bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationships between biomechanical parameters, neurological recovery, and neuropathology following concussion in swine
Authors: Wofford Kathryn L. , Grovola Michael R. , Adewole Dayo O. , Browne Kevin D. , Putt Mary E. , O’Donnell John C. , Cullen D. Kacy 
Published: February 2021

ABSTRACTMild traumatic brain injury (mTBI) affects millions of individuals annually primarily through falls, traffic collisions, or blunt trauma and can generate symptoms that persist for years. Closed-head rotational injury is the most common form of mTBI and is defined by a rapid change in acceleration within an intact skull. Injury kinematics – the mechanical descriptors of injury-inducing motion – explain movement of the head, energy transfer to the brain, and, therefore, determine injury severity. However, the relationship between closed-head rotational injury kinematics – such as angular velocity, angular acceleration, and injury duration – and outcome after mTBI is currently unknown. To address this gap in knowledge, we analyzed archived surgical records of 24 swine experiencing a diffuse closed-head rotational acceleration mTBI against 12 sham animals. Kinematics were contrasted against acute recovery outcomes, specifically apnea, extubation time, standing time, and recovery duration. Compared to controls, animals with mTBI were far more likely to have apnea (p<0.001) along with shorter time to extubation (p=0.023), and longer time from extubation to recovery (p=0.006). Using regression analyses with variable selection, we generated simplified linear models relating kinematics to apnea (R2=0.27), standing time (R2=0.39) and recovery duration (R2=0.42). Neuropathology was correlated with multiple kinematics, with maximum acceleration exhibiting the strongest correlation (R2=0.66). Together, these data suggest the interplay between multiple injury kinematics, including minimum velocity and middle to minimum acceleration time, best explain acute recovery parameters and neuropathology after mTBI in swine. Future experiments that independently manipulate individual kinematics could be instrumental in developing translational diagnostics for clinical mTBI.HIGHLIGHTSAcute recovery parameters including apnea, extubation time, and recovery duration were altered after a single closed-head mTBI in swine.Lasso-based regressions utilized kinematic parameters, including minimum velocity and middle to minimum acceleration time, to relate kinematics to apnea time, standing time, and recovery duration.Lasso regression equations were able to modestly predict apnea time (R2=0.27) and moderately predict standing time (R2=0.39) and recovery duration (R2=0.42).Injury kinematic parameters, primarily maximum acceleration, were correlated with white matter pathology after mTBI.
Decrease of Functional Connectivity within the Default Mode Network by a Brief Training of Focused Attention on the Breath in Novices
Authors: Trova Sara , Tsuji Yuki , Horiuchi Haruka , Shimada Sotaro 
Published: February 2021

AbstractExperienced meditators reduce the activity of the default mode network (DMN), a brain system preferentially active when people are not engaged in specific tasks. However, the neural modulation of the DMN in novices remain largely unexplored. By using electroencephalography, we investigated the DMN functional connectivity in two groups of novices: the meditation group practiced six consecutive days of focused attention on the breath; the control group practiced only on the first and last days. After the brief training, results showed a decrease in the DMN functional connectivity between the ventromedial prefrontal cortex and the posterior cingulate cortex in theta and alpha bands during the focused attention condition, in the meditation group compared to the control group. The change in DMN functional connectivity was significantly correlated with the increase in state-level mindfulness scores. These data elucidate DMN modifications already arising at the initial stages of mindfulness meditation training in novices.HighlightsAn effect of brief meditation training on brain activity in novices was examined by using EEG.A six-day training of focused attention on the breath improved state-level mindfulness scores.Brief meditation training also reduced the functional connectivity within anterior-posterior DMN.The amount of change in DMN functional connectivity was significantly correlated with the subjective score.
tDCS modulates effective connectivity during motor command following; a potential therapeutic target for disorders of consciousness
Authors: Aloi Davide , Jalali Roya , Tilsley Penelope , Miall R. Chris , Fernández-Espejo Davinia 
Published: February 2021

AbstractTranscranial direct current stimulation (tDCS) is attracting increasing interest as a potential therapeutic route for unresponsive patients with prolonged disorders of consciousness (PDOC). However, research to date has had mixed results. Here, we propose a new direction by directly addressing the mechanisms underlying lack of responsiveness in PDOC, and using these to define our targets and the success of our intervention in the healthy brain first. We report 2 experiments that assess whether tDCS to the primary motor cortex (M1-tDCS;Experiment 1) and the cerebellum (cb-tDCS;Experiment 2) administered at rest modulate thalamo-cortical coupling in a subsequent command following task typically used to clinically assess awareness. Both experiments use sham- and polarity-controlled, randomised, double-blind, crossover designs. InExperiment 1, 22 participants received anodal, cathodal, and sham M1-tDCS sessions while in the MRI scanner. A further 22 participants received the same protocol with cb-tDCS inExperiment 2. We use Dynamic Causal Modelling of fMRI to characterise the effects of tDCS on brain activity and dynamics during simple thumb movements in response to command. We found that M1-tDCS increased thalamic excitation and that Cathodal cb-tDCS increased excitatory coupling from thalamus to M1. All these changes were polarity specific. Combined, our experiments demonstrate that tDCS can successfully modulate long range thalamo-cortical dynamics during command following via targeting of cortical regions. This suggests that M1- and cb-tDCS may allow PDOC patients to overcome the motor deficits at the root of their reduced responsiveness, improving their rehabilitation options and quality of life as a result.
A Geometric Framework for Understanding Dynamic Information Integration in Context-Dependent Computation
Authors: Zhang Xiaohan , Liu Shenquan , Chen Zhe Sage 
Published: February 2021

AbstractPrefrontal cortex plays a prominent role in performing flexible cognitive functions and working memory, yet the underlying computational principle remains poorly understood. Here we trained a rate-based recurrent neural network (RNN) to explore how the context rules are encoded, maintained across seconds-long mnemonic delay, and subsequently used in a context-dependent decision-making task. The trained networks emerged key experimentally observed features in the prefrontal cortex (PFC) of rodent and monkey experiments, such as mixed-selectivity, sparse representations, neuronal sequential activity and rotation dynamics. To uncover the high-dimensional neural dynamical system, we further proposed a geometric framework to quantify and visualize population coding and sensory integration in a temporally-defined manner. We employed dynamic epoch-wise principal component analysis (PCA) to define multiple task-specific subspaces and task-related axes, and computed the angles between task-related axes and these subspaces. In low-dimensional neural representations, the trained RNN first encoded the context cues in a cue-specific subspace, and then maintained the cue information with a stable low-activity state persisting during the delay epoch, and further formed line attractors for sensor integration through low-dimensional neural trajectories to guide decision making. We demonstrated via intensive computer simulations that the geometric manifolds encoding the context information were robust to varying degrees of weight perturbation in both space and time. Overall, our analysis framework provides clear geometric interpretations and quantification of information coding, maintenance and integration, yielding new insight into the computational mechanisms of context-dependent computation.
Beyond massive univariate tests: Covariance regression reveals complex patterns of functional connectivity related to attention-deficit/hyperactivity disorder, age, sex, and response control
Authors: Zhao Yi , Nebel Mary Beth , Caffo Brian S. , Mostofsky Stewart H. , Rosch Keri S. 
Published: February 2021

AbstractWe applied a novel Covariate Assisted Principal (CAP) whole-matrix regression approach to identify resting-state functional connectivity (FC) brain networks associated with attention-deficit/hyperactivity disorder (ADHD) and response control. Participants included 8-12 year-old children with ADHD (n=115, 29 girls) and typically developing controls (n=102, 35 girls) with a resting-state fMRI scan and go/no-go task behavioral data. We modeled three sets of covariates to identify resting-state networks associated with ADHD, age, sex, and response control. Four networks were identified across models revealing complex interactions between subregions of cognitive control, default mode, subcortical, visual, and somatomotor networks that relate to age, response control, and a diagnosis of ADHD among girls and boys. Unique networks were also identified in each of the three models suggesting some specificity to the covariates of interest. These findings demonstrate the utility of our novel covariance regression approach to studying functional brain networks relevant for development, behavior, and psychopathology.
Thresholded Partial Least Squares: Fast Construction of Interpretable Whole-brain Decoders
Authors: Lee Sangil , Bradlow Eric T. , Kable Joseph W. 
Published: February 2021

AbstractRecent neuroimaging research has shown that it is possible to decode mental states and predict future consumer behavior from brain activity data (a time-series of images). However, the unique characteristics (and high dimensionality) of neuroimaging data, coupled with a need for neuroscientifically interpretable models, has largely discouraged the use of the entire brain’s data as predictors. Instead, most neuroscientific research uses “regionalized” (partial-brain) data to reduce the computational burden and to improve interpretability (i.e., localizability of signal), at the cost of losing potential information. Here we propose a novel approach that can build whole-brain neural decoders (using the entire data set and capitalizing on the full correlational structure) that are both interpretable and computationally efficient. We exploit analytical properties of the partial least squares algorithm to build a regularized regression model with variable selection that boasts (in contrast to most statistical methods) a unique ‘fit-once-tune-later’ approach where users need to fit the model only once and can choose the best tuning parameters post-hoc. We demonstrate its efficacy in a large neuroimaging dataset against off-the-shelf prediction methods and show that our new method scales exceptionally with increasing data size, yields more interpretable results, and uses less computational memory, while retaining high predictive power.
Elucidating Mechanisms of Antitumor Immunity Mediated by Live Oncolytic Vaccinia and Heat-Inactivated Vaccinia
Authors: Wang Weiyi , Dai Peihong , Liu Shuaitong , Yang Ning , Wang Yi , Giese Rachel A. , Merghoub Taha , Wolchok Jedd D. , Deng Liang 
Published: February 2021

AbstractBackgroundViral-based immunotherapy has the potential to overcome resistance to immune checkpoint blockade (ICB) and to fill the unmet needs of many cancer patients. Oncolytic viruses (OVs) are defined as engineered or naturally occurring viruses that selectively replicate in and kill cancer cells. OVs also induce antitumor immunity. The purpose of this study is to compare the antitumor effects of live OV-GM expressing murine granulocyte-macrophage colony-stimulating factor (mGM-CSF) versus inactivated OV-GM and elucidate the underlying immunological mechanisms.MethodsIn this study, we engineered a replication-competent, oncolytic vaccinia virus (OV-GM) by inserting a murine GM-CSF gene into the thymidine kinase (TK) locus of a mutant vaccinia E3LΔ83N, which lacks the Z-DNA-binding domain of vaccinia virulence factor E3. We compared the antitumor effects of intratumoral (IT) delivery of live OV-GM vs. heat-inactivated OV-GM (heat-iOV-GM) in a murine B16-F10 melanoma bilateral implantation model.ResultsHeat-iOV-GM infection of dendritic cells (DCs) and tumor cells in vitro induces type I IFN and pro inflammatory cytokines and chemokines, whereas live OV-GM does not. IT live OV-GM is less effective in generating systemic antitumor immunity compared with heat-iOV-GM. Similar to heat-iOV-GM, the antitumor effects of live OV-GM also require Batf3-dependent CD103+ dendritic cells. IT heat-iOV-GM induces higher numbers of infiltrating activated CD8+ and CD4+ T cells as well as higher levels of type I IFN, proinflammatory cytokines, and chemokines in the distant non-injected tumors, which is dependent on CD8+ T cells. When combined with systemic delivery of ICB, IT heat-iOV-GM is more effective in eradicating tumors compared with live OV-GM.ConclusionsTumor lysis induced by the replication of oncolytic DNA viruses has a limited effect on the generation of systemic antitumor immunity. The activation of Batf3-dependent CD103+ DCs is critical for antitumor effects induced by both live OV-GM and heat-iOV-GM. Heat-iOV-GM is more potent than live OV-GM in the induction of innate and adaptive immunity in both the injected and distant non-injected tumors. We propose that evaluations of both innate and adaptive immunity induced by IT oncolytic viral immunotherapy at injected and non-injected tumors should be included as potential biomarkers.
Lack of parent-of-origin effects in Nasonia jewel wasp: a replication and extension study
Authors: Olney Kimberly C. , Gibson Joshua D. , Natri Heini M. , Underwood Avery , Gadau Juergen , Wilson Melissa A. 
Published: February 2021

AbstractIn diploid cells, the paternal and maternal alleles are, on average, equally expressed. There are exceptions from this: a small number of genes express the maternal or paternal allele copy exclusively. This phenomenon, known as genomic imprinting, is common among eutherian mammals and some plant species; however, genomic imprinting in species with haplodiploid sex determination is not well characterized. Previous work reported no parent-of-origin effects in the hybrids of closely related haplodiploidNasonia vitripennisandNasonia giraultijewel wasps, suggesting a lack of epigenetic reprogramming during embryogenesis in these species. Here, we replicate the gene expression dataset and observations using different individuals and sequencing technology, as well as reproduce these findings using the previously published RNA sequence data following our data analysis strategy. The major difference from the previous dataset is that they used an introgression strain as one of the parents and we found several loci that resisted introgression in that strain. Our results from both datasets demonstrate a species-of-origin effect, rather than a parent-of-origin effect. We present a reproducible workflow that others may use for replicating the results. Overall, we reproduced the original report of no parent-of-origin effects in the haplodiploidNasoniausing the original data with our new processing and analysis pipeline and replicated these results with our newly generated data.
Postpartum corticosterone and fluoxetine shift the tryptophan-kynurenine pathway in dams
Authors: Qiu Wansu , Go Kimberly A. , Lamers Yvonne , Galea Liisa A. M. 
Published: February 2021

AbstractPerinatal depression (PND) affects 15% of mothers. Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line of treatment for PND but are not always efficacious. Previously, we found significant reductions in plasma tryptophan concentrations and higher hippocampal proinflammatory cytokine, IL-1b levels, due to maternal SSRI treatment. Both inflammation and tryptophan-kynurenine metabolic pathway (TKP) are associated with SSRI efficacy in individuals with major depressive disorder (MDD). TKP is divided into neuroprotective and neurotoxic pathways. Higher metabolite concentrations of the neurotoxic pathway are associated with depression onset and implicated in SSRI efficacy. Metabolites in TKP were investigated in a rodent model of de novo postpartum depression (PPD) given treatment with the SSRI, fluoxetine (FLX). Dams were administered corticosterone (CORT) (40mg/kg, s.c.), and treated with the SSRI, fluoxetine (FLX) (10mg/kg, s.c.), during the postpartum for 22 days after parturition. Plasma TKP metabolite concentrations were quantified on the last day of treatment. Maternal postpartum CORT increased neurotoxic metabolites and co-enzyme/cofactors in dams (3-hydroxykynurenine, 3-hydroxyanthranilic acid, vitamin B2, flavin adenine dinucleotide). The combination of both CORT and FLX shifted the neuroprotective-to-neurotoxic ratio towards neurotoxicity. Postpartum FLX decreased plasma xanthurenic acid concentrations. Together, our data indicate higher neurotoxic TKP expression due to maternal postpartum CORT treatment, similar to clinical presentation of MDD. Moreover, maternal FLX treatment showed limited efficacy to influence TKP metabolites, which may correspond to its limited efficacy to treat depressive-like endophenotypes. Overall suggesting changes in TKP may be used as a biomarker of de novo PPD and antidepressant efficacy and targeting this pathway may serve as a potential therapeutic target.HighlightsTryptophan-kynurenine pathway (TKP) is altered by postpartum corticosterone (CORT)Postpartum CORT upregulated neurotoxic more metabolites (3HK, 3HAA)Postpartum fluoxetine (FLX) increased xanthurenic acid concentrationsPostpartum CORT and FLX together shifted the TKP balance towards neurotoxicity
The clinical and functional effects ofTERTvariants in myelodysplastic syndrome
Authors: Reilly Christopher R. , Myllymäki Mikko , Redd Robert , Padmanaban Shilpa , Karunakaran Druha , Tesmer Valerie , Tsai Frederick D. , Gibson Christopher J. , Rana Huma Q. , Zhong Liang , Saber Wael , Spellman Stephen R. , Hu Zhen-Huan , Orr Esther H. , Chen Maxine M. , De Vivo Immaculata , Cutler Corey , Antin Joseph H. , Neuberg Donna , Garber Judy E. , Nandakumar Jayakrishnan , Agarwal Suneet , Lindsley R. Coleman 
Published: February 2021

ABSTRACTGermline pathogenicTERTvariants are associated with short telomeres and an increased risk of developing myelodysplastic syndrome (MDS) among patients with a telomere biology disorder. We identifiedTERTrare variants in 41 of 1514 MDS patients (2.7%) without a clinical diagnosis of telomere biology disorder who underwent allogeneic transplantation. Patients withTERTrare variants had shorter telomere length (p<0.001) and younger age at MDS diagnosis (52 vs. 59 years, p=0.03) than patients without aTERTrare variant. In multivariable analyses,TERTrare variants were associated with inferior overall survival (p=0.034) driven by an increased incidence of non-relapse mortality (NRM) (p=0.015). Death from a non-infectious pulmonary cause was more frequent among patients with aTERTrare variant. According to ACMG/AMP guidelines and Sherloc criteria, 39TERTrare variants were classified as VUS and one as likely pathogenic. Therefore, we cloned all rare missense variants and quantified their impact on telomere elongation in a cell-based assay. We found that 36 of 40 variants had severe or intermediate impairment in their capacity to elongate telomeres. Using a homology model of human TERT bound to the shelterin protein TPP1, we inferred that TERT rare variants disrupt domain-specific functions, including catalysis, protein-RNA interactions, and recruitment to telomeres. Our results indicate that the contribution ofTERTrare variants to MDS pathogenesis and NRM risk is underrecognized and routine screening forTERTrare variants in MDS patients regardless of age or clinical suspicion could identify clinically inapparent telomere biology disorders and improve transplant outcomes through risk-adapted approaches.
Abrupt remapping in human CA3/dentate gyrus signals resolution of memory interference
Authors: Guo Wanjia , Favila Serra E. , Kim Ghootae , Molitor Robert J. , Kuhl Brice A. 
Published: February 2021

ABSTRACTRemapping refers to a decorrelation of hippocampal representations of similar spatial environments. While it has been speculated that remapping may contribute to the resolution of episodic memory interference in humans, direct evidence is surprisingly limited. Here, we tested this idea using high-resolution, pattern-based fMRI analyses. We show that activity patterns in human CA3/dentate gyrus exhibit an abrupt, temporally-specific decorrelation of highly similar memory representations that is precisely coupled with behavioral expressions of successful learning. Strikingly, the magnitude of this learning-related decorrelation was predicted by the amount of pattern overlap during initial stages of learning, with greater initial overlap leading to stronger decorrelation. Finally, we show that remapped activity patterns carry relatively more information about learned episodic associations compared to competing associations, further validating the learning-related significance of remapping. Collectively, these findings establish a critical link between hippocampal remapping and episodic memory interference and provide novel insight into why remapping occurs.