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bioRxiv2018

Mutations in Pan species are shaped by demographic history and harbor lineage-specific functions

Chimpanzees (Pan troglodytes) and bonobos (Pan paniscus) are the closest living relatives of humans, but they show distinct behavioral and physiological differences, particularly regarding female reproduction. Despite their recent rapid decline, the demographic histories of the two species have been different during the past one to two million years, likely having an impact on their genomic diversity. Here, we analyze the inferred functional consequences of genetic variation across 69 individuals, making use of the most complete dataset of genomic variation in the Pan clade to date. We test to which extent the demographic history influences the efficacy of purifying selection in these species. We find that small historical effective population sizes (Ne) correlate not only with small genetic diversity, but also with more homozygous deleterious alleles, and an increased proportion of deleterious changes at low frequencies. Furthermore, we exploit the catalog of deleterious protein-coding changes on each lineage to investigate the putative genetic basis for phenotypic differences between chimpanzees and bonobos. We show that bonobo-specific non-synonymous changes are enriched in genes related to age at menarche in humans, suggesting that the prominent physiological differences in the female reproductive system between chimpanzees and bonobos might be explained, in part, by putatively adaptive changes on the bonobo lineage.

genomics↗

bioRxiv2018

Expected reward value and reward uncertainty have temporally dissociable effects on memoryformation

Anticipating rewards has been shown to enhance memory formation. While substantial evidence implicates dopamine in this behavioral effect, the precise mechanisms remain ambiguous. Because dopamine nuclei show two distinct physiological signatures of reward prediction, we hypothesized two dissociable effects on memory formation. These two signatures are a phasic dopamine response immediately following a reward cue that encodes its expected value, and a sustained, ramping dopamine response that is greater during high reward uncertainty (Fiorillo, Tobler, & Schultz, 2003). Here, we show in humans that the impact of reward anticipation on memory for an event depends on its timing relative to these physiological signatures. By manipulating reward probability (100%, 50%, or 0%) and the timing of the event to be encoded (just after the reward cue versus just before expected reward outcome), we demonstrated the predicted double dissociation: early during reward anticipation, memory formation was improved by increased expected reward value, whereas late during reward anticipation, memory formation was enhanced by reward uncertainty. Moreover, while the memory benefits of high expected reward in the early interval were consolidation-dependent, the memory benefits of high uncertainty in the later interval were not. These findings support the view that expected reward benefits memory consolidation via phasic dopamine release. The novel finding of a dissociable memory enhancement, temporally consistent with sustained anticipatory dopamine release, points toward new mechanisms of memory modulation by reward now ripe for further investigation.

neuroscience↗

bioRxiv2018

Expression of fatty acid transport protein in retinal pigment cells promotes lipid droplet expansion and photoreceptor homeostasis

Increasing evidence suggests that dysregulation of lipid metabolism is associated with neurodegeneration in retinal diseases such as age-related macular degeneration and in brain disorders such as Alzheimers and Parkinsons diseases. Lipid storage organelles (lipid droplets, LDs), accumulate in many cell types in response to stress, and it is now clear that LDs function not only as lipid stores but also as dynamic regulators of the stress response. However, whether these LD functions are always protective or can also be deleterious to the cell is unknown. Here, we investigated the consequences of LD accumulation on retinal cell homeostasis in transgenic flies and mice overexpressing fatty acid transport protein (FATP) in retinal pigment cells (RPCs). In wild-type Drosophila, overexpression of dFatp specifically in RPCs resulted in an expansion of LD size in both RPCs and in neighboring photoreceptors but was non-toxic. Similarly, in mice, LD accumulation induced by RPC-specific expression of human FATP1 was non-toxic and promoted mitochondrial energy metabolism in both RPCs and photoreceptor cells. In contrast, RPC-specific dFatp knockdown reduced neurodegeneration in Aats-metFB Drosophila mutants, which carry a defective respiratory chain, indicating that abnormal LD accumulation can be toxic under pathological conditions. Collectively, these findings indicate that FATP-mediated LD formation in RPCs induces a non-autonomous increase of LDs in photoreceptors that promotes homeostasis under physiological conditions but can be deleterious under pathological conditions.\n\nAuthor SummaryLipids are major cell constituents and are present in the membranes, as free lipids in the cytoplasm, or stored in vesicles called lipid droplets (LDs). Under conditions of stress, lipids stored in LDs can be released to serve as substrates for energy metabolism by mitochondria. However, lipid storage is deregulated in many degenerative disorders such as age-related macular degeneration and Alzheimers disease. Thus, it is unclear whether accumulation of LDs is protective or can also be toxic. To address this question, we examined the consequences of enforced LD accumulation on the health of retinal cells in flies and mice. Like humans, fly and mouse retinas contain retinal pigment cells (RPC) that support the functions of neighboring photoreceptor cells. We found that overexpression of the fatty acid transport protein (FATP) in RPCs induced accumulation of LDs in both transgenic flies and mice. Moreover, LD accumulation in RPCs had a beneficial effect on juxtaposed photoreceptors under normal physiological conditions, but was toxic under pathological stress conditions. We propose that lipid storage is a mechanism of cellular communication that is essential to maintain photoreceptor health.

cell biology↗

bioRxiv2018

Expansion, retention and loss in the Acyl-CoA Synthetase \"Bubblegum\" (Acsbg) gene family in vertebrate history

AO_SCPLOWBSTRACTC_SCPLOWFatty acids (FAs) constitute a considerable fraction of all lipid molecules with a fundamental role in numerous physiological processes. In animals, the majority of complex lipid molecules are derived from the transformation of FAs through several biochemical pathways. Yet, for FAs to enroll in these pathways they require an activation step. FA activation is catalyzed by the rate limiting action of Acyl-CoA synthases. Several Acyl-CoA enzyme families have been previously described and classified according to the chain length of FA they process. Here, we address the evolutionary history of the ACSBG gene family which activates, FA with more than 16 carbons. Currently, two different ACSBG gene families, ACSBG1 and ACSBG2, are recognized in vertebrates. We provide evidence that a wider and unequal ACSBG gene repertoire is present in vertebrate lineages. We identify a novel ACSBG-like gene lineage which occurs specifically in amphibians, ray finned fish, coelacanths and chondrichthyes named ACSBG3. Also, we show that the ACSBG2 gene lineage duplicated in the Theria ancestor. Our findings, thus offer a far richer understanding on FA activation in vertebrates and provide key insights into the relevance of comparative and functional analysis to perceive physiological differences, namely those related with lipid metabolic pathways.

genetics↗

bioRxiv2018

Ecological and evolutionary consequences of viral plasticity

Viruses can infect any organism. Because viruses use the host machinery to replicate, their performance depends on the host physiological state. For bacteriophages, this host-viral performance link has been characterized empirically and with intracellular theories. Such theories are too detailed to be included in models that study host-phage interactions in the long term, which hinders our understanding of systems that range from pathogens infecting gut bacteria to marine phage shaping present and future oceans. Here, we combined data and models to study the short- and long-term consequences that host physiology has on bacteriophage performance. We compiled data showing the dependence of lytic-phage traits on host growth rate (viral phenotypic \"plasticity\") to deduce simple expressions representing such plasticity. We included these expressions in a standard host-phage model, to understand how viral plasticity can break the expected evolutionary trade-off between infection time and viral offspring number. Furthermore, viral plasticity influences dramatically dynamic scenarios (e.g. sudden nutrient pulses or host starvation). We show that the effect of plasticity on offspring number, not generation time, drives the phage ecological and evolutionary dynamics. Standard models do not account for this plasticity, which handicaps their predictability in realistic environments. Our results highlight the importance of viral plasticity to unravel host-phage interactions, and the need of laboratory and field experiments to characterize viral plastic responses across systems.

microbiology↗

bioRxiv2018

Cullin1 represses systematic inflammasome activation by binding and catalyzing NLRP3 ubiquitination

Activation of the NLRP3 inflammasome is a key process of host immune response, the first line of defense against cellular stresses and pathogen infections. However, excessive inflammasome activation damages the hosts, and thus it must be precisely controlled. The mechanism underlying the repression of systematic inflammasome activation remains largely unknown. This study reveals that CUL1, a key component of the SCF E3 ligase, plays a critical role in regulation of the inflammasome. CUL1 suppresses the inflammasome activation in HEK293T cells, inhibits endogenous NLRP3 in macrophages, and represses inflammatory responses in C57BL/6 mice. Under normal physiological conditions, CUL1 interacts with NLRP3 to disrupt the inflammasome assembly, and catalyzes NLRP3 ubiquitination to repress the inflammasome activation. In response to inflammatory stimuli, CUL1 disassociates from NLRP3 to release the repression of NLRP3 inflammasome activation. This work reveals a distinct mechanism underlying the repression of inflammasome activation under physiological conditions and the induction of inflammasome activation in response to inflammatory stimuli, and thus provides insights into the prevention and treatment of infectious and inflammatory diseases.

immunology↗

bioRxiv2018

GPRIN1 modulates neuronal signal transduction and affects mouse-learning behavior

In the adult and developing brain, G protein-regulated inducer of neurite outgrowth 1 (GPRIN1) is a downstream effector for Go/i/z proteins that promotes neurite outgrowth. However, so far, the physiological role of GPRIN1 in brain health has not been reported. We generated a viable GPRIN1 whole-body knockout mouse to assess its physiological role in synaptic function both ex vivo and in vivo. In adult neurons, GPRIN1 is highly localized to the plasma membrane and synapses where it regulates neuronal signal transduction and Ca2+ homeostasis. Our results reveal that GPRIN1 might be a novel protein involved in agonist-stimulated cytoskeletal reorganization, which is crucial for early neuronal network development and in functionally mature neurons. Finally, we show that loss of GPRIN1 leads to a learning deficit in vivo and sensitizes neurons to stress, suggesting a modulatory role in brain health and disease.

neuroscience↗

bioRxiv2018

Axin proteolysis by Iduna is required for the regulation of stem cell proliferation and intestinal homeostasis in Drosophila

The self-renewal of intestinal stem cell is controlled by Wingless/Wnt-{beta} catenin signaling both in Drosophila and mammals. Since Axin is a rate-limiting factor in Wingless signaling its regulation is essential. Iduna is an evolutionarily conserved ubiquitin E3 ligase that has been identified as a critical regulator for degradation of ADP-ribosylated Axin and thus of Wnt/{beta}-catenin signaling. However, its physiological significance remains to be demonstrated. Here, we generated loss-of-function mutants of Iduna to investigate its physiological role in Drosophila. Genetic depletion of Iduna causes the accumulation of both Tankyrase and Axin. Increase of Axin protein in enterocytes non-autonomously enhanced stem cell divisions in the Drosophila midgut. Enterocytes secreted Unpaired and thereby stimulated the activity of the JAK-STAT pathway in intestinal stem cells. A decrease in Axin gene expression suppressed both the over-proliferation of stem cells and restored their numbers to normal levels in Iduna mutants. These findings suggest that Iduna-mediated regulation of Axin proteolysis is essential to maintain tissue homeostasis in the Drosophila midgut.

developmental biology↗

bioRxiv2018

Parameterizing neural power spectra

Electrophysiological signals across species and recording scales exhibit both periodic and aperiodic features. Periodic oscillations have been widely studied and linked to numerous physiological, cognitive, behavioral, and disease states, while the aperiodic \"background\" 1/f component of neural power spectra has received far less attention. Most analyses of oscillations are conducted on a priori, canonically-defined frequency bands without consideration of the underlying aperiodic structure, or verification that a periodic signal even exists in addition to the aperiodic signal. This is problematic, as recent evidence shows that the aperiodic signal is dynamic, changing with age, task demands, and cognitive state. It has also been linked to the relative excitation/inhibition of the underlying neuronal population. This means that standard analytic approaches easily conflate changes in the periodic and aperiodic signals with one another because the aperiodic parameters--along with oscillation center frequency, power, and bandwidth--are all dynamic in physiologically meaningful, but likely different, ways. In order to overcome the limitations of traditional narrowband analyses and to reduce the potentially deleterious effects of conflating these features, we introduce a novel algorithm for automatic parameterization of neural power spectral densities (PSDs) as a combination of the aperiodic signal and putative periodic oscillations. Notably, this algorithm requires no a priori specification of band limits and accounts for potentially-overlapping oscillations while minimizing the degree to which they are confounded with one another. This algorithm is amenable to large-scale data exploration and analysis, providing researchers with a tool to quickly and accurately parameterize neural power spectra.

neuroscience↗

bioRxiv2018

Widespread cis-regulation of RNA-editing in a large mammal

Post-transcriptional RNA editing may regulate transcript expression and diversity in cells, with potential impacts on various aspects of physiology and environmental adaptation. A small number of recent genome-wide studies in Drosophila, mouse, and human have shown that RNA editing can be genetically modulated, highlighting loci that quantitatively impact editing of transcripts. The potential gene expression and physiological consequences of these RNA editing quantitative trait loci (edQTL), however, are almost entirely unknown. Here, we present analyses of RNA editing in a large domestic mammal (Bos taurus), where we use whole genome and high depth RNA sequencing to discover, characterise, and conduct genetic mapping studies of novel transcript edits. Using a discovery population of nine deeply-sequenced cows, we identify 2,001 edit sites in the mammary transcriptome, the majority of which are adenosine to inosine edits (97.4%). Most sites are predicted to reside in double-stranded secondary structures (85.7%), and quantification of the rates of editing in an additional 355 cows reveals editing is negatively correlated with gene expression in the majority of cases. Genetic analyses of RNA editing and gene expression highlights 67 cis-regulated edQTL, of which seven appear to co-segregate with expression QTL effects. Trait association analyses in a separate population of 9,988 lactating cows also shows nine of the cis-edQTL coincide with at least one co-segregating lactation QTL. Together, these results enhance our understanding of RNA editing dynamics in mammals, and suggest mechanistic links by which loci may impact phenotype through RNA-editing mediated processes.

genomics↗

bioRxiv2018

h-channels contribute to divergent electrophysiological properties of supragranular pyramidal neurons in human versus mouse cerebral cortex

Gene expression studies suggest that differential ion channel expression contributes to differences in rodent versus human neuronal physiology. We tested whether h-channels more prominently contribute to the physiological properties of human compared to mouse supragranular pyramidal neurons. Single cell/nucleus RNA sequencing revealed ubiquitous HCN1-subunit expression in excitatory neurons in human, but not mouse supragranular layers. Using patch-clamp recordings, we found stronger h-channel-related membrane properties in supragranular pyramidal neurons in human temporal cortex, compared to mouse supragranular pyramidal neurons in temporal association area. The magnitude of these differences depended upon cortical depth and was largest in pyramidal neurons in deep L3. Additionally, pharmacologically blocking h-channels produced a larger change in membrane properties in human compared to mouse neurons. Finally, using biophysical modeling, we provided evidence that h-channels promote the transfer of theta frequencies from dendrite-to-soma in human L3 pyramidal neurons. Thus, h-channels contribute to between-species differences in a fundamental neuronal property.

neuroscience↗

bioRxiv2018

Comparison of the 3-D patterns of the parasympathetic nervous system in the lung at late developmental stages between mouse and chicken

Although the basic schema of the body plan is similar among different species of amniotes (mammals, birds, and reptiles), the lung is an exception. Here, anatomy and physiology are considerably different, particularly between mammals and birds. In mammals, inhaled and exhaled airs mix in the airways, whereas in birds the inspired air flows unidirectionally without mixing with the expired air. This bird-specific respiration system is enabled by the complex tubular structures called parabronchi where gas exchange takes place, and also by the bellow-like air sacs appended to the main part of the lung. That the lung is predominantly governed by the parasympathetic nervous system has been shown mostly by physiological studies in mammals. However, how the parasympathetic nervous system in the lung is established during late development has largely been unexplored both in mammals and birds. In this study, by combining immunocytochemistry, the tissue-clearing CUBIC method, and ink-injection to airways, we have visualized the 3-D distribution patterns of parasympathetic nerves and ganglia in the lung at late developmental stages of mice and chickens. These patterns were further compared between these species, and three prominent similarities emerged: (1) parasympathetic postganglionic fibers and ganglia are widely distributed in the lung covering the proximal and distal portions, (2) the gas exchange units, alveoli in mice and parabronchi in chickens, are devoid of parasympathetic nerves, (3) parasympathetic nerves are in close association with smooth muscle cells, particularly at the base of the gas exchange units. These observations suggest that despite gross differences in anatomy, the basic mechanisms underlying parasympathetic control of smooth muscles and gas exchange might be conserved between mammals and birds.\n\nHighlightsO_LI3-D patterns of parasympathetic nerves are visualized in mouse and chicken lungs.\nC_LI\n\nComparison of these patterns reveals three prominent similarities between mouse and chicken: O_LIVAChT-positive postganglionic fibers and ganglia are widely distributed in the lung.\nC_LIO_LIGas exchange units are devoid of parasympathetic nerves.\nC_LIO_LIParasympathetic nerves are in close association with smooth muscle cells.\nC_LI

developmental biology↗

bioRxiv2018

Escherichia coli ZipA organizes FtsZ polymers into dynamic ring-like protofilament structures

ZipA is an essential cell division protein in Escherichia coli. Together with FtsA, ZipA tethers dynamic polymers of FtsZ to the cytoplasmic membrane, and these polymers are required to guide synthesis of the cell division septum. This dynamic behavior of FtsZ has been reconstituted on planar lipid surfaces in vitro, visible as GTP-dependent chiral vortices several hundred nm in diameter, when anchored by FtsA or when fused to an artificial membrane binding domain. However, these dynamics largely vanish when ZipA is used to tether FtsZ polymers to lipids at high surface densities. This, along with some in vitro studies in solution, has led to the prevailing notion that ZipA reduces FtsZ dynamics by enhancing bundling of FtsZ filaments. Here, we show that this is not the case. When lower, more physiological levels of the soluble, cytoplasmic domain of ZipA (sZipA) were attached to lipids, FtsZ assembled into highly dynamic vortices similar to those assembled with FtsA or other membrane anchors. Notably, at either high or low surface densities, ZipA did not stimulate lateral interactions between FtsZ protofilaments. We also used E. coli mutants that are either deficient or proficient in FtsZ bundling to provide evidence that ZipA does not directly promote bundling of FtsZ filaments in vivo. Together, our results suggest that ZipA does not dampen FtsZ dynamics as previously thought, and instead may act as a passive membrane attachment for FtsZ filaments as they treadmill.\n\nIMPORTANCEBacterial cells use a membrane-attached ring of proteins to mark and guide formation of a division septum at mid-cell that forms a wall separating the two daughter cells and allows cells to divide. The key protein in this ring is FtsZ, a homolog of tubulin that forms dynamic polymers. Here, we use electron microscopy and confocal fluorescence imaging to show that one of the proteins required to attach FtsZ polymers to the membrane during E. coli cell division, ZipA, can promote dynamic swirls of FtsZ on a lipid surface in vitro. Importantly, these swirls are only observed when ZipA is present at low, physiologically relevant surface densities. Although ZipA has been thought to enhance bundling of FtsZ polymers, we find little evidence for bundling in vitro. In addition, we present several lines of in vivo evidence indicating that ZipA does not act to directly bundle FtsZ polymers.

microbiology↗

bioRxiv2018

Glycosylation-associated dysregulation of pyocyanin production in Pseudomonas aeruginosa: Implications for quorum sensing regulation

Pseudomonas aeruginosa (P. aeruginosa) is an important opportunistic pathogen associated with high mortality in pneumonia, sepsis, and cystic fibrosis. Lending to its ability to cause severe disease and death is its arsenal of virulence factors and host evasion tactics. In addition to various other regulatory systems, many of P. aeruginosas virulence factors are regulated by a population density dependent regulatory network known as quorum sensing (QS). Many regulatory systems are impacted by post-translational modifications of proteins. An underexplored physiological aspect of P. aeruginosa is its ability to glycosylate proteins and the subsequent impact of glycosylation on P. aeruginosa physiology and behavior. The goal of this study was to determine whether P. aeruginosa QS is regulated by glycosylation. Here we demonstrate that disruption of glycosylation dysregulates QS phenotypes, notably pyocyanin production, in P. aeruginosa PAO1. In this study, it was initially observed that deletion of the P. aeruginosa neuraminidase, PaNA, caused an increased production of pyocyanin in LB-Lennox broth compared to wildtype bacteria at identical population densities. To confirm that the increased pyocyanin production was due to QS, we performed induction experiments using 10% cell-free media harvested from overnight cultures. To determine whether the QS phenotype observed is specific to pseudaminic acid, the target of PaNA, or if it is a reflection of global changes in glycosylation, we measured QS in a library of mutant bacteria generated in an MPAO1 background containing transposon insertions in various glycosyl-associated enzymes. The pattern of dysregulated QS held true in these mutant strains as well. Overall these data indicate that in P. aeruginosa, glycosylation is an important determinant of QS.

microbiology↗

bioRxiv2018

Clustering of Type 2 Diabetes Genetic Loci by Multi-Trait Associations Identifies Disease Mechanisms and Subtypes

BackgroundType 2 diabetes (T2D) is a heterogeneous disease for which 1) disease-causing pathways are incompletely understood and 2) sub-classification may improve patient management. Unlike other biomarkers, germline genetic markers do not change with disease progression or treatment. In this paper we test whether a germline genetic approach informed by physiology can be used to deconstruct T2D heterogeneity. First, we aimed to categorize genetic loci into groups representing likely disease mechanistic pathways. Second, we asked whether the novel clusters of genetic loci we identified have any broad clinical consequence, as assessed in four independent cohorts of individuals with T2D.\n\nMethods and FindingsIn an effort to identify mechanistic pathways driven by established T2D genetic loci, we applied Bayesian nonnegative matrix factorization clustering to genome-wide association results for 94 independent T2D genetic loci and 47 diabetes-related traits. We identified five robust clusters of T2D loci and traits, each with distinct tissue-specific enhancer enrichment based on analysis of epigenomic data from 28 cell types. Two clusters contained variant-trait associations indicative of reduced beta-cell function, differing from each other by high vs. low proinsulin levels. The three other clusters displayed features of insulin resistance: obesity-mediated (high BMI, waist circumference), \"lipodystrophy-like\" fat distribution (low BMI, adiponectin, HDL-cholesterol, and high triglycerides), and disrupted liver lipid metabolism (low triglycerides). Increased cluster GRSs were associated with distinct clinical outcomes, including increased blood pressure, coronary artery disease, and stroke risk. We evaluated the potential for clinical impact of these clusters in four studies containing participants with T2D (METSIM, N=487; Ashkenazi, N=509; Partners Biobank, N=2,065; UK Biobank N=14,813). Individuals with T2D in the top genetic risk score decile for each cluster reproducibly exhibited the predicted cluster-associated phenotypes, with ~30% of all participants assigned to just one cluster top decile.\n\nConclusionOur approach identifies salient T2D genetically anchored and physiologically informed pathways, and supports use of genetics to deconstruct T2D heterogeneity. Classification of patients by these genetic pathways may offer a step toward genetically informed T2D patient management.

genetics↗

bioRxiv2018

Cell type-dependent effects of ellagic acid on cellular metabolism

Ellagic acid is a botanical polyphenol which has been shown to have numerous effects on cellular function. Ellagic acid can induce apoptosis and inhibit the proliferation of various cancer cell types in vitro and in vivo. As such, ellagic acid has attracted significant interest as a potential chemotherapeutic compound. One mechanism by which ellagic acid has been proposed to affect cellular physiology is by regulating metabolic pathways. Here we show the dose-dependent effects of ellagic acid on cellular energy production and downstream induction of the apoptotic program in HEK293, HeLa, MCF7, and HepG2 cells. At physiologically relevant doses, eallgic acid has pleiotropic and cell-type specific effects on mitochondrial function. At high doses ellagic acid can also influence glycolytic pathways and induce cell death. Our results demonstrate that ellagic acid can influence mitochondrial function at therapeutically relevant concentrations. The observed effects of ellagic acid on cellular respiration are complex and cell type-specific, which may limit the chemotherapeutic utility of this compound.

cell biology↗

bioRxiv2018

Arterial smooth muscle cell PKD2 (TRPP1) channels control systemic blood pressure

Systemic blood pressure is determined, in part, by arterial smooth muscle cells (myocytes). Several Transient Receptor Potential (TRP) channels are proposed to be expressed in arterial myocytes, but it is unclear if these proteins control physiological blood pressure and contribute to hypertension in vivo. We generated the first inducible, smooth muscle-specific knockout for a TRP channel, namely for PKD2 (TRPP1), to investigate arterial myocyte and blood pressure regulation by this protein. Using this model, we show that intravascular pressure and 1-receptors activate PKD2 channels in arterial myocytes of different systemic organs. PKD2 channel activation in arterial myocytes leads to an inward Na+ current, membrane depolarization and vasoconstriction. Inducible, smooth muscle cell-specific PKD2 knockout lowers both physiological blood pressure and hypertension and prevents pathological arterial remodeling during hypertension. In summary, we show for the first time that arterial myocyte PKD2 channels control systemic blood pressure and targeting reduces high blood pressure.

neuroscience↗

bioRxiv2018

Machine characterization of rat toxin responses identifies disease states, tolerance mechanisms and organ to whole-body communication

BackgroundLiving organisms are constantly exposed to toxic xenobiotics and have therefore evolved protective responses. In mammals, the liver and kidney play central roles in protecting the organism from xenobiotics, and are at high risk of xenobiotic-induced injury. Liver and kidney damage by drugs and industrial toxins have been extensively studied from both classical histopathologic and biochemical perspectives.\n\nMethods and FindingsWe introduce a machine learning approach for the analysis of toxicological response. Unsupervised characterization of physiological and histological changes in a large toxicogenomic dataset revealed nine discrete toxin-induced disease states. Transcriptome analysis showed that some of the machine-identified disease states correspond to known pathology, and to known effects of certain toxin classes, but others were novel. Analysis of dynamics revealed transitions between disease states at constant toxin exposure, mostly in the direction of decreased pathology, which implies induction of tolerance. Tolerance correlated with induction of known xenobiotic defense genes and novel decreased ferroptosis sensitivity biomarkers. These data reinforce emerging evidence that ferroptosis drives organ pathology, and suggest that its downreagulation may promote tolerance and recovery. Lastly, mechanism of body weight decrease, a known primary marker for toxicity, was investigated. Combined analysis of food consumption, body weight, and molecular biomarkers indicated that organ disease states promote cachexia by whole-body signaling through Gdf15 and Igf1, suggesting strategies for therapeutic intervention that may be broadly relevant to human disease.\n\nConclusionsApplication of machine learning to systematic data collection of physiology, histopathology, transcriptome reveals multiple disease states, tolerance mechanisms and organ to whole-body communication.

systems biology↗