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bioRxiv2024

Estimating Organ-to-Plasma Ratios in physiologically based PK modeling: a simplified approach for early drug discovery

Physiologically based pharmacokinetics (PBPK) modeling is a valuable tool in drug development and candidate selection. However, its widespread adoption in early stages of drug discovery remains limited. This study proposes a novel simplified approach to estimate organ-to-plasma ratio (Kp) values based on measured or estimated volume of distribution (VDss) to eliminate the reliance on additional in vitro data such as blood to plasma partition, LogP and pKa, which may not be available for newly synthesized molecules. The study includes 11 simulations across 4 compounds and 5 species. When simulations were based on ideal VDss and clearance (CL) values determined through non-compartmental analysis (NCA), the observed average absolute fold error (AAFE) aligned with experimental variability in the in vivo experiments (AAFE=1.3). However, when in vitro to in vivo correlation approaches were used to predict VDss and CL starting from in vitro intrinsic CL, plasma protein binding and microsomal binding, the AAFE increased to 1.7, reflecting the additional error introduced by the use of in vitro data to determine PK properties. Overall, this work provides a starting point for the facile implementation of PBPK models to meet the needs of early drug discovery projects.

pharmacology and toxicology↗

bioRxiv2024

Screening and characterization of 133 physiologically-relevant environmental chemicals for reproductive toxicity

Reproduction is a functional outcome that relies on complex cellular, tissue, and organ interactions that span the developmental period to adulthood. Thus, the assessment of its disruption by environmental chemicals is remarkably painstaking in conventional toxicological animal models and does not scale up to the number of chemicals present in our environment and requiring testing. We adapted a previously described low-throughput in vivo chromosome segregation assay using C. elegans predictive of reproductive toxicity and leveraged available public data sources (ToxCast, ICE) to screen and characterize 133 physiologically-relevant chemicals in a high-throughput manner. The screening outcome was further validated in a second, independent in vivo assay assessing embryonic viability. In total, 13 chemicals were classified as reproductive toxicants with the two most active chemicals belonging to the large family of Quaternary Ammonium Compounds (QACs) commonly used as disinfectants but with limited available reproductive toxicity data. We compared the results from the C. elegans assay with ToxCast in vitro data compiled from 700+ cell response assays and 300+ signaling pathways-based assays. We did not observe a difference in the bioactivity or in average potency (AC50) between the top and bottom chemicals. However, the intended target categories were significantly different between the classified chemicals with, in particular, an over-representation of steroid hormone targets for the high Z-score chemicals. Taken together, these results point to the value of in vivo models that scale to high-throughput level for reproductive toxicity assessment and to the need to prioritize the assessment of QACs impacts on reproduction.

pharmacology and toxicology↗

bioRxiv2024

Establishing Primary and Stable Cell Lines from Frozen Wing Biopsies for Cellular, Physiological, and Genetic Studies in Bats

Bats stand out among mammalian species for their exceptional traits, including the capacity to navigate through flight and echolocation, conserve energy through torpor/hibernation, harbor a multitude of viruses, exhibit resistance to disease, survive harsh environmental conditions, and demonstrate exceptional longevity compared to other mammals of similar size. In vivo studies of bats can be challenging for several reasons such as ability to locate and capture them in their natural environments, limited accessibility, low sample size, environmental variation, long lifespans, slow reproductive rates, zoonotic disease risks, species protection, and ethical concerns. Thus, establishing alternative laboratory models is crucial for investigating the diverse physiological adaptations observed in bats. Obtaining quality cells from tissues is a critical first step for successful primary cell derivation. However, it is often impractical to collect fresh tissue and process the samples immediately for cell culture due to the resources required for isolating and expanding cells. As a result, frozen tissue is typically the starting resource for bat primary cell derivation. Yet, cells in frozen tissue are usually damaged and represent low integrity and viability. As a result, isolating primary cells from frozen tissues poses a significant challenge. Herein, we present a successfully developed protocol for isolating primary dermal fibroblasts from frozen bat wing biopsies. This protocol marks a significant milestone, as this the first protocol specially focused on fibroblasts isolation from bat frozen tissue. We also describe methods for primary cell characterization, genetic manipulation of primary cells through lentivirus transduction, and the development of stable cell lines. Basic Protocol 1: Bat wing biopsy collection and preservation Support Protocol 1: Blood collection from bat-venipuncture Basic Protocol 2: Isolation of primary fibroblasts from adult bat frozen wing biopsy Support Protocol 2: Maintenance of primary fibroblasts Support Protocol 3: Cell banking and thawing of primary fibroblasts Support Protocol 4: Growth curve and doubling time Support Protocol 5: Lentiviral transduction of bat primary fibroblasts Basic Protocol 3: Bat stable fibroblasts cell lines development Support Protocol 6: Bat fibroblasts validation by immunofluorescence staining Support Protocol 7: Chromosome counting

cell biology↗

bioRxiv2024

Human visual performance for identifying letters affected by physiologically-inspired scrambling

AO_SCPLOWBSTRACTC_SCPLOWIn the geniculostriate pathway of the human visual system, neuronal projections carry signals from a particular retinal locus in parallel from one anatomical area to the next. Imprecision in the fidelity of these projections would place constraints on the ability of the system to perform tasks requiring positional information. We investigated the impact that "spatial scrambling" between stages would have on visual performance. We consider two stages in a simple canonical model of the early visual cortex where scrambling might occur: either the input to the first orientation-tuned mechanisms (analogous to V1 simple cells), or the output from those mechanisms. These are referred as "subcortical" (SCS) and "cortical scrambling" (CS). We developed a wavelet decomposition and resynthesis algorithm to mimic these effects, and measured human performance in letter identification affected by the two types of scrambling. Our results showed SCS and CS have distinguishable effects on both perceived noisiness of letters and letter identification threshold. Comparing human performance against a suite of pre-trained and custom convolutional neural networks (CNNs) that were trained on the scrambled stimuli, relative efficiency (calculated from the ratio of human:CNN thresholds) is higher for CS than SCS. However, in modelling human inefficiency by reducing the proportion of wavelets available to the CNNs, humans are less efficient in CS than SCS. These differences in efficiencies show humans are better at processing orientation redundant stimuli (CS) than orientation noisy stimuli (SCS). We hypothesize this reflects differences in integration properties at the input and output stages of simple cells in the cortex. Author SummaryThe brain makes sense of the input from our eyes through a system where features are extracted and combined in successive stages. Our study concerns the spatial fidelity of the connections between visual areas. Previous behavioural and physiological evidence has suggested a scrambling of neuronal projections is present in biological visual systems. In our study, we investigate the ability of the human visual system to perform letter identification with stimuli affected by different types of on-screen distortions. These distortions simulate internal scrambling occurring at two early stages in the visual hierarchy. We used convolutional neural network (CNN) models as a benchmark, against which we compared human performance to find human efficiency in handling the distortions. We found that the type of scrambling in which humans were determined to have greater "efficiency" (relative to the CNNs) depended on the analysis used. The threshold magnitude of scrambling at which the letters could no longer be identified was greater for letters scrambled after the oriented features were extracted. Conversely, when efficiency was calculated by starving the CNNs of samples until their performance declined to the human level we instead found that the effective "number of samples" used by our humans was much higher for stimuli simulating scrambling before the oriented feature stage. These differences reflect how information is pooled and combined for these two stages.

neuroscience↗

bioRxiv2024

Nuclear release of eIF1 globally increases stringency of start-codon selection to preserve mitotic arrest physiology

Regulated start-codon selection has the potential to reshape the proteome through the differential production of uORFs, canonical proteins, and alternative translational isoforms. However, conditions under which start-codon selection is altered remain poorly defined. Here, using transcriptome-wide translation initiation site profiling, we reveal a global increase in the stringency of start-codon selection during mammalian mitosis. Low-efficiency initiation sites are preferentially repressed in mitosis, resulting in pervasive changes in the translation of thousands of start sites and their corresponding protein products. This increased stringency of start-codon selection during mitosis results from increased interactions between the key regulator of start-codon selection, eIF1, and the 40S ribosome. We find that increased eIF1-40S ribosome interactions during mitosis are mediated by the release of a nuclear pool of eIF1 upon nuclear envelope breakdown. Selectively depleting the nuclear pool of eIF1 eliminates the changes to translational stringency during mitosis, resulting in altered mitotic proteome composition. In addition, preventing mitotic translational rewiring results in substantially increased cell death and decreased mitotic slippage following treatment with anti-mitotic chemotherapeutics. Thus, cells globally control translation initiation stringency with critical roles during the mammalian cell cycle to preserve mitotic cell physiology.

molecular biology↗

bioRxiv2024

Silversol (a colloidal nanosilver formulation) inhibits growth of antibiotic-resistant Staphylococcus aureus by disrupting its physiology in multiple ways

Antibacterial effect of a colloidal nanosilver formulation Silversol(R) was investigated against an antibiotic-resistant strain of Staphylococcus aureus. Lower concentrations of the test formulation exerted bacteriostatic and, its higher concentrations exerted bactericidal effect against this pathogen. Silversol(R) at sub-lethal concentration was found to disturb multiple physiological traits of S. aureus such as growth, antibiotic susceptibility, membrane permeability, efflux, protein synthesis and export, biofilm and exopolysaccharide production, etc. Transcriptome data revealed the genes coding for transcriptional regulators, efflux machinery, transferases, {beta}-lactam resistance, oxidoreductases, metal homeostasis, virulence factors, and arginine biosynthesis to get expressed differently under influence of the test formulation. Genes (argG and argH) involved in arginine biosynthesis emerged among the major targets of Silversol(R) in S. aureus.

microbiology↗

bioRxiv2024

A Continuous Attractor Model with Realistic Neural and Synaptic Properties Quantitatively Reproduces Grid Cell Physiology

Computational simulations with data-driven physiological detail can foster a deeper understanding of the neural mechanisms involved in cognition. Here, we utilize the wealth of cellular properties from Hippocampome.org to study neural mechanisms of spatial coding with a spiking continuous attractor network model of medial entorhinal cortex circuit activity. The primary goal was to investigate if adding such realistic constraints could produce firing patterns similar to those measured in real neurons. Biological characteristics included in the work are excitability, connectivity, and synaptic signaling of neuron types defined primarily by their axonal and dendritic morphologies. We investigate the spiking dynamics in specific neuron types and the synaptic activities between groups of neurons. Modeling the rodent hippocampal formation keeps the simulations to a computationally reasonable scale while also anchoring the parameters and results to experimental measurements. Our model generates grid cell activity that well matches the spacing, size, and firing rates of grid fields recorded in live behaving animals from both published datasets and new experiments performed for this study. Our simulations also recreate different scales of those properties, e.g., small and large, as found along the dorsoventral axis of the medial entorhinal cortex. Computational exploration of neuronal and synaptic model parameters reveals that a broad range of neural properties produce grid fields in the simulation. These results demonstrate that the continuous attractor network model of grid cells is compatible with a spiking neural network implementation sourcing data-driven biophysical and anatomical parameters from Hippocampome.org. The software is released as open source to enable broad community reuse and encourage novel applications.

neuroscience↗

bioRxiv2024

Species richness patterns in Fijian bees are explained by constraints in physiological traits

Determining the ecological and evolutionary mechanisms that underpin patterns of species richness across elevational gradients is a key question in evolutionary ecology, and can help to understand species extinction risk under changing climates. In the tropical montane islands of Fiji, there are 28 species of endemic bee in the subgenus Lasioglossum (Homalictus), where species richness increases with elevation despite decreasing land surface (habitat) areas. We used a combination of spatially explicit phylogenetic diversity analyses and phylogenetic trait analyses to examine the factors shaping species distributions in these bees. We found that species at higher elevations had lower heat tolerance and desiccation resistance than those at lower elevations, consistent with these traits constraining species elevational ranges. We also found high species phylogenetic diversity within mountains, and high phylogenetic signal in species heat tolerance and minimum elevational ranges, consistent with these traits being evolutionarily conserved among mountain-top taxa following vicariant (allopatric) speciation. We found no evidence to suggest that interspecific competition is shaping species elevational ranges. In all, our findings indicate that phylogenetic conservatism in physiological traits related to climatic niche, such as heat tolerance, can explain why species richness is highest at mountain tops in this system, with species having tracked their climatic niches over time towards ever higher (cooler and wetter) elevations. Because high elevations in this archipelago are extremely limited ([~]2.3% of total land area), only miniscule elevational islands in the sky remain into which this diverse, but climate-restricted fauna, can retreat as climates warm.

evolutionary biology↗

bioRxiv2024

The impact of physiological state and environmental stress on bacterial load estimation methodologies for Mycobacterium tuberculosis

SynopsisO_ST_ABSBackgroundC_ST_ABSSolid and liquid medium cultures from patient samples recover different proportions of a heterogenous bacterial community over the duration of treatment. In vitro experiments were designed to study the population composition at early-logarithmic and stationary phases of growth as well as under drug pressure. ObjectivesTo derive a relationship between methodologies for bacterial load determination and assess the effect of the growth phase of the parent culture and its exposure to stress on the results. MethodsMycobacterium tuberculosis H37Rv was grown with and without drug (isoniazid or rifampicin) and sampled on day 0, 3, 11 and 21 of growth in broth culture. The bacterial load was estimated by colony counts and the BD BACTEC MGIT automated mycobacterial detection system. Linear and nonlinear mixed-effects models were used to describe the relationship between time-to-positivity (TTP) and time-to-growth (TTG) vs colony forming units (CFU), and growth units (GU) vs time. ResultsFor samples with the same CFU, drug-treated and stationary phase cells had a shorter TTP than the drug-free control and early-logarithmic phase cells respectively. Similarly, stationary phase samples reached higher GUs and had shorter time to start growing than early-log phase ones. ConclusionsThe growth phase affects the relationship between CFU-TTP/TTG and previous exposure to drugs affects only the relationship between CFU-TTP. This suggests that there is a population of bacterial cells that can be differentially recovered in liquid medium giving us an insight into the physiological states of the original culture which aids in the interpretation of clinical trial outputs.

microbiology↗

bioRxiv2024

Morphological, physiological and metabolic responses of diverse barley inbreds to dry down and moderate drought stress

Drought stress alters the metabolic activity, physiological processes, and plant growth and such responses might differ with the intensity of stress. We evaluated the genotypic diversity on plant morphology, photosynthetic responses, metabolite shift and their relationship in diverse barley inbreds under dry down (DD) and moderate drought (MD) stress using 23 genetically diverse parental inbreds of genetic mapping population of barley. MD stress caused a strong growth reduction, while DD stress triggered inhibition of photosynthetic health. We observed that the induced changes occurred in a genotype-dependent manner. Compared to control conditions, the metabolism of simple sugars and polyhydroxy acids increased in MD and DD, while the maximum accumulation of amino acid, lipids and phosphates occurred in DD stress. Accumulation of hexose and metabolites with unknown classification was the metabolic signature of drought tolerant inbreds. The inbreds tolerant to MD originated from the temperate regions while those tolerant to both MD and DD came from semi-arid regions. Low stomata density, reduced water loss and retarded growth under drought stress were the key features of inbreds with better survival capacity under severe dehydration. We identified drought tolerant barley inbreds and our study offers resources for future genetic research on various drought tolerance strategies.

plant biology↗

bioRxiv2024

Impact of Maximal Overexpression of a Non-toxic Protein on Yeast Cell Physiology

While it is recognized that excess expression of non-essential proteins burdens cell growth, the physiological state of cells under such stress is largely unknown. This is because it is challenging to distinguish between adverse effects arising from the properties of the expressed excess protein (cytotoxicity) and those caused solely by protein overexpression. In this study, we attempted to identify the model protein with the lowest cytotoxicity in yeast cells by introducing a new neutrality index. We found that a non-fluorescent fluorescent protein (mox-YG) and an inactive glycolytic enzyme (Gpm1- CCmut) showed the lowest cytotoxicity. These proteins can be expressed at levels exceeding 40% of total protein while maintaining yeast growth. The transcriptome of cells expressing mox-YG to the limit indicated that the cells were in a nitrogen source requirement state. Proteome analysis revealed increased mitochondrial protein and decreased ribosome abundance, similar to the inactivated state of the TORC1 pathway. The decrease in ribosome abundance was presumably due to defective nucleolus formation, partially rescued by a mutation in the nuclear exosome. These findings suggest that massive overexpression of excess protein, termed protein burden, causes nitrogen source starvation, a metabolic shift toward more energy-efficient respiration, and a ribosomal biosynthesis defect due to an imbalance between ribosomal protein and rRNA synthesis in the nucleolus.

cell biology↗

bioRxiv2024

Exploring Kp,uu,BBB Values Smaller than Unity in Remoxipride: A Physiologically-Based CNS Model Approach Highlighting Brain Metabolism in Drugs with Passive Blood-Brain Barrier Transport

(Aim)Kp,uu,BBB values are crucial indicators of drug distribution into the brain, representing the steady-state relationship between unbound concentrations in plasma and in brain extracellular fluid (brainECF). Kp,uu,BBB values < 1 are often interpreted as indicators of dominant active efflux transport processes at the blood-brain barrier (BBB). However, the potential impact of brain metabolism on this value is typically not addressed. In this study, we investigated the brain distribution of remoxipride, as a paradigm compound for passive BBB transport with yet unexplained brain elimination that was hypothesized to represent brain metabolism. (Methods)The physiologically-based LeiCNS pharmacokinetic predictor (LeiCNS-PK model) was used to compare brain distribution of remoxipride with and without Michaelis-Menten kinetics at the BBB and/or brain cell organelle levels. To that end, multiple in-house (IV 0.7, 3.5, 4, 5.2, 7, 8, 14 and 16 mg/kg) and external (IV 4 and 8 mg/kg) rat microdialysis studies plasma and brainECF data were analysed. (Results)The incorporation of active elimination through presumed brain metabolism of remoxipride in the LeiCNS-PK model significantly improved the prediction accuracy of experimentally observed brainECF profiles of this drug. The model integrated with brain metabolism in both barriers and organelles levels is named LeiCNS-PK3.5. (Conclusion)For drugs with Kp,uu,BBB values < 1, not only the current interpretation of dominant BBB efflux transport, but also potential brain metabolism needs to be considered, especially because these may be concentration dependent. This will improve the mechanistic understanding of the processes that determine brain PK profiles.

pharmacology and toxicology↗

bioRxiv2024

Mimicking physiological stiffness or oxygen levels in vitro reorganizes mesenchymal stem cells machinery toward a more naive phenotype

Mesenchymal stem cells (MSCs) offer a promising therapeutic potential for a wide variety of pathologies. However, obtaining minimal effective doses requires an extensive in vitro expansion, which compromises their stemness and therapeutic properties. The stiffness of the umbilical cord ranges between 2 and 5kPa, and the oxygen levels fluctuate from 2.4% to 3.8%, differing from the standard in vitro culture conditions where MSCs are exposed to the stiffness of the Petri dish (2-3 GPa) and near atmospheric oxygen levels (18.5% O2). Since MSCs can sense and respond to biomechanical and chemical characteristics of the microenvironment, it was hypothesized that expanding MSCs on 3kPa platforms - mechanomodulation - or at 5% O2 levels - physioxia - could potentially impact the cellular proteome of MSCs, for long (7-10 days) or short (48h) periods. Data analysis has unveiled that culturing MSCs on soft substrates for long periods promotes the expression of various proteins related to cell redox homeostasis, such as thioredoxins and peroxiredoxins. Conversely, culturing these cells during the same period but under low oxygen levels leads to an increase in chaperone machinery proteins, such as HSP90 or TRiC. These proteins can favor the clearance of misfolded proteins and telomerase maintenance processes, possibly preventing MSCs from being driven to a senescent phenotype. Although mechanomodulation and physioxia are two distinct stimuli, both converge in downregulating the expression of histones and several ribosomal subunits, possibly decreasing translational complexity, which could hypothetically favor a more naive phenotype for MSCs. Interestingly, priming UC-MSCs (48h) leads to a differential expression of proteins of the extracellular matrix and histone subtypes. Understanding the role of these proteins in transducing environmental cues might provide insights into how conventional culture conditions significantlyalter fundamental cellular processes and support the development of a more efficient protocol to expand and empower the therapeutic potential of MSCs. In the future, employing a combination of reduced stiffness and lower oxygen levels may present a promising strategic approach. HighlightsO_LICulturing MSCs on a soft substrate (3kPa) enhances the expression of antioxidant proteins, such as thioredoxins and peroxiredoxins C_LIO_LIProtein homeostasis is remodeled in MSCs cultured under physiological levels of oxygen (5% O2) through the differential expression of the chaperone machinery C_LIO_LILowering stiffness or oxygen levels during in vitro MSCs expansion decreases histones and ribosomal subunits expression, possibly favoring a more naive phenotype C_LI

cell biology↗

bioRxiv2024

The physiology of deterrence: Flicker vertigo and its application in avian management

Human-bird conflicts are in a critical state, involving economic losses such as agricultural losses, bird strikes on aircraft and avian influenza. Traditional technologies leveraging bird vision and hearing often lose their effectiveness over time as birds become habituated to these stimuli. To address these challenges, our study introduces a novel countermeasure technology based on neurophysiology. The human brain reacts to flickering light, which can cause symptoms like headaches, nausea, and dizziness. In extremely rare cases, it can even lead to epilepsy. This led us to consider the possibility that similar stimuli could be applicable to birds. In our experiments conducted during the day, we used long-range flashlights. White flickering light had no effect on bird escape behavior. However, when cellophane film was attached to the flashlights to restrict the wavelength, the emitted red light induced escape behavior in birds. Additionally, employing two types of flashlights to generate flickering red+blue or red+green lights elicited escape behavior. However, the blue and green combination proved to be less effective. These results are highly similar to those found in human neurophysiology, showing that red light alone and the combination of red and blue lights have the most significant impact on the brain. By measuring the flight initiation distance (FID) of birds, we found that illuminated areas had a significantly higher FID (137m) compared to non-illuminated areas (12m). These findings suggest that applying principles of human physiology to wildlife management can offer new solutions for bird damage control.

ecology↗

bioRxiv2024

Endothelial Zmiz1 modulates physiological and pathophysiological angiogenesis during retinal development

Angiogenesis is a highly coordinated process involving the control of various endothelial cell behaviors. Mechanisms for transcription factor involvement in the regulation of endothelial cell dynamics and angiogenesis have become better understood, however much remains unknown, especially the role of non-DNA binding transcriptional cofactors. Here, we show that Zmiz1, a transcription cofactor, is enriched in the endothelium and critical for embryonic vascular development, postnatal retinal angiogenesis, and pathological angiogenesis in oxygen induced retinopathy (OIR). In mice, endothelial cell-specific deletion of Zmiz1 during embryogenesis led to lethality due to abnormal angiogenesis and vascular defects. Inducible endothelial cell-specific ablation of Zmiz1 postnatally resulted in impaired retinal vascular outgrowth, decreased vascular density, and increased vessel regression. In addition, angiogenic sprouting in the superficial and deep layers of the retina was markedly reduced. Correspondingly, vascular sprouting in fibrin bead assays was significantly reduced in the absence of Zmiz1, while further in vitro and in vivo evidence also suggested deficits in EC migration. In agreement with the defective sprouting angiogenesis phenotype, gene expression analysis of isolated retinal endothelial cells revealed downregulation of tip-cell enriched genes upon inactivation of Zmiz1. Lastly, our study suggested that endothelial Zmiz1 is critical for intraretinal revascularization following hypoxia exposure in the OIR model. Taken together, these findings begin to define the previously unspecified role of endothelial Zmiz1 in physiological and pathological angiogenesis.

developmental biology↗

bioRxiv2024

Food texture preference reveals multisensory contributions of gustatory organs in behaviour and physiology

Food presents a multisensory experience, with visual, taste, and olfactory cues being important in allowing an animal to determine the safety and nutritional value of a given substance1. Texture, however, remains a surprisingly unexplored aspect, despite providing key information about the state of the food through properties such as hardness, liquidity, and granularity. Food perception is achieved by specialised sensory neurons, which themselves are defined by the receptor genes they express. While it was assumed that sensory neurons respond to one or few closely-related stimuli, more recent findings challenge this notion and support evidence that certain sensory neurons are more broadly tuned. In the Drosophila taste system, gustatory neurons respond to cues of opposing hedonic valence or to olfactory cues. Here, we identified that larvae ingest and navigate towards specific food substrate hardnesses, and probed the role of gustatory organs in this behaviour. By developing a genetic tool targeting specifically gustatory organs, we show that these organs are major contributors for evaluation of food texture and ingestion decision-making. We find that ablation of gustatory organs not only results in loss of chemosensation, but also navigation and ingestion preference to varied substrate textures. Furthermore, we show that certain neurons in the primary taste organ exhibit varied and concurrent physiological responses to mechanical and multimodal stimulation. We show that individual neurons house independent mechanisms for multiple sensory modalities, challenging assumptions about capabilities of sensory neurons. We propose that further investigations, across the animal kingdom, may reveal higher sensory complexity than currently anticipated.

neuroscience↗

bioRxiv2024

Potato cultivars use different root physiological and molecular mechanisms to acclimate to salt stress

O_LISoil salinity induces osmotic stress and ion toxicity in plants, detrimentally affecting their growth and development. Potato (Solanum tuberosum) faces yield reductions due to salt stress. The mechanisms of salt stress resilience, especially in adventitious roots, remain unknown. C_LIO_LIWe investigated the resilience of three potato cultivars - Desiree, Innovator, and Mozart - by studying their physiological and transcriptomic responses to salt stress. C_LIO_LIOur findings reveal that under salt stress, the growth of stolons and stolon node roots is similarly reduced unlike tubers, even though they are physically connected. Surprisingly, tubers accumulate Cl- but not Na+ under salt stress, suggesting an active Na+ exclusion mechanism. Innovator showed the lowest suberin and lignin deposition before salt stress and higher K+ leakage, leading to a stronger initial stress response with high ABA content and a distinct transcriptomic pattern. Nevertheless, Innovator was the most resilient, displaying lower growth, salt-tolerance index and tuber yield reduction. Transcriptomic analysis revealed several K+/Na+ channel genes which might regulate ions homeostasis during salt stress, in particular in Innovator. C_LIO_LIAltogether, we conclude that acclimation ability, rather than initial protection of roots against salt, prevails in long term salt-stress resilience of potato. C_LI

plant biology↗

bioRxiv2024

Acute rapamycin treatment reveals novel mechanisms of behavioral, physiological, and functional dysfunction in a maternal inflammation mouse model of autism and sensory over-responsivity

Maternal inflammatory response (MIR) during early gestation in mice induces a cascade of physiological and behavioral changes that have been associated with autism spectrum disorder (ASD). In a prior study and the current one, we find that mild MIR results in chronic systemic and brain inflammation, mTOR pathway activation, mild brain overgrowth followed by regionally specific volumetric changes, sensory processing dysregulation, and social and repetitive behavior abnormalities. Prior studies of rapamycin treatment in autism models have focused on chronic treatments that alter or prevent physical brain changes. Here, we have focused on the acute effects of rapamycin to uncover novel mechanisms of dysfunction related to mTOR pathway signaling. We find that within 2 hours, rapamycin treatment could rapidly rescue neuronal hyper-excitability, seizure susceptibility, functional network connectivity and brain community structure, repetitive behaviors, and sensory over-responsivity in adult offspring with persistent mild brain overgrowth. These CNS-mediated effects are also associated with alteration of the expression of several ASD-, ion channel-, and epilepsy-associated genes in the same time frame. Reduction of microglia with CSF1R inhibitors or inhibition of NADPH oxidase in young animals reduces the development of some of the behavioral phenotypes, but neither is as effective as acute mTOR inhibition. Our findings indicate that mTOR dysregulation in MIR offspring is a key contributor to various levels of brain dysfunction. However, we demonstrate that the adult MIR brain is also amenable to rapid normalization of these functional changes which results in the rescue of both core and comorbid ASD-like behaviors in adult animals without requiring long-term physical alterations to the brain. Restoring excitatory/inhibitory imbalance and sensory functional network modularity may therefore be important targets for therapeutically addressing both primary sensory and compensatory repetitive behavior phenotypes.

neuroscience↗