host in different contexts.

microbiology↗

bioRxiv2023

Defining metabolic flexibility in hair follicle stem cell induced squamous cell carcinoma

Among the numerous changes associated with the transformation to cancer, cellular metabolism is one of the first discovered and most prominent[1, 2]. However, despite the knowledge that nearly every cancer is associated with the strong upregulation of various metabolic pathways, there has yet to be much clinical progress on the treatment of cancer by targeting a single metabolic enzyme directly[3-6]. We previously showed that inhibition of glycolysis through lactate dehydrogenase (LDHA) deletion in cancer cells of origin had no effect on the initiation or progression of cutaneous squamous cell carcinoma[7], suggesting that these cancers are metabolically flexible enough to produce the necessary metabolites required for sustained growth in the absence of glycolysis. Here we focused on glutaminolysis, another metabolic pathway frequently implicated as important for tumorigenesis in correlative studies. We genetically blocked glutaminolysis through glutaminase (GLS) deletion in cancer cells of origin, and found that this had little effect on tumorigenesis, similar to what we previously showed for blocking glycolysis. Tumors with genetic deletion of glutaminolysis instead upregulated lactate consumption and utilization for the TCA cycle, providing further evidence of metabolic flexibility. We also found that the metabolic flexibility observed upon inhibition of glycolysis or glutaminolysis is due to post-transcriptional changes in the levels of plasma membrane lactate and glutamine transporters. To define the limits of metabolic flexibility in cancer initiating hair follicle stem cells, we genetically blocked both glycolysis and glutaminolysis simultaneously and found that frank carcinoma was not compatible with abrogation of both of these carbon utilization pathways. These data point towards metabolic flexibility mediated by regulation of nutrient consumption, and suggest that treatment of cancer through metabolic manipulation will require multiple interventions on distinct pathways.

cancer biology↗

bioRxiv2023

Extracellular vesicles, syntaxin 2 and SNAP23 collectively play a role in the receptive uterine microenvironment

Uterine luminal fluid (ULF) composition plays a major role in cell-to-cell communication between the receptive endometrium and an invading blastocyst. ULF is made up of secretions from the uterine glands and uterine epithelial cells (UEC). However, the cellular mechanisms regulating these exocytotic secretions are not yet understood. This study investigated the role of extracellular vesicles (EVs) during early pregnancy using Transmission Electron Microscopy (TEM). TEM analysis at time of fertilisation (TOF) Day 1 and at time of receptivity (TOR) Day 5.5 revealed EVs present, with an abundance at TOR. Exocytosis signalling in UECs, by SNARE proteins syntaxin 2 (syn2) and SNAP23, was also examined. Immunofluorescence microscopy showed both syn2 and SNAP23 to be present in the apical area of UECs at TOR. Western blot and immunofluorescence quantification revealed a significant increase in syn2 and SNAP23 at TOR compared to TOF. SNAP23 colocalization with apical actin showed SNAP23 was in the luminal space contributing to ULF. Overall, this data shows EVs, syn2 and SNAP23 (potential receptivity marker) are present in ULF and may together create a favourable microenvironment for blastocyst implantation. Summary statementDuring uterine receptivity SNAREs participate in the secretion of ULF. EVs and SNAP23 are present in the uterine luminal space during uterine receptivity. SNAP23 has the potential to be used as a receptivity marker.

cell biology↗

bioRxiv2023

Analysis of the Neuron-specific IIS/FOXO Transcriptome in Aged Animals Reveals Regulators of Neuronal and Cognitive Aging

Cognitive decline is a significant health concern in our aging society. Here, we used the model organism C. elegans to investigate the impact of the IIS/FOXO pathway on age-related cognitive decline. The daf-2 Insulin/IGF-1 receptor mutant exhibits a significant extension of learning and memory span with age compared to wild-type worms, an effect that is dependent on the DAF-16 transcription factor. To identify possible mechanisms by which aging daf-2 mutants maintain learning and memory with age while wild-type worms lose neuronal function, we carried out neuron-specific transcriptomic analysis in aged animals. We observed downregulation of neuronal genes and upregulation of transcriptional regulation genes in aging wild-type neurons. By contrast, IIS/FOXO pathway mutants exhibit distinct neuronal transcriptomic alterations in response to cognitive aging, including upregulation of stress response genes and downregulation of specific insulin signaling genes. We tested the roles of significantly transcriptionally-changed genes in regulating cognitive functions, identifying novel regulators of learning and memory. In addition to other mechanistic insights, comparison of the aged vs young daf-2 neuronal transcriptome revealed that a new set of potentially neuroprotective genes is upregulated; instead of simply mimicking a young state, daf-2 may enhance neuronal resilience to accumulation of harm and take a more active approach to combat aging. These findings suggest a potential mechanism for regulating cognitive function with age and offer insights into novel therapeutic targets for age-related cognitive decline.

neuroscience↗

bioRxiv2022

Future COVID-19 surges prediction based on SARS-CoV-2 mutations surveillance

COVID19 has aptly revealed that airborne viruses such as SARS-CoV-2 with the ability to rapidly mutate, combined with high rates of transmission and fatality can cause a deadly world-wide pandemic in a matter of weeks.1 Apart from vaccines and post-infection treatment options, strategies for preparedness will be vital in responding to the current and future pandemics. Therefore, there is wide interest in approaches that allow predictions of increase in infections ("surges") before they occur. We describe here real time genomic surveillance particularly based on mutation analysis, of viral proteins as a methodology for a priori determination of surge in number of infection cases. The full results are available for SARS-CoV-2 at http://pandemics.okstate.edu/covid19/, and are updated daily as new virus sequences become available. This approach is generic and will also be applicable to other pathogens.

genomics↗

bioRxiv2022

Synthetic glycans that control gut microbiome structure mitigate colitis in mice

Relative abundances of bacterial species in the gut microbiome have been linked to many diseases. Species of gut bacteria are ecologically differentiated by their abilities to metabolize different glycans, making glycan delivery a powerful way to alter the microbiome to promote health. We describe the properties and therapeutic potential of chemically diverse synthetic glycans (SGs). Fermentation of SGs by gut microbiome cultures resulted in compound-specific shifts in taxonomic and metabolite profiles not observed with reference glycans, including prebiotics. Model enteric pathogens grow poorly on most SGs, potentially increasing their safety for at-risk populations. SGs increased survival, reduced weight loss, and improved clinical scores in mouse models of colitis. Synthetic glycans are thus a promising modality to improve health through selective changes to the gut microbiome.

microbiology↗

bioRxiv2021

Novel elasticity measurement techniques reveal that the C. elegans cuticle is required for physical integrity with age

Changes in biomechanical properties have profound impacts on human health. C. elegans might serve as a model for studying the molecular genetics of mammalian tissue decline. Previously, we found that collagens are required for insulin signaling mutants long lifespan and that overexpression of specific collagens extends wild-type lifespan. However, whether these effects on lifespan are due to mechanical changes during aging has not yet been established. Here, we have developed two novel methods to study the cuticle: we measure mechanical properties of live animals using osmotic shock (OS), and we directly perform the tensile test (TT) on isolated cuticles using microfluidic technology. Using these tools, we find that cuticle, not the muscle, is responsible for changes in stretchiness of C. elegans, and that cuticle stiffness is highly non-linear and anisotropic. We also found that collagen mutations alter integrity of the cuticle by significantly altering elasticity. Additionally, aging stiffens the cuticle under mechanical loads beyond the cuticles healthy stretched state. Measurements of elasticity showed that long-lived daf-2 mutants were considerably better at preventing progressive mechanical changes with age. These tests of C. elegans biophysical properties suggest that the cuticle is responsible for their resilience.

biophysics↗

bioRxiv2021

Connectivity between the hippocampus and default mode network during the relief, but not elicitation, of curiositysupports curiosity-enhanced memory enhancements

Consistent with the idea that curiosity enhances information seeking, it has been shown that activity within both the dopaminergic circuit and hippocampus supports curiosity-enhanced learning. However, the role of whole-brain mechanisms involved in cognitive control (fronto-parietal network; FPN) and memory integration (default mode network; DMN) that might underpin curiosity states and their effects on memory remain elusive. We hypothesised that the FPN and DMN should distinguish between high- and low-curiosity conditions and be recruited more heavily for later remembered information associated with high-curiosity. Here, we used functional magnetic resonance imaging whilst participants completed a trivia paradigm, in which we presented trivia questions associated with high- and low-curiosity, followed by the associated answer. After a short delay, we tested memory for trivia answers. We adopted a network-based parcellation of the brain into subnetworks of the FPN and DMN to examine how neural activity within, and functional connectivity between, each subnetwork predicts curiosity-enhanced memory. Across elicitation and relief of curiosity, we found focal recruitment of FPNA and widespread recruitment of DMN subnetworks in support of curiosity and curiosity-enhanced memory. Most importantly, during the elicitation of curiosity, functional subcortical connectivity and across cortical networks, but not subcortical-cortical coupling, correlated with curiosity-enhanced memory. However, during the relief of curiosity, coupling between subcortical regions and DMNA emerged in support of curiosity-enhanced memory. Taken together, our results provide the first evidence about how neuromodulatory mechanisms via the hippocampal-dopaminergic circuit trigger states of curiosity and thereby communicate to higher-order cortical regions to facilitate curiosity-enhanced memory. Significant statementDoes neural activity within, and functional connectivity between, the dopaminergic-hippocampal network, fronto-parietal network (FPN), and default mode network (DMN) underpin curiosity states and their effects on memory? Here, we show how the dopaminergic system together with the hippocampus interact specifically with subnetwork DMNA potentially reflecting how subcortical regions support the enhancement of memory intergration of semantic information associated with curiosity. As DMNA (the core DMN subnetwork) was also functionally coupled with the whole DMN network and the semantic control network (FPNA), these findings provide a plausible neuromodulatory mechanism through which hippocampal-dopaminergic input triggers curiosity and then communicates to higher-order brain regions via DMNA to facilitate curiosity-enhanced memory.

neuroscience↗