bluuebunny/crossref_metadata_2025_split huggingface dataset:
CDKL5 deficiency results in atypical subregion-specific expression of perineuronal nets during mouse visual critical period
Authors: Emery Brett Addison , Everett Matthew , Dunn Logan Reid , Bun Lau Billy You , Krishnan Keerthi 
Published: September 2022

ABSTRACTPerineuronal nets (PNNs) in the primary visual cortex (V1) are specialized extracellular matrix structures that form predominantly on parvalbumin+ GABAergic neurons, marking the closure of visual critical period plasticity. More recently, PNNs are used to characterize deficits in critical period plasticity in mouse models for neurodevelopmental disorders such as Rett syndrome, Fragile X syndrome, and CDKL5 deficiency disorder. Within the mouse V1, studies typically focus on the expression and function of PNNs within the binocular zone, though PNNs are expressed in other subregions of the V1. The expression and role of these PNNs in other subregions are unknown. Here, we performed a systematic whole V1 characterization of PNN expression usingWisteria floribundaagglutinin (WFA) staining, with hemisphere-, subregion-, and anatomical axes-specificity, using a null male mouse model for CDKL5 deficiency disorder during the visual critical period. Patients with CDKL5 deficiency disorder often exhibit cerebral cortical visual impairment, though the underlying mechanisms are unclear. Compared to wild-type controls,Cdkl5-null males show increased WFA expression at both P15 and P30, with nuanced differences in the subregions, suggesting precocious increase in PNN expression in theCdkl5-null V1. In both genotypes, the binocular zone has significantly higher density of PNNs at both ages, compared to the monocular zone and the rostral V1. These results lay the groundwork to probe the roles for PNNs beyond the binocular zone and cumulatively suggest that, during visual critical period, subregion-specific variations in PNN expression may lead to functional consequences within theCdkl5-null cortex.
Transcriptome changes in chlorsulfuron-treated plants are caused by acetolactate synthase inhibition and not induction of a herbicide detoxification system inMarchantia polymorpha
Authors: Casey Alexandra , Köcher Thomas , Caygill Samuel , Champion Clément , Bonnot Clémence , Dolan Liam 
Published: September 2022

AbstractA sensing mechanism in mammals perceives xenobiotics and induces the transcription of genes encoding proteins that detoxify these molecules. However, it is unclear if plants sense xenobiotics, and activate an analogous signalling system leading to their detoxification. Using the liverwortMarchantia polymorpha, we tested the hypothesis that there is a sensing system in plants that perceives herbicides resulting in the increased transcription of genes encoding proteins that detoxify these herbicides. Consistent with the hypothesis, we show that chlorsulfuron-treatment induces changes in theM. polymorphatranscriptome. However, these transcriptome changes do not occur in chlorsulfuron (CS)-treated target site resistant mutants, where the gene encoding the target carries a mutation that confers resistance to chlorsulfuron. Instead, we show that inactivation of the chlorsulfuron target, acetolactate synthase (ALS) (also known as acetohydroxyacid synthase (AHAS)), is required for the transcriptome response. These data are consistent with the changes in the transcriptome of chlorsulfuron-treated plants being caused by disrupted amino acid synthesis and metabolism resulting from acetolactate synthase inhibition. These conclusions suggest that chlorsulfuron is not sensed inM. polymorphaleading to induce a detoxification system.Author SummaryHerbicide use is increasing throughout the world, however we know little about how plants respond to herbicide treatment and regulate their metabolism. Some plants have evolved resistance to herbicides such as chlorsulfuron by increasing the detoxification of the herbicide compared to sensitive plants. It has been suggested that plants can directly sense the herbicide chemical which activates a detoxification response, in a similar way to the detoxification of foreign chemicals in mammalian cells. The liverwortMarchantia polymorphais an excellent system to study plant herbicide responses due to its short generation time, ease of propagation and low genetic redundancy. We show that chlorsulfuron treatment alters the expression of many genes inM. polymorpha, however plants with a resistance-conferring mutation in the molecular target of chlorsulfuron do not show any changes in gene expression in response to chlorsulfuron treatment. This result indicates that transcriptome changes caused by chlorsulfuron depend on the inhibition of the target by chlorsulfuron. This suggests that plants do not sense chlorsulfuron and activate a detoxification system. This finding has implications for herbicide use and discovery.
Neuroinvasion and anosmia are independent phenomena upon infection with SARS-CoV-2 and its variants
Authors: de Melo Guilherme Dias , Perraud Victoire , Alvarez Flavio , Vieites-Prado Alba , Kim Seonhee , Kergoat Lauriane , Coleon Anthony , Trüeb Bettina Salome , Tichit Magali , Piazza Aurèle , Thierry Agnès , Hardy David , Wolff Nicolas , Munier Sandie , Koszul Romain , Simon-Lorière Etienne , Thiel Volker , Lecuit Marc , Lledo Pierre-Marie , Renier Nicolas , Larrous Florence , Bourhy Hervé 
Published: September 2022

SUMMARYAnosmia was identified as a hallmark of COVID-19 early in the pandemic, however, with the emergence of variants of concern, the clinical profile induced by SARS-CoV-2 infection has changed, with anosmia being less frequent. Here, we assessed the clinical, olfactory and neuroinflammatory conditions of golden hamsters infected with the original Wuhan SARS-CoV-2 strain, its isogenic ORF7-deletion mutant and three variants: Gamma, Delta, and Omicron/BA.1. We show that infected animals developed a variant-dependent clinical disease including anosmia, and that the ORF7 of SARS-CoV-2 contributes to the induction of olfactory dysfunction. Conversely, all SARS- CoV-2 variants were found to be neuroinvasive, regardless of the clinical presentation they induce. Taken together, this confirms that neuroinvasion and anosmia are independent phenomena upon SARS-CoV-2 infection. Using newly generated nanoluciferase-expressing SARS-CoV-2, we validated the olfactory pathway as a major entry point into the brainin vivoand demonstratedin vitrothat SARS-CoV-2 travels retrogradely and anterogradely along axons in microfluidic neuron-epithelial networks.Graphical abstract
Targeting of the human nasal microbiota by secretory IgA antibodies
Authors: van Dalen Rob , Elsherbini Ahmed M. A. , Harms Mareike , Alber Svenja , Stemmler Regine , Peschel Andreas 
Published: September 2022

AbstractThe human nasal microbiome is critical for health and disease, since it is associated with the occurrence of respiratory disorders and hosting of opportunistic pathogens. The host therefore protects this vulnerable mucosal barrier from infection and maintains homeostasis of the microbiota through various mechanisms, including the production of secretory IgA (sIgA) antibodies. However, we currently lack a comprehensive understanding of how sIgA affects the nasal microbiota. Through IgA-seq analysis of nasal microbiome samples and sIgA deposition experiments using nasal sIgA from healthy volunteers, we identified which bacterial genera and species are targeted by sIgA on the level of the individual host. We observed that the amount of sIgA secreted into the nasal mucosa by the host varied substantially and was negatively correlated with the bacterial density. The interaction between mucosal sIgA antibodies and the nasal microbiome was highly individual, and was not dependent on the microbiome composition, or the age or gender of the host. Importantly, we showed that for the clinically relevant opportunistic pathogen S. aureus, sIgA reactivity was in part the result of epitope-independent interaction of sIgA with the antibody binding protein SpA through binding of sIgA Fab regions. This study thereby offers a first comprehensive insight of targeting of nasal microbiota by sIgA antibodies, which may help to better understand the shaping and homeostasis of the nasal microbiome by the host and offer new targets for intervention in disease-associated microbiota.
A twin UGUA motif directs the balance between gene isoforms through CFIm and the mTORC1 signaling pathway
Authors: Herron R. Samuel , Kunisky Alexander K. , Madden Jessica R. , Anyaeche Vivian I. , Hwang Hun-Way 
Published: September 2022

SUMMARYAlternative polyadenylation (APA) generates mRNA isoforms and diversifies gene expression. Here we report the identification of a twin UGUA motif, UGUAYUGUA, and its function in APA. Applying cTag-PAPERCLIP to Tsc1 conditional knockout mice, we discovered that the mTORC1 pathway balances expression of Trim9 isoforms. We showed that CFIm components, CPSF6 and NUDT21, promote Trim9/TRIM9-S expression in mouse and human, and we identified an evolutionarily conserved UGUAYUGUA motif that is critical for this regulation. We found additional CPSF6-regulated polyadenylation sites (PASs) with similar twin UGUA motifs in human, and we experimentally validated the twin UGUA motif functionality in BMPR1B, MOB4, and BRD4-L. Importantly, we showed that inserting a twin UGUA motif into a heterologous PAS was sufficient to confer regulation by CPSF6 and mTORC1. Our study reveals an evolutionarily conserved mechanism to regulate gene isoform expression and implicates possible gene isoform imbalance in cancer and neurologic disorders with mTORC1 pathway dysregulation.
Lack of the glycine receptor alpha 2 increases striatal activity and motivated behavior
Authors: Devoght Jens , Comhair Joris , Morelli Giovanni , Rigo Jean-Michel , D’Hooge Rudi , Touma Chadi , Palme Rupert , Dewachter Ilse , vandeVen Martin , Harvey Robert J. , Schiffmann Serge , Piccart Elisabeth , Brône Bert 
Published: September 2022

AbstractDistinct developmental pathologies, including autism spectrum disorder and schizophrenia, exhibit impaired reward-motivated behavior. Key to proper reward-motivated behavior is dopamine-mediated modulation of striatal activity. The glycine alpha 2 receptor (GlyRα2) is the single functionally expressed glycine receptor in adult striatum, and is therefore ideally positioned to modulate striatal behavior and cellular activity. Here, we report excessive appetitive conditioning in male GlyRα2 knockout mice. We next show that depletion of GlyRα2 enhances dopamine-induced increases in the activity of putative dopamine D1-expressing striatal projection neurons, while not affecting dopamine neuron activity. Moreover, we found that excessive locomotor responses to amphetamine in GlyRα2 KO mice correlate with immediate early gene c-fos expression in the dorsal striatum. 3-D modeling revealed an increase in the number of activated cell ensembles in the striatum in response to D-amphetamine in GlyRα2 KO mice. Taken together, we show that depletion of GlyRα2 impairs reward-motivated behavior and altered striatal signal integration. This sheds important light onto the cellular mechanisms that underlie reward function, and pave the way towards novel therapeutics for the treatment of e.g. schizophrenia and addiction.Significance statementThe glycine receptor alpha 2 has long been studied for its role in development, with expression assumed to decline throughout adulthood in favor of the glycine receptor alpha 1 and 3. Yet, we showed that in the dorsal striatum, the glycine alpha 2 receptor is the only functionally expressed glycine receptor at adult age (Molchanova et al., 2017).In the present work, we show for the first time that the glycine alpha 2 receptor crucially affects striatal cell activity, which lies at the basis of reward-motivated behaviors, and which is impaired in many psychiatric pathologies. Indeed, a link between the mutations in the glycine alpha 2 receptor and autism as well as schizophrenia has been described, but a functional role for the glycine alpha 2 receptor in adult brain structures that are involved in psychiatric pathologies, was never shown before.
Application of Temperature-Responsive HIS-Tag Fluorophores to Differential Scanning Fluorimetry Screening of Small Molecule Libraries
Authors: Ronzetti Michael H. , Baljinnyam Bolormaa , Itkin Zina , Jain Sankalp , Rai Ganesha , Zakharov Alexey V. , Pal Utpal , Simeonov Anton 
Published: September 2022

AbstractDifferential scanning fluorimetry is a rapid and economical biophysical technique used to monitor perturbations to protein structure during a thermal gradient most often by detecting protein unfolding events through an environment-sensitive fluorophore. By employing an NTA-complexed fluorophore that is sensitive to nearby structural changes in 6xHIS-tagged protein, a robust and sensitive differential scanning fluorimetry (DSF) assay is established with the specificity of an affinity tag-based system. We developed, optimized, and miniaturized this histidine-tag DSF assay (HIS-DSF) into a 1536-well high-throughput biophysical platform using the Borrelial high temperature requirement A protease (BbHtrA) as a proof of concept for the workflow. A production run of the BbHtrA HIS-DSF assay showed a tight negative control group distribution of Tm values with an average coefficient of variation of 0.51% and median coefficient of variation of compound Tm of 0.26%. The HIS-DSF platform will provide an additional assay platform for future drug discovery campaigns with applications in buffer screening and optimization, target engagement screening, and other biophysical assay efforts.
The Secreted Tyrosine Phosphatase PtpA promotes Staphylococcus aureus Intramacrophagic Survival Through Decrease of the SUMOylation Host Response
Authors: Youssouf Nadhuma , Martin Marianne , Bischoff Markus , Soubeyran Philippe , Gannoun-Zaki Laila , Molle Virginie 
Published: September 2022

AbstractS. aureus is a human pathogen that is extremely adaptable and is the cause of a variety of nosocomial and community-acquired infectious illnesses. During infection, S. aureus affect the host cell in many ways to enable its own multiplication, spread, and evasion of host immune defense. One of S. aureus mechanism to survive is to inhibit the SUMOylation of host proteins in order to increase its intracellular survival and persistence for longer period of time. Here, we show that the reduction in the levels of cellular SUMO-conjugated proteins is associated to the PtpA secreted virulence factor, which results in a reduction of Ubc9 protein level, the essential enzyme of the SUMOylation modification. In addition, we demonstrated that the critical residue D120A, essential for PtpA phosphatase activity, is required. This study shows for the first time that the secreted phosphatase PtpA impedes the host SUMOylation response, thus promoting S. aureus survival at long-term infection.
Experience, not time, determines representational drift in the hippocampus
Authors: Khatib Dorgham , Ratzon Aviv , Sellevoll Mariell , Barak Omri , Morris Genela , Derdikman Dori 
Published: September 2022

SummaryMemories of past events can be recalled long after the event, indicating stability. But new experiences are also integrated into existing memories, indicating plasticity. In the hippocampus, spatial representations are known to remain stable, but have also been shown to drift over long periods of time. We hypothesized that experience, more than the passage of time, is the driving force behind memory plasticity. We compared the stability of place cells in the hippocampus of mice traversing two similar, familiar tracks for different durations. We found that the more time spent in an environment, the greater the representational drift, regardless of the total elapsed time. Our results suggest that spatial representation is a dynamic process, related to the ongoing experiences within a specific context, and is related to the accumulation of new memories rather than to passive forgetting.HighlightsRepresentational drift is related to experience within an environment.Representational drift is a dynamic context-wide process.Place cell number decreases with experience, spatial information content increases.
Nonlinear computation by a habenula-driven recurrent inhibitory network in the raphe
Authors: Lynn Michael B. , Geddes Sean , Chahrour Mohamad , Maillé Sébastien , Caya-Bissonnette Léa , Harkin Emerson , Harvey-Girard Érik , Haj-Dahmane Samir , Naud Richard , Béïque Jean-Claude 
Published: September 2022

AbstractSerotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) receive a constellation of long-range inputs, yet guiding principles of local circuit organization and underlying computations in this nucleus are largely unknown. Using inputs from the lateral habenula (LHb) to interrogate the processing features of the DRN, we uncovered 5-HT1A receptor-mediated recurrent connections between 5-HT neurons, refuting classical theories of autoinhibition. Cellular electrophysiology and imaging of a genetically encoded 5-HT sensor revealed that these recurrent inhibitory connections spanned the raphe, were slow, stochastic, strongly facilitating, and gated spike output. These features collectively conveyed highly non-linear dynamics to this network, generating excitation-driven inhibition and winner-take-all computations.In vivooptogenetic activation of LHb inputs to DRN, at frequencies where these computations are predicted to ignite, transiently disrupted expression of a reward-conditioned response in an auditory conditioning task. Together, these data identify a core computation supported by an unsuspected slow serotonergic recurrent inhibitory network.
Pharmacological profiling of a Brugia malayi muscarinic acetylcholine receptor as a putative antiparasitic target
Authors: Gallo Kendra J , Wheeler Nicolas J , Elmi Abdifatah M , Airs Paul M , Zamanian Mostafa 
Published: September 2022

AbstractThe diversification of anthelmintic targets and mechanisms of action will help ensure the sustainable control of nematode infections in response to the growing threat of drug resistance. G protein-coupled receptors (GPCRs) are established drug targets in human medicine but remain unexploited as anthelmintic substrates despite their important roles in nematode neuromuscular and physiological processes. Bottlenecks in exploring the druggability of parasitic nematode GPCRs include a limited helminth genetic toolkit and difficulties establishing functional heterologous expression. In an effort to address some of these challenges, we profile the function and pharmacology of muscarinic acetylcholine receptors in the human parasite Brugia malayi, an etiological agent of human lymphatic filariasis. While acetylcholine-gated ion channels are intensely studied as targets of existing anthelmintics, comparatively little is known about metabotropic receptor contributions to parasite cholinergic signaling. Using multivariate phenotypic assays in microfilariae and adults, we show that nicotinic and muscarinic compounds disparately affect parasite fitness traits. We identify a putative G protein-linked acetylcholine receptor (Bma-GAR-3) that is highly expressed across intra-mammalian life stages and adapt spatial RNA in situ hybridization to map receptor transcripts to critical parasite tissues. Tissue-specific expression of Bma-gar-3 in Caenorhabditis elegans (body wall muscle, sensory neurons, and pharynx) enabled receptor deorphanization and pharmacological profiling in a nematode physiological context. Lastly, we developed an image-based feeding assay as a reporter of pharyngeal activity to facilitate GPCR screening in parasitized strains. We expect that these receptor characterization approaches and improved knowledge of GARs as putative drug targets will further advance the study of GPCR biology across medically important nematodes.
Single amino acid residues control potential-dependent inactivation of an inner membrane bc-cytochrome
Authors: Joshi Komal , Chan Chi Ho , Levar Caleb E. , Bond Daniel R. 
Published: September 2022

AbstractDuring extracellular electron transfer, Geobacter sulfurreducens constitutively expresses the bc-cytochrome CbcL, yet cells containing only this menaquinone oxidase fail to respire above –0.1 V vs. SHE. By identifying mutations within cbcL that permit growth at higher potentials, we provide evidence that this cytochrome is regulated by redox potential. Strains expressing CbcLV205A, CbcLV205G, and CbcLF525Y were capable of growth with high potential electron acceptors including Fe(III) citrate, Mn(IV) oxides, and electrodes poised at +0.1 V vs. SHE. Electrochemical characterization of wild type CbcL revealed oxidative inactivation of electron transfer above -0.1 V, while CbcLV205A, CbcLV205G, and CbcLF525Y remained active. Growth yields of CbcLV205A, CbcLV205G, and CbcLF525Y were only 50% of WT, consistent with CbcL-dependent electron transfer conserving less energy. These data support the hypothesis that CbcL has evolved to rapidly shut off in response to redox potential to divert electrons to higher yield oxidases that coexist in the Geobacter membrane.TOC image and captionTunnel diode behaviorElectron flux from cells utilizing the menaquinone oxidase CbcL is attenuated by increased redox potential, preventing use of this low-efficiency pathway when driving forces are high enough to conserve energy via other oxidases. Single amino acid substitutions eliminate this switch-off effect and allow function at all potentials.
Embryonic cortical layer 5 pyramidal neurons form an active, transient circuit motif perturbed by autism-associated mutations
Authors: Munz Martin , Bharioke Arjun , Kosche Georg , Moreno-Juan Verónica , Brignall Alexandra , Graff-Meyer Alexandra , Ulmer Talia , Rodrigues Tiago M. , Haeuselmann Stephanie , Pavlinic Dinko , Ledergeber Nicole , Gross-Scherf Brigitte , Rózsa Balázs , Krol Jacek , Picelli Simone , Cowan Cameron S. , Roska Botond 
Published: September 2022

SummaryCortical circuits are composed predominantly of pyramidal-to-pyramidal neuron connections, yet their assembly during embryonic development is not well understood. We show that embryonic layer 5 pyramidal neurons, identified through single cell transcriptomics, display two phases of circuit assembly in vivo. At E14.5, a multi-layered circuit motif, composed of a single layer 5 cell type, forms. This motif is transient, switching to a second circuit motif, involving all three types, by E17.5. In vivo targeted single cell recordings and two-photon calcium imaging of embryonic layer 5 neurons reveal that, in both phases, neurons have active somas and neurites, tetrodotoxin-sensitive voltage-gated conductances, and functional glutamatergic synapses. Embryonic layer 5 neurons strongly express autism-associated genes, and perturbing these genes disrupts the switch between the two motifs. Hence, layer 5 pyramidal neurons form transient active pyramidal-to-pyramidal circuits, at the inception of neocortex, and studying these circuits could yield insights into the etiology of autism.