bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of AT1 receptor blockade on cardiovascular outcome after cardiorespiratory arrest: an experimental study in rats
Authors: Araújo Filho EAF , Carmona MJC , Otsuki DA , Maia DRR , Lima LGCA , Vane MF 
Published: May 2023

BackgroundAT1 angiotensin II receptor (ATI) antagonists are beneficial in focal ischemia/reperfusion (I/R) cases. However, in cases of global I/R, such as cardiorespiratory arrest (CRA), ATI blocker’s effects are still unknown.MethodsRats were allocated into four groups: Sham group (SG) – animals submitted to surgical interventions, without CRA; Control group (CG) – animals submitted to CRA and ventricular fibrillation; Group AT1 (GAT1) – like CG, plus 0.2 mg/kg of Candesartan; Vehicle Group (VG): animals equally induced to CRA, and administration of 0.2 ml/kg of dimethyl sulfoxide. The rate of return of spontaneous circulation (ROSC), survival, hemodynamic variables, histopathology, and markers of tissue injury were analyzed.ResultsCompared to CG, the GAT1 group had a higher rate of ROSC (62.5% vs. 42.1%, p<0.0001), survival (100% vs. 62.5%, CI: 0.014-0.034; p = 0.027), lower incidence of arrhythmia after 10 minutes of ROSC, (10% vs. 62.5%, p=0.000) and lower neuronal and cardiac injury scores (p=0.025 and p=0.021, respectively). The groups did not differ regarding CRA duration, number of adrenaline doses, or number of defibrillations.ConclusionATI receptor blockade was responsible for higher rates of ROSC and survival, in addition to demonstrating neuronal and myocardial protection.HighlightsAT1 receptor block was responsible per higher rates of ROSC and survival in intervention group.The AT1 receptor block can be neuroprotector in ischemic injury caused by CPR.The candesartan administration during CPR can contribute with reduction of ventricular arrythmias.
Vagus nerve stimulation rescues persistent pain following orthopedic surgery in adult mice
Authors: Wu Pau Yen , Caceres Ana Isabel , Chen Jiegen , Sokoloff Jamie , Huang Mingjian , Baht Gurpreet Singh , Nackley Andrea G , Jordt Sven-Eric , Terrando Niccolò 
Published: May 2023

AbstractPostoperative pain is a major clinical problem imposing a significant burden on our patients and society. Up to 57% of patients experience persistent postoperative pain 2 years after orthopedic surgery [49]. Although many studies have contributed to the neurobiological foundation of surgery-induced pain sensitization, we still lack safe and effective therapies to prevent the onset of persistent postoperative pain. We have established a clinically relevant orthopedic trauma model in mice that recapitulates common insults associated with surgery and ensuing complications. Using this model, we have started to characterize how induction of pain signaling contributes to neuropeptides changes in dorsal root ganglia (DRG) and sustained neuroinflammation in the spinal cord [62]. Here we have extended the characterization of pain behaviors for >3 months after surgery, describing a persistent deficit in mechanical allodynia in both male and female C57BL/6J mice after surgery. Notably, we have applied a novel minimally invasive bioelectronic approach to percutaneously stimulate the vagus nerve (termed pVNS) [24] and tested its anti-nociceptive effects in this model. Our results show that surgery induced a strong bilateral hind-paw allodynia with a slight decrease in motor coordination. However, treatment with pVNS for 30-minutes at10 Hz weekly for 3 weeks prevented pain behavior compared to naïve controls. pVNS also improved locomotor coordination and bone healing compared to surgery without treatment. In the DRGs, we observed that vagal stimulation fully rescued activation of GFAP positive satellite cells but did not affect microglial activation. Overall, these data provide novel evidence for the use of pVNS to prevent postoperative pain and may inform translational studies to test anti-nociceptive effects in the clinic.
Food odours associated with conspecific corpses cause food avoidance in an invasive ant
Authors: Wagner Thomas , Czaczkes Tomer J. 
Published: May 2023

AbstractInvasive ants, such asLinepithema humile(the Argentine ant), pose a global threat, necessitating a better understanding of their behaviour in order to improve management strategies. Traditional eradication methods, including baiting, have had limited success, but the causes of control failure are not always clear. Here we propose that ants may learn to avoid toxic baits in part due to their association with ant corpses. Ants were tested on a Y-maze after exposure to scented corpses or dummies. 69% (n = 64) of ants avoided branches bearing the scent of scented corpses. At a collective level, colonies neglected food sources associated with scented ant corpses in favour of a food source with a novel odour, with only 42% (n = 273) of foragers feeding from the corpse-scent associated food source. However, if corpses were produced by feeding ants scented toxicant, focal ants encountering these corpses did not avoid the corpse-associated scent on a Y maze (53%, n = 65). Moreover, in a dual-feeder test, ants did not avoid feeding at food sources scented with an odour associated with conspecific corpses. The study demonstrates that conspecific corpses can act as a negative stimulus forLinepithema humile, leading to avoidance of odours associated with corpses, which can lead to potential avoidance of toxic baits. Why the more realistic Y-maze trial with corpses of ants that had ingested the toxicant elicited no avoidance is unclear: it may be due to weaker odour cues from ingested food, or a counterbalancing of the negative corpse stimulus by the positive presence of food remains on the corpse. Nonetheless, this study demonstrates that conspecific corpses act as a negative stimulus for ants, and this should be kept in mind when planning control efforts. A simple solution to this issue would be adding odours to baits, and cycling baits between treatments. This would disrupt the association between bait odour and corpses.
Identification of Novel Allosteric Sites of SARS-CoV-2 Papain-Like Protease (PLpro) for the Development of COVID-19 Antivirals
Authors: Ferreira Juliana C. , Villanueva Adrian J. , Al Adem Kenana , Fadl Samar , Alzyoud Lara , Ghattas Mohammad A , Rabeh Wael M. 
Published: May 2023

AbstractCoronaviruses such as SARS-CoV-2 encode a conserved papain-like protease (PLpro) that is crucial for viral replication and immune evasion, making it a prime target for antiviral drug development. In this study, three surface pockets on SARS-CoV-2 PLpro that may function as sites for allosteric inhibition were computationally identified. To evaluate the effects of these pockets on proteolytic activity, 52 residues were separately mutated to alanine. In Pocket 1, located between the Ubl and thumb domains, the introduction of alanine at T10, D12, T54, Y72, or Y83 reduced PLpro activity to <12% of that of WT. In Pocket 2, situated at the interface of the thumb, fingers, and palm domains, Q237A, S239A, H275A, and S278A inactivated PLpro. Finally, introducing alanine at five residues in Pocket 3, between the fingers and palm domains, inactivated PLpro: S212, Y213, Y251, K254, and Y305. Pocket 1 has a higher druggability score than Pockets 2 and 3. MD simulations showed that interactions within and between domains play critical roles in PLpro activity and thermal stability. The essential residues in Pockets 1 and 2 participate in a combination of intra- and inter-domain interactions. By contrast, the essential residues in Pocket 3 predominantly participate in inter-domain interactions. The most promising targets for therapeutic development are Pockets 1 and 3, which have the highest druggability score and the largest number of essential residues, respectively. Non-competitive inhibitors targeting these pockets may be antiviral agents against COVID-19 and related coronaviruses.
Microtubule-mediated cell shape regulation contributes to efficient cell packing inArabidopsis thalianacotyledons
Authors: Matz Timon W. , Eng Ryan C. , Sampathkumar Arun , Nikoloski Zoran 
Published: May 2023

AbstractRecent advances have started to uncover the mechanisms involved in organ and cell shape regulation. However, organizational principles of epidermal cells in different tissues remain poorly understood. Here, we show that polygonal representations of cotyledon pavement cells (PCs) inArabidopsis thalianaexhibit increasing irregularity in side lengths and internal vertex angles during early stages of development. While the shape of PCs in cotyledons is more complex than that of cells in the shoot apical meristem (SAM), the polygonal representations of these cells share similar irregularity of side length. Comparison of the surface cell area with the area of the regular polygons, having optimally spaced tri-cellular junctions, reveals suboptimal junction placement for coverage in cotyledons and SAM. We also found that cotyledons show increased packing density compared to the SAM, indicating that PCs forgo coverage of larger areas to potentially increase tissue stability. The identified shape irregularity and cell packing is associated with microtubule cytoskeleton. Our study provides a framework to analyze reasons and consequences of irregularity of polygonal shapes for biological as well as artificial shapes in larger organizational context.SummaryWe provide a polygonal cell representation in a tissue context and use it to draw conclusions about cell packing in epidermis ofA. thalianacotyledon.
Unravelling a novel role for Cannabidivarin in the modulation of subventricular zone postnatal neurogenesis
Authors: Lourenço Diogo M. , Soares Rita , Santos Sónia Sá , Mateus Joana M. , Rodrigues Rui S. , Moreira João B. , Vaz Sandra H. , Sebastião Ana M. , Solá Susana , Xapelli Sara 
Published: May 2023

AbstractPostnatal neurogenesis has been shown to rely on the endocannabinoid system. Here we aimed at unravelling the role of Cannabidivarin (CBDV), a non-psychoactive cannabinoid, with high affinity for the non-classical cannabinoid receptor TRPV1, on subventricular zone (SVZ) postnatal neurogenesis. Using the neurosphere assay, SVZ-derived neural stem/progenitor cells (NSPCs) were incubated with CBDV and/or 5’-Iodoresinferotoxin (TRPV1 antagonist), and their role on cell viability, proliferation, and differentiation were dissected. CBDV was able to promote, through a TRPV1-dependent mechanism, cell survival, cell proliferation and neuronal differentiation. Furthermore, pulse-chase experiments revealed that CBDV-induced neuronal differentiation was a result of cell cycle exit of NSPCs. Regarding oligodendrocyte differentiation, CBDV inhibited oligodendrocyte differentiation and maturation. Since our data suggested that the CBDV-induced modulation of NSPCs acted via TRPV1, a sodium-calcium channel, and that intracellular calcium levels are known regulators of NSPCs fate and neuronal maturation, single cell calcium imaging was performed to evaluate the functional response of SVZ-derived cells. We observed that CBDV-responsive cells displayed a two-phase calcium influx profile, being the initial phase dependent on TRPV1 activation. Taken together, this work unveiled a novel and untapped neurogenic potential of CBDV via TRPV1 modulation. These findings pave the way to future neural stem cell biological studies and repair strategies by repurposing this non-psychoactive cannabinoid as a valuable therapeutic target.
Quantifying network behavior in the rat prefrontal cortex: a reproducibility crisis
Authors: Sha Congzhou M. , Wang Jian , Mailman Richard B. , Yang Yang , Dokholyan Nikolay V. 
Published: May 2023

AbstractThe question of how consciousness and behavior arise from neural activity is fundamental to understanding the brain, and to improving the diagnosis and treatment of neurological and psychiatric disorders. There is significant murine and primate literature on how behavior is related to the electrophysiological activity of the medial prefrontal cortex and its role in working memory processes such as planning and decision-making. Existing experimental designs, however, have insufficient statistical power to unravel the complex processes of the prefrontal cortex. We therefore examined the theoretical limitations of such experiments, providing concrete guidelines for robust and reproducible science. We piloted the use of dynamic time warping and associated statistical tests to data from neuron spike trains and local field potentials, to quantify neural network synchronicity and correlate neuroelectrophysiology with rat behavior. Our results indicate the statistical limitations of existing data, making meaningful comparison between dynamic time warping with traditional Fourier and wavelet analysis currently impossible until larger and cleaner datasets are available.Significance StatementThe prefrontal cortex is important in decision-making, yet no robust method currently exists to correlate neuron firing in the PFC to behavior. We argue that existing experimental designs are ill-suited to addressing these scientific questions, and we propose a potential method using dynamic time warping to analyze PFC neural electrical activity. We conclude that careful curation of experimental controls is needed to separate true neural signals from noise accurately.
CENTRE: A gradient boosting algorithm for Cell-type-specific ENhancer-Target pREdiction
Authors: Rapakoulia Trisevgeni , Lopez Ruiz De Vargas Sara , Omgba Persia Akbari , Laupert Verena , Ulitsky Igor , Vingron Martin 
Published: May 2023

AbstractMotivationIdentifying target promoters of active enhancers is a crucial step for realizing gene regulation and deciphering phenotypes and diseases. Up to now, several computational methods were developed to predict enhancer gene interactions but they require either many epigenomic and transcriptomic experimental assays to generate cell-type-specific predictions or a single experiment applied to a large cohort of cell types to extract correlations between activities of regulatory elements. Thus, inferring cell-type-specific enhancer gene interactions in unstudied or poorly annotated cell types becomes a laborious and costly task.ResultsHere, we aim to infer cell-type-specific enhancer target interactions, using minimal experimental input. We introduce CENTRE, a machine learning framework that predicts enhancer target interactions in a cell-type-specific manner, using only gene expression and ChIP-seq data for three histone modifications for the cell type of interest. CENTRE exploits the wealth of available datasets and extracts cell-type agnostic statistics to complement the cell-type specific information. CENTRE is thoroughly tested across many datasets and cell types and achieves equivalent or superior performance than existing algorithms that require massive experimental data.AvailabilityCENTRE’s open source code is available at GitHub viahttps://github.com/slrvv/CENTRE
Tractable and Expressive Generative Models of Genetic Variation Data
Authors: Dang Meihua , Liu Anji , Wei Xinzhu , Sankararaman Sriram , Van den Broeck Guy 
Published: May 2023

AbstractPopulation genetic studies often rely on artificial genomes (AGs) simulated by generative models of genetic data. In recent years, unsupervised learning models, based on hidden Markov models, deep generative adversarial networks, restricted Boltzmann machines, and variational autoencoders, have gained popularity due to their ability to generate AGs closely resembling empirical data. These models, however, present a tradeoff between expressivity and tractability. Here, we propose to use hidden Chow-Liu trees (HCLTs) and their representation as probabilistic circuits (PCs) as a solution to this tradeoff. We first learn an HCLT structure that captures the long-range dependencies among SNPs in the training data set. We then convert the HCLT to its equivalent PC as a means of supporting tractable and efficient probabilistic inference. The parameters in these PCs are inferred with an expectation-maximization algorithm using the training data. Compared to other models for generating AGs, HCLT obtains the largest log-likelihood on test genomes across SNPs chosen across the genome and from a contiguous genomic region. Moreover, the AGs generated by HCLT more accurately resemble the source data set in their patterns of allele frequencies, linkage disequilibrium, pairwise haplotype distances, and population structure. This work not only presents a new and robust AG simulator but also manifests the potential of PCs in population genetics.
Ranked Subtree Prune and Regraft
Authors: Collienne Lena , Whidden Chris , Gavryushkin Alex 
Published: May 2023

AbstractPhylogenetic trees are a mathematical formalisation of evolutionary histories between organisms, species, genes, cancer cells, etc. For many applications, e.g. when analysing virus transmission trees or cancer evolution, (phylogenetic) time trees are of interest, where branch lengths represent times. Computational methods for reconstructing time trees from (typically molecular) sequence data, for example Bayesian phylogenetic inference using Markov Chain Monte Carlo (MCMC) methods, rely on algorithms that sample the treespace. They employ tree rearrangement operations such as SPR (Subtree Prune and Regraft) and NNI (Nearest Neighbour Interchange) or, in the case of time tree inference, versions of these that take times of internal nodes into account. While the classic SPR tree rearrangement is well-studied, its variants for time trees are less understood, limiting comparative analysis for time tree methods.In this paper we consider a modification of the classical SPR rearrangement on the space of ranked phylogenetic trees, which are trees equipped with a ranking of all internal nodes. This modification results in two novel treespaces, which we propose to study. We begin this study by discussing algorithmic properties of these treespaces, focusing on those relating to the complexity of computing distances under the ranked SPR operations as well as similarities and differences to known tree rearrangement based treespaces. Surprisingly, we show the counterintuitive result that adding leaves to trees can actually decrease their ranked SPR distance, which may have an impact on the results of time tree sampling algorithms given uncertain “rogue taxa”.
Sex-dependent improvement in traumatic brain injury outcomes after liposomal delivery of dexamethasone in mice
Authors: Baudo Gherardo , Flinn Hannah , Holcomb Morgan , Tiwari Anjana , Soriano Sirena , Taraballi Francesca , Godin Biana , Zinger Assaf , Villapol Sonia 
Published: May 2023

ABSTRACTTraumatic Brain Injury (TBI) can have long-lasting physical, emotional, and cognitive consequences due to the neurodegeneration caused by its robust inflammatory response. Despite advances in rehabilitation care, effective neuroprotective treatments for TBI patients are lacking. Furthermore, current drug delivery methods for TBI treatment are inefficient in targeting inflamed brain areas. To address this issue, we have developed a liposomal nanocarrier (Lipo) encapsulating dexamethasone (Dex), an agonist for the glucocorticoid receptor utilized to alleviate inflammation and swelling in various conditions. In vitro studies show that Lipo-Dex were well tolerated in human and murine neural cells. Lipo-Dex showed significant suppression of inflammatory cytokines, IL-6 and TNF-α, release after induction of neural inflammation with lipopolysaccharide. Further, the Lipo-Dex were administered to young adult male and female C57BL/6 mice immediately after a controlled cortical impact injury. Our findings demonstrate that Lipo-Dex can selectively target the injured brain, thereby reducing lesion volume, cell death, astrogliosis, the release of proinflammatory cytokines, and microglial activation compared to Lipo-treated mice in a sex-dependent manner, showing a major impact only in male mice. This highlights the importance of considering sex as a crucial variable in developing and evaluating new nano-therapies for brain injury. These results suggest that Lipo-Dex administration may effectively treat acute TBI.
What can Ribo-seq and proteomics tell us about the non-canonical proteome?
Authors: Prensner John R. , Abelin Jennifer G. , Kok Leron W. , Clauser Karl R. , Mudge Jonathan M. , Ruiz-Orera Jorge , Bassani-Sternberg Michal , Deutsch Eric W. , van Heesch Sebastiaan 
Published: May 2023

AbstractRibosome profiling (Ribo-seq) has proven transformative for our understanding of the human genome and proteome by illuminating thousands of non-canonical sites of ribosome translation outside of the currently annotated coding sequences (CDSs). A conservative estimate suggests that at least 7,000 non-canonical open reading frames (ORFs) are translated, which, at first glance, has the potential to expand the number of human protein-coding sequences by 30%, from ∼19,500 annotated CDSs to over 26,000. Yet, additional scrutiny of these ORFs has raised numerous questions about what fraction of them truly produce a protein product and what fraction of those can be understood as proteins according to conventional understanding of the term. Adding further complication is the fact that published estimates of non-canonical ORFs vary widely by around 30-fold, from several thousand to several hundred thousand. The summation of this research has left the genomics and proteomics communities both excited by the prospect of new coding regions in the human genome, but searching for guidance on how to proceed. Here, we discuss the current state of non-canonical ORF research, databases, and interpretation, focusing on how to assess whether a given ORF can be said to be “protein-coding”.In briefThe human genome encodes thousands of non-canonical open reading frames (ORFs) in addition to protein-coding genes. As a nascent field, many questions remain regarding non-canonical ORFs. How many exist? Do they encode proteins? What level of evidence is needed for their verification? Central to these debates has been the advent of ribosome profiling (Ribo-seq) as a method to discern genome-wide ribosome occupancy, and immunopeptidomics as a method to detect peptides that are processed and presented by MHC molecules and not observed in traditional proteomics experiments. This article provides a synthesis of the current state of non-canonical ORF research and proposes standards for their future investigation and reporting.HighlightsCombined use of Ribo-seq and proteomics-based methods enables optimal confidence in detecting non-canonical ORFs and their protein products.Ribo-seq can provide more sensitive detection of non-canonical ORFs, but data quality and analytical pipelines will impact results.Non-canonical ORF catalogs are diverse and span both high-stringency and low-stringency ORF nominations.A framework for standardized non-canonical ORF evidence will advance the research field.Graphical Abstract