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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2017

Neurohormonal signalling controls insulin sensitivity and specificity in C. elegans

Insulin and insulin-like growth factor signalling regulates a broad spectrum of growth and metabolic responses to a variety of internal and environmental stimuli. Such responses can be tailored to the environment so that changes in insulin signalling result in distinct physiological responses to different stimuli. For example, the inhibition of insulin-like signalling by osmotic stress or by starvation of C. elegans results in physiologically distinct states and patterns of gene expression. How does insulin-like signalling elicit different responses to different environmental stimuli? We report that neurohormonal signalling involving the C. elegans cytosolic sulfotransferase SSU-1 controls developmental arrest in response to osmotic stress but not to starvation; that SSU-1 functions in a single pair of sensory neurons to control signalling via the nuclear hormone receptor NHR-1; that signalling controlled by SSU-1 acts antagonistically to insulin-like signalling; and that the FOXO transcription factor DAF-16, a downstream effector of insulin-like signalling, enters the nucleus in response to osmotic stress but activates gene expression only if SSU-1 is active. We propose that neurohormonal signalling controlled by one or more cytosolic sulfotransferases similarly regulates the specificity of responses to changes in insulin signalling during periods of environmental stress in other organisms and that abnormalities in such sulfotransferase-controlled neurohormonal signalling might contribute to human disorders that involve insulin signalling, such as obesity and type 2 diabetes.

genetics↗
bioRxiv2017

fluxweb: a package to easily estimate energy fluxes in food webs

O_LIUnderstanding how changes in biodiversity will impact the stability and functioning of ecosystems is a central challenge in ecology. Food-web approaches have been advocated to link community composition with ecosystem functioning by describing the fluxes of energy among species or trophic groups. However, estimating such fluxes remains problematic because current methods become unmanageable as network complexity increases.\nC_LIO_LIWe developed a generalisation of previous indirect estimation methods assuming a steady state system [1, 2, 3]: the model estimates energy fluxes in a top-down manner assuming system equilibrium; each nodes losses (consumption and physiological) balances its consumptive gains. Jointly, we provide theoretical and practical guidelines to use the fluxweb R package (available on CRAN at https://bit.ly/2OC0uKF).\nWe also present how the framework can merge with the allometric theory of ecology [4] to calculate fluxes based on easily obtainable organism-level data (i.e. body masses and species groups -eg, plants animals), opening its use to food webs of all complexities. Physiological losses (metabolic losses or losses due to death other than from predation within the food web) may be directly measured or estimated using allometric relationships based on the metabolic theory of ecology, and losses and gains due to predation are a function of ecological efficiencies that describe the proportion of energy that is used for biomass production.\nC_LIO_LIThe primary output is a matrix of fluxes among the nodes of the food web. These fluxes can be used to describe the role of a species, a function of interest (e.g. predation; total fluxes to predators), multiple functions, or total energy flux (system throughflow or multitrophic functioning). Additionally, the package includes functions to calculate network stability based on the Jacobian matrix, providing insight into how resilient the network is to small perturbations at steady state.\nC_LIO_LIOverall, fluxweb provides a flexible set of functions that greatly increase the feasibility of implementing food-web energetic approaches to more complex systems. As such, the package facilitates novel opportunities for mechanistically linking quantitative food webs and ecosystem functioning in real and dynamic natural landscapes.\nC_LI

ecology↗
bioRxiv2017

Growth and extended survival of Escherichia coli O157:H7 in soil organic matter

Enterohaemorrhagic Escherichia coli such as serotype O157:H7 are a leading cause of food-associated outbreaks. While the primary reservoir is associated with cattle, plant foods have been associated as sources of human infection. E. coli is able to grow in the tissue of food plants such as spinach. While fecal contamination is the primary suspect, soil has been underestimated as a potential reservoir. Persistence of bacterial populations in open systems is the product of growth, death, predation, and competition. Here we report that E. coli O157:H7 can grow using the soluble compounds in soil, and characterize the effect of soil growth in the stationary phase proteome. E. coli 933D (stxII-) was cultured in Soil Extracted Soluble Organic Matter (SESOM) and the culturable count determined for 24 d. The proteomes of exponential and stationary phase populations were characterized by 2D gel electrophoresis and protein spots were identified by MALDI-TOF mass spectrometry. While LB controls displayed a death phase, SESOM grown population remained culturable for 24 d, indicating an altered physiological state with superior longevity. This was not due to decreased cell density on entry to stationary phase as 24h SESOM populations concentrated 10-fold retained their longevity. Principal component analysis showed that stationary phase proteomes from SESOM and LB were different. Differences included proteins involved in stress response, motility, membrane and wall composition, nutrient uptake, translation and protein turnover, and anabolic and catabolic pathways, indicating an altered physiological state of soil-grown cells entering stationary phase. The results suggest that E. coli may be a soil commensal that in absence of predation and competition maintains stable populations in soil.

microbiology↗
bioRxiv2017

Cooperativity in Plant Plasma Membrane Intrinsic Proteins (PIPs): Mechanism of Increased Water Transport in Maize PIP1 Channels in Hetero-tetramers

Plant aquaporins (AQPs) play vital roles in several physiological processes. Plasma membrane intrinsic proteins (PIPs) belong to the subfamily of plant AQPs and they are further divided into two closely related subgroups PIP1s and PIP2s. Members of the two subgroups have been shown to have different transport properties. While PIP2 members are efficient water channels, PIP1s from some plant species have been shown to be functionally inactive. Aquaporins form tetramers under physiological conditions. PIP2s can enhance the water transport of PIP1s when they form hetero-tetramers. However, the role of monomer-monomer interface and the significance of specific residues in enhancing the water permeation of PIP1s have not been investigated at atomic level. We have performed all-atom molecular dynamics (MD) simulations of homo-tetramers of ZmPIP1;2 and ZmPIP2;5 from Zea mays and hetero-tetramers containing ZmPIP1;2 and ZmPIP2;5 with different stoichiometries and configurations. ZmPIP1;2 in a tetramer assembly will have two interfaces, one formed by transmembrane segments TM4 and TM5 and the other formed by TM1 and TM2. We have analyzed channel radius profiles, water transport and potential of mean force profiles of ZmPIP1;2 monomers with different types of interfaces. Results of MD simulations clearly revealed that TM4-TM5 interface and not the TM1-TM2 interface is important in modulating the water transport of ZmPIP1;2. We generated in silico mutants of specific residues that are involved in contacts with adjacent monomers. MD simulations of mutant tetramers highlighted the importance of I93 residue from the TM2 segment of ZmPIP2;5 for the increased water transport in ZmPIP1;2.

biophysics↗
bioRxiv2018

Rapid sensing of L-leucine by human and murine hypothalamic neurons: neurochemical and mechanistic insights

ObjectiveDietary proteins are sensed by hypothalamic neurons and strongly influence multiple aspects of metabolic health, including appetite, weight gain and adiposity. However, little is known about the mechanisms by which hypothalamic neural circuits controlling behavior and metabolism sense protein availability. The aim of this study is to characterize how neurons from the mediobasal hypothalamus respond to a signal of protein availability: the amino acid L-leucine.\n\nMethodsWe used primary cultures of post-weaning murine mediobasal hypothalamic neurons, hypothalamic neurons derived from human induced pluripotent stem cells, and calcium imaging to characterize rapid neuronal responses to physiological changes in extracellular L-Leucine concentration.\n\nResultsA neurochemically diverse subset of both mouse and human hypothalamic neurons responded rapidly to L-leucine. Consistent with L-leucines anorexigenic role, we found that 25% of mouse MBH POMC neurons were activated by L-leucine. 10% MBH NPY neurons were inhibited by L-leucine, and leucine rapidly reduced AGRP secretion, providing a mechanism for the rapid leucine-induced inhibition of foraging behaviour in rodents. Surprisingly, none of the candidate mechanisms previously implicated in hypothalamic leucine sensing (KATP channels, mTORC1 signaling, amino-acid decarboxylation) were involved in the acute activity changes produced by L-leucine. Instead, our data indicate that leucine-induced neuronal activation involves a plasma membrane Ca2+ channel, whereas leucine-induced neuronal inhibition is mediated by inhibition of a store-operated Ca2+ current.\n\nConclusionsA subset of neurons in the mediobasal hypothalamus rapidly respond to physiological changes in extracellular leucine concentration. Leucine can produce both increases and decreases in neuronal Ca2+ concentrations in a neurochemically-diverse group of neurons, including some POMC and NPY/AGRP neurons. Our data reveal that leucine can signal through novel mechanisms to rapidly affect neuronal activity.\n\nHighlights- A neurochemically diverse group of mouse and human hypothalamic neurons rapidly sense and respond to L-leucine\n- Leucine can produce neuronal activation or neuronal inhibition via distinct and novel Ca2+ signaling mechanisms.\n- Leucine activates 25% ARH POMC neurons\n- Leucine inhibits 10% ARH NPY/AGRP neurons and reduces AGRP secretion from fasted mediobasal hypothalamic slices

neuroscience↗
bioRxiv2018

A metaproteomics method to determine carbon sources and assimilation pathways of species in microbial communities

Measurements of the carbon stable isotope ratio ({delta}13C) are widely used in biology to address major questions regarding food sources and metabolic pathways used by organisms. Measurement of these so called stable carbon isotope fingerprints (SIFs) for microbes involved in biogeochemical cycling and microbiota of plants and animals have led to major discoveries in environmental microbiology. Currently, obtaining SIFs for microbial communities is challenging as the available methods either only provide limited taxonomic resolution, such as with the use of lipid biomarkers, or are limited in throughput, such as NanoSIMS imaging of single cells.\n\nHere we present \"direct Protein-SIF\" and the Calis-p software package (https://sourceforge.net/projects/calis-p/), which enable high-throughput measurements of accurate {delta}13C values for individual species within a microbial community. We benchmark the method using 20 pure culture microorganisms and show that the method reproducibly provides SIF values consistent with gold standard bulk measurements performed with an isotope ratio mass spectrometer. Using mock community samples, we show that SIF values can also be obtained for individual species within a microbial community. Finally, a case study of an obligate bacteria-animal symbiosis showed that direct Protein-SIF confirms previous physiological hypotheses and can provide unexpected new insights into the symbionts metabolism. This confirms the usefulness of this new approach to accurately determine {delta}13C values for different species in microbial community samples.\n\nSignificanceTo understand the roles that microorganisms play in diverse environments such as the open ocean and the human intestinal tract, we need an understanding of their metabolism and physiology. A variety of methods such as metagenomics and metaproteomics exist to assess the metabolism of environmental microorganisms based on gene content and gene expression. These methods often only provide indirect evidence for which substrates are used by a microorganism in a community. The direct Protein-SIF method that we developed allows linking microbial species in communities to the environmental carbon sources they consume by determining their stable carbon isotope signature. Direct Protein-SIF also allows assessing which carbon fixation pathway is used by autotrophic microorganisms that directly assimilate CO2.

microbiology↗
bioRxiv2018

The molecular recognition of phosphatidic acid by an amphipathic helix in Opi1

A key event in cellular physiology is the decision between membrane biogenesis and fat storage. Phosphatidic acid (PA) is an important lipid intermediate and signaling lipid at the branch point of these pathways and constantly monitored by the transcriptional repressor Opi1 to orchestrate lipid metabolism. Here, we report on the mechanism of membrane recognition by Opi1 and identify an amphipathic helix (AH) for the selective binding to membranes containing PA over phosphatidylserine (PS). The insertion of the AH into the hydrophobic core of the membrane renders Opi1 sensitive to the lipid acyl chain composition as an important factor contributing to the regulation of membrane biogenesis. Based on these findings, we rationally designed the membrane binding properties of Opi1 to control its responsiveness in the physiological context. Using extensive molecular dynamics (MD) simulations, we identified two PA-selective three-finger grips that tightly bind the phosphate headgroup, while interacting less intimately and more transiently with PS. This work establishes lipid headgroup selectivity as a new feature in the family of AH-containing membrane property sensors.

biochemistry↗
bioRxiv2018

Using imaging photoplethysmography for heart rate estimation in non-human primates

For humans and for non-human primates heart rate is a reliable indicator of an individuals current physiological state, with applications ranging from health checks to experimental studies of cognitive and emotional state. In humans, changes in the optical properties of the skin tissue correlated with cardiac cycles (imaging photoplethysmogram, iPPG) allow non-contact estimation of heart rate by its proxy, pulse rate. Yet, there is no established simple and non-invasive technique for pulse rate measurements in awake and behaving animals. Using iPPG, we here demonstrate that pulse rate in rhesus monkeys can be accurately estimated from facial videos. We computed iPPGs from seven color facial videos of three awake head-stabilized rhesus monkeys. Pulse rate estimated from iPPGs was in good agreement with reference data from a pulse-oximeter with error of pulse rate estimation below 5% for 82% of all epochs, and below 10% for 98% of the epochs. We conclude that iPPG allows non-invasive and non-contact estimation of pulse rate in non-human primates, which is useful for physiological studies and can be used toward welfare-assessment of non-human primates in research.

bioengineering↗
bioRxiv2018

Two Novel Forms of ERG Oscillation in Drosophila: Age and Activity Dependence

Over an animals lifespan, neuronal circuits and systems often decline in an inherently heterogeneous fashion. To compare the age-dependent progression of changes in visual behavior with alterations in retinal physiology, we examined phototaxis and electroretinograms (ERGs) in a wild-type D. melanogaster strain (Canton-S) across their lifespan. In aged flies (beyond 50% median lifespan), we found a marked decline in phototaxis, while motor coordination was less disrupted, as indicated by relatively stronger negative geotaxis. These aged flies displayed substantially reduced ERG transient amplitudes while the receptor potentials (RP) remained largely intact. Using a repetitive light flash protocol, we serendipitously discovered two forms of activity-dependent oscillation in the ERG waveforms of young flies: \"light-off and \"light-on\" oscillations. After repeated 500 ms light flashes, light-off oscillations appeared during the ERG off-transients (frequency: 50-120 Hz, amplitude: ~1 mV). Light-on oscillations (100-200 Hz, ~0.3 mV) were induced by a series of 50 ms flashes, and were evident during the ERG on-transients. Both forms of oscillation were observed in other strains of D. melanogaster(Oregon-R, Berlin), additional Drosophila species (funerbris, euronotus, hydei, americana), and were evoked by a variety of light sources. Both light-off and light-on oscillations were distinct from previously described ERG oscillations in visual mutants, such as rosA, in terms of location within the waveform and frequency. However, within rosA mutants, light-off oscillations, but not light-on oscillations could be recruited by the repetitive light flash protocol. Importantly though, we found that both forms of oscillation were rarely observed in aged flies. Although the physiological bases of these oscillations remain to be elucidated, they may provide important clues to age-related changes in neuronal excitability and synaptic transmission.

neuroscience↗
bioRxiv2018

Evolutionary trajectories to amoxicillin-clavulanic acid resistance in Escherichia coli are affected by growth media.

In the face of an accelerating global antimicrobial resistance crisis, the determination of bacterial fitness following acquisition of resistance is an expanding area of research, and increased understanding of this process will be crucial to translate in vitro fitness data to successful therapies. Given that crucial clinical treatment situations are guided by in vitro diagnostic testing in an artificial environment far removed from human physiological niches, we used Escherichia coli and amoxicillin-clavulanic acid (AMC) resistance as a model to understand how such environments could affect the emergence of resistance, associated fitness costs and the predictive value of this data when strains were grown in the more physiologically relevant environments of urine and urothelial organoids. Resistant E. coli isolates were selected for following 24-hour exposure to sub-inhibitory concentrations of AMC in either M9, ISO or LB broth, followed by growth on LB agar containing AMC. No resistant colonies emerged following growth in M9, whereas resistant isolates were detected from cultures grown in ISO and LB broth. We observed both within and between media-type variability in the levels of resistance and fitness of the resistant mutants grown in LB. MICs and fitness of these resistant strains in different media (M9, ISO, LB, human urine and urothelial organoids) showed considerable variation. Media can therefore have a direct effect on the isolation of mutants that confer resistance to AMC and these mutants can exhibit unpredictable MIC and fitness profiles under different growth conditions. This study highlights the risks in relying on a single culture protocol to predict the behaviour and treatment response of bacteria in vivo and highlights the importance of developing comprehensive experimental designs to ensure effective translation of diagnostic procedures to successful clinical outcomes.

microbiology↗
bioRxiv2018

Drosophila melanogaster establishes a species-specific mutualistic interaction with stable gut-colonizing bacteria

Animals live together with diverse bacteria that can impact their biology. In Drosophila melanogaster, gut-associated bacterial communities are relatively simple in composition but also have a strong impact on host development and physiology. However, it is still unknown if bacteria can proliferate and stably associate with the gut of D. melanogaster. In fact, it is generally assumed that bacteria are transient and their constant ingestion with food is required to maintain their presence in the gut. Here, we identify bacterial species from wild-caught D. melanogaster that stably associate with the host independently of continuous inoculation. Moreover, we show that specific Acetobacter wild isolates can proliferate in the gut. We further demonstrate that the interaction between D. melanogaster and the wild isolated Acetobacter thailandicus is mutually beneficial and that the stability of the gut association is key to this mutualism. The stable population in the gut of D. melanogaster allows continuous bacterial spreading into the environment, which is advantageous to the bacterium itself. The bacterial dissemination is in turn advantageous to the host since the next generation of flies develops in the presence of this particularly beneficial bacterium. Ac. thailandicus leads to a faster host development and higher fertility of emerging adults, when compared to other bacteria isolated from wild-caught flies. Furthermore, Ac. thailandicus is sufficient and advantageous when D. melanogaster develops in axenic or freshly collected figs, respectively. This isolate of Ac. thailandicus colonizes several genotypes of D. melanogaster but not of the closely related Drosophila simulans, indicating that the stable association is host specific. This work establishes a new conceptual model to understand D. melanogaster- gut microbiota interactions in an ecological context; stable interactions can be mutualistic through microbial farming, a common strategy in insects. Moreover, these results develop the use of D. melanogaster as a model to study gut microbiota proliferation and colonization.\n\nAuthor summaryAnimals, including humans, live together with complex bacterial communities in their gut that influence their physiology and health. The fruit fly Drosophila melanogaster has been an excellent model organism to study host-microbe interactions and harbours a relative simple gut bacterial community. However, it is not known which of these bacteria can proliferate and form stable communities in the gut, and the current hypothesis is that these bacteria are only transiently associated with the gut. Here, we show that in D. melanogaster collected from a natural population stable gut bacteria do exist. We isolated specific species that can proliferate in the gut and form a stable association. This is beneficial to the bacteria since they can be constantly spread by the flies as they move around. On the other hand, this is a form of farming as the next generation of flies benefit from the association with these particular bacteria during development. They become adults faster and are more fertile than if they develop with other bacteria encountered in nature. These advantages are also observed when flies develop in figs, a natural food source. Our findings show that D. melanogaster has stable colonizing bacteria in the gut and establish a new framework to study host-gut bacteria interactions.

microbiology↗
bioRxiv2018

Adaptive diversification of growth allometry in the plant Arabidopsis thaliana

Seed plants vary tremendously in size and morphology. However, variation and covariation between plant traits may at least in part be governed by universal biophysical laws and biological constants. Metabolic Scaling Theory (MST) posits that whole-organismal metabolism and growth rate are under stabilizing selection that minimizes the scaling of hydrodynamic resistance and maximizes the scaling of resource uptake. This constrains variation in physiological traits and in the rate of biomass accumulation, so that they can be expressed as mathematical functions of plant size with near constant allometric scaling exponents across species. However, observed variation in scaling exponents questions the evolutionary drivers and the universality of allometric equations. We have measured growth scaling and fitness traits of 451 Arabidopsis thaliana accessions with sequenced genomes. Variation among accessions around the scaling exponent predicted by MST correlated with relative growth rate, seed production and stress resistance. Genomic analyses indicate that growth allometry is affected by many genes associated with local climate and abiotic stress response. The gene with the strongest effect, PUB4, has molecular signatures of balancing selection, suggesting that intraspecific variation in growth scaling is maintained by opposing selection on the trade-off between seed production and abiotic stress resistance. Our findings support a core MST prediction and suggest that variation in allometry contributes to local adaptation to contrasting environments. Our results help reconcile past debates on the origin of allometric scaling in biology, and begin to link adaptive variation in allometric scaling to specific genes.\n\nSignificance statementAre there biological constants unifying phenotypic diversity across scales? Metabolic Scaling Theory (MST) predicts mathematical regularity and constancy in the allometric scaling of growth rate with body size across species. Here, we show that adaptation to climate in Arabidopsis thaliana is associated with local strains that substantially deviate from the values predicted by MST. This deviation can be linked to increased stress tolerance at the expense of seed production, and it occurs through selection on genes that are involved in abiotic stress response and that are geographically correlated with climatic conditions. This highlights the evolutionary role of allometric diversification and helps establish the physiological bases of plant adaptation to contrasting environments.

ecology↗
bioRxiv2018

Nicotinic cholinergic receptors in VTA glutamate neurons modulate excitatory transmission

Ventral tegmental area (VTA) glutamate neurons are important components of brain reward circuitry, but whether they are subject to cholinergic modulation is unknown. To study this, we used an array of molecular, physiological, and photostimulation techniques to examine nicotinic acetylcholine receptors (nAChRs) in VTA glutamate neurons. VTA neurons positive for the vesicular glutamate transporter 2 (VGLUT2+) are responsive to acetylcholine (ACh) released from mesopontine cholinergic axons. VTA VGLUT2+ neurons express mRNA and protein subunits known to comprise typical heteromeric nAChRs. Electrophysiology, coupled with 2-photon microscopy and laser flash photolysis of a photoactivatable nicotine probe, was used to demonstrate nAChR functional activity in the somatodendritic subcellular compartment of VTA VGLUT2+ neurons. Finally, optogenetic isolation of intrinsic VTA glutamatergic microcircuits demonstrated that nicotine potently modulates excitatory transmission within the VTA. These results indicate that VTA glutamate neurons are modulated by cholinergic mechanisms and participate in the cascade of physiological responses to nicotine exposure.

neuroscience↗
bioRxiv2018

Metabolomics and proteomics analyses of grain yield reduction in rice under abrupt drought-flood alternation

HighlightAbrupt drought-flood alteration is a frequent meteorological disaster that occurs during summer in southern China and the Yangtze river basin, which often causes a large area reduction of rice yield. We previously reported abrupt drought-flood alteration effects on yield and its components, physiological characteristics, matter accumulation and translocation, rice quality of rice. However, the molecular mechanism of rice yield reduction caused by abrupt drought-flood alternation has not been reported.\n\nIn this study, four treatments were provided, no drought and no floods (control), drought without floods (duration of drought 10 d), no drought with floods (duration of floods 8 d), and abrupt drought-flood alteration (duration of drought 10 d and floods 8 d). The quantitative analysis of spike metabolites was proceeded by LC-MS (liquid chromatograph-mass spectrometry) firstly. Then the Heat-map, PCA, PLS-DA, OPLS-DA and response ranking test of OPLS-DA model methods were used to analysis the function of differential metabolites (DMs) during the rice panicle differentiation stage under abrupt drought-flood alteration. In addition, relative quantitative analysis of spike total proteins under the treatment was conducted iTRAQ (isobaric tags for relative and absolute quantification) and LC-MS. In this study, 5708 proteins were identified and 4803 proteins were quantified. The identification and analysis of DEPs function suggested that abrupt drought-flood alteration treatment can promote carbohydrate metabolic, stress response, oxidation-reduction, defense response, and energy reserve metabolic process, etc, during panicle differentiation stage. In this study relative quantitative proteomics, metabolomics and physiology data (soluble protein content, superoxide dismutase activity, hydrogen peroxidase activity, peroxidase activity, malondialdehyde content, free proline content, soluble sugar content and net photosynthetic rate) analysis were applied to explicit the response mechanism of rice panicle differentiation stage under abrupt drought-flood alteration and provides a theoretical basis for the disaster prevention and mitigation.\n\nAbstractAbrupt drought-flood alternation is a meteorological disaster that frequently occurs during summer in southern China and the Yangtze river basin, often causing a significant loss of rice production. In this study, a quantitative analysis of spike metabolites was conducted via liquid chromatograph-mass spectrometry (LC-MS), and Heat-map, PCA, PLS-DA, OPLS-DA, and a response ranking test of OPLS-DA model methods were used to analyze functions of differential metabolites (DMs) during the rice panicle differentiation stage under abrupt drought-flood alternation. The results showed that 102 DMs were identified from the rice spike between T1 (abrupt drought-flood alternation) and CK0 (control) treatment, 104 DMs were identified between T1 and CK1 (drought) treatment and 116 DMs were identified between T1 and CK2 (flood) treatment. In addition, a relative quantitative analysis of spike total proteins was conducted using isobaric tags for relative and absolute quantification (iTRAQ) and LC-MS. The identification and analysis of DEPs functions indicates that abrupt drought-flood alternation treatment can promote carbohydrate metabolic, stress response, oxidation-reduction, defense response, and energy reserve metabolic process during the panicle differentiation stage. In this study, relative quantitative metabolomics and proteomics analyses were applied to explore the response mechanism of rice panicle differentiation in response to abrupt drought-flood alternation.\n\nAbbreviations

plant biology↗
bioRxiv2018

Plasma redox imbalance caused by albumin oxidation promotes lung-predominant NETosis and pulmonary cancer metastasis

Neutrophil extracellular traps (NETs) entrap circulating tumor cells (CTCs) and promote metastasis within distant organs in preclinical models1,2. In these models, NETosis is triggered by exogenous massive inflammatory stimuli, and thus it remains unknown whether cancer hosts under physiologic inflammation-free conditions experience NETosis and consequent cancer metastasis. Here we show that plasma redox imbalance caused by albumin oxidation promotes inflammation-independent NETosis and cancer metastasis specifically in the lungs. Albumin is the major source of free thiol that maintains redox balance in vitro and in vivo. Oxidation of albumin-derived free thiol is sufficient to trigger NETosis via accumulation of reactive oxygen species within neutrophils. The resultant NETs are found predominantly within lungs where they contribute to the colonization of CTCs leading to pulmonary metastases in mouse models. These effects are abrogated by pharmacologic inhibition of NET formation. Moreover, albumin oxidation and the resultant decline of plasma free thiol are associated with pulmonary metastasis in a cohort of head and neck cancer patients. These results implicate plasma redox balance as an endogenous and physiologic regulator of NETosis and pulmonary cancer metastasis, providing new therapeutic and diagnostic opportunities for combatting cancer progression.

cancer biology↗
bioRxiv2018

A new function for Prokineticin 2: recruitment of SVZ-derived neuroblasts to the injured cortex in a mouse model of traumatic brain injury

Traumatic brain injury is an important cause of mortality and morbidity all over the world. After the initial injury there is a cascade of cellular and molecular events that ultimately lead to cell death. Therapies aim not only to counteract these mechanisms but also to replenish the lost cell population in order to achieve a better recovery. The adult mammal brain in not as plastic as the postnatal, but it has at least two neurogenic regions that maintains physiological functions in the brain; the subgranular zone of the dentate gyrus of the hippocampus, which produces neurons that integrate locally, and the subventricular zone (SVZ) of the lateral ventricles, that produces neuroblasts that migrate through the rostral migratory stream (RMS) to the olfactory bulbs. Brain injuries, as well as neurodegenerative diseases, induce the SVZ to respond by increasing cell proliferation and migration to the injured areas. Here we report that SVZ cells migrate to the injured cortex after traumatic brain injury in mice, and that the physiological RMS migration is not impaired. We also show that Prokineticin 2 (PROK2), a chemokine important for the olfactory bulb neurogenesis by promoting the directional migration of neuroblasts, is induced in the injured cortex. Using PROK2 receptor antagonist and recombinant PROK2 we show for the first time that PROK2 can directionally attract SVZ cells in vitro and in vivo. The data we present here links one more element of the inflammatory process, PROK2 secreted by microglia, to the attempt to regenerate an acutely injured mammalian cortex.\n\nAbbreviations

neuroscience↗
bioRxiv2018

An Array of Gut-on-a-Chips for Drug Development

Drug development is a time and cost-consuming long process. Conventionally, this involves the use of two-dimensional (2D) cell culture and animal testing. However, these methods often fail to mimic normal human physiology and drug metabolism, and sometimes complications may occur later because they do not appear in preclinical studies. With recent development of organ-on-a-chip devices, these biomimetic systems try to recapitulate human physiology more than other methods, and promise to largely replace animal studies and reduce costs and complications. Because gut is an important route for drug administration and absorption, gut-on-a-chip platform was developed. To develop a high throughput system, a recent work reported on using a multiplication array of several chip devices, demonstrating the efficiency in studying drug effect on gut barrier function as compared to conventional methods. Huge data was generated, and thus new multidisciplinary approach is needed where data collection, communication and analysis platforms need to be developed. This will enable validation of organ-on-a-chip approach and lay basis for its establishment as efficient and cost-effective tool in drug development. Because of the importance of the work, this commentary highlights important aspects of the topic and try to stimulate new the development of innovations in the field.\n\nDisclosureNo conflict of interest.

cell biology↗
bioRxiv2018

Chromatin accessibility dynamics across C. elegans development and ageing

An essential step for understanding the transcriptional circuits that control development and physiology is the global identification and characterization of regulatory elements. Here we present the first map of regulatory elements across the development and ageing of an animal, identifying 42,245 elements accessible in at least one C. elegans stage. Based on nuclear transcription profiles, we define 15,714 protein-coding promoters and 19,231 putative enhancers, and find that both types of element can drive orientation-independent transcription. Additionally, hundreds of promoters produce transcripts antisense to protein coding genes, suggesting involvement in a widespread regulatory mechanism. We find that the accessibility of most elements is regulated during development and/or ageing and that patterns of accessibility change are linked to specific developmental or physiological processes. The map and characterization of regulatory elements across C. elegans life provides a platform for understanding how transcription controls development and ageing.

genomics↗