bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neural substrates of top-down processing during perceptual duration-based timing and beat-based timing
Authors: Niida Mitsuki , Haruki Yusuke , Imai Fumihito , Ogawa Kenji 
Published: June 2023

AbstractTemporal context is a crucial factor in timing. Previous studies have revealed that the timing of regular stimuli, such as isochronous beats or rhythmic sequences (termed beat-based timing), activated the basal ganglia, whereas the timing of single intervals or irregular stimuli (termed duration-based timing) activated the cerebellum. We conducted a functional magnetic resonance imaging (fMRI) experiment to determine whether top-down processing of perceptual duration-based and beat-based timings affected brain activation patterns. Our participants listened to auditory sequences containing both single intervals and isochronous beats and judged either the duration of the intervals or the tempo of the beats. Whole-brain analysis revealed that both duration judgments and tempo judgments activated similar areas, including the basal ganglia and cerebellum, with no significant difference in the activated regions between the two conditions. In addition, an analysis of the regions of interest revealed no significant differences between the activation levels measured for the two tasks in the basal ganglia as well as the cerebellum. These results suggested that a set of common brain areas were involved in top-down processing of both duration judgments and tempo judgments. Our findings indicate that perceptual duration-based timing and beat-based timing are driven by stimulus regularity irrespective of top-down processing.
Humans Exploit the Trade-Off Between Lateral Stability and Manoeuvrability During Walking
Authors: Kulkarni Rucha , Grover Francis M. , Shafer Anna , Schmitz Xenia , Gordon Keith E. 
Published: June 2023

AbstractPeople use the mechanical interplay between stability and manoeuvrability to successfully walk. During single limb support, body states (position and velocity) that increase lateral stability will inherently resist lateral manoeuvres, decrease medial stability, and facilitate medial manoeuvres. Although not well understood, people can make behavioural decisions exploiting this relationship in anticipation of perturbations or direction changes. To characterize the behavioural component of the stability-manoeuvrability relationship, twenty-four participants performed many repetitions of a discrete stepping task involving mid-trial reactive manoeuvres (medial or lateral direction) in a Baseline (no external perturbations) and Perturbed (random mediolateral perturbations applied to their pelvis) environment. We hypothesized people would make systematic changes in lateral stability dependent on both environment (increasing lateral stability in the Perturbed environment) and anticipated manoeuvre direction (reducing lateral stability to facilitate lateral manoeuvres). Participants increased lateral stability in the Perturbed environment, coinciding with an increase in manoeuvre reaction time for laterally but not medially directed manoeuvres. Moreover, we observed lower lateral stability in both environments when people anticipated making a lateral manoeuvre when compared to medial manoeuvres. These results support the hypothesis that people behaviourally exploit the mechanical relationship between lateral stability and manoeuvrability depending on walk task goals and external environment.
A Spatiotemporal Compartmentalization of Glucose Metabolism Guides Mammalian Gastrulation Progression
Authors: Cao Dominica , Zhong Liangwen , Hemalatha Anupama , Bergmann Jenna , Cox Andy L. , Greco Valentina , Sozen Berna 
Published: June 2023

AbstractGastrulation is considered thesine qua nonof embryogenesis, establishing a multidimensional structure and the spatial coordinates upon which all later developmental events transpire. At this time, the embryo adopts a heavy reliance on glucose metabolism to support rapidly accelerating changes in morphology, proliferation, and differentiation. However, it is currently unknown how this conserved metabolic shift maps onto the three-dimensional landscape of the growing embryo and whether it is spatially linked to the orchestrated cellular and molecular processes necessary for gastrulation. Here we identify that glucose is utilised during mouse gastrulation via distinct metabolic pathways to instruct local and global embryonic morphogenesis, in a cell type and stage-specific manner. Through detailed mechanistic studies and quantitative live imaging of mouse embryos, in parallel with tractablein vitrostem cell differentiation models and embryo-derived tissue explants, we discover that cell fate acquisition and the epithelial-to-mesenchymal transition (EMT) relies on the Hexosamine Biosynthetic Pathway (HBP) branch of glucose metabolism, while newly-formed mesoderm requires glycolysis for correct migration and lateral expansion. This regional and tissue-specific difference in glucose metabolism is coordinated with Fibroblast Growth Factor (FGF) activity, demonstrating that reciprocal crosstalk between metabolism and growth factor signalling is a prerequisite for gastrulation progression. We expect these studies to provide important insights into the function of metabolism in other developmental contexts and may help uncover mechanisms that underpin embryonic lethality, cancer, and congenital disease.
Continuous Measures of Decision-Difficulty Captured Remotely: II. Webcam eye-tracking reveals early decision processing
Authors: Bertrand Jennifer K. , Zuk Alexandra A. Ouellette , Chapman Craig S. 
Published: June 2023

AbstractAs decisions require the gathering of relevant information, eye-tracking measures that capture the way visual information is typically acquired offer powerful indices of the dynamic decision-making process. This study is the second of a pair of studies that explore continuous measures of decision-making using remote, online tools in naturalistic settings. While cursor-tracking, used in the companion paper (Ouellette Zuk et al., 2023), enabled access to dynamic decision processes expressed during movement, in the present study, we now employ webcam eye-tracking to examine the dynamics of information gathering during decision making prior to movement initiation. Using three previously published binary choice tasks, we explored indices of decision difficulty in the gaze dynamics that would complement the motor measures in our companion paper. We find that harder choices elicit more eye dwells and longer final dwells, reflecting a decision resolution process that Ouellette Zuk et al. index during the final choice movement. Beyond this, we identify distinct gaze patterns uniquely employed in each task, revealing the utility and sensitivity of gaze metrics in illuminating the early difficulty-independent information gathering processes at play. Together, this paper series demonstrates the power of remote, online methods as tools for deeply understanding the complete, dynamic and continuous decision process, from the first glance to the final response.
Role of Mce proteins inMycobacterium avium paratuberculosisinfection
Authors: Blake Rose , Jensen Kirsty , Alfituri Omar , Mabbott Neil , Hope Jayne , Stevens Jo 
Published: June 2023

AbstractMycobacterium aviumsubspeciesparatuberculosis(MAP) is the causative agent of Johne’s Disease, a chronic granulomatous enteritis of ruminants. MAP establishes an infection in the host via the small intestine. This requires the bacteria to adhere to and be internalised by cells of the intestinal tract. The effector molecules expressed by MAP for this remain to be fully identified and understood. The mammalian cell entry (Mce) proteins play an essential role for other Mycobacterial species to facilitate the attachment and invasion of host epithelial cells. Here, we have expressed Mce1A, Mce1D, Mce3C and Mce4A proteins derived from MAP on the surface of a non-invasiveE. colihost to characterise their role in the initial interaction between MAP and the host. To this end,mce1Awas found to significantly increase the ability of theE. colito attach and survive intracellularly in THP-1 cells, andmce1Dwas found to significantly increase attachment and invasion of MDBK cells. Both genes were implicated in the increased ability ofE. colito infect 3D bovine basal-out enteroids. Together, these results have identified two effector molecules used by MAP with a degree of cell-type specificity.
Structural snapshots along K48-linked ubiquitin chain formation by the HECT E3 UBR5
Authors: Hehl Laura A. , Horn-Ghetko Daniel , Prabu J. Rajan , Vollrath Ronnald , Vu D. Tung , Pérez Berrocal David A. , Mulder Monique P. C. , van der Heden van Noort Gerbrand J , Schulman Brenda A. 
Published: June 2023

ABSTRACTUbiquitin chain formation by HECT catalytic domain-containing E3 ligases regulates vast biology, yet the structural mechanisms remain unknown. We employed chemistry and cryo-EM to visualize stable mimics of the intermediates along K48-linked ubiquitin chain formation by the human E3, UBR5. The structural data reveal a ≈620 kDa UBR5 dimer as the functional unit, comprising a scaffold with flexibly-tethered ubiquitin-binding UBA domains, and elaborately arranged HECT domains. Chains are forged by a UBA domain capturing an acceptor ubiquitin, with its K48 lured into the active site by numerous interactions between the acceptor ubiquitin, manifold UBR5 elements, and the donor ubiquitin. The cryo-EM reconstructions allow defining conserved HECT domain conformations catalyzing ubiquitin transfer from E2 to E3, and from E3. Our data show how a full-length E3, ubiquitins to be adjoined, E2, and intermediary products guide a feed-forward HECT domain conformational cycle establishing a highly efficient, broadly targeting, K48-linked ubiquitin chain forging machine.
The microbial derived bile acid lithocholate and its epimers inhibitClostridioides difficilegrowth and pathogenicity while sparing members of the gut microbiota
Authors: Kisthardt Samantha C , Thanissery Rajani , Pike Colleen M , Foley Matthew H , Theriot Casey M 
Published: June 2023

AbstractC. difficileinfection (CDI) is associated with antibiotic usage, which disrupts the indigenous gut microbiota and causes the loss of microbial derived secondary bile acids that normally provide protection againstC. difficilecolonization. Previous work has shown that the secondary bile acid lithocholate (LCA) and its epimer isolithocholate (iLCA) have potent inhibitory activity against clinically relevantC. difficilestrains. To further characterize the mechanisms by which LCA and its epimers iLCA and isoallolithocholate (iaLCA) inhibitC. difficile,we tested their minimum inhibitory concentration (MIC) againstC. difficileR20291, and a commensal gut microbiota panel. We also performed a series of experiments to determine the mechanism of action by which LCA and its epimers inhibitC. difficilethrough bacterial killing and effects on toxin expression and activity. Here we show that epimers iLCA and iaLCA strongly inhibitC. difficilegrowthin vitrowhile sparing most commensal Gram-negative gut microbes. We also show that iLCA and iaLCA have bactericidal activity againstC. difficile,and these epimers cause significant bacterial membrane damage at subinhibitory concentrations. Finally, we observe that iLCA and iaLCA decrease the expression of the large cytotoxintcdAwhile LCA significantly reduces toxin activity. Although iLCA and iaLCA are both epimers of LCA, they have distinct mechanisms for inhibitingC. difficile. LCA epimers, iLCA and iaLCA, represent promising compounds that targetC. difficilewith minimal effects on members of the gut microbiota that are important for colonization resistance.ImportanceIn the search for a novel therapeutic that targetsC. difficile, bile acids have become a viable solution. Epimers of bile acids are particularly attractive as they may provide protection againstC. difficilewhile leaving the indigenous gut microbiota largely unaltered. This study shows that iLCA and iaLCA specifically are potent inhibitors ofC. difficile, affecting key virulence factors including growth, toxin expression and activity. As we move toward the use of bile acids as therapeutics, further work will be required to determine how best to deliver these bile acids to a target site within the host intestinal tract.
Effects of growth feedback on adaptive gene circuits: A dynamical understanding
Authors: Kong Ling-Wei , Shi Wenjia , Tian Xiao-Jun , Lai Ying-Cheng 
Published: June 2023

AbstractThe successful integration of engineered gene circuits into host cells remains a significant challenge in synthetic biology due to circuit-host interactions, such as growth feedback, where the circuit influences cell growth and vice versa. Understanding the dynamics of circuit failures and identifying topologies resilient to growth feedback are crucial for both fundamental and applied research. Utilizing transcriptional regulation circuits with adaptation as a paradigm, we systematically study more than four hundred topological structures and uncover various categories of failures. Three dynamical mechanisms of circuit failures are identified: continuous deformation of the response curve, strengthened or induced oscillations, and sudden switching to coexisting attractors. Our extensive computations also uncover a scaling law between a circuit robustness measure and the strength of growth feedback. Despite the negative effects of growth feedback on the majority of circuit topologies, we identify several circuits that maintain optimal performance as designed, a feature important for applications.
Single cell RNA-seq analysis of spinal locomotor circuitry in larval zebrafish
Authors: Kelly Jimmy J. , Wen Hua , Brehm Paul 
Published: June 2023

AbstractIdentification of the neuronal types that form the specialized circuits controlling distinct behaviors has benefited greatly from the simplicity offered by zebrafish. Electrophysiological studies have shown that additional to connectivity, understanding of circuitry requires identification of functional specializations among individual circuit components, such as those that regulate levels of transmitter release and neuronal excitability. In this study we use single cell RNA sequencing (scRNAseq) to identify the molecular bases for functional distinctions between motoneuron types that are causal to their differential roles in swimming. The primary motoneuron (PMn) in particular, expresses high levels of a unique combination of voltage-dependent ion channel types and synaptic proteins termed functional ‘cassettes’. The ion channel types are specialized for promoting high frequency firing of action potentials and augmented transmitter release at the neuromuscular junction, both contributing to greater power generation. Our transcriptional profiling of spinal neurons further assigns expression of this cassette to specific interneuron types also involved in the central circuitry controlling high speed swimming and escape behaviors. Our analysis highlights the utility of scRNAseq in functional characterization of neuronal circuitry, in addition to providing a gene expression resource for studying cell type diversity.
High-throughput mRNA-seq atlas of human placenta shows vast transcriptome remodeling from first to third trimester
Authors: Gonzalez Tania L , Wertheimer Sahar , Flowers Amy E , Wang Yizhou , Santiskulvong Chintda , Clark Ekaterina L , Jefferies Caroline A , Lawrenson Kate , Chan Jessica L , Joshi Nikhil V , Zhu Yazhen , Tseng Hsian-Rong , Karumanchi S. Ananth , Williams John , Pisarska Margareta D 
Published: June 2023

AbstractBackgroundThe placenta, composed of chorionic villi, changes dramatically across gestation. Understanding differences in ongoing pregnancies are essential to identify the role of chorionic villi at specific times in gestation and develop biomarkers and prognostic indicators of maternal- fetal health.MethodsThe normative mRNA profile is established using next-generation sequencing of 124 first trimester and 43 third trimester human placentas from ongoing healthy pregnancies. Stably expressed genes not different between trimesters and with low variability are identified. Differential expression analysis of first versus third trimester adjusted for fetal sex is performed, followed by a subanalysis with 23 matched pregnancies to control for subject variability using the same genetic and environmental background.ResultsPlacenta expresses 14,979 mRNAs above sequencing noise (TPM>0.66), with 1,545 stably expressed genes across gestation. Differentially expressed genes account for 86.7% of genes in the full cohort (FDR<0.05). Fold changes highly correlate between the full cohort and subanalysis (Pearson = 0.98). At stricter thresholds (FDR<0.001, fold change>1.5), there are 6,941 differentially expressed protein coding genes (3,206 upregulated in first and 3,735 upregulated in third trimester).ConclusionThis is the largest mRNA atlas of healthy human placenta across gestation, controlling for genetic and environmental factors, demonstrating substantial changes from first to third trimester in chorionic villi. Specific differences and stably expressed genes may be used to understand the specific role of the chorionic villi throughout gestation and develop first trimester biomarkers of placental health that transpire across gestation, which can be used for future development of biomarkers in maternal-fetal disease.
TheCaulobacterNtrB-NtrC two-component system bridges nitrogen assimilation and cell development
Authors: North Hunter , McLaughlin Maeve , Fiebig Aretha , Crosson Sean 
Published: June 2023

AbstractA suite of molecular sensory systems enablesCaulobacterto control growth, development, and reproduction in re-sponse to levels of essential elements. The bacterial enhancer binding protein (bEBP) NtrC, and its cognate sensor histidine kinase NtrB, are key regulators of nitrogen assimilation in many bacteria, but their roles inCaulobactermetab-olism and development are not well defined. Notably,CaulobacterNtrC is an unconventional bEBP that lacks the σ54- interacting loop commonly known as the GAFTGA motif. Here we show that deletion ofC. crescentus ntrCslows cell growth in complex medium, and thatntrBandntrCare essential when ammonium is the sole nitrogen source due to their requirement for glutamine synthetase (glnA) expression. Random transposition of a conserved IS3-family mobile genetic element frequently rescued the growth defect ofntrCmutant strains by restoring transcription of theglnBAoperon, revealing a possible role for IS3 transposition in shaping the evolution ofCaulobacterpopulations during nutri-ent limitation. We further identified dozens of direct NtrC binding sites on theC. crescentuschromosome, with a large fraction located near genes involved in polysaccharide biosynthesis. The majority of binding sites align with those of the essential nucleoid associated protein, GapR, or the cell cycle regulator, MucR1. NtrC is therefore predicted to directly impact the regulation of cell cycle and cell development. Indeed, loss of NtrC function led to elongated polar stalks and elevated synthesis of cell envelope polysaccharides. This study establishes regulatory connections between NtrC, nitrogen metabolism, polar morphogenesis, and envelope polysaccharide synthesis inCaulobacter.ImportanceBacteria balance cellular processes with the availability of nutrients in their environment. The NtrB-NtrC two-component signaling system is responsible for controlling nitrogen assimilation in many bacteria. We have characterized the effect ofntrBandntrCdeletion onCaulobactergrowth and development and uncovered a role for spontaneous IS element transposition in the rescue of transcriptional and nutritional deficiencies caused byntrCmutation. We further defined the regulon ofCaulobacterNtrC, a bacterial enhancer binding protein, and demonstrate that it shares specific binding sites with essential proteins involved in cell cycle regulation and chromosome organization. Our work provides a com-prehensive view of transcriptional regulation mediated by a distinctive NtrC protein, establishing its connection to nitro-gen assimilation and developmental processes inCaulobacter.
Hybridization breaks species barriers in long-term coevolution of a cyanobacterial population
Authors: Birzu Gabriel , Muralidharan Harihara Subrahmaniam , Goudeau Danielle , Malmstrom Rex R. , Fisher Daniel S. , Bhaya Devaki 
Published: June 2023

AbstractBacterial species often undergo rampant recombination yet maintain cohesive genomic identity. Ecological differences can generate recombination barriers between species and sustain genomic clusters in the short term. But can these forces prevent genomic mixing during long-term coevolution? Cyanobacteria in Yellowstone hot springs comprise several diverse species that have coevolved for hundreds of thousands of years, providing a rare natural experiment. By analyzing more than 300 single-cell genomes, we show that despite each species forming a distinct genomic cluster, much of the diversity within species is the result of hybridization driven by selection, which has mixed their ancestral genotypes. This widespread mixing is contrary to the prevailing view that ecological barriers can maintain cohesive bacterial species and highlights the importance of hybridization as a source of genomic diversity.
Cholinergic input to mouse visual cortex signals a movement state and acutely enhances layer 5 responsiveness
Authors: Yogesh Baba , Keller Georg B. 
Published: June 2023

ABSTRACTAcetylcholine is released in visual cortex by axonal projections from the basal forebrain. The signals conveyed by these projections and their computational significance are still unclear. Using two-photon calcium imaging in behaving mice, we show that basal forebrain cholinergic axons in the mouse visual cortex provide a binary locomotion state signal. In these axons, we found no evidence of responses to visual stimuli or visuomotor prediction errors. While optogenetic activation of cholinergic axons in visual cortex in isolation did not drive local neuronal activity, when paired with visuomotor stimuli, it resulted in layer-specific increases of neuronal activity. Responses in layer 5 neurons to both top-down and bottom-up inputs were increased in amplitude and decreased in latency, whereas those in layer 2/3 neurons remained unchanged. Using opto- and chemogenetic manipulations of cholinergic activity, we found acetylcholine to underlie the locomotion-associated decorrelation of activity between neurons in both layer 2/3 and layer 5. Our results suggest that acetylcholine augments the responsiveness of layer 5 neurons to inputs from outside of the local network, possibly enabling faster switching between internal representations during locomotion.