Cortical determinants of loudness perception and auditory hypersensitivity

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 30, 2024

Parvalbumin-expressing inhibitory neurons (PVNs) stabilize cortical network activity, generate gamma rhythms, and regulate experience-dependent plasticity. Here, we observed that activation or inactivation of PVNs functioned like a volume knob in the mouse auditory cortex (ACtx), turning neural behavioral classification sound level up down over 20dB range. PVN loudness adjustments were "sticky", such single bout 40Hz stimulation sustainably suppressed ACtx responsiveness, potentiated feedforward inhibition, behaviorally desensitized mice to loudness. Sensory sensitivity is cardinal feature autism, aging, peripheral neuropathy, prompting us ask whether can persistently desensitize with hyperactivity, hypofunction, hypersensitivity triggered by cochlear sensorineural damage. We found 16-minute session restored normal perception for one week, showing perceptual deficits irreversible injuries be reversed through targeted circuit interventions.

Language: Английский

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Domain Coupling in Allosteric Regulation of SthK Measured Using Time-Resolved Transition Metal Ion FRET

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 5, 2025

Cyclic nucleotide-binding domain (CNBD) ion channels are vital for cellular signaling and excitability, with activation regulated by cyclic adenosine- or guanosine-monophosphate (cAMP, cGMP) binding. However, the allosteric mechanisms underlying this activation, particularly energetics that describe conformational changes within individual domains between domains, remain unclear. The prokaryotic CNBD channel SthK has been a useful model better understanding these mechanisms. Here, we applied time-resolved transition metal Förster resonance energy transfer (tmFRET) to investigate dynamics in of both soluble C-terminal fragment protein, Cterm , full-length channel, Full . We incorporated noncanonical amino acid Acd as FRET donor bound chelator conjugated cysteine an acceptor. used time correlated single photon counting (TCSPC) measure fit TCSPC data obtain donor-acceptor distance distributions absence presence cAMP. allowed us quantify coupling transmembrane comparing Our indicate makes activating change more favorable. These findings highlight power tmFRET uncover structural energetic landscapes proteins ligand-mediated mechanism specifically.

Language: Английский

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Neuroanatomical Predictors of Transcranial Direct Current Stimulation (tDCS)-Induced Modifications in Neurocognitive Task Performance in Typically Developing Individuals

Journal of Neuroscience, Journal Year: 2024, Volume and Issue: 44(22), P. e1372232024 - e1372232024

Published: March 28, 2024

Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation technique gaining more attention in neurodevelopmental disorders (NDDs). Due to the phenotypic heterogeneity of NDDs, tDCS unlikely be equally effective all individuals. The present study aimed establish neuroanatomical markers typically developing (TD) individuals that may used for prediction individual responses tDCS. Fifty-seven male and female children received 2 mA anodal sham tDCS, targeting left dorsolateral prefrontal cortex (DLPFC

Language: Английский

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Temporal changes in SARS-CoV-2 clearance kinetics and the optimal design of antiviral pharmacodynamic studies: an individual patient data meta-analysis of a randomised, controlled, adaptive platform study (PLATCOV)

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 17, 2024

Abstract Background Effective antiviral drugs prevent hospitalisation and death in COVID-19. Antiviral efficacy can be assessed efficiently in-vivo by measuring rates of SARS-CoV-2 clearance estimated from serial viral genome densities quantitated nasopharyngeal or oropharyngeal swab eluates. We carried out an individual patient data meta-analysis unblinded arms the PLATCOV platform trial to characterise changes kinetics infer optimal design interpretation pharmacometric evaluations. is registered at ClinicalTrials.gov, NCT05041907 . Methods Serial density were analysed symptomatic, previously healthy, adult patients (within 4 days symptom onset) enrolled a large multicentre randomised adaptive pharmacodynamic (PLATCOV) comparing interventions for SARS-CoV-2. Viral over one week under hierarchical Bayesian linear model with B-splines used temporal enrolment rates. Bootstrap re-sampling was assess duration follow-up assessment, where defined as maximising expected z-score when effective antivirals no treatment. Results Between 29 September 2021 20 October 2023, 1262 randomised. Unblinded available 800 (16,818 qPCR measurements) whom 63% (504/800) female. 98% (783/800) had received least vaccine dose 88% (703/800) fully vaccinated. biphasic (bi-exponential). The first phase ( α ) accelerated interventions. For all studied, maximum discriminative power (maximum z-score) obtained evaluating 5 after enrolment. Over two-year period median half-lives 7 have shortened 16.6 hours (interquartile range [IQR]: 15.3 18.2) 9.2 (IQR: 8.0 10.6) 2023 receiving drugs, equivalent relative reduction 44% [95% credible interval (CrI): 19 64%]. A parallel trend observed treated patients. In 158 ritonavir-boosted nirmatrelvir (3,380 measurements), half-life declined 6.4 5.7 7.3) June 2022 4.8 4.2 5.5) 26% [95%CrI: –4 42%]. Conclusions symptomatic vaccinated individuals substantially past two years. COVID-19 now using qPCRs duplicate eluates taken daily drug administration. Funding Wellcome Trust Grant ref: 223195/Z/21/Z through Therapeutics Accelerator.

Language: Английский

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Lerch $\Phi$ Asymptotics

Symmetry Integrability and Geometry Methods and Applications, Journal Year: 2024, Volume and Issue: unknown

Published: March 21, 2024

We use a Mellin-Barnes integral representation for the Lerch transcendent $\Phi(z,s,a)$ to obtain large $z$ asymptotic approximations. The simplest divergent approximation terminates in case that $s$ is an integer. For non-integer approximations consists of sum two series. first one powers $(\ln z)^{-1}$ and second $z^{-1}$. Although series converges, it completely hidden tail resummation optimal truncation make visible.

Language: Английский

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Ligand-Coupled Conformational Changes in a Cyclic Nucleotide-Gated Ion Channel Revealed by Time-Resolved Transition Metal Ion FRET

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 27, 2024

Abstract Cyclic nucleotide-binding domain (CNBD) ion channels play crucial roles in cellular-signaling and excitability are regulated by the direct binding of cyclic adenosine- or guanosine-monophosphate (cAMP, cGMP). However, precise allosteric mechanism governing channel activation upon ligand binding, particularly energetic changes within domains, remains poorly understood. The prokaryotic CNBD SthK offers a valuable model for investigating this mechanism. In study, we investigated conformational dynamics energetics C-terminal region using combination steady-state time-resolved transition metal Förster resonance energy transfer (tmFRET) experiments. We engineered donor-acceptor pairs at specific sites fragment incorporating fluorescent noncanonical amino acid donor acceptors. Measuring tmFRET with fluorescence lifetimes, determined intramolecular distance distributions absence presence cAMP cGMP. probability between states without were used to calculate free (ΔG) differences change (ΔΔG) context simple four-state model. Our findings reveal that produces large structural changes, very favorable ΔΔG. contrast cAMP, cGMP behaved as partial agonist only weakly promoted active state. Furthermore, assessed impact protein oligomerization ionic strength on structure states. This study demonstrates effectiveness determining ligand-dependent region. Significance Statement Allosteric regulation is pivotal function most proteins, especially like channels. examines tmFRET. uncovered significant induced full-agonist weak approach also highlights lifetimes heterogeneity proteins. These deepen our understanding overall lay groundwork more comprehensive characterization effects mutations pharmacological agents these

Language: Английский

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Cortex deviates from criticality during action and deep sleep: a temporal renormalization group approach

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 1, 2024

Abstract The hypothesis that the brain operates near criticality explains observations of complex, often scale-invariant, neural activity. However, is not static, its dynamical state varies depending on what an organism doing. Neurons become more synchronized (ordered) during unconsciousness and desynchronized (disordered) in highly active awake conditions. Are all these states equidistant from criticality; if not, which closest? fundamental physics how systems behave came renormalization group (RG) theory, but RG for remains largely undeveloped. Here we developed a temporal (tRG) theory analysis typical neuroscience data. We mathematically identified multiple types (tRG fixed points) tRG-driven data analytic methods to assess proximity each point based relatively short time series. Unlike traditional studying systems, our tRG approach allows time-resolved measurements distance experiments at behaviorally relevant timescales. apply recordings spike activity mouse visual cortex, showing relaxed, closest criticality. When arousal shifts away this – either increasing or decreasing deep sleep cortical dynamics deviate

Language: Английский

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Designing symmetrical multi-component proteins using a hybrid generative AI approach

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 15, 2024

Abstract Proteins, the fundamental building blocks of biological function, orchestrate complex cellular processes by assembling into intricate structures through meticulous interactions. The design specific protein-protein interfaces to create customized protein assemblies holds immense potential for various biotechnological applications. To address current limitations in designing heteromeric interactions multi-component assemblies, we developed a hybrid generative AI approach. This method combines deep learning and automated reasoning, explicitly considering both positive negative interaction states favor desired over undesired approach leverages Effie, deep-learned pairwise decomposable scoring an advanced reasoning tool extended multicriteria optimization this function. Here, tested ability redesign homomeric bacterial microcompartment components (BMC-H) assemblies. We benchmarked its performance against ProteinMPNN, sequence autoregressive model. Our silico assessment, complemented experimental validation, highlights outperformance approach, unlock engineering self-assembling entities.

Language: Английский

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Accumulation of Oncogenic Mutations During Progression from Healthy Tissue to Cancer

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 21, 2024

Abstract Cancers typically result from sequential accumulation of driver mutations in a previously healthy cell. Some these mutations, such as inactivation the first copy tumor suppressor gene, can be neutral, and some, like those resulting activation oncogenes, may provide cells with selective growth advantage. We study multi-type branching process that starts tissue home-ostasis models neutral advantageous on way to cancer. results regarding sizes premalignant populations waiting times cell particular combination including time malignancy. Finally, we apply our two specific biological settings: initiation colorectal cancer age incidence chronic myeloid leukemia. Our model allows for any order applied other evolutionary settings.

Language: Английский

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Life on the edge: microbial diversity, resistome, and virulome in soils from the Union Glacier cold desert

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 14, 2024

ABSTRACT The high-latitude regions of Antarctica remain among the most remote, extreme, and least explored areas on Earth. Despite highly restrictive conditions, microbial life has been found in these environments, although with limited information their genetic properties functional capabilities. Moreover, accelerated melting Antarctic permafrost, increasing exposure soils, growing human transit pose question whether environments could be a source microbes or genes that emerge cause global health problems. In this line, high bacterial diversity autochthonous multidrug-resistant bacteria have soils Peninsula, we still lack regarding resistome closer to South Pole. no previous studies evaluated pathogenic potential inhabiting soils. work, combined metagenomic culture-dependent approaches investigate diversity, resistome, virulome, mobile elements (MGEs) from Union Glacier, cold desert West Antarctica. low organic matter content, diverse lineages were found, predominating Actinomycetota Pseudomonadota, archaeal fungal taxa. We recovered more than 80 species-level representative genomes (SRGs) predominant taxa archaeon Nitrosocosmicus sp. Diverse putative resistance virulence predicted SRGs, reads, contigs. Furthermore, characterized isolates resistant up 24 clinical antibiotics, mainly Pseudomonas , Arthrobacter Plantibacter, Flavobacterium . some produced factors, including siderophores, pyocyanins, exoenzymes hemolytic, lecithinase, protease, DNAse activity. This evidence uncovers largely unexplored virulome hosted by deep Antarctica’s soil communities presence potential, highlighting relevance One Health for environmental surveillance white continent. HIGHLIGHTS -Union Glacier host community dominated bacteria, phylum Actinomycetota. -Archaea genus (family Nitrosphaeraceae) ubiquitously detected. -Although extreme potentially bacteria. Some cultured tested vitro -Metagenomes revealed genes. -Part antimicrobial factors associated genomes.

Language: Английский

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