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Biology subjects

Kozlov, A.

Publications and source records attributed to Kozlov, A..

17 recordsLinked to original sources

Surrogate Gradients for Gradient-Based Parameter Estimation in Simplified Neuron Models

Simplified spiking neuron models such as the Adaptive Exponential Integrate-and-Fire (AdEx) model reproduce the firing behaviour of diverse neuron types at a fraction of the cost of biophysically detailed models, making them attractive for large-scale brain simulation. Fitting their parameters to recordings, however, still relies on derivative-free search such as grid search or evolutionary algorithms, because the discrete spike-and-reset mechanism renders these models non-differentiable. Surrogate gradients, used in deep spiking networks, replace the spike derivative with a smooth approximation on the backward pass. Whether they also enable efficient gradient-based parameter estimation for single simplified neurons is untested. We implement a differentiable AdEx model with a surrogate-gradient variant in the Jaxley framework. The implementation is on par with target-compiled C++ Brian2 code while remaining end-to-end differentiable, vmap-batchable and GPU/TPU-portable. It is 200 times faster than Brian2's default runtime mode. Across a recovery-radius benchmark of 2,700 paired runs, gradient-based fitting never matched a gradient-free Nelder-Mead baseline. At sub- threshold levels, gradient descent instead beats Nelder-Mead. The obstacle is therefore the spike mechanism and the loss geometry it induces, not gradient descent itself.

bioinformatics↗

Indigenous gut microbes modulate neural cell state and neurodegenerative disease susceptibility

The native microbiome influences a plethora of host processes, including neurological function. However, its impacts on diverse brain cell types remains poorly understood. Here, we performed single nucleus RNA sequencing on hippocampi from wildtype, germ-free mice and reveal the microbiome-dependent transcriptional landscape across all major neural cell types. We found conserved impacts on key adaptive immune and neurodegenerative transcriptional pathways, underscoring the microbiomes contributions to disease-relevant processes. Mono-colonization with select indigenous microbes identified species-specific effects on the transcriptional state of brain myeloid cells. Colonization by Escherichia coli induced a distinct adaptive immune and neurogenerative disease-associated cell state, suggesting increased disease susceptibility. Indeed, E. coli exposure in the 5xFAD mouse model resulted in exacerbated cognitive decline and amyloid pathology, demonstrating its sufficiency to worsen Alzheimers disease-relevant outcomes. Together, these results emphasize the broad, species-specific, microbiome-dependent consequences on neurological transcriptional state and highlight the capacity of specific microbes to modulate disease susceptibility. HighlightsO_LIThe microbiome impacts the transcriptional landscape of all major brain cell types. C_LIO_LIDiscrete microbes specifically modulate resident myeloid cell status. C_LIO_LIGut E. coli triggers dynamic transcriptional responses across neural cell types. C_LIO_LIExposure to E. coli exacerbates behavioral and cellular pathologies in 5xFAD mice. C_LI

neuroscience↗

A multiscale model of striatum microcircuit dynamics

The striatum is the largest structure in the basal ganglia, and is known for its key role in functions such as learning and motor control. Studying these aspects requires investigating cellular/microcircuits mechanisms, in particular related to learning, and how these small-scale mechanisms affect large-scale behavior, and its interactions with other structures, such as the cerebral cortex. In this paper, we provide a multiscale approach to investigate these aspects. We first investigate striatum dynamics using spiking networks, and derive a mean-field model that captures these dynamics. We start with a brief introduction to the microcircuit of the striatum and we describe, step by step, the construction of a spiking network model, and its mean-field, for this area. The models include explicitly the different cell types and their intrinsic electrophysiological properties, and the synaptic receptors implicated in their recurrent interactions. Then we test the mean-field model by analyzing the response of the striatum network to the main brain rhythms observed experimentally, and compare this response to that predicted by the mean-field. We next study the effects of dopamine, a key neuromodulator in the basal ganglia, on striatal neurons. Integrating dopamine receptors in the spiking network model leads to emerging dynamics, which are also seen in the mean-field model. Finally, we introduce a basic implementation of reinforcement learning (one of the main known functions of the basal-ganglia) using the mean-field model of the striatum microcircuit. In conclusion, we provide a multiscale study of the striatum microcircuits and mean-field, that capture its response to periodic inputs, the effect of dopamine and can be used in reinforcement learning paradigms. Given that several mean-field models have been previously proposed for the cerebral cortex, the mean-field model presented here should be a key tool to investigate large-scale interactions between basal ganglia and cerebral cortex, for example in motor learning paradigms, and to integrate it in large scale and whole-brain simulations.

neuroscience↗

Biomimetic computations improve neural network robustness

Object recognition by natural and artificial sensory systems requires a combination of selectivity and invariance. Both natural and artificial neural networks achieve selectivity and invariance by propagating sensory information though layers of neurons organised in a functional hierarchy. Both employ computational units performing AND-like operations for selectivity and OR-like operations for invariance. However, while biological neurons are intrinsically capable of switching between these operations, their artificial counterparts are hard-wired to perform only one of them. We wanted to test whether the flexible mapping between neurons and computations observed in biological neural networks is compatible with, or perhaps even useful to, artificial neural networks. To answer this question, we have developed a deep learning layer in which both selectivity and invariance operations can be performed by the same neurons. As with biological neurons, the choice of which operation an artificial neuron performs on a given input can be governed by the input strength. This flexible layer successfully outputs a combination of the two operations and, surprisingly, confers additional robustness to adversarial examples, which are inputs deliberately crafted to promote misclassification. The flexible mapping also improves accuracy when the training dataset is small, as well as when data are corrupted by certain types of noise. These results narrow the gap between biological and artificial neural networks and add a new bio-inspired approach to the arsenal of defenses against adversarial examples, which are known threats to model-based optimization and network security. Author summaryThe biophysical properties of a biological neuron enable it to perform both OR-like and AND-like operations over its inputs. In contrast, artificial neural networks use units that always perform only one specific operation. We wondered whether the flexibility observed in individual biological neurons could be incorporated into artificial neural networks without breaking them. If artificial neural networks required their units to perform single operations, then this requirement would either point to a fundamental difference between biological and artificial neural networks or indicate that biological neurons are somehow constrained to perform only one type of operations during object recognition. If, on the other hand, artificial units can flexibly switch between different operations, then such a result would indicate that biological and artificial neural networks are more similar than previously thought and would be an important step towards biomimetic AI. To find out, we introduced a new computational structure we call a flexible layer, in which individual units can switch between operations according to a rule (e.g., depending on input strength, or even randomly). We found that inserting the flexible layer in one or several positions in different artificial neural networks trained on several benchmark datasets not only preserves their accuracy but also makes them more robust to various perturbations and improves learning when training data is scarce.

neuroscience↗

Microbubble dynamics in brain microvessels

BackgroundFocused ultrasound stimulation of microbubbles is being tested in clinical trials for its ability to deliver drugs across the blood-brain barrier (BBB). This technique has the potential to treat neurological diseases by preferentially delivering drugs to targeted regions. Yet despite its potential, the physical mechanisms by which microbubbles alter the BBB permeability remain unclear, as direct observations of microbubbles oscillating in cerebral capillaries have never been previously recorded. The purpose of this study was to reveal how microbubbles respond to ultrasound when within the microvessels of living brain tissue. MethodsMicrobubbles in acute brain slices acquired from juvenile rats perfused with a concentrated solution of SonoVue(R) and dye were exposed to ultrasound pulses typically used in BBB disruption (center frequency: 1 MHz, peak-negative pressure: 0.2-1 MPa, pulse length: up to 10 ms) and observed using high-speed microscopy at up to 10 million frames per second. ResultsWe observed that microbubbles can exert mechanical stresses on a wide region of tissue beyond their initial location and immediate surroundings. A single microbubble can apply mechanical stress to parenchymal tissues several micrometers away from the vessel. Microbubbles can travel at high velocities within the microvessels, extending their influence across tens of micrometers during a single pulse. With longer pulses and higher pressures, microbubbles could penetrate the vessel wall and move through the parenchyma, refuting a previous assumption that microbubbles are confined to vessels. The probability of extravasation scales approximately with mechanical index, being rare at low pressures, but much more common at a mechanical index [≥] 0.6. ConclusionsThese observations provide important insight into microbubble dynamics in microvessels, and are critical leads into ultimately identifying the microbubble activities that lead to both safe drug delivery and into activities we seek to avoid, such as petechiae and other bioeffects.

bioengineering↗

The impact of Parkinson's disease on striatal network connectivity and cortico-striatal drive: an in-silico study

Striatum, the input stage of the basal ganglia, is important for sensory-motor integration, initiation and selection of behaviour, as well as reward learning. Striatum receives glutamatergic inputs from mainly cortex and thalamus. In rodents, the striatal projection neurons (SPNs), giving rise to the direct and the indirect pathway (dSPNs and iSPNs, respectively), account for 95% of the neurons and the remaining 5% are GABAergic and cholinergic interneurons. Interneuron axon terminals as well as local dSPN and iSPN axon collaterals form an intricate striatal network. Following chronic dopamine depletion as in Parkinsons disease (PD), both morphological and electrophysiological striatal neuronal features have been shown to be altered in rodent models. Our goal with this in-silico study is twofold: a) to predict and quantify how the intrastriatal network connectivity structure becomes altered as a consequence of the morphological changes reported at the single neuron level, and b) to investigate how the effective glutamatergic drive to the SPNs would need to be altered to account for the activity level seen in SPNs during PD. In summary we predict that the richness of the connectivity motifs in the striatal network is significantly decreased during PD, while at the same time a substantial enhancement of the effective glutamatergic drive to striatum is present. AUTHOR SUMMARYThis in-silico study predicts the impact that the single cell neuronal morphological alterations will have on the striatal microcircuit connectivity. We find that the richness in the topological striatal motifs is significantly reduced in Parkinsons disease, highlighting that just measuring the pairwise connectivity between neurons gives an incomplete description of network connectivity. Moreover, we predict how the resulting electrophysiological changes of SPN excitability together with their reduced number of dendritic branches affect their response to the glutamatergic drive from cortex and thalamus. We find that the effective glutamatergic drive is likely significantly increased in PD, in accordance with the hyperglutamatergic hypothesis.

neuroscience↗

Crucial neuroprotective roles of the metabolite BH4 in dopaminergic neurons

Dopa-responsive dystonia (DRD) and Parkinsons disease (PD) are movement disorders caused by the dysfunction of nigrostriatal dopaminergic neurons. Identifying druggable pathways and biomarkers for guiding therapies is crucial due to the debilitating nature of these disorders. Recent genetic studies have identified variants of GTP cyclohydrolase-1 (GCH1), the rate-limiting enzyme in tetrahydrobiopterin (BH4) synthesis, as causative for these movement disorders. Here, we show that genetic and pharmacological inhibition of BH4 synthesis in mice and human midbrain-like organoids accurately recapitulates motor, behavioral and biochemical characteristics of these human diseases, with severity of the phenotype correlating with extent of BH4 deficiency. We also show that BH4 deficiency increases sensitivities to several PD-related stressors in mice and PD human cells, resulting in worse behavioral and physiological outcomes. Conversely, genetic and pharmacological augmentation of BH4 protects mice from genetically- and chemically induced PD-related stressors. Importantly, increasing BH4 levels also protects primary cells from PD-affected individuals and human midbrain-like organoids (hMLOs) from these stressors. Mechanistically, BH4 not only serves as an essential cofactor for dopamine synthesis, but also independently regulates tyrosine hydroxylase levels, protects against ferroptosis, scavenges mitochondrial ROS, maintains neuronal excitability and promotes mitochondrial ATP production, thereby enhancing mitochondrial fitness and cellular respiration in multiple preclinical PD animal models, human dopaminergic midbrain-like organoids and primary cells from PD-affected individuals. Our findings pinpoint the BH4 pathway as a key metabolic program at the intersection of multiple protective mechanisms for the health and function of midbrain dopaminergic neurons, identifying it as a potential therapeutic target for PD.

neuroscience↗

A GPU-based computational framework that bridges Neuron simulation and Artificial Intelligence

Biophysically detailed multi-compartment models are powerful tools to explore computational principles of the brain and also serve as a theoretical framework to generate algorithms for artificial intelligence (AI) systems. However, the expensive computational cost severely limits the applications in both the neuroscience and AI fields. The major bottleneck during simulating detailed compartment models is the ability of a simulator to solve large systems of linear equations. Here, we present a novel Dendritic Hierarchical Scheduling (DHS) method to markedly accelerate such process. We theoretically prove that the DHS implementation is computationally optimal and accurate. This GPU-based method performs at 2-3 orders of magnitude higher speed than that of the classic serial Hines method in the conventional CPU platform. We build a DeepDendrite framework, which integrates the DHS method and the GPU computing engine of the NEURON simulator and demonstrate applications of DeepDendrite in neuroscience and AI tasks. We investigated how spatial patterns of spine inputs affect neuronal excitability in a detailed human pyramidal neuron model with 25,000 spines; and examined how dendrites protect morphologically detailed neural networks against adversarial attacks in typical image classification tasks.

neuroscience↗

PCYT2 controls muscle health and muscle aging

Muscle degeneration is the most prevalent cause for frailty and dependency in inherited diseases and ageing, affecting hundreds of millions of people. Elucidation of pathophysiological mechanisms, as well as effective treatments for muscle diseases represents an important goal in improving human health. Here, we show that phosphatidylethanolamine cytidyltransferase (PCYT2/ECT), the critical enzyme of the Kennedy branch of phosphatidylethanolamine (PE) synthesis pathway, has an essential role in muscle health. Human genetic deficiency in PCYT2 causes a severe disease with failure to thrive and progressive muscle weakness. Pcyt2 mutant zebrafish recapitulate the patient phenotypes, indicating that the role of PCYT2/PE in muscle is evolutionary conserved. Muscle specific Pcyt2 knockout mice exhibited failure to thrive, impaired muscle development, progressive muscle weakness, muscle loss, accelerated ageing, and reduced lifespan. Mechanistically, Pcyt2 deficiency affects mitochondrial bioenergetics and physicochemical properties of the myofiber membrane lipid bilayer, in particular under exercise strain. We also show that PCYT2 activity declines in the aging muscles of humans and mice. AAV-based delivery of PCYT2 rescued muscle weakness in Pcyt2 knock-out mice and, importantly, improved muscle strength in old mice, offering a novel therapeutic avenue for rare disease patients and muscle aging. Thus, PCYT2 plays a fundamental, specific, and conserved role in vertebrate muscle health, linking PCYT2 and PCYT2 synthesized PE lipids to severe muscle dystrophy, exercise intolerance and aging.

genetics↗

Interplay between mitochondria and reactive oxygen and nitrogen species in metabolic adaptation to hypoxia in facioscapulohumeral muscular dystrophy: potential therapeutic targets.

Facioscapulohumeral muscular dystrophy (FSHD) is characterised by descending skeletal muscle weakness and wasting. FSHD is caused by mis-expression of the transcription factor DUX4, which is linked to oxidative stress, a condition especially detrimental to skeletal muscle with its high metabolic activity and energy demands. Oxidative damage characterises FSHD and recent work suggests metabolic dysfunction and perturbed hypoxia signalling as novel pathomechanisms. However, redox biology of FSHD remains poorly understood, and integrating the complex dynamics of DUX4-induced metabolic changes is lacking. Here we pinpoint the kinetic involvement of altered mitochondrial RONS metabolism and impaired mitochondrial function in aetiology of oxidative stress in FSHD. Transcriptomic analysis in FSHD muscle biopsies reveals strong enrichment for pathways involved in mitochondrial complex I assembly, nitrogen metabolism, oxidative stress response and hypoxia signalling. We found elevated ROS levels correlate with increases in steady-state mitochondrial membrane potential in FSHD myogenic cells. DUX4 triggers mitochondrial membrane polarisation prior to oxidative stress generation and apoptosis through mitochondrial ROS, and affects NO{middle dot} bioavailability via mitochondrial peroxidation. We identify complex I as the primary target for DUX4-induced mitochondrial dysfunction, with strong correlation between complex I-linked respiration and cellular oxygenation/hypoxia signalling activity in environmental hypoxia. Thus, FSHD myogenesis is uniquely susceptible to hypoxia-induced oxidative stress as a consequence of metabolic mis-adaptation. Importantly, mitochondria-targeted antioxidants rescue FSHD pathology more effectively than conventional antioxidants, highlighting the central involvement of disturbed mitochondrial RONS metabolism. This work provides a pathomechanistic model by which DUX4-induced changes in oxidative metabolism impair muscle function in FSHD, amplified when metabolic adaptation to varying O2 tension is required. HighlightsO_LITranscriptomics data from FSHD muscle indicates enrichment for disturbed mitochondrial pathways C_LIO_LIDisturbed RONS metabolism correlates with mitochondrial membrane polarisation and myotube hypotrophy C_LIO_LIDUX4-induced changes in mitochondrial function precede oxidative stress through mitoROS and affect hypoxia signalling via complex I C_LIO_LIFSHD is sensitive to environmental hypoxia, which increases ROS levels in FSHD myotubes C_LIO_LIHypotrophy in hypoxic FSHD myotubes is efficiently rescued with mitochondria-targeted antioxidants C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/459509v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@16ae1a8org.highwire.dtl.DTLVardef@517caorg.highwire.dtl.DTLVardef@5d0734org.highwire.dtl.DTLVardef@183ef50_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

Predicting synaptic connectivity for large-scale microcircuit simulations using Snudda

Simulation of large-scale networks of neurons is an important approach to understanding and interpreting experimental data from healthy and diseased brains. Owing to the rapid development of simulation software and the accumulation of quantitative data of different neuronal types, it is possible to predict both computational and dynamical properties of local microcircuits in a bottom-up manner. Simulated data from these models can be compared with experiments and top-down modelling approaches, successively bridging the scales. Here we describe an open source pipeline, using the software Snudda, for predicting microcircuit connectivity and for setting up simulations using the NEURON simulation environment in a reproducible way. We also illustrate how to further curate data on single neuron morphologies acquired from public databases. This model building pipeline was used to set up a first version of a full-scale cellular level model of mouse dorsal striatum. Model components from that work are here used to illustrate the different steps that are needed when modelling subcortical nuclei, such as the basal ganglia.

neuroscience↗

Rapid mechanical stimulation of inner-ear hair cells by photonic pressure

Hair cells, the receptors of the inner ear, detect sounds by transducing mechanical vibrations into electrical signals. From the top surface of each hair cell protrudes a mechanical antenna, the hair bundle, which the cell uses to detect and amplify auditory stimuli, thus sharpening frequency selectivity and providing a broad dynamic range. Current methods for mechanically stimulating hair bundles are too slow to encompass the frequency range of mammalian hearing and are plagued by inconsistencies. To overcome these challenges, we have developed a method to move individual hair bundles with photonic force. This technique uses an optical fiber whose tip is tapered to a diameter of a few micrometers and endowed with a ball lens to minimize divergence of the light beam. Here we describe the fabrication, characterization, and application of this optical system and demonstrate the rapid application of photonic force to vestibular and cochlear hair cells.

neuroscience↗

Phylogenetic analysis of SARS-CoV-2 data is difficult

Numerous studies covering some aspects of SARS-CoV-2 data analyses are being published on a daily basis, including a regularly updated phylogeny on nextstrain.org. Here, we review the difficulties of inferring reliable phylogenies by example of a data snapshot comprising all virus sequences available on May 5, 2020 from gisaid.org. We find that it is difficult to infer a reliable phylogeny on these data due to the large number of sequences in conjunction with the low number of mutations. We further find that rooting the inferred phylogeny with some degree of confidence either via the bat and pangolin outgroups or by applying novel computational methods on the ingroup phylogeny does not appear to be possible. Finally, an automatic classification of the current sequences into sub-classes based on statistical criteria is also not possible, as the sequences are too closely related. We conclude that, although the application of phylogenetic methods to disentangle the evolution and spread of COVID-19 provides some insight, results of phylogenetic analyses, in particular those conducted under the default settings of current phylogenetic inference tools, as well as downstream analyses on the inferred phylogenies, should be considered and interpreted with extreme caution.

evolutionary biology↗

GeneRax: A tool for species tree-aware maximum likelihood based gene tree inference under gene duplication, transfer, and loss.

Inferring phylogenetic trees for individual homologous gene families is difficult because alignments are often too short, and thus contain insufficient signal, while substitution models inevitably fail to capture the complexity of the evolutionary processes. To overcome these challenges species tree-aware methods also leverage information from a putative species tree. However, only few methods are available that implement a full likelihood framework or account for horizontal gene transfers. Furthermore, these methods often require expensive data pre-processing (e.g., computing bootstrap trees), and rely on approximations and heuristics that limit the degree of tree space exploration. Here we present GeneRax, the first maximum likelihood species tree-aware phylogenetic inference software. It simultaneously accounts for substitutions at the sequence level as well as gene level events, such as duplication, transfer, and loss relying on established maximum likelihood optimization algorithms. GeneRax can infer rooted phylogenetic trees for multiple gene families, directly from the per-gene sequence alignments and a rooted, yet undated, species tree. We show that compared to competing tools, on simulated data GeneRax infers trees that are the closest to the true tree in 90% of the simulations in terms of relative Robinson-Foulds distance. On empirical datasets, GeneRax is the fastest among all tested methods when starting from aligned sequences, and it infers trees with the highest likelihood score, based on our model. GeneRax completed tree inferences and reconciliations for 1099 Cyanobacteria families in eight minutes on 512 CPU cores. Thus, its parallelization scheme enables large-scale analyses. GeneRax is available under GNU GPL at https://github.com/BenoitMorel/GeneRax.

bioinformatics↗

Nitric Oxide Mediates Neuro-Glial Interaction that Shapes Drosophila Circadian Behavior

Drosophila circadian behavior relies on the network of heterogeneous groups of clock neurons. Short -and long-range signaling within the pacemaker circuit coordinates molecular and neural rhythms of clock neurons to generate coherent behavioral output. The neurochemistry of circadian behavior is complex and remains incompletely understood. Here we demonstrate that the gaseous messenger nitric oxide (NO) is a signaling molecule linking circadian pacemaker to rhythmic locomotor activity. We show that two independent mutants lacking nitric oxide synthase (NOS) have severely disturbed locomotor behavior both in light-dark cycles and constant darkness, although molecular clocks in the main pacemaker neurons are unaffected. Behavioral phenotypes are due in part to the malformation of neurites of the main pacemaker neurons, s-LNvs. Using cell-type selective and stage-specific gain -and loss-of-function of NOS, we demonstrate that NO secreted from diverse cellular clusters non-cell-autonomously affect molecular and behavioral rhythms. We further identify glia as a major source of NO that regulates circadian locomotor output. These results reveal for the first time the critical role of NO signaling in the Drosophila circadian system and highlight the importance of neuro-glial interaction in the neural circuit output.\n\nAuthor summaryCircadian rhythms are daily cycles of physiological and behavioral processes found in most plants and animals on our planet from cyanobacteria to humans. Circadian rhythms allow organisms to anticipate routine daily and annual changes of environmental conditions and efficiently adapt to them. Fruit fly Drosophila melanogaster is an excellent model to study this phenomenon, as its versatile toolkit enables the study of genetic, molecular and neuronal mechanisms of rhythm generation. Here we report for the first time that gasotransmitter nitric oxide (NO) has a broad, multi-faceted impact on Drosophila circadian rhythms, which takes place both during the development and the adulthood. We also show that one of the important contributors of NO to circadian rhythms are glial cells. The second finding highlights that circadian rhythms of higher organisms are not simply controlled by the small number of pacemaker neurons but are generated by the system that consists of many different players, including glia.

neuroscience↗

The development of cooperative channels explains the maturation of hair cell’s mechanotransduction

Hearing relies on the conversion of mechanical stimuli into electrical signals. In vertebrates, this process of mechano-electrical transduction (MET) is performed by specialized receptors of the inner ear, the hair cells. Each hair cell is crowned by a hair bundle, a cluster of microvilli that pivot in response to sound vibrations, causing the opening and closing of mechanosensitive ion channels. Mechanical forces are projected onto the channels by molecular springs called tip links. Each tip link is thought to connect to a small number of MET channels that gate cooperatively and operate as a single transduction unit. Pushing the hair bundle in the excitatory direction opens the channels, after which they rapidly reclose in a process called fast adaptation. It has been experimentally observed that the hair cells biophysical properties mature gradually during postnatal development: the maximal transduction current increases, sensitivity sharpens, transduction occurs at smaller hair-bundle displacements, and adaptation becomes faster. Similar observations have been reported during tip-link regeneration after acoustic damage. Moreover, when measured at intermediate developmental stages, the kinetics of fast adaptation varies in a given cell depending on the magnitude of the imposed displacement. The mechanisms underlying these seemingly disparate observations have so far remained elusive. Here, we show that these phenomena can all be explained by the progressive addition of MET channels of constant properties, which populate the hair bundle first as isolated entities, then progressively as clusters of more sensitive, cooperative MET channels. As the proposed mechanism relies on the difference in biophysical properties between isolated and clustered channels, this work highlights the importance of cooperative interactions between mechanosensitive ion channels for hearing.\n\nSIGNIFICANCEHair cells are the sensory receptors of the inner ear that convert mechanical stimuli into electrical signals transmitted to the brain. Sensitivity to mechanical stimuli and the kinetics of mechanotransduction currents change during hair-cell development. The same trend, albeit on a shorter timescale, is also observed during hair-cell recovery from acoustic trauma. Furthermore, the current kinetics in a given hair cell depends on the stimulus magnitude, and the degree of that dependence varies with development. These phenomena have so far remained unexplained. Here, we show that they can all be reproduced using a single unifying mechanism: the progressive formation of channel pairs, in which individual channels interact through the lipid bilayer and gate cooperatively.

biophysics↗

RAxML-NG: A fast, scalable, and user-friendly tool for maximum likelihood phylogenetic inference

MotivationPhylogenies are important for fundamental biological research, but also have numerous applications in biotechnology, agriculture, and medicine. Finding the optimal tree under the popular maximum like-lihood (ML) criterion is known to be NP-hard. Thus, highly optimized and scalable codes are needed to analyze constantly growing empirical datasets.\n\nResultsWe present RAxML-NG, a from scratch re-implementation of the established greedy tree search algorithm of RAxML/ExaML. RAxML- NG offers improved accuracy, flexibility, speed, scalability, and usability compared to RAxML/ExaML. On taxon-rich datasets, RAxML-NG typically finds higher-scoring trees than IQTree, an increasingly popular recent tool for ML-based phylogenetic inference (although IQ-Tree shows better stability). Finally, RAxML-NG introduces several new features, such as the detection of terraces in tree space and a the recently introduced transfer bootstrap support metric.\n\nAvailabilityThe code is available under GNU GPL at https://github.com/amkozlov/raxml-ng.RAxML-NG web service (maintained by Vital- IT) is available at https://raxml-ng.vital-it.ch/.\n\nContactalexey.kozlov@h-its.org

bioinformatics↗