bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacologic modulation of brain metabolism by valproic acid can induce a neuroprotective environment
Authors: Bhatti Umar F. , Karnovsky Alla , Dennahy Isabel S. , Kachman Maureen , Williams Aaron M. , Nikolian Vahagn C. , Biesterveld Ben E. , Siddiqui Ali , O’Connell Rachel L. , Liu Baoling , Li Yongqing , Alam Hasan B. 
Published: November 2020

OBJECTIVE
Traumatic brain injury (TBI) is a leading cause of trauma-related morbidity and mortality. Valproic acid (VPA) has been shown to attenuate brain lesion size and swelling within the first few hours following TBI. Because injured neurons are sensitive to metabolic changes, we hypothesized that VPA treatment would alter the metabolic profile in the perilesional brain tissues to create a neuroprotective environment.

METHODS
We subjected swine to combined TBI (12-mm cortical impact) and hemorrhagic shock (40% blood volume loss and 2 hours of hypotension) and randomized them to two groups (n = 5/group): (1) normal saline (NS; 3× hemorrhage volume) and (2) NS-VPA (NS, 3× hemorrhage volume; VPA, 150 mg/kg). After 6 hours, brains were harvested, and 100 mg of the perilesional tissue was used for metabolite extraction. Samples were analyzed using reversed-phase liquid chromatography–mass spectrometry in positive and negative ion modes, and data were analyzed using MetaboAnalyst software (McGill University, Quebec, Canada).

RESULTS
In untargeted reversed-phase liquid chromatography–mass spectrometry analysis, we detected 3,750 and 1,955 metabolites in positive and negative ion modes, respectively. There were no significantly different metabolites in positive ion mode; however, 167 metabolite features were significantly different (p < 0.05) in the negative ion mode, which included VPA derivates. Pathway analysis showed that several pathways were affected in the treatment group, including the biosynthesis of unsaturated fatty acids (p = 0.001). Targeted amino acid analysis on glycolysis/tricarboxylic acid (TCA) cycle revealed that VPA treatment significantly decreased the levels of the excitotoxic amino acid serine (p = 0.001).

CONCLUSION
Valproic acid can be detected in perilesional tissues in its metabolized form. It also induces metabolic changes in the brains within the first few hours following TBI to create a neuroprotective environment.
Combined Assessment of Functional and Metabolic Performance of Human Donor Hearts: Possible Application in Donation After Circulatory Death
Authors: Bhaskaran Prasanna , Ou Ruchong , Marasco Silvana , Perera Shanaka , Brookes John , Rosenfeldt Franklin 
Published: November 2020

Background.
Donation after circulatory death (DCD) represents an increasing source of organs. However, evaluating the suitability of DCD hearts for transplantation represents a challenge. Contractile function is the ultimate determinant of recovery. We developed a novel technique in an ex vivo rig for the measurement of contractility using intraventricular balloons. We compared this technique with the measurement of lactate metabolism, the current gold standard.

Methods.
Human DCD (n = 6) and donation after brain death (n = 6) hearts were preserved by perfusion with a cold oxygenated crystalloid solution for 4 h, transferred to a blood perfusion rig at 37 °C where balloons were inserted into the left (LV) and right (RV) ventricles to measure developed pressure (DP = systolic minus diastolic). Perfusate lactate levels were measured for metabolic assessment. Concordance between LVDP and lactate was assessed during 4 h using cutoffs for LVDP of 70 mm Hg and for lactate of 10 mmol/L.

Results.
Measurements of contractile function (LVDP) and metabolism (lactate levels) were deemed concordant in 7 hearts with either a high LVDP (mean 100 mm Hg) with low lactate (mean 6.7 mmol/L)) or a low LVDP (15 mm Hg) with high lactate (mean 17.3 mmol/). In the remaining 5 hearts, measurements were deemed discordant: 4 hearts had high LVDP (mean 124 mm Hg), despite high lactate levels 17.3 mmol/L) and 1 had low LVDP (54 mm Hg) but low lactate (6.9 mmol/L).

Conclusions.
The intraventricular balloon technique provides useful information regarding contractile recovery of donor hearts that if combined with lactate metabolism has potential application for the evaluation of DCD and marginal donation after brain death hearts before transplant.
Longitudinal Analysis of the T-cell Receptor Repertoire in Graft-infiltrating Lymphocytes Following Hand Transplantation
Authors: Kim Joseph Y. , Lei Zhengdeng , Maienschein-Cline Mark , Chlipala George E. , Balamurugan Arumugam , McDiarmid Sue V. , Azari Kodi , Yang Otto O. 
Published: November 2020

Background.T lymphocyte–mediated acute rejection is a significant complication following solid organ transplantation. Standard methods of monitoring for acute rejection rely on assessing histological tissue damage but do not define the immunopathogenesis. Additionally, current therapies for rejection broadly blunt cellular immunity, creating a high risk for opportunistic infections. There is, therefore, a need to better understand the process of acute cellular rejection to help develop improved prognostic tests and narrowly targeted therapies.Methods.Through next-generation sequencing, we characterized and compared the clonal T-cell receptor (TCR) repertoires of graft-infiltrating lymphocytes (GILs) and blood-derived lymphocytes from a hand transplant recipient over 420 days following transplantation. We also tracked the TCR clonal persistence and V beta (BV) gene usage, evaluating overlap between these 2 compartments.Results.TCR repertoires of blood and GIL populations remained distinct throughout the sampling period, and differential BV usage was consistently seen between these compartments. GIL TCR clones persisted over time and were seen in only limited frequency in the blood T-lymphocyte populations.Conclusions.We demonstrate that blood monitoring of TCR clones does not reveal the pathogenic process of acute cellular rejection in transplanted tissue. GILs show clonal persistence with biased BV usage, suggesting that tissue TCR clonal monitoring could be useful, although a deeper understanding is necessary to prognosticate rejection based on TCR clonal repertoires. Finally, the distinct TCR BV usage bias in GILs raises the possibility for prevention and therapy of acute cellular rejection based on targeting of specific TCR clones.
Achieving engagement with a Deliberate Practice programme using portable laparoscopy simulators - “Incentivised Laparoscopy Practice”
Authors: Walker Kenneth G , Cleland Jennifer , Brennan Paul M , Blackhall Vivienne I , Nicol Laura G , Shah Adarsh , Yalamarthi Satheesh , Vella Mark 
Published: November 2020

ABSTRACTBackgroundThe transfer validity of portable laparoscopy simulation is well established. However, attempts to integrate take-home simulation into surgical training have met with inconsistent engagement, as reported in our 2014-15 study of an Incentivised Laparoscopy Practice (ILP) programme. Our subsequent multi-centre study examined barriers and facilitators, informing revisions of the programme for 2018-20. We now report engagement with the revised versions.MethodsIn ILP v2.1 and 2.2, two consecutive year-groups of new CSTs (n= 48 and 46) were loaned portable simulators. The 6-month programme included induction, technical support, and intermittent feedback. Six tasks were prescribed, with video instruction and charting of metric scores. Video uploads were required and scored by faculty. A pass resulted in an eCertificate, expected at Annual Review. ILP was set within a wider reform, “Improving Surgical Training”.ResultsILP v2.1 and 2.2 saw pass rates of 94% and 76% (45/48 and 35/46 trainees respectively), compared with only 26% (7/27) in v1, despite the v2.1 and v2.2 groups having less electronic gaming experience. In the ILP v2.2 group, 73% reported their engagement was adversely affected by COVID19 redeployments.ConclusionsSimply providing kit, no matter how good, is not enough. To achieve trainee engagement with take- home simulators, as in ILP v2, a whole programme is required, with motivated learning, individual and group practice, intermittent feedback, and clear goals and assessments. ILP is a complex intervention, best understood as a “reform within a reform, within a context.” This may explain why trainee engagement fell away during early pandemic conditions.WHAT IS ALREADY KNOWN ON THIS SUBJECTAttaining automation of motor skills is essential to free up operating surgeons’ attention for higher cognitive functions.Laparoscopic operating skills can transfer from simulation to the operating room, and deliberate practice is the most important variable in the development of expertise.Simply providing take-home portable simulators to surgical trainees, even with online training programmes, is insufficient to facilitate consistent deliberate practice by more than a minority of trainees.WHAT THIS STUDY ADDSA package of evidence-based reforms transformed participation of Core Surgical trainees in a 6-month programme of practice using take-home portable simulators, resulting in near- 100% engagement.Such reforms are complex, including motivators for learning, individual and group practice, intermittent feedback, clear goals and assessments, and adoption into a wider curriculum reform called “Improving Surgical Training”.The improved engagement with this form of remote simulation-based training did not continue in the face of a national “lockdown” for the COVID19 pandemic, where there was widespread redeployment of trainees.
The effect of body image dissatisfaction on goal-directed decision making in a population marked by negative appearance beliefs and disordered eating
Authors: Onysk Jakub , Seriès Peggy 
Published: November 2020

AbstractEating disorders are associated with one of the highest mortality rates among all mental disorders, yet there is very little research about them within the newly emerging and promising field of computational psychiatry. As such, we focus on investigating a previously unexplored, yet a core aspect of eating disorders – body image dissatisfaction. We continue a freshly opened debate about model-based learning and its trade-off against model-free learning – a proxy for goal-directed and habitual behaviour. We perform a behavioural study that utilises a two-step decision-making task and a reinforcement learning model to understand the effect of body image dissatisfaction on model-based learning in a population characterised by high scores of disordered eating and negative appearance beliefs, as recruited using Prolific. We find a significantly reduced model-based contribution in the body image dissatisfaction task condition in the population of interest as compared to a healthy control.
Multisensory integration-attention trade-off in cochlear-implanted deaf individuals
Authors: van de Rijt Luuk P.H. , van Opstal A. John , van Wanrooij Marc M. 
Published: November 2020

AbstractThe cochlear implant (CI) allows profoundly deaf individuals to partially recover hearing. Still, due to the coarse acoustic information provided by the implant, CI users have considerable difficulties in recognizing speech, especially in noisy environments. CI users therefore rely heavily on visual cues to augment speech comprehension, more so than normal-hearing individuals. However, it is unknown how attention to one (focused) or both (divided) modalities plays a role in multisensory speech recognition. Here we show that unisensory speech listening and reading were negatively impacted in divided-attention tasks for CI users - but not for normal-hearing individuals. Our psychophysical experiments revealed that, as expected, listening thresholds were consistently better for the normal-hearing, while lipreading thresholds were largely similar for the two groups. Moreover, audiovisual speech recognition for normal-hearing individuals could be described well by probabilistic summation of auditory and visual speech recognition, while CI users were better integrators than expected from statistical facilitation alone. Our results suggest that this benefit in integration comes at a cost. Unisensory speech recognition is degraded for CI users when attention needs to be divided across modalities. We conjecture that CI users exhibit an integration-attention trade-off. They focus solely on a single modality during focused-attention tasks, but need to divide their limited attentional resources in situations with uncertainty about the upcoming stimulus modality. We argue that in order to determine the benefit of a CI for speech comprehension, situational factors need to be discounted by presenting speech in realistic or complex audiovisual environments.Significance statementDeaf individuals using a cochlear implant require significant amounts of effort to listen in noisy environments due to their impoverished hearing. Lipreading can benefit them and reduce the burden of listening by providing an additional source of information. Here we show that the improved speech recognition for audiovisual stimulation comes at a cost, however, as the cochlear-implant users now need to listen and speech-read simultaneously, paying attention to both modalities. The data suggests that cochlear-implant users run into the limits of their attentional resources, and we argue that they, unlike normal-hearing individuals, always need to consider whether a multisensory benefit outweighs the unisensory cost in everyday environments.
Inhibition of VCP preserves retinal structure and function in autosomal dominant retinal degeneration
Authors: Arango-Gonzalez Blanca , Sen Merve , Guarascio Rosellina , Ziaka Kalliopi , del Amo Eva M. , Hau Kwan , Poultney Hannah , Asfahani Rowan , Urtti Arto , Chou Tsui-Fen , Bolz Sylvia , Deshaies Raymond J. , Haq Wadood , Cheetham Michael E. , Ueffing Marius 
Published: November 2020

ABSTRACTDue to continuously high production rates of rhodopsin (RHO) and high metabolic activity, photoreceptor neurons are especially vulnerable to defects in proteostasis. A proline to histidine substitution at position 23 (P23H) leads to production of structurally misfolded RHO, causing the most common form of autosomal dominant Retinitis Pigmentosa (adRP) in North America. The AAA-ATPase valosin-containing protein (VCP) extracts misfolded proteins from the ER membrane for cytosolic degradation. Here, we provide the first evidence that inhibition of VCP activity rescues degenerating P23H rod cells and improves their functional properties in P23H transgenic rat and P23H knock-in mouse retinae, bothin vitroandin vivo. This improvement correlates with the restoration of the physiological RHO localization to rod outer segments (OS) and properly-assembled OS disks. As a single intravitreal injection suffices to deliver a long-lasting benefitin vivo, we suggest VCP inhibition as a potential therapeutic strategy for adRP patients carrying mutations in theRHOgene.
The Mutational Signature Comprehensive Analysis Toolkit (musicatk) for the discovery, prediction, and exploration of mutational signatures
Authors: Chevalier Aaron , Yang Shiyi , Khurshid Zainab , Sahelijo Nathan , Tong Tong , Huggins Jonathan , Yajima Masanao , Campbell Joshua D. 
Published: November 2020

AbstractMutational signatures are patterns of somatic alterations in the genome caused by carcinogenic exposures or aberrant cellular processes. To provide a comprehensive workflow for preprocessing, analysis, and visualization of mutational signatures we created the Mutational Signature Comprehensive Analysis Toolkit (musicatk) package.musicatkenables users to select different schemas for counting mutation types and easily combine count tables from different schemas. Multiple distinct methods are available to deconvolute signatures and exposures or to predict exposures in individual samples given a pre-existing set of signatures. Additional exploratory features include the ability to compare signatures to the COSMIC database, embed tumors in two dimensions with UMAP, cluster tumors into subgroups based on exposure frequencies, identify differentially active exposures between tumor subgroups and plot exposure distributions across user-defined annotations such as tumor type. Overall,musicatkwill enable users to gain novel insights into the patterns of mutational signature observed in cancer cohorts.
Selective vulnerability of supragranular layer neurons in schizophrenia
Authors: Batiuk Mykhailo Y. , Tyler Teadora , Mei Shenglin , Rydbirk Rasmus , Petukhov Viktor , Sedmak Dora , Frank Erzsebet , Feher Virginia , Habek Nikola , Hu Qiwen , Igolkina Anna , Roszik Lilla , Pfisterer Ulrich , Petanjek Zdravko , Adorjan Istvan , Kharchenko Peter V. , Khodosevich Konstantin 
Published: November 2020

ABSTRACTSchizophrenia is one of the most wide-spread mental brain disorders with complex and largely unknown etiology. To characterize the impact of schizophrenia at a cellular level, we performed single nucleus RNA sequencing of >190,000 neurons from the dorsolateral prefrontal cortex of patients with schizophrenia and matched controls (7 vs 11, respectively). In addition, to correlate data with cortical anatomy, >100,000 neurons were analyzed topographically by immunohistochemistry in an extended cohort of cases with schizophrenia and controls (10 vs 10). Compositional analysis of RNA sequencing data revealed reduction in relative abundance across all families of GABAergic neurons and a concomitant increase in principal neurons, which was most pronounced for supragranular subtypes (layers 2-3). Moreover, supragranular subtypes of GABAergic interneurons showed most dramatic transcriptomic changes. These results were substantiated by histological analysis, which revealed a reduction in the density of calretinin, calbindin and parvalbumin GABAergic interneurons particularly in layer 2. Common effect of schizophrenia on supragranular neuronal networks was underlined by downregulation of protein processing genes and upregulation of neuronal development/plasticity genes across supragranular subtypes of principal neurons and GABAergic interneurons.In situhybridization and spatial transcriptomics further confirmed supragranular layer neuron vulnerability, revealing complexity of schizophrenia-affected cortical circuits. These point towards general network impairment within supragranular layers being a core substrate associated with schizophrenia symptomatology.
Hundreds of nuclear and plastid loci yield insights into orchid relationships
Authors: Pérez-Escobar Oscar Alejandro , Dodsworth Steven , Bogarín Diego , Bellot Sidonie , Balbuena Juan A. , Schley Rowan , Kikuchi Izai , Morris Sarah K. , Epitawalage Niroshini , Cowan Robyn , Maurin Olivier , Zuntini Alexandre , Arias Tatiana , Serna Alejandra , Gravendeel Barbara , Torres Maria Fernanda , Nargar Katharina , Chomicki Guillaume , Chase Mark W. , Leitch Ilia J. , Forest Félix , Baker William J. 
Published: November 2020

ABSTRACTPremise of the studyEvolutionary relationships in the species-rich Orchidaceae have historically relied on organellar DNA sequences and limited taxon sampling. Previous studies provided a robust plastid-maternal phylogenetic framework, from which multiple hypotheses on the drivers of orchid diversification have been derived. However, the extent to which the maternal evolutionary history of orchids is congruent with that of the nuclear genome has remained uninvestigated.MethodsWe inferred phylogenetic relationships from 294 low-copy nuclear genes sequenced/obtained using the Angiosperms353 universal probe set from 75 species representing 69 genera, 16 tribes and 24 subtribes. To test for topological incongruence between nuclear and plastid genomes, we constructed a tree from 78 plastid genes, representing 117 genera, 18 tribes and 28 subtribes and compared them using a co-phylogenetic approach. The phylogenetic informativeness and support of the Angiosperms353 loci were compared with those of the 78 plastid genes.Key ResultsPhylogenetic inferences of nuclear datasets produced highly congruent and robustly supported orchid relationships. Comparisons of nuclear gene trees and plastid gene trees using the latest co-phylogenetic tools revealed strongly supported phylogenetic incongruence in both shallow and deep time. Phylogenetic informativeness analyses showed that the Angiosperms353 genes were in general more informative than most plastid genes.ConclusionsOur study provides the first robust nuclear phylogenomic framework for Orchidaceae plus an assessment of intragenomic nuclear discordance, plastid-nuclear tree incongruence, and phylogenetic informativeness across the family. Our results also demonstrate what has long been known but rarely documented: nuclear and plastid phylogenetic trees are not fully congruent and therefore should not be considered interchangeable.
Topology-based Sparsification of Graph Annotations
Authors: Danciu Daniel , Karasikov Mikhail , Mustafa Harun , Kahles André , Rätsch Gunnar 
Published: November 2020

AbstractSince the amount of published biological sequencing data is growing exponentially, efficient methods for storing and indexing this data are more needed than ever to truly benefit from this invaluable resource for biomedical research. Labeled de Bruijn graphs are a frequently-used approach for representing large sets of sequencing data. While significant progress has been made to succinctly represent the graph itself, efficient methods for storing labels on such graphs are still rapidly evolving. In this paper, we present RowDiff, a new technique for compacting graph labels by leveraging expected similarities in annotations of vertices adjacent in the graph. RowDiff can be constructed in linear time relative to the number of vertices and labels in the graph, and in space proportional to the graph size. In addition, construction can be efficiently parallelized and distributed, making the technique applicable to graphs with trillions of nodes. RowDiff can be viewed as an intermediary sparsification step of the original annotation matrix and can thus naturally be combined with existing generic schemes for compressed binary matrices. Experiments on 10,000 RNA-seq datasets show that RowDiff combined with Multi-BRWT results in a 30% reduction in annotation footprint over Mantis-MST, the previously known most compact annotation representation. Experiments on the sparser Fungi subset of the RefSeq collection show that applying RowDiff sparsification reduces the size of individual annotation columns stored as compressed bit vectors by an average factor of 42. When combining RowDiff with a Multi-BRWT representation, the resulting annotation is 26 times smaller than Mantis-MST.
Signatures Of Tspan8 Variants Associated With Human Metabolic Regulation And Diseases
Authors: De Tisham , Goncalves Angela , Speed Doug , Froguel Phillipe ,   NFBC consortium, Gaffney Daniel , Johnson Michael R. , Jarvelin Maarjo-Riitta , Coin Lachlan JM 
Published: November 2020

AbstractHere, with the example of common copy number variation (CNV) in the TSPAN8 gene, we present an important piece of work in the field of CNV detection, CNV association with complex human traits such as1H NMR metabolomic phenotypes and an example of functional characterization of CNVs among human induced pluripotent stem cells (HipSci). We report TSPAN8 exon 11 as a new locus associated with metabolomic regulation and show that its biology is associated with several metabolic diseases such as type 2 diabetes (T2D), obesity and cancer. Our results further demonstrate the power of multivariate association models over univariate methods and define new metabolomic signatures for several new genomic loci, which can act as a catalyst for new diagnostics and therapeutic approaches.