bluuebunny/crossref_metadata_2025_split huggingface dataset:
“Distinct inhibitory neurons differently shape neuronal codes for sound intensity in the auditory cortex”
Authors: Tobin Melanie , Sheth Janaki , Wood Katherine C. , Michel Erin K. , Geffen Maria N. 
Published: February 2023

ABSTRACTCortical circuits contain multiple types of inhibitory neurons which shape how information is processed within neuronal networks. Here, we asked whether somatostatin-expressing (SST) and vasoactive intestinal peptide-expressing (VIP) inhibitory neurons have distinct effects on population neuronal responses to noise bursts of varying intensities. We optogenetically stimulated SST or VIP neurons while simultaneously measuring the calcium responses of populations of hundreds of neurons in the auditory cortex of male and female awake, head-fixed mice to sounds. Upon SST neuronal activation, noise bursts representations became more discrete for different intensity levels, relying on cell identity rather than strength. By contrast, upon VIP neuronal activation, noise bursts of different intensity level activated overlapping neuronal populations, albeit at different response strengths. At the single-cell level, SST and VIP neuronal activation differentially modulated the response-level curves of monotonic and nonmonotonic neurons. SST neuronal activation effects were consistent with a shift of the neuronal population responses toward a more localist code with different cells responding to sounds of different intensity. By contrast, VIP neuronal activation shifted responses towards a more distributed code, in which sounds of different intensity level are encoded in the relative response of similar populations of cells. These results delineate how distinct inhibitory neurons in the auditory cortex dynamically control cortical population codes. Different inhibitory neuronal populations may be recruited under different behavioral demands, depending on whether categorical or invariant representations are advantageous for the task.SIGNIFICANCEInformation about sounds is represented in the auditory cortex by neuronal population activity that has a characteristic sparse structure. Cortical neuronal populations comprise multiple types of excitatory and inhibitory neurons. Here, we find that activating different types of inhibitory neurons differentially controls population neuronal representations, with one type of inhibitory neurons increasing the differences in the identity of the cells recruited to represent the different sounds, and another inhibitory neuron type changing the relative activity level of overlapping neuronal populations. Such transformations may be beneficial for different types of auditory behaviors, suggesting that these different types of inhibitory neurons may be recruited under different behavioral constraints in optimizing neuronal representations of sounds.
Design approaches to expand the toolkit for building cotranscriptionally encoded RNA strand displacement circuits
Authors: Schaffter Samuel W. , Wintenberg Molly E. , Murphy Terence M. , Strychalski Elizabeth A. 
Published: February 2023

AbstractCotranscriptionally encoded RNA strand displacement (ctRSD) circuits are an emerging tool for programmable molecular computation with potential applications spanningin vitrodiagnostics to continuous computation inside living cells. In ctRSD circuits, RNA strand displacement components are continuously produced togetherviatranscription. These RNA components can be rationally programmed through base pairing interactions to execute logic and signaling cascades. However, the small number of ctRSD components characterized to date limits circuit size and capabilities. Here, we characterize 220 ctRSD gate sequences, exploring different input, output, and toehold sequences and changes to other design parameters, including domain lengths, ribozyme sequences, and the order in which gate strands are transcribed. This characterization provides a library of sequence domains for engineering ctRSD components,i.e., a toolkit, enabling circuits with up to four-fold more inputs than previously possible. We also identify specific failure modes and systematically develop design approaches that reduce the likelihood of failure across different gate sequences. Lastly, we show ctRSD gate design is robust to changes in transcriptional encoding, opening a broad design space for applications in more complex environments. Together, these results deliver an expanded toolkit and design approaches for building ctRSD circuits that will dramatically extend capabilities and potential applications.
tRNA m1G9 modification depends on substrate-specific RNA conformational changes induced by the methyltransferase Trm10
Authors: Strassler Sarah E. , Bowles Isobel E. , Krishnamohan Aiswarya , Kim Hyejeong , Edgington Catherine B. , Kuiper Emily G. , Hancock Clio J. , Comstock Lindsay R. , Jackman Jane E. , Conn Graeme L. 
Published: February 2023

ABSTRACTThe methyltransferase Trm10 modifies a subset of tRNAs on the base N1 position of the 9th nucleotide in the tRNA core. Trm10 is conserved throughout Eukarya and Archaea, and mutations in the human gene (TRMT10A) have been linked to neurological disorders such as microcephaly and intellectual disability, as well as defects in glucose metabolism. Of the 26 tRNAs in yeast with guanosine at position 9, only 14 are substrates for Trm10. However, no common sequence or other posttranscriptional modifications have been identified among these substrates, suggesting the presence of some other tRNA feature(s) which allow Trm10 to distinguish substrate from nonsubstrate tRNAs. Here, we show that substrate recognition bySaccharomyces cerevisiaeTrm10 is dependent on both intrinsic tRNA flexibility and the ability of the enzyme to induce specific tRNA conformational changes upon binding. Using the sensitive RNA structure-probing method SHAPE, conformational changes upon binding to Trm10 in tRNA substrates, but not nonsubstrates, were identified and mapped onto a model of Trm10-bound tRNA. These changes may play an important role in substrate recognition by allowing Trm10 to gain access to the target nucleotide. Our results highlight a novel mechanism of substrate recognition by a conserved tRNA modifying enzyme. Further, these studies reveal a strategy for substrate recognition that may be broadly employed by tRNA-modifying enzymes which must distinguish between structurally similar tRNA species.
Eukaryotic-like gephyrin and cognate membrane receptor coordinate corynebacterial cell division and polar elongation
Authors: Martinez M. , Petit J. , Leyva A. , Sogues A. , Megrian D. , Rodriguez A. , Gaday Q. , Ben Assaya M. , Portela M. , Haouz A. , Ducret A. , Grangeasse C. , Alzari P. M. , Durán R. , Wehenkel A. 
Published: February 2023

ABSTRACTThe orderCorynebacterialesincludes major industrial and pathogenic actinobacteria such asCorynebacterium glutamicumorMycobacterium tuberculosis. Their elaborate multi-layered cell wall, composed primarily of the mycolyl-arabinogalactan-peptidoglycan complex, and their polar growth mode impose a stringent coordination between the septal divisome, organized around the tubulin-like protein FtsZ, and the polar elongasome, assembled around the tropomyosin-like protein Wag31. Here, we report the identification of two new divisome members, a gephyrin-like repurposed molybdotransferase (GLP) and its membrane receptor (GLPR). We show that the interplay between the GLPR/GLP module, FtsZ and Wag31 is crucial for orchestrating cell cycle progression. Our results provide a detailed molecular understanding of the crosstalk between two essential machineries, the divisome and elongasome, and reveal thatCorynebacterialeshave evolved a protein scaffold to control cell division and morphogenesis similar to the gephyrin/GlyR system that in higher eukaryotes mediates synaptic signaling through network organization of membrane receptors and the microtubule cytoskeleton.
Host-microbiome transplants of the schistosome snail hostBiomphalaria glabratareflect species-specific associations
Authors: Schols Ruben , Vanoverberghe Isabel , Huyse Tine , Decaestecker Ellen 
Published: February 2023

AbstractSnail-borne diseases affect more than a quarter of a billion people worldwide and pose a high burden in the livestock industry. A fundamental understanding of the drivers of the epidemiology of these diseases is crucial for the development of sustainable control measures. The microbiome is increasingly being recognized as an important player in the tripartite interaction between parasitic flatworms, snail intermediate hosts and the snail microbiome. In order to better understand these interactions, transplant experiments are needed, which rely on the development of a reliable and reproducible protocol to obtain microbiome-disturbed snails. Here we report on the first successful snail microbiome transplants, which indicate thatBiomphalaria glabratacan accrue novel bacterial assemblies depending on the available environmental bacteria obtained from donor snails. Moreover, the phylogenetic relatedness to the donor significantly affected the survival probability of the recipients, corroborating the phylosymbiosis pattern in freshwater snails. The transplant technique described here, complemented by field-based studies, could facilitate future research endeavors to investigate the role of specific bacteria or bacterial communities in parasitic flatworm resistance ofB. glabrataand might ultimately pave the way for microbiome-mediated control of snail-borne diseases.
Abemaciclib restricts HCMV replication by suppressing pUL97-mediated phosphorylation of SAMHD1
Authors: Syrigos Georgios Vavouras , Feige Maximilian , Dirlam Alicia , Businger Ramona , Gruska Iris , Wiebusch Lüder , Hamprecht Klaus , Schindler Michael 
Published: February 2023

ABSTRACTHuman cytomegalovirus (HCMV) is a herpesvirus that causes life-threatening infections in newborns or immunosuppressed patients. For viral replication, HCMV establishes a network of cellular interactions, among others cyclin-dependent kinases (CDK). Furthermore, HCMV encodes pUL97, a viral kinase, which is a CDK-homologue. HCMV uses pUL97 in order to phosphorylate and thereby antagonize SAMHD1, an antiviral host cell factor. Since HCMV has several mechanisms to evade restriction by SAMHD1, we first analyzed the kinetics of SAMHD1-inactivation and found that phosphorylation of SAMHD1 by pUL97 occurs directly after infection of macrophages. We hence hypothesized that inhibition of this process qualifies as efficient antiviral target and FDA approved CDK-inhibitors (CDKIs) might be potent antivirals that prevent the inactivation of SAMHD1. Indeed, Abemaciclib, a 2ndgeneration CDKI exhibited superior IC50s against HCMV in infected macrophages and the antiviral activity largely relied on its ability to block pUL97-mediated SAMHD1-phosphorylation. Altogether, our study highlights the therapeutic potential of clinically-approved CDKIs as antivirals against HCMV, sheds light on their mode of action and establishes SAMHD1 as a valid and highly potent therapeutic target.
Segregational drift hinders the evolution of antibiotic resistance on polyploid replicons
Authors: Garoña Ana , Santer Mario , Hülter Nils F. , Uecker Hildegard , Dagan Tal 
Published: February 2023

AbstractThe emergence of antibiotic resistance under treatment depends on the availability of resistance alleles and their establishment in the population. Novel resistance alleles are encoded either in chromosomal or extrachromosomal genetic elements; both types may be present in multiple copies within the cell. However, the effect of polyploidy on the emergence of antibiotic resistance remains understudied. Here we show that the establishment of resistance alleles in microbial populations depends on the ploidy level. Evolving bacterial populations under selection for antibiotic resistance, we demonstrate that resistance alleles in polyploid elements are lost frequently in comparison to alleles in monoploid elements due to segregational drift. Integrating the experiments with a mathematical model, we find an agreement between the theoretical and empirical allele dynamics, confirming our understanding of the allele segregation process. Using the mathematical model, we further show that the effect of polyploidy on the establishment probability of beneficial alleles is strongest for low replicon copy numbers and plateaus for high replicon copy numbers. Our results suggest that the distribution of fitness effects for mutations that get fixed in a population depends on the replicon ploidy level. Our study indicates that strategies for drug treatment of bacterial infections should take into consideration the pathogen ploidy level.
Lianas in tropical dry forests have higher embolism resistance but similar hydraulic efficiency than lianas in rainforests
Authors: Gerolamo Caian S. , Pereira Luciano , Costa Flavia R. C. , Jansen Steven , Angyalossy Veronica , Nogueira Anselmo 
Published: February 2023

AbstractLianas are increasing in relative abundance and biomass, mainly in seasonally dry forests, but it is unclear if this is associated with their hydraulic strategy. Here, we ask whether liana of seasonally dry forests are safer and more efficient in water transport than those of rainforest, which could explain liana distribution patterns and their recent increases. We measured hydraulic traits on five pairs of congeneric liana species (tribe Bignonieae) on one seasonal dry Atlantic forest and one Amazon rainforest. The predawn and minimum water potential, and the water potential at which 50% of the maximum gas amount was discharged were, on average, more negative in the liana species of the seasonal forest. However, these patterns were not constant at the genus level. The positive hydraulic safety margins and hydraulic efficiency were similar among species congeners across sites. The Bignonieae lianas studied likely experience equally low levels of embolism during drought, and maintain a high conductive capacity with efficient use of xylem space, which may favor survival and growth across tropical forests. The likely evolutionary convergence of high hydraulic safety associated with the opportunistic strategy of rapid growth, especially in disturbed areas can favor the abundant liana species in seasonal forests.HighlightTropical forest liana species have high hydraulic efficiency and high interspecific variability in hydraulic safety. Despite this variability, some seasonal forest liana species have greater hydraulic safety than rainforest lianas, indicating an evolutionary convergence across lineages.
Congruent visual cues speed dynamic motor adaptation
Authors: Franklin Sae , Leib Raz , Dimitriou Michael , Franklin David W. 
Published: February 2023

AbstractMotor adaptation to novel dynamics occurs rapidly using sensed errors to update the current motor memory. This adaption is strongly driven by proprioceptive and visual signals, that indicate errors in the motor memory. Here we extend this previous work by investigating whether the presence of additional visual cues could increase the rate of motor adaptation, specifically when the visual motion cue is congruent with the dynamics. Six groups of participants performed reaching movements while grasping the handle of a robotic manipulandum while an additional cue (red object) was connected to the cursor. After a baseline, either a unidirectional (3 groups) or bidirectional (3 groups) velocity dependent force field was applied during the reach. For each group, the movement of the red object relative to the cursor was either congruent with the force field dynamics, incongruent with the force field dynamics or constant (fixed distance). Participants adapted more to the unidirectional force fields than to the bidirectional force field groups. However, across both force fields, groups in which the visual cues matched the type of force field (congruent visual cue) exhibited higher final adaptation level at the end of learning compared to either the control or incongruent conditions. In all groups, we observed an additional congruent cue assisted the formation of the motor memory of the external dynamics. We then demonstrate that a state estimation based model that integrates proprioceptive and visual information can successfully replicate the experimental data.New & NoteworthyWe demonstrate that adaptation to novel dynamics is stronger when additional online visual cues that are congruent with the dynamics are presented during adaptation, compared to either a constant or incongruent visual cue. This effect was found regardless of whether a bidirectional or unidirectional velocity dependent force field was presented to the participants. We propose that this effect might arise through the inclusion of this additional visual cue information within the state estimation process.
Regional and age-dependent changes in ubiquitination in cellular and mouse models of Spinocerebellar ataxia type 3
Authors: Luo Haiyang , Todi Sokol V. , Paulson Henry L. , Costa Maria do Carmo 
Published: February 2023

1AbstractSpinocerebellar ataxia type 3 (SCA3), also known as Machado–Joseph disease, is the most common dominantly inherited ataxia. SCA3 is caused by a CAG repeat expansion in theATXN3gene that encodes an expanded tract of polyglutamine (polyQ) in the disease protein ataxin-3 (ATXN3). As a deubiquitinating enzyme, ATXN3 regulates numerous cellular processes including proteasome- and autophagy-mediated protein degradation. In SCA3 disease brain, polyQ-expanded ATXN3 accumulates with other cellular constituents, including ubiquitin (Ub)-modified proteins, in select areas like the cerebellum and the brainstem, but whether pathogenic ATXN3 affects the abundance of ubiquitinated species is unknown. Here, in mouse and cellular models of SCA3, we investigated whether elimination of murineAtxn3or expression of wild-type or polyQ-expanded human ATXN3 alters soluble levels of overall ubiquitination, as well as K48-linked (K48-Ub) and K63-linked (K63-Ub) chains. Levels of ubiquitination were assessed in the cerebellum and brainstem of 7- and 47-week-oldAtxn3knockout and SCA3 transgenic mice, and also in relevant mouse and human cell lines. In older mice, we observed that wild-type ATXN3 impacts the cerebellar levels of K48-Ub proteins. In contrast, pathogenic ATXN3 leads to decreased brainstem abundance of K48-Ub species in younger mice and changes in both cerebellar and brainstem K63-Ub levels in an age-dependent manner: younger SCA3 mice have higher levels of K63-Ub while older mice have lower levels of K63-Ub compared to controls. Human SCA3 neuronal progenitor cells also show a relative increase in K63-Ub proteins upon autophagy inhibition. We conclude that wild-type and mutant ATXN3 differentially impact K48-Ub- and K63-Ub-modified proteins in the brain in a region- and age-dependent manner.
Heat-induced seizures, premature mortality, and hyperactivity in a novelScn1anonsense model for Dravet syndrome
Authors: Mavashov Anat , Brusel Marina , Liu Jiaxing , Woytowicz Victoria , Bae Haneui , Chen Ying-Hsin , Dani Vardhan S. , Cardenal Elena , Spinosa Vittoria , Aibar José Ángel , Rubinstein Moran 
Published: February 2023

AbstractDravet syndrome (Dravet) is a severe congenital developmental genetic epilepsy caused byde novomutations in theSCN1Agene. Nonsense mutations are found in ~20% of the patients, and the R613X mutation was identified in multiple patients. Here we characterized the epileptic and non-epileptic comorbidities of a novel preclinical Dravet mouse model harboring this nonsenseScn1amutation. HeterozygousScn1aR613X mutation on a mixed C57BL/6J:129S1/SvImJ background exhibited spontaneous seizures, susceptibility to heat-induced seizures, and premature mortality, recapitulating the core epileptic phenotypes of Dravet. In addition, these mice, available as an open-access model, demonstrated increased locomotor activity in the open-field test, mimicking some non-epileptic Dravet-associated comorbidities. Conversely,Scn1aWT/R613Xmice on the pure 129S1/SvImJ background had a normal life span and were easy to breed. HomozygousScn1aR613X/R613Xmice died before P16.Our molecular analyses of hippocampal and cortical expression demonstrated that the premature stop codon induced by the R613X mutation reducedScn1amRNA and Nav1.1 protein levels to ~50% in heterozygousScn1aWT/R613Xmice, with marginal expression in homozygousScn1aR613X/R613Xmice. Together, we introduce a novel Dravet model carrying the R613XScn1anonsense mutation that can. be used to study the molecular and neuronal basis of Dravet, as well as the development of new therapies associated withSCN1Anonsense mutations in Dravet.
Bacterial toxin-antitoxin system MazEF as a native defense mechanism against RNA phages inEscherichia coli
Authors: Nikolic Nela , Bergmiller Tobias , Pleška Maroš , Guet Călin C. 
Published: February 2023

ABSTRACTBacteria have evolved a wide range of defense strategies to protect themselves against bacterial viruses (phages). However, the known mechanisms almost exclusively target phages with DNA genomes. While several bacterial toxin-antitoxin systems have been considered to cleave single-stranded bacterial RNA in response to stressful conditions, their role in protecting bacteria against phages with single-stranded RNA genomes has not been studied. Here we investigate the role of a representative toxin-antitoxin system, MazEF, in protectingEscherichia coliagainst two RNA phages – MS2 and Qβ. Our population-level experiments revealed that amazEFdeletion strain is more susceptible to RNA phage infection than the wild-type. At the single-cell level, deletion of themazEFlocus significantly shortened the time to lysis of individual bacteria challenged with RNA phage. At the genomic level, we found that the adenine-cytosine-adenine sequence, directly recognized and cleaved by the MazF toxin, is systematically underrepresented in the genomes of RNA phages that are known to infectE. coli, indicating selection for decreased probability of cleavage. These results suggest that in addition to other physiological roles, RNA-degrading toxin-antitoxin modules can function as a primitive immune system against RNA phages.
Intravital microscopy of satellite cell dynamics and their interaction with myeloid cells during skeletal muscle regeneration
Authors: He Yingzhu , Heng Youshan , Qin Zhongya , Wei Xiuqing , Wu Zhenguo , Qu Jianan 
Published: February 2023

AbstractSkeletal muscle regeneration requires the highly coordinated cooperation of muscle satellite cells (MuSCs) with other cellular components. However, due to technical limitations, it remains unclear how MuSCs dynamically interact with non-myogenic cells, especially myeloid cells, in live animals. In this work, we developed a dual-laser multimodal nonlinear optical microscope platform to serve as an effective tool for studying the real-time interaction between MuSCs and non-myogenic cells during the early phase of muscle regeneration. Increased cell volume and mitochondrial mass, cell density, and myotube formation are indicative of MuSCs activation/growth, proliferation, and differentiation, respectively. Using 3D time-lapse imaging on live reporter mice containing both red fluorescence protein (RFP)-labeled macrophages and yellow fluorescence protein (YFP)-labeled MuSCs, and taking advantages of the autofluorescence of reduced nicotinamide adenine dinucleotide (NADH), we monitored the real-time spatiotemporal interaction between RFP+macrophages/RFP-non-myogenic cells and YFP+muscle stem/progenitor cells during the activation and the proliferation stages of regeneration. Our results indicated that their cell-cell contact was transient in nature. By inhibiting macrophage infiltration, we further showed that direct cell-cell contact between macrophages and MuSCs was not required for early activation of MuSCs before the proliferation stage. However, decreased macrophage infiltration impeded the proliferation and differentiation of MuSCs and also led to intramuscular fibrosis. Besides, neutrophil depletion in the CCR2 deficient mice did not delay the initial growth of MuSCs. These findings provide a new perspective on myeloid cells’ role during muscle regeneration.