bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uncovering and exploiting the return of voluntary motor programs after paralysis using a bi-cortical neuroprosthesis
Authors: Duguay Maude , Bonizzato Marco , Delivet-Mongrain Hugo , Fortier-Lebel Nicolas , Martinez Marina 
Published: March 2023

AbstractRehabilitative and neuroprosthetic approaches after spinal cord injury (SCI) aim to reestablish voluntary control of movement. Promoting recovery requires a mechanistic understanding of the return of volition over action, but the relationship between re-emerging cortical commands and the return of locomotion is not well established. We introduced a neuroprosthesis delivering targeted bi-cortical stimulation in a clinically relevant contusive SCI model. In healthy and SCI cats, we controlled hindlimb locomotor output by tuning stimulation timing, duration, amplitude, and site. In intact cats, we unveiled a large repertoire of motor programs. After SCI, the evoked hindlimb lifts were highly stereotyped, yet effective in modulating gait and alleviating bilateral foot drag. Results suggest that the neural substrate underpinning motor recovery had traded-off selectivity for efficacy. Longitudinal tests revealed that the return of locomotion after SCI was time-locked with recovery of the descending drive, which advocates for rehabilitation interventions directed at the cortical target.HighlightsA bilateral cortical implant allowed for the delivery of alternate bilateral stimulation coherently with locomotion, which modulated gait trajectories.We analyzed the effects of stimulation parameters - timing, duration, amplitude, and site of stimulation - to maximize the improvement of locomotor output after paralysis.A varied repertoire of motor programs evoked in intact cats was reduced to one stereotyped response after spinal cord injury (SCI) consisting in flexion modulation that efficiently alleviated hindlimb dragging.After SCI, the return of cortical gait control emerged in synchrony with locomotor recovery.
Disentangling Mixed Classes of Covariability in Large-Scale Neural Data
Authors: Pellegrino Arthur , Stein Heike , Cayco-Gajic N Alex 
Published: March 2023

AbstractRecent work has argued that large-scale neural recordings are often well described by low-dimensional ‘latent’ dynamics identified using dimensionality reduction. However, the view that task-relevant variability is shared across neurons misses other types of structure underlying behavior, including stereotyped neural sequences or slowly evolving latent spaces. To address this, we introduce a new framework that simultaneously accounts for variability that is shared across neurons, trials, or time. To identify and demix these covariability classes, we develop a new unsupervised dimensionality reduction method for neural data tensors called sliceTCA. In three example datasets, including motor cortical dynamics during a classic reaching task and recent multi-region recordings from the International Brain Laboratory, we show that sliceTCA can capture more task-relevant structure in neural data using fewer components than traditional methods. Overall, our theoretical framework extends the classic view of low-dimensional population activity by incorporating additional classes of latent variables capturing higher-dimensional structure.
Monocarboxylate transporters facilitate succinate uptake into brown adipocytes
Authors: Reddy Anita , Winther Sally , Tran Nhien , Xiao Haopeng , Jakob Josefine , Garrity Ryan , Smith Arianne , Mills Evanna L. , Chouchani Edward T. 
Published: March 2023

AbstractUptake of circulating succinate by brown adipose tissue (BAT) and beige fat elevates whole body energy expenditure, counteracts obesity, and antagonizes systemic tissue inflammation in mice. The plasma membrane transporters that facilitate succinate uptake in these adipocytes remain undefined. Here we elucidate a mechanism underlying succinate import into BAT via monocarboxylate transporters (MCTs). We show that succinate transport is strongly dependent on the proportion of it present in the monocarboxylate form. MCTs facilitate monocarboxylate succinate uptake, which is promoted by alkalinization of the cytosol driven by adrenoreceptor stimulation. In brown adipocytes, we show that MCT1 primarily facilitates succinate import, however other members of the MCT family can partially compensate and fulfill this role in the absence of MCT1. In mice, we show that acute pharmacological inhibition of MCT1 and 2 decreases succinate uptake into BAT. Conversely, congenital genetic depletion of MCT1 alone has little effect on BAT succinate uptake, indicative of additional transport mechanisms with high capacityin vivo. In sum, we define a mechanism of succinate uptake in BAT that underlies its protective activity in mouse models of metabolic disease.
AVibrio choleraeviral satellite maximizes its spread and inhibits phage by remodeling hijacked phage coat proteins into small capsids
Authors: Boyd Caroline M. , Subramanian Sundharraman , Dunham Drew T. , Parent Kristin N. , Seed Kimberley D. 
Published: March 2023

AbstractPhage satellites commonly remodel capsids they hijack from the phages they parasitize, but only a few mechanisms regulating the change in capsid size have been reported. Here, we investigated how a satellite fromVibrio cholerae, PLE, remodels the capsid it has been predicted to steal from the phage ICP1 (1). We identified that a PLE-encoded protein, TcaP, is both necessary and sufficient to form small capsids during ICP1 infection. Interestingly, we found that PLE is dependent on small capsids for efficient transduction of its genome, making it the first satellite to have this requirement. ICP1 isolates that escaped TcaP-mediated remodeling acquired substitutions in the coat protein, suggesting an interaction between these two proteins. With a procapsid-like-particle (PLP) assembly platform inEscherichia coli, we demonstrated that TcaP is abona fidescaffold that regulates the assembly of small capsids. Further, we studied the structure of PLE PLPs using cryogenic electron microscopy and found that TcaP is an external scaffold, that is functionally and somewhat structurally similar to the external scaffold, Sid, encoded by the unrelated satellite P4 (2). Finally, we showed that TcaP is largely conserved across PLEs. Together, these data support a model in which TcaP directs the assembly of small capsids comprised of ICP1 coat proteins, which inhibits the complete packaging of the ICP1 genome and permits more efficient packaging of replicated PLE genomes.
Predictors for estimating subcortical EEG responses to continuous speech
Authors: Kulasingham Joshua P. , Bachmann Florine L. , Eskelund Kasper , Enqvist Martin , Innes-Brown Hamish , Alickovic Emina 
Published: March 2023

AbstractPerception of sounds and speech involves structures in the auditory brainstem that rapidly process ongoing auditory stimuli. The role of these structures in speech processing can be investigated by measuring their electrical activity using scalp-mounted electrodes. However, typical analysis methods involve averaging neural responses to many short repetitive stimuli that bear little relevance to daily listening environments. Recently, subcortical responses to more ecologically relevant continuous speech were detected using linear encoding models. These methods estimate the temporal response function (TRF), which is a regression model that minimises the error between the measured neural signal and a predictor derived from the stimulus. Using predictors that model the highly non-linear peripheral auditory system may improve linear TRF estimation accuracy and peak detection. Here, we compare predictors from both simple and complex peripheral auditory models for estimating brainstem TRFs on electroencephalography (EEG) data from 24 participants listening to continuous speech. We also discuss the data length required for estimating subcortical TRFs with clear peaks. Interestingly, predictors from simple models resulted in TRFs that were similar to those estimated using complex models, and were much faster to compute. This work paves the way for efficient modelling and detection of subcortical processing of continuous speech, which may lead to improved diagnosis metrics for hearing impairment and assistive hearing technology.
Silk Fibroin Particles as Carriers in the Development of All-Natural Hemoglobin-Based Oxygen Carriers (HBOCs)
Authors: Pacheco Marisa O , Lutz Henry M , Armada Jostin , Davies Nickolas , Gerzenshtein Isabelle K , Cakley Alaura S , Spiess Bruce D , Stoppel Whitney L 
Published: March 2023

AbstractOxygen therapeutics have a range of applications in transfusion medicine and disease treatment. Synthetic molecules and all-natural or semi-synthetic hemoglobin-based oxygen carriers (HBOCs) have seen success as potential circulating oxygen carriers. However, many early HBOC products were removed from the market due to side effects from excess hemoglobin in the blood stream and hemoglobin entering the tissue. To overcome these issues, research has focused on increasing the molecular diameter of hemoglobin by polymerizing hemoglobin molecules or encapsulating hemoglobin in liposomal carriers, where immune responses and circulation times remain a challenge. This work looks to leverage the properties of silk fibroin, a cytocompatible and non-thrombogenic biopolymer, known to entrap protein-based cargo, to engineer a silk fibroin-hemoglobin-based oxygen carrier (sfHBOC). Herein, an all-aqueous solvent evaporation technique was used to form silk fibroin particles with and without hemoglobin to tailor the formulation for specific particle sizes. The encapsulation efficiency and ferrous state of hemoglobin were analyzed, resulting in 60% encapsulation efficiency and a maximum of 20% ferric hemoglobin, yielding 100 µg/mL active hemoglobin in certain sfHBOC formulations. The system did not elicit a strong inflammation responsein vitro, demonstrating the potential for this particle system to serve as an injectable HBOC.Table of Contents FigureTable of Contents Figure:In this manuscript, we generate silk fibroin particles using an all-aqueous processing technique starting from silk fibroin polymer systems of differing molecular weights. We analyze the extent to which silk concentration and extraction time affect particle size. Further, we analyze the encapsulation of hemoglobin in the particle system and assess immune activation in macrophage-like cultures.
If not a fake, what’s in the lake?
Authors: Foxon Floe 
Published: March 2023

AbstractAn animal dubbed ‘Champ’ has been sighted by hundreds of eyewitnesses in a large, near-oligotrophic lake in North America. A widely-publicised photograph taken by Mansi purportedly depicting the animal was published to much fanfare. In the present study, sightings were coded and analysed using interrupted time-series models, Pearson correlation coefficients, and descriptive statistics. The number of sightings per year was statistically significantly higher after publication of the Mansi photograph compared to before, which may be evidence of expectant attention, or publicity leading to more lake-goers and therefore more animal sightings. Sightings were consistent in condition (mostly Summer, from Noon to Evening, > 1 witness, and a calm lake surface) which may be interpreted as consistency of when lake-goers visit Champlain, or as evidence of consistent behavioural characteristics of Champ animals. Sightings were highly inconsistent in reported Champ characteristics with widely varying morphology, and most sightings were missing morphological data entirely. More than a quarter of sightings were likened to logs, land mammals, birds, fish, and boats, which are all found in the lake. There were no associations between distance to sighting, estimated length, and estimated height of objects witnessed, which may suggest that eyewitnesses provide inaccurate estimates of these measurements in lake settings. If not a fake, what’s in the lake may be ordinary phenomena mistaken for Champ. Alternatively, Lake Champlain is inhabited by as-yet undiscovered multi-humped, dark-coloured serpents approximately seven meters in length, which locomote in a fast and sinuous fashion, and which enjoy pleasant Summer evenings and crowds. Deciding which explanation best accounts for the data is left as an exercise for the reader.
Tafazzin knockdown in murine mesenchymal stem cells enhances the tafazzin knockdown mediated elevation in interleukin-10 secretion from murine B lymphocytes
Authors: Zegallai Hana M. , Abu-El-Rub Ejlal , Hatch Grant M. 
Published: March 2023

AbstractBarth Syndrome is a rare X-linked genetic disorder caused by mutations in theTAFAZZINgene. We recently demonstrated that tafazzin (Taz) protein deficiency in murine mesenchymal stems (MSCs) reduces immune function of activated wild type (WT) B lymphocytes. Interleukin-10 (IL-10) is a key anti-inflammatory cytokine capable of exerting immunosuppressive effects on myeloid cells. Here we examined if Taz deficiency in murine MSCs altered proliferation and IL-10 production in Taz deficient lipopolysaccharide (LPS)-activated murine B lymphocytes. Bone marrow MSCs and splenic B lymphocytes were isolated from WT or Taz knockdown (TazKD) mice. WT or Taz deficient MSCs were co-cultured with either LPS-activated WT or LPS-activated Taz deficient B lymphocytes for 24 h and B cell proliferation and IL-10 production determined. Taz deficient MSCs exhibited increased phosphatidylinositol-3-kinase (PI3K) mRNA expression compared to WT MSCs indicative of enhanced immunosuppression. Co-culture of Taz deficient MSCs with Taz deficient LPS-activated B cells resulted in a greater reduction in proliferation of B cells compared to Taz deficient MSCs co-cultured with LPS-activated WT B cells. In addition, co-culture of Taz deficient MSCs with Taz deficient LPS-activated B cells resulted in an enhanced production of IL-10 compared to Taz deficient MSCs co-cultured with LPS-activated WT B cells. Thus, Taz deficiency in murine MSCs potentiates the Taz knockdown-mediated elevation in IL-10 secretion from LPS-activated Taz knockdown B lymphocytes. These data suggest that Taz deficient MSCs may modulate the activity of other Taz deficient immune cells potentially promoting an enhanced immunosuppressive state.
Active cortical networks promote shunting fast synaptic inhibitionin vivo
Authors: Burman Richard J. , Brodersen Paul J.N. , Raimondo Joseph V. , Sen Arjune , Akerman Colin J. 
Published: March 2023

AbstractFast synaptic inhibition determines neuronal response properties in the mammalian brain and is mediated by chloride-permeable ionotropic GABA-A receptors (GABAARs). Despite their fundamental role, it is still not known how GABAARs signal in the intact brain. Here we usein vivogramicidin recordings to investigate synaptic GABAAR signaling in mouse cortical pyramidal neurons under conditions that preserve native transmembrane chloride gradients. In anaesthetized cortex, synaptic GABAARs exert classic hyperpolarizing effects. In contrast, GABAAR-mediated synaptic signaling in awake cortex is found to be predominantly shunting. This is due to more depolarized GABAAR equilibrium potentials (EGABAAR), which are shown to result from the high levels of synaptic activity that characterize awake cortical networks. The EGABAARobserved in awake cortex can facilitate the decoupling of local networks, which improves the ability of the network to discriminate stimuli. Our findings therefore suggest that GABAAR signaling adapts to optimize cortical functions.
Tyrosyl-DNA phosphodiesterase 1 (TDP1) and SPRTN protease repair histone 3 and topoisomerase 1 DNA-protein crosslinksin vivo
Authors: Anticevic Ivan , Otten Cecile , Vinkovic Luka , Jukic Luka , Popovic Marta 
Published: March 2023

AbstractDNA-protein crosslinks (DPCs) are frequent and damaging DNA lesions that affect all DNA transactions, which in turn can lead to the formation of DSBs, genomic instability and cell death. At the organismal level, impaired DPC repair (DPCR) is associated with cancer, aging, and neurodegeneration. Despite the severe consequences of DPCs, little is known about the processes underlying repair pathways at the organism level. SPRTN is a protease that removes most cellular DPCs during replication, whereas tyrosyl-DNA phosphodiesterase 1 repairs one of the most abundant enzymatic DPCs, topoisomerase 1-DPC (TOP1-DPC). How these two enzymes repair DPCs at the organism level is currently unknown. We perform phylogenetic, syntenic, structural and expression analysis to compare TDP1 orthologs between human, mouse and zebrafish. Using the zebrafish animal model and human cells, we demonstrate that TDP1 and SPRTN repair endogenous, camptothecin- and formaldehyde-induced DPCs, including histone H3- and TOP1-DPCs. We show that resolution of H3-DNA crosslinks depends on upstream proteolysis by SPRTN and subsequent peptide removal by TDP1 in RPE1 cells and zebrafish embryos, whereas SPRTN and TDP1 function in different pathways in the repair of endogenous TOP1-DPCs and total DPCs. Furthermore, our results suggest that TDP2 could potentially compensate for the impairment of TDP1 functionin vivoand in human cells. Understanding the role of TDP1 in DPC repair at the cellular and organismal levels could provide an impetus for the development of new drugs and combination therapies with TOP1-DPC inducing drugs.
Chromatin opening ability of pioneer factor Pax7 depends on unique isoform and C-terminal domain
Authors: Bascunana Virginie , Pelletier Audrey , Gouhier Arthur , Bemmo Amandine , Balsalobre Aurelio , Drouin Jacques 
Published: March 2023

AbstractPioneer factors are transcription factors (TFs) that have the unique ability to recognise their target DNA sequences within closed chromatin. Whereas their interactions with cognate DNA is similar to other TFs, their ability to interact with chromatin remains poorly understood. Having previously defined the modalities of DNA interactions for the pioneer factor Pax7, we have now used natural isoforms of this pioneer as well as deletion and replacement mutants to investigate the Pax7 structural requirements for chromatin interaction and opening. We show that the GL+ natural isoform of Pax7 that has two extra amino acids within the DNA binding paired domain is unable to activate the melanotrope transcriptome and to fully activate a large subset of melanotrope-specific enhancers targeted for Pax7 pioneer action. This enhancer subset remains in the primed state rather than being fully activated, despite the GL+ isoform having similar intrinsic transcriptional activity as the GL-isoform. C-terminal deletions of Pax7 lead to the same loss of pioneer ability, with similar reduced recruitments of the cooperating TF Tpit and of the co-regulators Ash2 and BRG1. This suggests complex interrelations between the DNA binding and C-terminal domains of Pax7 that are crucial for its chromatin opening pioneer ability.
Spatially-resolved single cell transcriptomics reveal a critical role for γδ T cells in the control of skin inflammation and subcutaneous adipose wasting during chronicTrypanosoma bruceiinfection
Authors: Quintana Juan F. , Sinton Matthew C. , Chandrasegaran Praveena , Lestari Agatha Nabilla , Heslop Rhiannon , Cheaib Bachar , Ogunsola John , Ngoyi Dieudonne Mumba , Swar Nono-Raymond Kuispond , Cooper Anneli , Coffelt Seth B. , MacLeod Annette 
Published: March 2023

AbstractAfrican trypanosome parasites colonise the skin in a process important for parasite transmission. However, how the skin responses to trypanosome infection remain unresolved. Here, using a combination of spatial and single cell transcriptomics, coupled within vivogenetic models, we investigated the local immune response of the skin in a murine model of infection. First, we detected a significant expansion of IL-17A-producing γδ T cells (primarily Vγ6+) in the infected murine skin compared to naïve controls that occur mainly in the subcutaneous adipose tissue. Second, interstitial preadipocytes located in the subcutaneous adipose tissue upregulate several genes involved in inflammation and antigen presentation, including T cell activation and survival.In silicocell-cell communication suggests that adipocytes trigger γδ T cell activation locallyvia Cd40, Il6, Il10,andTnfsf18signalling, amongst others. Third, mice deficient in IL-17A-producing γδ T cells show extensive inflammation, increased frequency of skin-resident IFNγ-producing CD8+T cells and limited subcutaneous adipose tissue wasting compared to wild-type infected controls, independent of TH1 CD4+T cells and parasite burden. Based on these observations, we proposed a model whereby adipocytes as well as Vγ6+cells act concertedly in the subcutaneous adipose tissue to limit skin inflammation and tissue wasting. These studies shed light onto the mechanisms of γδ T cell-mediated immunity in the skin in the context of African trypanosome infection, as well as a potential role of immature and mature adipocytes as homeostatic regulators in the skin during chronic infection.
Spatiotemporal cell landscape of human embryonic tooth development
Authors: Shi Yueqi , Yu Yejia , Li Jutang , Sun Shoufu , Han Li , Wang Shaoyi , Guo Ke , Yang Jingang , Wei Wenjia , Qiu Jin 
Published: March 2023

AbstractUnderstanding the cellular composition and trajectory of human tooth development is valuable for dentistry and stem cell engineering research. Previous single-cell studies have focused on mature human tooth and developing mice tooth, but cell landscape on human embryonic dental development is still lacking. We collected tooth germ tissues from aborted fetus (17-24 week) for single cell RNA sequence and spatial transcriptome. We classified all cells into seven subclusters of epithelium, seven clusters of mesenchyme and other cell types like Schwann cell precursor and pericyte. For epithelium, the Stratum intermedium branch and the ameloblast branch diverged from a same set of KRT15+-HOPX+-ALCAM+ epithelial stem cell lineage, but the spatial distribution of two branches were not clearly distinct. This trajectory received spatially adjacent regulation signals from mesenchyme and pericyte, including JAG1 and APP. The differentiation of pulp cell and pre-odontoblast showed four waves of temporally distinct gene expression, which involved regulation networks of LHX9, DLX5 and SP7 and were regulated by upstream ligands like BMP family. Taken together, we provided a reference landscape for the research on human early tooth development, covering different spatial structures and developmental periods.
Chemically Tunable FOXM1-D Sensor Revealed FOXM1 Direct Influence on Cell Cycle
Authors: Phongkitkarun Kriengkrai , Chusorn Porncheera , Kamkaew Maliwan , Lam Eric W.-F. , Promptmas Chamras , Sampattavanich Somponnat 
Published: March 2023

AbstractForkhead box protein M1 (FOXM1) is a proliferation-associated transcription factor contributing to the G2/M phase transition of the cell cycle. Although the upregulation of FOXM1 has been observed in different cancer types, how the regulation of FOXM1 dynamically alters during cell cycles and potentially contributes to tumorigenesis is not well understood. We showed here the development and application of a tunable FOXM1-DHFR (FOXM1-D) sensor that enables surveillance and manipulation of the FOXM1 abundance. Using trimethoprim (TMP) to stabilize the sensor, we measured the kinetics of FOXM1-D production, degradation, and cytosolic-to-nuclear translocation in the G1 and G2 cell-cycle phases. By controlling FOXM1-D stability in different synchronized cell cycle pools, we found that the G1- and S-synchronized cells finished their first cell division faster, although the G2-synchronized cells were unaffected. Our analysis of single-cell FOXM1-D dynamics revealed that the two-round dividing cells had a lower amplitude and later peak time than those arrested in the first cell division. Destabilizing FOXM1-D in the single-round dividing cells enabled these cells to re-enter the second cell division, proving that overproduction of FOXM1 causes cell cycle arrest and prevents unscheduled proliferation.