bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Exploration of the Impact of Initial Timing of Physical Therapy on Safety and Outcomes After Concussion in Adolescents
Authors: Lennon Anne , Hugentobler Jason A. , Sroka Mary Claire , Nissen Katharine S. , Kurowski Brad G. , Gagnon Isabelle , Quatman-Yates Catherine C. 
Published: May 2018

Background and Purpose:Physical therapy (PT) is a management strategy increasingly recognized to facilitate recovery after concussion. The purpose of this study was to investigate the safety and outcomes of multimodal impairment-based PT at varying time points after injury in youth diagnosed with concussion.Methods:Data were extracted retrospectively from medical records for patients who received PT for concussion-related impairments. Patient records were categorized into 3 cohorts on the basis of the timing of PT implementation: 0-20 days following injury (early intervention), 21 to 41 days following injury (middle intervention), and 42 or more days following injury (late intervention). The primary outcome measure was Post-Concussion Symptom Inventory score from the beginning to the end of the PT episode of care. Additional outcome measures included number of PT sessions, duration of PT episode of care (days), and occurrence of unplanned visits to a health care provider.Results:A total of 120 patient records (mean age of 14.77 years) were analyzed. Thirty-three, 39, and 48 individuals were categorized into the early, middle, and late intervention cohorts, respectively. There were no significant differences between intervention cohorts with regard to symptom change on the Post-Concussion Symptom Inventory from the beginning to the end of the PT episode of care, unplanned health care visits, number of PT sessions, or duration of PT episode of care.Discussion and Conclusions:Early initiation of PT may be safe and tolerable. Future prospective studies are needed to explore the efficacy of PT services administered early following injury to help characterize an optimal care plan for youth following concussion.Video Abstract availablefor more insights from the authors (see Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A210).
Neuropathic pain drives anxiety behavior in mice, results consistent with anxiety levels in diabetic neuropathy patients
Authors: Sieberg Christine B. , Taras Caitlin , Gomaa Aya , Nickerson Chelsea , Wong Cindy , Ward Catherine , Baskozos Georgios , Bennett David L.H. , Ramirez Juan D. , Themistocleous Andreas C. , Rice Andrew S.C. , Shillo Pallai R. , Tesfaye Solomon , Edwards Robert R. , Andrews Nick A. , Berde Charles , Costigan Michael 
Published: May 2018

AbstractBackground:Epidemiological studies in patients with neuropathic pain demonstrate a strong association with psychiatric conditions such as anxiety; however, the precipitating pathology between these symptoms remains unclear. To investigate this, we studied the effects of lifelong stress on levels of neuropathic pain–like behavior and conversely, the effects of chronic neuropathic injury on anxiety-like status in male and female mice. In addition, we assayed this link in painful and painless diabetic peripheral neuropathy patients.Methods:Male and female mice were subject to ongoing life-stress or control living conditions. Baseline sensitivity and anxiety tests were measured followed by spared nerve injury (SNI) to the sciatic nerve. Subsequent sensory testing occurred until 3 weeks after SNI followed by anxiety tests between 4 and 6 weeks after SNI.Results:Levels of tactile or cold allodynia did not differ between adult mice subject to lifelong chronic stress, relative to nonstressed controls, for at least 3 weeks after SNI. By contrast, longer-term neuropathic mice of both sexes displayed pronounced anxiety-like behavior, regardless of exposure to stress. If sex differences were present, females usually exhibited more pronounced anxiety-like behavior. These ongoing anxiety behaviors were corroborated with plasma corticosterone levels in distinct animal groups. In addition, data from patients with painful and nonpainful diabetic neuropathy showed a clear relationship between ongoing pain and anxiety, with females generally more affected than males.Discussion:Taken together, these data demonstrate a strong link between chronic neuropathic pain and chronic anxiety, with the driver of this comorbidity being neuropathic pain as opposed to on-going stress.
Deficiency of the Transcription Factor NR4A1 Enhances Bacterial Clearance and Prevents Lung Injury During Escherichia Coli Pneumonia
Authors: Cui Ping , Wu Shuijing , Xu Xia , Ye Hui , Hou Jinchao , Liu Xu , Wang Haihong , Fang Xiangming 
Published: May 2018

ABSTRACT

Background:
Bacterial pneumonia is one of the most common diagnoses and a leading cause of death in the intensive care unit. NR4A1 is an early response gene that has been identified as a vital regulator of immune and inflammatory responses. This study aims to explore the role of NR4A1 in Escherichia coli (E. coli) pneumonia.

Methods:
Alveolar macrophages (AMs) were isolated from wild-type (WT) and NR4A1 knock out (Nr4a1

−/−
) mice, and the NR4A1 expression and phagocytic capacity against E. coli were measured in vitro. WT and Nr4a1

−/−
mice were subjected to E. coli or sham pneumonia. Bacterial load, lung injury severity, inflammatory cell infiltration, and cytokines were assessed at 0, 4, and 18 h after surgery. Survival rates within 48 h were evaluated in WT and Nr4a1

−/−
mice. In addition, NR4A1 antagonist (DIM-C-pPhCO2Me) was also used to confirm the role of NR4A1 in vivo and ex vivo.

Results:
NR4A1 was rapidly induced in AMs at 15 min after E. coli stimulation. Compared with untreated WT AMs, NR4A1 deficiency and DIM-C-pPhCO2Me treatment showed an enhanced phagocytic function (47.72 ± 0.74% vs. 62.3 ± 0.9%, P < 0.001; 11.79 ± 1.21% vs. 30.08 ± 0.79%, P < 0.001, respectively) at 30 min after the E. coli challenge in vitro. NR4A1 deficiency significantly improved the survival rate (33.3% in WT vs. 82.4% in Nr4a1

−/−
, P < 0.01), which is comparable with DIM-C-pPhCO2Me pretreatment. The survival advantage of Nr4a1

−/−
mice was associated with decreased bacterial burden and inflammation and alleviated lung damage.

Conclusions:
These data demonstrate that NR4A1 impairs the phagocytic capacity of AMs and disrupts the host defense against invading bacteria, worsening the outcome of E. coli pneumonia in mice.
Effects of Multiday Ethanol Intoxication on Postburn Inflammation, Lung Function, and Alveolar Macrophage Phenotype
Authors: Curtis Brenda J. , Boe Devin M. , Shults Jill A. , Ramirez Luis , Kovacs Elizabeth J. 
Published: May 2018

ABSTRACT
Burn patients who consumed alcohol before injury have worse clinical outcomes, including longer hospital stays, increased ventilator days, and more respiratory infections. Most alcohol consumers are binge drinkers and not chronic alcoholics, and binge drinking patterns fluctuate over the week, with consecutive days of drinking over the weekend followed by relative abstinence during the week. We used a murine model simulating this drinking pattern in the context of burn injury. Mice were given ethanol for 3 days, rested for 4 days, given ethanol for 3 more days, followed by a sham or 15% total body surface area full-thickness burn. We previously demonstrated that mice exposed to the combined insult exhibited respiratory dysfunction and 50% mortality, with those that succumbed to injury dying between 24 and 72 h, thus identifying a therapeutic intervention window. Our goal herein is to characterize inflammatory and respiratory parameters during this critical time frame. We saw that mice exposed to the combined insult had the highest circulating and pulmonary cytokine levels at 24 h, which were normalized by 72 h in survivors. Alveolar macrophage activation was observed at 24 h in burned mice, regardless of intoxication (P < 0.05). However, at 72 h, alveolar macrophages from intoxicated burned mice had elevated CD206, relative to controls (P < 0.05), indicative of an anti-inflammatory phenotype. Taken together, these findings suggest that although lung function and inflammation are normalized by 72 h, the alterations in alveolar macrophage phenotype shed light on a potential mechanism underlying increased infection susceptibility in intoxicated burn patients.
The Sheep and the Goats: Distinguishing transcriptional enhancers in a complex chromatin landscape
Authors: Sonnenschein Anne , Dworkin Ian , Arnosti David N. 
Published: May 2018

ABSTRACTPredicting regulatory function of non-coding DNA using genomic information remains a major goal in genomics, and an important step in interpreting the cis-regulatory code. Regulatory capacity can be partially inferred from transcription factor occupancy, histone modifications, motif enrichment, and evolutionary conservation. However, combinations of these features in well-studied systems such asDrosophilahave limited predictive accuracy. Here we examine the current limits of computational enhancer prediction by applying machine-learning methods to an extensive set of genomic features, validating predictions with the Fly Enhancer Resource, which characterized the transcriptional activity of approximately fifteen percent of the genome. Supervised machine learning trained on a range of genomic features identify active elements with a high degree of accuracy, but are less successful at distinguishing tissue-specific expression patterns. Consistent with previous observations of their widespread genomic interactions, many transcription factors were associated with enhancers not known to be direct functional targets. Interestingly, no single factor was necessary for enhancer identification, although binding by the ′pioneer′ transcription factor Zelda was the most predictive feature for enhancer activity. Using an increasing number of predictive features improved classification with diminishing returns. Thus, additional single-timepoint ChIP data may have only marginal utility for discerning true regulatory regions. On the other hand, spatially- and temporally-differentiated genomic features may provide more power for this type of computational enhancer identification. Inclusion of new types of information distinct from current chromatin-immunoprecipitation data may enable more precise identification of enhancers, and further insight into the features that distinguish their biological functions.
Pleotropic effects of PPARD accelerate colorectal tumor progression and invasion
Authors: Liu Yi , Deguchi Yasunori , Tian Rui , Wei Daoyan , Chen Weidong , Xu Min , Wu Ling , Liu Fuyao , Gao Shen , Jaoude Jonathan C. , Chrieki Sarah P. , Moussalli Micheline J. , Gagea Mihai , Morris Jeffrey S. , Broaddus Russell , Zuo Xiangsheng , Shureiqi Imad 
Published: May 2018

AbstractColorectal carcinogenesis (CRC) progression requires additional molecular mechanisms to APC mutations/aberrant β-catenin signaling. PPARD is a druggable ligand-activated nuclear receptor that regulates essential genes involved in cell fate. PPARD is upregulated in intestinal epithelial cells (IECs) of human colorectal adenomas and adenocarcinomas. The mechanistic significance of PPARD upregulation in CRC remains unknown. Here we show that targeted PPARD overexpression in IECs of mice strongly augmented β-catenin activation via BMP7/TAK1 signaling, promoted intestinal tumorigenesis in Apcmin mice, and accelerated CRC progression and invasiveness in mice with IEC-targeted ApcΔ580 mutation. Human CRC invasive fronts had higher PPARD expression than their paired adenomas. A PPARD agonist (GW501516) enhanced APCΔ580 mutation-driven CRC, while a PPARD antagonist (GSK3787) suppressed it. Functional proteomics analyses and subsequent validation studies uncovered PPARD upregulation of multiple pro-invasive pathways that drive CRC progression (e.g. PDGFRβ, AKT1, CDK1 and EIF4G1). Our results identify novel mechanisms by which PPARD promotes CRC invasiveness and provide the rational for the development of PPARD antagonists to suppress CRC.
doublesexregulates sexually dimorphic beetle horn formation by integrating spatial and temporal developmental contexts in the Japanese rhinoceros beetleTrypoxylus dichotomus
Authors: Morita Shinichi , Ando Toshiya , Maeno Akiteru , Mizutani Takeshi , Mase Mutsuki , Shigenobu Shuji , Niimi Teruyuki 
Published: May 2018

Abstract:Many scarab beetles have sexually dimorphic exaggerated horns that are an evolutionary novelty. Since the shape, number, size, and location of horns are highly diverged within Scarabaeidae, beetle horns are an attractive model for studying the evolution of sexually dimorphic and novel traits. In beetles including the Japanese rhinoceros beetleTrypoxylus dichotomus, the sex determination genedoublesex(dsx) plays a crucial role in sexually dimorphic horn formation during larval-pupal development. However, knowledge of when and howdsxdrives the gene regulatory network (GRN) for horn formation to form sexually dimorphic horns during development remains elusive. To address this issue, we identified aTrypoxylus-ortholog of the sex determination gene,transformer(tra), that regulates sex-specific splicing of thedsxpre-mRNA, and whose loss of function results in sex transformation. By knocking downtrafunction at multiple developmental timepoints during larval-pupal development, we estimated the onset when the sex-specific GRN for horn formation is driven. In addition, we also revealed thatdsxregulates different aspects of morphogenetic activities during the prepupal and pupal developmental stages to form appropriate morphologies of pupal head and thoracic horn primordia as well as those of adult horns. Based on these findings, we discuss the evolutionary developmental background of sexually dimorphic trait growth in horned beetles.Author Summary:Beetle horns are highly enriched in a particular family Scarabaeidae, although the shape, size and number of horns are diversified within the group. In addition, many scarab beetle horns are sexually dimorphic. It has been questioned how a particular group of beetles has originated and diversified evolutionary novel horns. Here we found the exact time when morphological sexual dimorphism of horn primordia appeared, estimated the onset of the developmental program for sexually dimorphic horn formation driven by Doublesex, and revealed that Doublesex regulates different aspects of cell activities of horn primordia depending on the spatiotemporal contexts. Our study provides our understanding regarding regulatory shifts in these mechanisms during the evolution of sexually dimorphic traits in horned beetles.
Attend and Predict: Understanding Gene Regulation by Selective Attention on Chromatin
Authors: Singh Ritambhara , Lanchantin Jack , Sekhon Arshdeep , Qi Yanjun 
Published: May 2018

AbstractThe past decade has seen a revolution in genomic technologies that enabled a flood of genome-wide profiling of chromatin marks. Recent literature tried to understand gene regulation by predicting gene expression from large-scale chromatin measurements. Two fundamental challenges exist for such learning tasks: (1) genome-wide chromatin signals are spatially structured, high-dimensional and highly modular; and (2) the core aim is to understand what the relevant factors are and how they work together. Previous studies either failed to model complex dependencies among input signals or relied on separate feature analysis to explain the decisions. This paper presents an attention-based deep learning approach, AttentiveChrome, that uses a unified architecture to model and to interpret dependencies among chromatin factors for controlling gene regulation. AttentiveChrome uses a hierarchy of multiple Long Short-Term Memory (LSTM) modules to encode the input signals and to model how various chromatin marks cooperate automatically. AttentiveChrome trains two levels of attention jointly with the target prediction, enabling it to attend differentially to relevant marks and to locate important positions per mark. We evaluate the model across 56 different cell types (tasks) in humans. Not only is the proposed architecture more accurate, but its attention scores provide a better interpretation than state-of-the-art feature visualization methods such as saliency maps.1
Systematic Discovery of the Functional Impact of Somatic Genome Alterations in Individual Tumors through Tumor-specific Causal Inference
Authors: Cai Chunhui , Cooper Gregory F. , Lu Kevin N. , Ma Xiaojun , Xu Shuping , Zhao Zhenlong , Chen Xueer , Xue Yifan , Lee Adrian V. , Clark Nathan , Chen Vicky , Lu Songjian , Chen Lujia , Yu Liyue , Hochheiser Harry S , Jiang Xia , Jane Wang Q. , Lu Xinghua 
Published: May 2018

AbstractWe report a tumor-specific causal inference (TCI) framework, which discovers causative somatic genome alterations (SGAs) through inferring causal relationships between SGAs and molecular phenotypes (e.g., transcriptomic, proteomic, or metabolomic changes) within an individual tumor. We applied the TCI algorithm to tumors from The Cancer Genome Atlas (TCGA) and identified those SGAs that causally regulate the differentially expressed genes (DEGs) within each tumor. Overall, TCI identified 634 SGAs that cause cancer-related DEGs in a significant number of tumors, including most of the previously known drivers and many novel candidate cancer drivers. The inferred causal relationships are statistically robust and biologically sensible, and multiple lines of experimental evidence support the predicted functional impact of both well-known and novel candidate drivers. By identifying major candidate drivers and revealing their functional impact in a tumor, TCI shed light on disease mechanisms of each tumor, providing useful information for advancing cancer biology and precision oncology.Significance statementsCancer is mainly caused by SGAs. Precision oncology involves identifying and targeting tumor-specific aberrations resulting from causative SGAs. TCI is a novel computational framework for discovering the causative SGAs and their impact on oncogenic processes, thus revealing tumor-specific disease mechanisms. This information can be used to guide precision oncology.
It’s not you, it’s me: Corollary discharge in precerebellar nuclei of sleeping infant rats
Authors: Mukherjee Didhiti , Sokoloff Greta , Blumberg Mark S. 
Published: May 2018

AbstractIn week-old rats, somatosensory input arises predominantly from stimuli in the external environment or from sensory feedback associated with myoclonic twitches during active (REM) sleep. A previous study of neural activity in cerebellar cortex raised the possibility that the brainstem motor structures that produce twitches also send copies of motor commands (or corollary discharge, CD) to the cerebellum. Here, by recording from two precerebellar nuclei—the inferior olive and lateral reticular nucleus—we demonstrate that CD does indeed accompany the production of twitches. Within both structures, the CD signal comprises a surprisingly sharp activity peak within 10 ms of twitch onset. In the inferior olive, this sharp peak is attributable to the opening of slow potassium channels. We conclude that a diversity of neural activity is conveyed to the developing cerebellum preferentially during sleep-related twitching, enabling cerebellar processing of convergent input from CD and reafferent signals.
Modelling structural determinants of ventilation heterogeneity: a perturbative approach
Authors: Whitfield Carl A. , Horsley Alex , Jensen Oliver E. 
Published: May 2018

AbstractWe have developed a computational model of gas mixing and ventilation in the human lung represented as a bifurcating network. We have simulated multiple-breath washout (MBW), a clinical test for measuring ventilation heterogeneity (VH) in patients with obstructive lung conditions. By applying airway constrictions inter-regionally, we have predicted the response of MBW indices to obstructions and found that they detect a narrow range of severe constrictions that reduce airway radius to 10%–30% of healthy values. These results help to explain the success of the MBW test to distinguish obstructive lung conditions from healthy controls. Further, we have used a perturbative approach to account for intra-regional airway heterogeneity that avoids modelling each airway individually. We have found, for random airway heterogeneity, that the variance in MBW indices is greater when indices are already elevated due to constrictions. By quantifying this effect, we have shown that variability in lung structure and mechanical properties alone can lead to clinically significant variability in LCI and Scond, but only in cases simulating obstructive lung conditions. This method is a computationally efficient way to probe the lung’s sensitivity to structural changes, and to quantify uncertainty in predictions due to random variations in lung mechanical and structural properties.
Patterns of tumor progression predict small and tissue-specific tumor-originating niches
Authors: Buder Thomas , Deutsch Andreas , Klink Barbara , Voss-Böhme Anja 
Published: May 2018

AbstractCancer development is a multistep process in which cells increase in malignancy through progressive alterations. The early phase of this process is hardly observable which aggravates an understanding of later tumor development. We shed light on this initial phase with a cell-based stochastic model calibrated with epidemiological data from the tissue scale. Our model allows to estimate the number of tumor cells needed for tumor formation in human tissues based on data on the diagnosed ratios of benign and malignant tumors. We find that the minimal number of cells needed for tumor formation is surprisingly small and largely depends on the tissue type. Our results point towards the existence of tumor-originating niches in which the fate of tumor development is early decided. Our estimate for the human colon agrees well with the size of the stem cell niche in colonic crypts. Our estimates might help to identify the tumor-originating cell type, e.g. our analysis suggests for glioblastoma that the tumors originate from a cell type competing in a range of 300 - 1900 cells.SummaryWe estimate the number of tumor cells needed for tumor formation in human tissues and propose the existence of small and tissue-specific tumor-originating niches which might help to find tumor-originating cell types, in particular in glioblastoma.