bluuebunny/crossref_metadata_2025 huggingface dataset:
Norepinephrine regulates Ca2+ signals and fate of oligodendrocyte progenitor cells in the cortex
Authors: Fiore Frederic , Dereddi Ram R. , Alhalaseh Khaleel , Coban Ilknur , Harb Ali , Agarwal Amit
Published: September 2022

Oligodendrocyte precursor cells (OPCs) represent the most abundant group of proliferating cells in the adult central nervous system. OPCs serve as progenitors for oligodendrocyte (OLs) throughout the life, and contribute to developmental and adaptive myelination, and myelin repair during diseased state. OPCs make synaptic and extra-synaptic contacts with axons, and detect and respond to neuronal activity. How OPCs translate the information relayed by the neuronal activity into Ca2+ signals, which in turn influence their fate and survival, is less understood. We developed novel transgenic mouse lines expressing a cytosolic and membrane anchored variants of genetically encoded Ca2+ sensors (GCaMP6f or mGCaMP6s) in OPCs, performed 2-photon microscopy in the somatosensory cortex of the awake behaving mice, and simultaneously monitored intracellular Ca2+ signals and their cell-fate progression. We found Ca2+ signals in OPCs mainly occur within processes and confine to micrometer-size segments called Ca2+ microdomains. Microdomain Ca2+ signals enhanced in OPCs when mice engage in exploratory behavior. OPCs exhibit distinct Ca2+ signals while they proliferate to maintain their precursor pool or differentiate to generate new OL. When mice engaged in exploratory behavior, the cortical projections of noradrenergic neurons in locus coeruleus showed increased firing rate and norepinephrine release. Norepinephrine activated all three subtypes of alpha1 adrenergic receptor expressed by OPCs and evoked intracellular Ca2+ increase in OPCs. A chemogenetic activation of noradrenergic neurons, promoted differentiation of cortical OPCs into OL, and at the same time suppressed OPC proliferation rate. Hence, we uncovered that various cell types of oligodendrocyte lineage exhibits unique signatures of Ca2+ activity, which these cells might integrate for making their fate decisions, and norepinephrine signaling can be a potent regulator of OPC fate.
Interaction with C21ORF2 controls the cellular functioning of the NEK1 kinase
Authors: Gregorczyk Mateusz , Pastore Graziana , Lis Pawel , Lange Sven , Lamoliatte Frederic , Macartney Thomas , Toth Rachel , Brown Fiona , Hastie James , Durocher Daniel , Rouse John
Published: September 2022

NEK1 is a pleiotropic protein kinase implicated in mitosis, ciliogenesis and DNA repair but little is known about its regulation or targets. Its relevance for human health is underscored by the association of NEK1 mutations with human diseases including axial spondylometaphyseal dyplasia (SMD) and amyotrophic lateral sclerosis (ALS). Mutations in the C21ORF2 gene are associated with a similar pattern of human diseases, suggesting close functional links with NEK1. Here we report that in unperturbed, untransformed cells, endogenous NEK1 and C21ORF2 form a tight complex that does not appear to contain other proteins. A small acidic domain “CID: C21ORF2 interaction domain” at the C-terminus of NEK1 is necessary and sufficient to interact with C21ORF2, and pathogenic mutations in this region disrupt the complex. AlphaFold modelling predicts with high confidence an extended binding interface between a leucine-rich repeat (LRR) domain in the N-terminal half of C21ORF2 and a stretch of the NEK1-CID; mutating residues mediating electrostatic interactions within this interface disrupts the NEK1-C21ORF2 interaction. This model also explains why pathogenic mutations disrupt the complex. We go on to show that the kinase activity of NEK1 and its interaction with C21ORF2 is critical for NEK1 function in cells. These data reveal C21ORF2 as a regulatory subunit of NEK1, illuminating our understanding of how this kinase is regulated and NEK1-C21ORF2-associated diseases.
Intestinal stem cell aging at single-cell resolution: functional perturbations alter cell developmental trajectory reversed by gerotherapeutics
Authors: Choi Jiahn , Houston Michele , Wang Ruixuan , Ye Kenny , Li Wenge , Zhang Xusheng , Huffman Derek M. , Augenlicht Leonard H.
Published: September 2022

The intestinal epithelium is consists of cells derived from continuously cycling Lgr5hi intestinal stem cells (Lgr5hi ISCs) that mature developmentally in an order fashion as the cells progress along the crypt-luminal axis. Perturbed function of Lgr5hi ISCs with aging is well documented but the consequent impact on overall mucosal homeostasis has not been defined. Using single-cell RNA sequencing, the progressive maturation of progeny was dissected in mouse intestine, which revealed that transcriptional reprogramming with aging in Lgr5hi ISCs retarded cell maturation in their progression along the crypt-luminal axis. Importantly, treatment with metformin or rapamycin at a late stage of mouse lifespan reversed the effects of aging on function of Lgr5hi ISCs and subsequent maturation of progenitors. The effects of metformin and rapamycin overlapped in reversing changes of transcriptional profiles, but were also complementary, with metformin more efficient than rapamycin in correcting the developmental trajectory. Therefore, our data identify novel effects of aging on stem cells and the maturation of their daughter cells contributing to the decline of functional Lgr5hi ISCs and the correction by geroprotectors.
Excel-SBOL Converter: Creating SBOL from Excel Templates and Vice Versa
Authors: Mante Jeanet , Abam Julian , Samineni Sai P. , Pötzsch Isabel M. , Singh Prubhtej , Beal Jacob , Myers Chris J.
Published: September 2022

Standards support synthetic biology research by enabling the exchange of component information. However, using formal representations, such as the Synthetic Biology Open Language (SBOL), typically requires either a thorough understanding of these standards or a suite of tools developed in concurrence with the ontologies. Since these tools may be a barrier for use by many practitioners, the Excel-SBOL Converter was developed to allow easier use of SBOL and integration into existing workflows. The converter consists of two Python libraries: one that converts Excel templates to SBOL, and another that converts SBOL to an Excel workbook. Both libraries can be used either directly or via a SynBioHub plugin. We illustrate the operation of the Excel-SBOL Converter with two case studies: uploading experimental data with the study’s metadata linked to the measurements and downloading the Cello part repository.

Graphical TOC Entry
Methanotrophs are vigorous H2S oxidizers using a sulfide:quinone oxidoreductase and a ba3-type terminal oxidase
Authors: Schmitz Rob A. , Peeters Stijn H. , Mohammadi Sepehr S. , Berben Tom , van Erven Timo , Iosif Carmen A. , van Alen Theo , Versantvoort Wouter , Jetten Mike S.M. , Op den Camp Huub J.M. , Pol Arjan
Published: September 2022

Hydrogen sulfide (H2S) is produced in a wide range of anoxic environments where sulfate (SO42−) reduction is coupled to decomposition of organic matter. In the same environments, methane (CH4) is the end product of an anaerobic food chain and both H2S and CH4 diffuse upwards into oxic zones where aerobic microorganisms can utilize these gases. Methane-oxidizing bacteria are known to oxidize a major part of the produced CH4 in these ecosystems, mitigating the emissions of this potent greenhouse gas to the atmosphere. However, how methanotrophy is affected by toxic H2S is largely unexplored. Here, we show that a single microorganism can oxidize CH4 and H2S simultaneously. By oxidizing H2S, the thermoacidophilic methanotroph Methylacidiphilum fumariolicum SolV can alleviate the inhibitory effects on CH4 oxidation. In response to H2S, strain SolV upregulated a type III sulfide:quinone oxidoreductase (SQR) and a sulfide-insensitive ba3-type terminal oxidase to dissipate the reducing equivalents derived from H2S oxidation. Through extensive chemostat cultivation of M. fumariolicum SolV we demonstrate that it converts high loads of H2S to elemental sulfur (S0). Moreover, we show chemolithoautotrophy by tracing 13CO2 fixation into new biomass by using H2S as sole energy source. Molecular surveys revealed several putative SQR sequences in a range of proteobacterial methanotrophs from various environments, suggesting that H2S detoxification is much more widespread in methanotrophs than previously assumed, enabling them to connect carbon and sulfur cycles in new ways.
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

Perineuronal 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

A 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 Summary

Herbicide 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

Anosmia 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

The 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

Alternative 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

Distinct 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 statement

The 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

Differential 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

S. 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

Memories 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.

Highlights

Representational 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

Serotonin (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

The 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

During 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 caption

Tunnel diode behavior

Electron 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

Cortical 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.
Dietary molybdenum cofactor promotes fitness by increasing Moco content and sulfite oxidase activity in the nematode C. elegans
Authors: Oliphant Kevin D. , Fettig Robin R. , Snoozy Jennifer , Mendel Ralf R. , Warnhoff Kurt
Published: September 2022

Molybdenum cofactor (Moco) is a prosthetic group necessary for the activity of 4 unique enzymes, including the essential sulfite oxidase (SUOX-1). Moco is required for life; humans with inactivating mutations in the genes encoding Moco-biosynthetic enzymes display Moco deficiency, a rare and lethal inborn error of metabolism. Despite its importance to human health, little is known about how Moco moves among and between cells, tissues, and organisms. The prevailing view is that cells that require Moco must synthesize Moco de novo. Although, the nematode Caenorhabditis elegans appears to be an exception to this rule and has emerged as a valuable system for understanding fundamental Moco biology. C. elegans has the seemingly unique capacity to both synthesize its own Moco as well as acquire Moco from its microbial diet. However, the relative contribution of Moco from the diet or endogenous synthesis has not been rigorously evaluated or quantified biochemically. We genetically removed dietary or endogenous Moco sources in C. elegans and biochemically determined their impact on animal Moco content and SUOX-1 activity. We demonstrate that dietary Moco deficiency dramatically reduces both animal Moco content and SUOX-1 activity. Furthermore, these biochemical deficiencies have physiological consequences; we show that dietary Moco deficiency alone causes sensitivity to sulfite, the toxic substrate of SUOX-1. This work establishes the biochemical consequences of depleting dietary Moco or endogenous Moco synthesis in C. elegans and quantifies the surprising contribution of the diet to maintaining Moco homeostasis in C. elegans.
The calcineurin regulator Sarah enables distinct forms of homeostatic plasticity at theDrosophilaneuromuscular junction
Authors: Armstrong Noah S. , Frank C. Andrew
Published: September 2022

The ability of synapses to maintain physiological levels of evoked neurotransmission is essential for neuronal stability. A variety of perturbations can disrupt neurotransmission, but synapses often compensate for disruptions and work to stabilize activity levels, using forms of homeostatic synaptic plasticity. Presynaptic homeostatic potentiation (PHP) is one such mechanism. PHP is expressed at theDrosophila melanogasterlarval neuromuscular junction (NMJ) synapse, as well as other NMJs. In PHP, presynaptic neurotransmitter release increases to offset the effects of impairing muscle transmitter receptors. PriorDrosophilawork has studied PHP using different ways to perturb muscle receptor function – either acutely (using pharmacology) or chronically (using genetics). Some of our prior data suggested that cytoplasmic calcium signaling was important for expression of PHP after genetic impairment of glutamate receptors. Here we followed up on that observation. We used a combination of transgenicDrosophilaRNA interference and overexpression lines, along with NMJ electrophysiology, synapse imaging, and pharmacology to test if regulators of the calcium/calmodulin-dependent protein phosphatase calcineurin are necessary for the normal expression of PHP. We found that either pre- or postsynaptic dysregulation of aDrosophilagene regulating calcineurin,sarah(sra), blocks PHP. Tissue-specific manipulations showed that either increases or decreases insraexpression are detrimental to PHP. Additionally, pharmacologically and genetically induced forms of expression of PHP are functionally separable depending entirely upon whichsragenetic manipulation is used. Surprisingly, dual-tissue pre- and postsynapticsraknockdown or overexpression can ameliorate PHP blocks revealed in single-tissue experiments. Pharmacological and genetic inhibition of calcineurin corroborated this latter finding. Our results suggest tight calcineurin regulation is needed across multiple tissue types to stabilize peripheral synaptic outputs.
The dual nature of the nucleolus
Authors: Tartakoff Alan , DiMario Patrick , Hurt Eduard , McStay Brian , Panse Vikram Govind , Tollervey David
Published: September 2022

The nucleolus is best known for housing the highly ordered assembly line that produces ribosomal subunits. The >100 ribosome assembly factors in the nucleolus are thought to cycle between two states: an operative state (when integrated into subunit assembly intermediates) and a latent state (upon release from intermediates). Although it has become commonplace to refer to the nucleolus as “being a multilayered condensate,” and this may be accurate for latent factors, there is little reason to think that such assertions pertain to the operative state of assembly factors.
Insemination in Aedes aegypti and Aedes albopictus
Authors: Parsana Dhwani , Nanfack-Minkeu Ferdinand , Sirot Laura K.
Published: September 2022

Aedes mosquitoes are the vectors of several arboviruses that cause human disease. A better understanding of their reproduction helps to improve their management and contributes insights into the fundamental biology of mosquitoes. During mating, inseminated mosquito females receive seminal fluids and sperm from males that they then store in the spermathecae. In Aedes aegypti and Aedes albopictus, most mated females become resistant to further insemination within 2 h of initial insemination. Although the male seminal fluids are known to be involved in initiating the resistance of inseminated females to further insemination, the mechanism underlying this resistance is not well-understood. The determination of insemination status is a key step in investigating the behavioral and molecular interactions between males and females and for exploring the proximate influences and evolutionary implications of interspecific copulations. Several methods exist for determining insemination status, as discussed here. The choice of method depends on the research question and the availability of resources.
Refining perovskite structures to pair distribution function data using collective Glazer modes as a basis
Authors: Skjærvø Sandra Helen , Karlsen Martin A. , Comin Riccardo , Billinge Simon J. L.
Published: September 2022

Structural modelling of octahedral tilts in perovskites is typically carried out using the symmetry constraints of the resulting space group. In most cases, this introduces more degrees of freedom than those strictly necessary to describe only the octahedral tilts. It can therefore be a challenge to disentangle the octahedral tilts from other structural distortions such as cation displacements and octahedral distortions. This paper reports the development of constraints for modelling pure octahedral tilts and implementation of the constraints in diffpy-CMI, a powerful package to analyse pair distribution function (PDF) data. The model in the program allows features in the PDF that come from rigid tilts to be separated from non-rigid relaxations, providing an intuitive picture of the tilting. The model has many fewer refinable variables than the unconstrained space group fits and provides robust and stable refinements of the tilt components. It further demonstrates the use of the model on the canonical tilted perovskite CaTiO3 which has the known Glazer tilt system α+β−β−. The Glazer model fits comparably to the corresponding space-group model Pnma below r = 14 Å and becomes progressively worse than the space-group model at higher r due to non-rigid distortions in the real material.
Social class as a blessing in disguise? Beyond the deficit model in working-class and higher education studies
Authors: Luczaj Kamil
Published: September 2022

Purpose

The overarching question of this paper is, “What are the advantages of being an upwardly mobile academic?” The extant academic research on working-class academics has usually emphasized various kinds of “deficits” of working-class academics. In this paper, the author demonstrates that although class positions can constitute a formidable burden, they can translate into specific advantages in academia.

Design/methodology/approach

This study is based on the narrative, phenomenological approach, which has been applied in working-class studies and higher-education research. The empirical material comprises the collection of 25 narrative interviews conducted and analyzed according to the biographical narrative interpretive method (BNIM).

Findings

This paper looks at the experience of working-class academics from a holistic perspective, including both the downsides and upsides of being an “outsider within,” or “insider without.” It uncovers four assets of a working-class background – referred to as “navigational capital,” “revolutionary potential,” “wisdom” and a distinct “working-class pedagogy.”

Practical implications

The working-class pedagogy can be turned into support programs for working-class individuals. Their navigational capital can foster evolutionary changes and small improvements for the benefit of the entire academic community. Their revolutionary dispositions can trigger major reforms, and their unique experiences can be utilized as case studies in teaching.

Originality/value

This paper engages with the literature on the cultural mismatch and cleft habitus in the academic context. It analyzes the positive but rarely discussed aspects of being an upwardly mobile academic with a working-class background. By recognizing these unique assets, it engages with the literature on inclusive universities and can help make higher education more inclusive and sustainable.
Ownership concentration, financial reporting quality and investment efficiency: an empirical analysis of Vietnamese listed firms
Authors: Dinh Thi Ha Thu , Nguyen Cuong Cao , Gan Christopher
Published: September 2022

Purpose

The purpose of this study is to investigate the relationships among financial reporting quality (FRQ), ownership concentration and investment efficiency (IE) of listed firms in Vietnam, an emerging market in Southeast Asia.

Design/methodology/approach

Multivariate regression models are estimated to test the impacts of FRQ, ownership concentration and the interaction effect of FRQ and ownership concentration on IE. Two-step system generalized method of moments (GMM) estimators are used to control for endogeneity.

Findings

The results show that ownership concentration is positively associated with the IE of Vietnamese listed firms. The results also reveal that overinvestment decreases when there is an increase in ownership concentration. In addition, the authors find that FRQ is positively associated with IE and negatively associated with overinvestment and underinvestment. Moreover, the impact of FRQ on overinvestment is weaker in firms with concentrated ownership.

Originality/value

To the best of the authors’ knowledge, this is the first study that attempts to investigate the influence of ownership concentration and the interaction effect of ownership concentration and FRQ on the IE of Vietnamese listed firms. The results provide some managerial implications for Vietnamese listed firms and policymakers on how to mitigate firm-level investment inefficiency.
Consumer research during the COVID-19 pandemic: a systematic review
Authors: Herjanto Halimin , Amin Muslim , Mahfooz Yasser
Published: September 2022

Purpose

This study aims to extend the study of COVID-19 effects by identifying different consumer behaviors beyond panic buying during the pandemic.

Design/methodology/approach

A systematic review was based on Herjantoet al.’s (2020a) thematic analysis and Paulet al.’s (2021) 5W1H framework, and the authors analyzed 52 related papers.

Findings

The result findings indicated that during the COVID-19 pandemic, consumers fell into five different consumer behavior categories: health-related behaviors, consumption behaviors, ethical behaviors, behavioral intentions, and other related behaviors, and social connectedness behaviors. Findings show that consumer behaviors were increasingly complex and dynamic during the pandemic.

Originality/value

This systematic review will provide significant contributions to academia by offering general and technical insights and to practitioners by presenting guidelines on dealing with such different behaviors.
Angiotensin‐receptor blocker losartan alleviates atrial fibrillation in rats by downregulating frizzled 8 and inhibiting the activation of WNT‐5A pathway
Authors: Feng Ronghua , Wan Jinjie , He Yongsheng , Gong Hui , Xu Zeqin , Feng Jiugeng
Published: September 2022

Atrial fibrillation (AF) is a common arrhythmia. Angiotensin‐receptor blocker (ARB) is related to AF treatment. This study explored the mechanism of ARB in AF. AF rat models were established by Ach‐CaCl2 mixed solution injection. Rats were treated with ARB by gavage and injected with pcDNA3.1‐based frizzled homolog 8 (FZD8) overexpression plasmids (oe‐FZD8) through the tail vein. The 12‐lead electrocardiogram was recorded by biological signal acquisition and processing system and AF duration was recorded, and atrial effective refractory period (AERP) was monitored by electrophysiology. Atrial fibrosis degree, FZD8 messenger RNA and protein levels, collagen I, collagen III, transforming growth factor β1 (TGF‐β1), fibronectin, α smooth muscle actin (α‐SMA), WBT‐5B, and p‐JNK1/2 levels, interleukin 1 β (IL‐1β) and interleukin 6 (IL‐6) levels were detected by Masson staining, reverse transcription quantitative polymerase chain reaction, western blot assay, immunohistochemistry, and enzyme‐linked immunosorbent assay. ACh‐CaCl2‐induced AF rats showed a large area of fused necrosis, abnormal collagen fibre proliferation, high atrial fibrosis degree, and increased atrial fibrosis area in atrial interstitium, elevated collagen I, collagen III, TGF‐β1, fibronectin, α‐SMA, IL‐1β, and IL‐6 levels, whereas these trends were averted by ARB treatment. FZD8 was highly expressed in AF rat myocardium. ARB repressed FZD8 expression, prolonged AERP and reduced AF incidence. FZD8 overexpression annulled the effects of ARB on improving AF rat myocardial fibrosis. ARB inactivated the WNT‐5A pathway by suppressing FZD8. ARB inactivated the WNT‐5A pathway by silencing FZD8, therefore, alleviating AF rat atrial fibrosis.
Resource availability drives bacteria community resistance to pathogen invasion via altering bacterial pairwise interactions
Authors: Li Mei , Pommier Thomas , Yin Yue , Cao Wenhui , Zhang Xiaohui , Hu Jie , Hautier Yann , Yang Tianjie , Xu Yangchun , Shen Qirong , Kowalchuk George A. , Jousset Alexandre , Wei Zhong
Published: September 2022

Microbial interactions within resident communities are a major determinant of resistance to pathogen invasion. Yet, interactions vary with environmental conditions, raising the question of how community composition and environments interactively shape invasion resistance. Here, we use resource availability (RA) as a model parameter altering the resistance of model bacterial communities to invasion by the plant pathogenic bacterium Ralstonia solanacearum. We found that at high RA, interactions between resident bacterial species were mainly driven by the direct antagonism, in terms of the means of invader inhibition. Consequently, the competitive resident communities with a higher production of antibacterial were invaded to a lesser degree than facilitative communities. At low RA, bacteria produced little direct antagonist potential, but facilitative communities reached a relatively higher community productivity, which showed higher resistance to pathogen invasion than competitive communities with lower productivities. This framework may lay the basis to understand complex microbial interactions and biological invasion as modulated by the dynamic changes of environmental resource availability.
When is an Insured Vehicle an Uninsured Vehicle?
Authors: Marson James , Ferris Katy
Published: September 2022

In Colley v Motor Insurers’ Bureau the Motor Insurers’ Bureau appealled against liability to satisfy a claim for damages for injuries suffered by a passenger in a motor vehicle accident. The driver was uninsured, but at the time of the accident the vehicle in which the victim was travelling was subject to a policy of motor insurance. By operation of national law, and in breach of the Motor Vehicle Insurance Directive (MVID), the insurer was allowed to recant the policy and leave the passenger a victim of an, ostensibly, uninsured vehicle. This note explains why the decision of the Court of Appeal was fundamentally flawed, how the Court continues to apply EU law incorrectly, and broader concerns the case presents for remaining EU law claims in the appeal courts. This is particularly the case for retained EU laws and the cases remaining to be heard under the MVID's application in national courts.