SEARCH · Search bioRxiv

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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 631 records · Page 35Linked to original sources

bioRxiv2016

Transcriptional regulatory logic of the diurnal cycle in the mouse liver

Many organisms exhibit temporal rhythms in gene expression that propel diurnal cycles in physiology. In the liver of mammals, these rhythms are controlled by transcription-translation feedback loops of the core circadian clock and by feeding-fasting cycles. To better understand the regulatory interplay between the circadian clock and feeding rhythms, we mapped DNase I hypersensitive sites (DHSs) in mouse liver during a diurnal cycle. The intensity of DNase I cleavages cycled at a substantial fraction of all DHSs, suggesting that DHSs harbor regulatory elements that control rhythmic transcription. Using ChIP-seq, we found that hypersensitivity cycled in phase with RNA polymerase II (Pol II) loading and H3K27ac histone marks. We then combined the DHSs with temporal Pol II profiles in wild-type (WT) and Bmal1-/- livers to computationally identify transcription factors through which the core clock and feeding-fasting cycles control diurnal rhythms in transcription. While a similar number of mRNAs accumulated rhythmically in Bmal1-/- compared to WT livers, the amplitudes in Bmal1-/- were generally lower. The residual rhythms in Bmal1-/- reflected transcriptional regulators mediating feeding-fasting responses as well as responses to rhythmic systemic signals. Finally, the analysis of DNase I cuts at nucleotide resolution showed dynamically changing footprint consistent with dynamic binding of CLOCK:BMAL1 complexes. Structural modeling suggested that these footprints are driven by a transient hetero-tetramer binding configuration at peak activity. Together, our temporal DNase I mappings allowed us to decipher the global regulation of diurnal transcription rhythms in mouse liver.

Genomics↗

bioRxiv2016

A forward model at Purkinje cell synapses facilitates cerebellar anticipatory motor control

How does our motor system solve the problem of anticipatory control in spite of a wide spectrum of response dynamics from different musculo-skeletal systems, transport delays as well as response latencies throughout the central nervous system? To a great extent, our highly-skilled motor responses are a result of a reactive feedback system, originating in the brain-stem and spinal cord, combined with a feed-forward anticipatory system, that is adaptively fine-tuned by sensory experience and originates in the cerebellum. Based on that interaction we design the counterfactual predictive control (CFPC) architecture, an anticipatory adaptive motor control scheme, in which a feed-forward module, based on the cerebellum, steers an error feedback controller with counterfactual error signals. Those are signals that trigger reactions as actual errors would, but that do not code for any current of forthcoming errors. In order to determine the optimal learning strategy, we derive a novel learning rule for the feed-forward module that involves an eligibility trace and operates at the synaptic level. In particular, our eligibility trace provides a mechanism beyond co-incidence detection in that it convolves a history of prior synaptic inputs with error signals. In the context of cerebellar physiology, this solution implies that Purkinje cell synapses should generate eligibility traces using a forward model of the system being controlled. From an engineering perspective, CFPC provides a general-purpose anticipatory control architecture equipped with a learning rule that exploits the full dynamics of the closed-loop system.

Neuroscience↗

bioRxiv2016

Mitochondrial DNA Density Homeostasis Accounts for the Threshold Effect in Human Mitochondrial Disease

Mitochondrial dysfunction is involved in a wide array of devastating diseases but the heterogeneity and complexity of these diseases symptoms challenges theoretical understanding of their causation. With the explosion of -omics data, we have the unprecedented ability to gain deep understanding of the biochemical mechanisms of mitochondrial dysfunction. However, there is also a need to make such datasets interpretable, and quantitative modelling allows us to translate such datasets into intuition and suggest rational biomedical treatments. Working towards this interdisciplinary goal, we use a recently published large-scale dataset, and develop a mathematical model of progressive increase in mutant load of the MELAS 3243A>G mtDNA mutation to develop a descriptive and predictive biophysical model. The experimentally observed behaviour is surprisingly rich, but we find that a simple, biophysically-motivated model intuitively accounts for this heterogeneity and yields a wealth of biological predictions. Our findings suggest that cells attempt to maintain wild-type mtDNA density through cell volume reduction, and thus energy demand reduction, until a minimum cell volume is reached. Thereafter, cells toggle from demand reduction to supply increase, upregulating energy production pathways. Our analysis provides further evidence for the physiological significance of mtDNA density, and emphasizes the need for performing single-cell volume measurements jointly with mtDNA quantification. We propose novel experiments to verify the hypotheses made here, to further develop our understanding of the threshold effect, and connect with rational choices for mtDNA disease therapies.\n\nAuthor SummaryMitochondria are organelles which produce the major energy currency of the cell: ATP. Mitochondrial dysfunction is associated with a multitude of devastating diseases, from Parkinsons disease to cancer. Large volumes of data related to these diseases are being produced, but translation of these data into rational biomedical treatment is challenged by a lack of theoretical understanding. We develop a mathematical model of progressive increase of mutant load in mitochondrial DNA, for the mutation associated with MELAS (the most common mitochondrial disease), to address this. We predict that cells attempt to maintain the ratio of healthy mtDNA to cell volume by reducing their cell volume until they reach a minimum cell volume. As mutant load continues to increase, cells switch strategy by increasing their energy supply pathways. Our work accounts for large-scale experimental data and makes testable predictions about mitochondrial dysfunction. It also provides support for increasing mitochondrial content, as well as reduction in dependence upon mitochondrial metabolism via the ketogenic diet, as relevant treatments for mitochondrial disease.

Cell Biology↗

bioRxiv2016

Sequencing of small RNAs of the fern Pleopeltis minima (Polypodiaceae) offers insight into the evolution of the microRNA repertoire in land plants

MicroRNAs (miRNAs) are short, single stranded RNA molecules that regulate the stability and translation of messenger RNAs in diverse eukaryotic groups. Several miRNA genes are of ancient origin and have been maintained in the genomes of animal and plant taxa for hundreds of millions of years, and functional studies indicate that ancient miRNAs play key roles in development and physiology. In the last decade, genome and small RNA (sRNA) sequencing of several plant species have helped unveil the evolutionary history of land plant miRNAs. Land plants are divided into bryophytes (liverworts, mosses), lycopods (clubmosses and spikemosses), monilophytes (ferns and horsetails), gymnosperms (cycads, conifers and allies) and angiosperms (flowering plants). Among these, the fern group occupies a key phylogenetic position, since it represents the closest extant cousin taxon of seed plants, i.e. gymno- and angiosperms. However, in spite of their evolutionary, economic and ecological importance, no fern genome has been sequenced yet and few genomic resources are available for this group. Here, we sequenced the small RNA fraction of an epiphytic South American fern, Pleopeltis minima (Polypodiaceae), and compared it to plant miRNA databases, allowing for the identification of miRNA families that are shared by all land plants, shared by all vascular plants (tracheophytes) or shared by euphyllophytes (ferns and seed plants) only. Using the recently described transcriptome of another fern, Lygodium japonicum, we also estimated the degree of conservation of fern miRNA targets in relation to other plant groups. Our results pinpoint the origin of several miRNA families in the land plant evolutionary tree with more precision and are a resource for future genomic and functional studies of fern miRNAs.

Plant Biology↗

bioRxiv2016

A Hypothesis to Explain Cancers in Confined Colonies of Naked Mole Rats

Naked mole rats (NMRs) are subterranean eusocial mammals, known for their virtual absence of aging in their first 20 to 30 years of life, and their apparent resistance to cancer development. As such, this species has become an important biological model for investigating the physiological and molecular mechanisms behind cancer resistance. Two recent studies have discovered middle and late-aged worker (that is, non-breeding) NMRs in captive populations exhibiting neoplasms, consistent with cancer development, challenging the claim that NMRs are cancer resistant. These cases are possibly artefacts of inbreeding or certain rearing conditions in captivity, but they are also consistent with evolutionary theory.\n\nWe present field data showing that worker NMRs live on average for 1 to 2 years. This, together with considerable knowledge about the biology of this species, provides the basis for an evolutionary explanation for why debilitating cancers in NMRs should be rare in captive populations and absent in the wild. Whereas workers are important for maintaining tunnels, colony defence, brood care, and foraging, they are highly vulnerable to predation. However, surviving workers either replace dead breeders, or assume other less active functions whilst preparing for possible dispersal. These countervailing forces (selection resulting in aging due to early-life investments in worker function, and selection for breeder longevity) along with the fact that all breeders derive from the worker morph, can explain the low levels of cancer observed by these recent studies in captive colonies. Because workers in the field typically never reach ages where cancer becomes a risk to performance or mortality, those rare observations of neoplastic growth should be confined to the artificial environments where workers survive to ages rarely if ever occurring in the wild. Thus, we predict that the worker phenotype fortuitously benefits from anti-aging and cancer protection in captive populations.

Cancer Biology↗

bioRxiv2016

Spatiotemporal patterns of desiccation tolerance in natural populations of Drosophila melanogaster

Water availability is a major environmental challenge to a variety of terrestrial organisms. In insects, desiccation tolerance varies predictably over various spatial and temporal scales and is an important physiological basis of fitness variation among natural populations. Here, we examine the dynamics of desiccation tolerance in North American populations of Drosophila melanogaster using: 1) natural populations sampled across latitudes and seasons in the eastern USA; 2) experimental evolution in the field in response to changing seasonal environments; 3) a sequenced panel of inbred lines (DGRP) to perform genome wide associations and examine whether SNPs/genes associated with variation in desiccation tolerance exhibit patterns of clinal and/or seasonal enrichment in pooled sequencing of populations. In natural populations we observed a shallow cline in desiccation tolerance, for which tolerance exhibited a positive association with latitude; the steepness of this cline increased with decreasing culture temperature, demonstrating a significant degree of thermal plasticity. No differences in desiccation tolerance were observed between spring and autumn collections from three mid-to-northern latitude populations, or as a function of experimental evolution to seasonality. Similarly, water loss rates did not vary significantly among latitudinal, seasonal or experimental evolution populations. However, changes in metabolic rates during prolonged exposure to dry conditions indicate increased tolerance in higher latitude populations. Genome wide association studies identified thirty-six SNPs in twenty-eight genes associated with sex-averaged drought tolerance. Among North American populations, genes associated with drought tolerance do not show increased signatures of spatially varying selection relative to the rest of the genome, whereas among Australian populations they do.

Evolutionary Biology↗

bioRxiv2016

Reproductive Isolation through Experimental Manipulation of Sexually Antagonistic Coevolution in Drosophila Melanogaster

Promiscuity can drive the evolution of sexual conflict before and after mating occurs. Post-mating, the male ejaculate can selfishly manipulate female physiology leading to a chemical arms race between the sexes. Theory suggests that drift and sexually antagonistic coevolution can cause allopatric populations to evolve different chemical interactions between the sexes, thereby leading to postmating reproductive barriers and speciation. There is, however, little empirical evidence supporting this form of speciation. We tested this theory by creating an experimental evolutionary model of Drosophila melanogaster populations undergoing different levels of interlocus sexual conflict. We found that allopatric populations under elevated sexual conflict show assortative mating indicating premating reproductive isolation. Further, these allopatric populations also show reduced copulation duration and sperm defense ability when mating happens between individuals between individuals across populations compared to that within the same population, indicating postmating prezygotic isolation. Sexual conflict can cause reproductive isolation in allopatric populations through the coevolution of chemical (postmating prezygotic) as well as behavioural (premating) interaction between the sexes. Thus, to our knowledge, we provide the first comprehensive evidence of postmating (as well as premating) reproductive isolation due to sexual conflict.

Evolutionary Biology↗

bioRxiv2016

Long-range suppressive influences from the visual surround can be explained by anatomically plausible recruitment of local competition in a model of columnar cortex

Although neurons in columns of visual cortex of adult carnivores and primates share similar orientation tuning preferences, responses of nearby neurons are surprisingly sparse and temporally uncorrelated, especially in response to complex visual scenes. The mechanisms underlying this counter-intuitive combination of response properties are still unknown. Here we present a computational model of columnar visual cortex which explains experimentally observed integration of complex features across the visual field, and which is consistent with anatomical and physiological profiles of cortical excitation and inhibition. In this model, sparse local excitatory connections within columns, coupled with strong unspecific local inhibition and functionally-specific long-range excitatory connections across columns, give rise to competitive dynamics that reproduce experimental observations. Our results explain surround modulation of responses to simple and complex visual stimuli, including reduced correlation of nearby excitatory neurons, increased excitatory response selectivity, increased inhibitory selectivity, and complex orientation-tuning of surround modulation.

neuroscience↗

bioRxiv2016

Degenerate time-dependent network dynamics anticipate seizures in human epileptic brain

Epileptic seizures are known to follow specific changes in brain dynamics. While some algorithms can nowadays robustly detect these changes, a clear understanding of the mechanism by which these alterations occur and generate seizures is still lacking. Here, we provide cross-validated evidence that such changes are initiated by an alteration of physiological network state dynamics. Specifically, our analysis of long intracranial EEG recordings from a group of 10 patients identifies a critical phase of a few hours in which time-dependent network states become less variable (\"degenerate\") and is followed by a global functional connectivity reduction before seizure onset. This critical phase is characterized by an abnormal occurrence of highly correlated network instances and is shown to particularly affect the activity of resection regions in patients with validated postsurgical outcome. Our approach characterizes pre-seizure networks dynamics as a cascade of two sequential events providing new insights into seizure prediction and control.

neuroscience↗

bioRxiv2016

Structure and culture of the gut microbiome of the Mormon cricket Anabrus simplex

The gut microbiome of insects plays an important role in their ecology and evolution, participating in nutrient acquisition, immunity, and behavior. Microbial community structure within the gut is thought to be heavily influenced by differences among gut regions in morphology and physiology, which determine the niches available for microbes to colonize. We present a high-resolution analysis of the structure of the gut microbiome in the Mormon cricket Anabrus simplex, an insect known for its periodic outbreaks in the Western United States and nutrition-dependent mating system. The Mormon cricket microbiome was dominated by eleven bacterial phylotypes from the Lactobacillaceae, Enterobacteriaceae, and Streptococcaeae. While most of these were represented in all gut regions, there were marked differences in their relative abundance, with lactic-acid bacteria (Lactobacillaceae) more common in the foregut and midgut and enteric (Enterobacteriaceae) bacteria more common in the hindgut. Differences in community structure were driven by variation in the relative prevalence of three groups: a Lactobacillus phylotype in the foregut, Pediococcus lactic-acid bacteria in the midgut, and Pantoea agglomerans, an enteric bacterium, in the hindgut. These taxa have been shown to have beneficial effects on their hosts in insects and other animals by improving nutrition, increasing resistance to pathogens, and modulating social behavior. Phylogenetic analysis of 16s rRNA sequences from cultured isolates indicated low levels of divergence from sequences derived from plants and other insects, suggesting that these bacteria are likely to be exchanged between Mormon crickets and the environment. Our study provides the foundation for future work on an economically important insect and emerging model for the study of how social interaction influence host-microbe symbiosis.

microbiology↗

bioRxiv2016

A shielded irradiation assay to investigate mechanisms of in vivo stem cell migration in planarians

Migration of stem cells underpins the physiology of metazoan animals. For tissues to be maintained, stem cells and their progeny must migrate and differentiate in the correct positions. This need is even more acute after tissue damage by wounding or pathogenic infections. Inappropriate migration also underpins the formation of metastasis. Despite this, few mechanistic studies address stem cell migration during repair or homeostasis in adult tissues. Here, we present a shielded X-ray irradiation assay that allows us to follow stem cell migration in the planarians. We demonstrate that we can use this system to study the molecular control of stem cell migration and show that snail and zeb-1 EMT transcription factors homologs are necessary for cell migration to wound sites and for the establishment of migratory cell morphology. Our work establishes planarians as a suitable model for further in depth study of the processes controlling stem cell migration in vivo.

developmental biology↗

bioRxiv2016

Loss of the habenula neuromodulator Kisspeptin1 disrupts learning

Learning how to actively avoid a predictable aversive stimulus involves two steps: recognizing the cue that predicts upcoming punishment, and learning a behavioral response that will lead to avoidance. In zebrafish, ventral habenula (vHb) neurons have been proposed to participate in both steps by encoding the expected aversiveness of a stimulus. vHb neurons increase their firing rate as expectation of punishment grows, but reduce their activity as avoidance learning occurs. How the change in vHb activity occurs is not known. Here, we ask whether the neuromodulator kisspeptin1, which is expressed in the ventral habenula, could be involved. Kiss1 mutants were generated with Cas9 using guide RNAs targeted to the signal sequence. Mutants, which have a stop codon upstream of the kisspeptin1 peptide, have a deficiency in learning to avoid a shock that is predicted by light. Electrophysiology indicates that kisspeptin1 has a concentration-dependent effect on vHb neurons: depolarizing at low concentrations and hyperpolarizing at high concentrations. These data suggest that as the fish learns to cope with a threat, kisspeptin1 may differentially modulate vHb neurons. This implies that learning a behavioral strategy to overcome a stressor is accompanied by physiological change in habenula neurons.\n\nSignificance statementLearning to deal with adversity can positively affect ones ability to cope with challenges in the immediate future. Control thus causes short-term change in the brain. Here, we show that the neuromodulator kisspeptin1 is required to learn to avoid a punishment. Expression and electrophysiological recordings suggest that this molecule functions by controlling the ventral habenula, a region of the brain that mediates fear by regulating serotonin release. Kisspeptin1 may be a potential player in resilience developed as a result of control, extending previous findings that it can reduce fear.

animal behavior and cognition↗

bioRxiv2016

A regulated environment for micro-organs defines essential conditions for intercellular Ca2+ waves

The mechanical stress state of an organ is a critical, but still poorly understood, driver of organogenesis and regeneration. Here we report a chip-based regulated environment for micro-organs (REM-Chip) that enables systematic investigations of the crosstalk between an organs mechanical stress environment and biochemical signaling under a multitude of genetic and chemical perturbations. This method has enabled us to identify essential conditions for generating organ-scale intercellular calcium (Ca2+) waves (ICWs) in Drosophila wing imaginal discs that are also observed in vivo. Spontaneous ICWs require the presence of components in fly extract-based growth serum (FEX). Using the REM-Chip, we demonstrate that the release and not the initial application of mechanical compression is sufficient but not necessary to initiate ICWs. Further, the extent of the Ca2+ response is heterogeneous between discs and correlates with the degree of spontaneous ICWs activity in the pre-stress state. This system and method enable detailed examinations of the interplay between mechanical stress state, biochemical regulatory networks, and physiology in complex, hierarchically organized organ cultures.

developmental biology↗

bioRxiv2016

Reactive Oxygen Species Regulate Activity-Dependent Neuronal Structural Plasticity

Neurons are inherently plastic, adjusting their structure, connectivity and excitability in response to changes in activity. How neurons sense changes in their activity level and then transduce these to structural changes remains to be fully elucidated. Working with the Drosophila larval locomotor network, we show that neurons use reactive oxygen species (ROS), metabolic byproducts, to monitor their activity. ROS signals are both necessary and sufficient for activity-dependent structural adjustments of both pre- and postsynaptic terminals and for network output, as measured by larval crawling behavior. We find the highly conserved Parkinsons disease-linked protein DJ-1{beta} acts as a redox sensor in neurons where it regulates pre- and postsynaptic structural plasticity, in part via modulation of the PTEN-PI3Kinase pathway. Neuronal ROS thus play an important physiological role as second messengers required for neuronal and network tuning, whose dysregulation in the ageing brain and under neurodegenerative conditions may contribute to synaptic dysfunction.

neuroscience↗

bioRxiv2016

Chimeric Genes Revealed in the Polyploidy Fish Hybrids of Carassius cuvieri (Female) x Megalobrama amblycephala (Male)

The genomes of newly formed natural or artificial polyploids may experience rapid gene loss and genome restructuring. In this study, we obtained tetraploid hybrids (4n=148, 4nJB) and triploid hybrids (3n=124, 3nJB) derived from the hybridization of two different subfamily species Carassius cuvieri ([female], 2n = 100, JCC) and Megalobrama amblycephala ([male], 2n = 48, BSB). Some significant morphological and physiological differences were detected in the polyploidy hybrids compared with their parents. To reveal the molecular traits of the polyploids, we compared the liver transcriptomes of 4nJB, 3nJB and their parents. The results indicated high proportion chimeric genes (31 > %) and mutated orthologous genes (17 > %) both in 4nJB and 3nJB. We classified 10 gene patterns within three categories in 4nJB and 3nJB orthologous gene, and characterized 30 randomly chosen genes using genomic DNA to confirm the chimera or mutant. Moreover, we mapped chimeric genes involved pathways and discussed that the phenotypic novelty of the hybrids may relate to some chimeric genes. For example, we found there is an intragenic insertion in the K+ channel kcnk5b, which may be related to the novel presence of the barbels in 4nJB. Our results indicated that the genomes of newly formed polyploids experienced rapid restructuring post-polyploidization, which may results in the phenotypic and phenotypic changes among the polyploidy hybrid offspring. The formation of the 4nJB and 3nJB provided new insights into the genotypic and phenotypic diversity of hybrid fish resulting from distant hybridization between subfamilies.

developmental biology↗

bioRxiv2016

Potent optogenetic inhibition of behavior with anion channelrhodopsins

Optogenetics employs light exposure to manipulate physiology in genetically modified organisms. There are abundant tools for optogenetic excitation of neuronal activity, but the limitations of current activity photo-inhibitors present an obstacle to demonstrating the necessity of specific neuronal circuits. Here we show that anion channelrhodopsins can be used to specifically and rapidly inhibit a range of systems involved in Drosophila locomotion, wing expansion, memory retrieval and gustation, demonstrating their broad utility to the circuit analysis of behavior.

neuroscience↗

bioRxiv2016

Compromised External Validity: Federally Produced Cannabis Does Not Reflect Legal Markets

As the most widely used illicit drug, the basis of the fastest growing major industry in the US, and as a source of numerous under-studied psychoactive compounds, understanding the psychological and physiological effects of Cannabis is essential. The National Institute on Drug Abuse (NIDA) is designated as the sole legal producer of Cannabis for use in US research studies. We sought to compare the chemical profiles of Cannabis varieties that are available to consumers in states that have state-legalized use versus what is available to researchers interested in studying the plant and its effects. Our results demonstrate that the federally produced Cannabis has significantly less variety and lower concentrations of cannabinoids. Current research, which has focused on material that is far less diverse and less potent than that used by the public, limits our understanding of the plants chemical, biological, psychological, medical, and pharmacological properties. Investigation is urgently needed on the diverse forms of Cannabis used by the public in state-legal markets.

plant biology↗

bioRxiv2016

The Tension-sensitive Ion Transport Activity of MSL8 is Critical for its Function in Pollen Hydration and Germination

All cells respond to osmotic challenges, including those imposed during normal growth and development. Mechanosensitive (MS) ion channels provide a conserved mechanism for regulating osmotic forces by conducting ions in response to increased membrane tension. We previously demonstrated that the MS ion channel MscS-Like 8 (MSL8) is required for pollen to survive multiple osmotic challenges that occur during the normal process of fertilization, and that it can inhibit pollen germination. However, it remained unclear whether these physiological functions required ion flux through a mechanically gated channel provided by MSL8. We introduced two point mutations into the predicted pore-lining domain of MSL8 that disrupted normal channel function in different ways. The Ile711Ser mutation increased the tension threshold of the MSL8 channel while leaving conductance unchanged, and the Phe720Leu mutation severely disrupted the MSL8 channel. Both of these mutations impaired the ability of MSL8 to preserve pollen viability during hydration and to maintain the integrity of the pollen tube when expressed at endogenous levels. When overexpressed in a msl8-4 null background, MSL8I711S could partially rescue loss-of-function phenotypes, while MSL8F720L could not. When overexpressed in the wild type Ler background, MSL8I711S suppressed pollen germination, similar to wild type MSL8. In contrast, MSL8F720L failed to suppress pollen germination and increased pollen bursting, thereby phenocopying the msl8-4 mutant. Thus, an intact MSL8 channel is required to for normal pollen function during hydration and germination. These data establish MSL8 as the first plant MS channel to fulfill previously established criteria for assignment as a mechanotransducer.

plant biology↗