bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative deep models for alternative splicing
Authors: Jha Anupama , Gazzara Matthew R , Barash Yoseph 
Published: April 2017

Abstract

Motivation
Advancements in sequencing technologies have highlighted the role of alternative splicing (AS) in increasing transcriptome complexity. This role of AS, combined with the relation of aberrant splicing to malignant states, motivated two streams of research, experimental and computational. The first involves a myriad of techniques such as RNA-Seq and CLIP-Seq to identify splicing regulators and their putative targets. The second involves probabilistic models, also known as splicing codes, which infer regulatory mechanisms and predict splicing outcome directly from genomic sequence. To date, these models have utilized only expression data. In this work, we address two related challenges: Can we improve on previous models for AS outcome prediction and can we integrate additional sources of data to improve predictions for AS regulatory factors.

Results
We perform a detailed comparison of two previous modeling approaches, Bayesian and Deep Neural networks, dissecting the confounding effects of datasets and target functions. We then develop a new target function for AS prediction in exon skipping events and show it significantly improves model accuracy. Next, we develop a modeling framework that leverages transfer learning to incorporate CLIP-Seq, knockdown and over expression experiments, which are inherently noisy and suffer from missing values. Using several datasets involving key splice factors in mouse brain, muscle and heart we demonstrate both the prediction improvements and biological insights offered by our new models. Overall, the framework we propose offers a scalable integrative solution to improve splicing code modeling as vast amounts of relevant genomic data become available.

Availability and implementation
Code and data available at: majiq.biociphers.org/jha_et_al_2017/

Supplementary information
Supplementary data are available at Bioinformatics online.
Expanding the conceptual framework of the spatial population structure and life history of jack mackerel in the eastern South Pacific: an oceanic seamount region as potential spawning/nursery habitat
Authors: Parada Carolina , Gretchina Alexandre , Vásquez Sebastián , Belmadani Ali , Combes Vincent , Ernst Billy , Di Lorenzo Emanuele , Porobic Javier , Sepúlveda Aquiles 
Published: April 2017

AbstractJuvenile jack mackerel were found in 2009 in the Challenger break and the East Pacific ridge (CHAEPR). This seamount region is ∼3500 km from the coastal historic jack mackerel nursery grounds off Chile (north of 30°S). We reviewed historic evidence of juveniles around this seamount and data on several local environmental conditions: sea surface temperature, chlorophyll-a, wind, turbulence levels, and Eddy kinetic energy (EKE). A Lagrangian model for the early life stages of jack mackerel in the eastern South Pacific was used to assess the potential of the seamount region as a permanent nursery ground. Transport/retention mechanisms were assessed by releasing virtual particles coupled to a growth model into the flow simulated by an eddy-resolving ocean model. Model simulations showed high inter-annual variability for particle retention in the seamount region; high retention levels were associated with low EKE such that the particles were retained for several months. Satellite altimetry has shown a local minimum in eddy activity in the region where the juveniles were observed; this minimum was consistent with the above temporal relationship. The inclusion of the CHAEPR oceanic seamount region as a potential nursery ground for jack mackerel expands the current conceptual framework for the spatial population structure of this species in the South Pacific off central Chile proposed by Arcos et al. (The jack mackerel fishery and El Niño 1997–98 effects off Chile. Progress in Oceanography 49: 597–617, 2001). Finally, we discuss the relevance of seamounts playing a double role (spawning and nursery grounds) from the standpoint of conservation and biodiversity.
Mining e-cigarette adverse events in social media using Bi-LSTM recurrent neural network with word embedding representation
Authors: Xie Jiaheng , Liu Xiao , Dajun Zeng Daniel 
Published: April 2017

Abstract

Objective
Recent years have seen increased worldwide popularity of e-cigarette use. However, the risks of e-cigarettes are underexamined. Most e-cigarette adverse event studies have achieved low detection rates due to limited subject sample sizes in the experiments and surveys. Social media provides a large data repository of consumers’ e-cigarette feedback and experiences, which are useful for e-cigarette safety surveillance. However, it is difficult to automatically interpret the informal and nontechnical consumer vocabulary about e-cigarettes in social media. This issue hinders the use of social media content for e-cigarette safety surveillance. Recent developments in deep neural network methods have shown promise for named entity extraction from noisy text. Motivated by these observations, we aimed to design a deep neural network approach to extract e-cigarette safety information in social media.

Methods
Our deep neural language model utilizes word embedding as the representation of text input and recognizes named entity types with the state-of-the-art Bidirectional Long Short-Term Memory (Bi-LSTM) Recurrent Neural Network.

Results
Our Bi-LSTM model achieved the best performance compared to 3 baseline models, with a precision of 94.10%, a recall of 91.80%, and an F-measure of 92.94%. We identified 1591 unique adverse events and 9930 unique e-cigarette components (ie, chemicals, flavors, and devices) from our research testbed.

Conclusion
Although the conditional random field baseline model had slightly better precision than our approach, our Bi-LSTM model achieved much higher recall, resulting in the best F-measure. Our method can be generalized to extract medical concepts from social media for other medical applications.
Discovery of a keV-X-ray excess in RX J1856.5–3754
Authors: Yoneyama Tomokage , Hayashida Kiyoshi , Nakajima Hiroshi , Inoue Shota , Tsunemi Hiroshi 
Published: April 2017

Abstract
RX J1856.5−3754 is the brightest and nearest (∼120 pc) source among thermally emitting isolated neutron stars. Its spectra observed with XMM-Newton and Chandra satellites are well-fitted with the two-temperature (kT∞ ∼ 32 and 63 eV) blackbody model. Fitting ten sets of the data from Suzaku XIS 0, XIS 1, XIS 3, and XMM-Newton EPIC-pn with the two-temperature blackbody model, we discover an excess emission, 16%–26% in 0.8–1.2 keV. We examine possible causes of this keV-X-ray excess; uncertainty in the background, pile-up of the low-energy photons, and confusion of other sources. None of them succeeds in explaining the keV-X-ray excess observed with different instruments. We thus consider that this keV-X-ray excess most likely originates in RX J1856.5−3754. However, it is difficult to constrain the spectral shape of the keV-X-ray excess. A third blackbody component with $kT^\infty = 137^{+18}_{-14}\:$eV, an additional power-law component with a photon index $\Gamma = 3.4^{+0.5}_{-0.6}$, or Comptonization of blackbody seed photons into a power law with a photon index $\Gamma _{\rm c} = 4.3^{+0.8}_{-0.8}$ can reproduce the keV-X-ray excess. We also search for the periodicity of 0.8–1.2 keV data, since 7.055 s pulsation is discovered in the 0.15–1.2 keV band in the XMM Newton EPIC-pn data (∼1.5%). We only obtain the upper limit of pulsed fraction &lt;3% in the keV-X-ray excess. We briefly discuss the possible origin of the keV-X-ray excess, such as synchrotron radiation and Comptonization of blackbody photons.
Nonhealing Ulcers in Patients with Tophaceous Gout: A Systematic Review
Authors: Lam Gretl , Ross Frank L. , Chiu Ernest S. 
Published: April 2017

GENERAL PURPOSE:To provide information from a review of the literature about chronic ulcers associated with tophaceous gout.TARGET AUDIENCE:This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care.LEARNING OBJECTIVES/OUTCOMES:After participating in this educational activity, the participant should be better able to:1. Identify the pathophysiology of tophaceous gout, its presentation, phases, and common comorbidities.2. Evaluate the findings in this review regarding effectiveness of interventions for chronic tophaceous ulcers.ABSTRACTOBJECTIVE:Treating chronic ulcers associated with tophaceous gout is an uncommon but important clinical challenge. However, treatments vary greatly from topical therapies, to debridements, to free flap wound coverage. To the authors’ knowledge, this is the first study to assemble and compare these different approaches in order to guide effective treatment.DATA SOURCES:An electronic search of MEDLINE (PubMed) was conducted. Search terms included (goutandulcer)not“peptic ulcer,” and (gout, chronic wound)or(gout, nonhealing wound).STUDY SELECTION:Studies that discussed the presentation, characterization, or treatment of gout-associated wounds were included. The literature search yielded 9 case reports and case series; there were no randomized controlled studies or reviews.DATA EXTRACTION:Patient and wound characteristics, treatment approaches, and outcomes were noted.DATA SYNTHESIS:The 82% of 22 patients were male, aged 36 to 95 years. Three patients had not been previously diagnosed with gout, whereas others had received a diagnosis 2 to 35 years prior to presentation with an ulcer. Many patients had comorbidities including diabetes and peripheral vascular disease. Most of the 43 total ulcers occurred on the feet. Treatments included topical 3% citric acid in petroleum jelly, allogeneic culture dermal substitute, silver-containing dressing and heterologous lyophilized collagen, debridements, and free flap coverage.CONCLUSIONS:Chronic tophaceous wounds are a worldwide problem. Although physicians report some successes with different treatments, controlled studies are needed to determine the most effective approach and to identify risk factors and preventive strategies.
High Mortality Among Patients With Opioid Use Disorder in a Large Healthcare System
Authors: Hser Yih-Ing , Mooney Larissa J. , Saxon Andrew J. , Miotto Karen , Bell Douglas S. , Zhu Yuhui , Liang Di , Huang David 
Published: April 2017

Objectives:
Elevated mortality has been observed among individuals with opioid use disorder (OUD) treated in addiction specialty clinics or programs. Information about OUD patients in general healthcare settings is needed in light of the current effort to integrate addiction services into primary healthcare systems. This study examined mortality rates, causes of death, and associated risk factors among patients with OUD in a large general healthcare system.

Methods:
Mortality data were linked with electronic health records of 2576 OUD patients cared for in a large university health system from 2006 to 2014.

Results:
There were 465 deaths confirmed (18.1% of the study participants), corresponding to a crude mortality rate of 48.6 per 1000 person-years and standardized mortality ratio of 10.3 (95% confidence interval [CI] 9.4–11.3). Drug overdose and disorder (19.8%), cardiovascular diseases (17.4%), cancer (16.8%), and infectious diseases (13.5%, including 12% hepatitis C virus [HCV]) were the leading causes of death. HCV (hazard ratio [HR] 1.99, 95% CI 1.62–2.46) and alcohol use disorder (HR 1.27, 95% CI 1.05–1.55) were 2 clinically important indicators of overall mortality risk. Tobacco use disorder (adjusted HR [AHR] 2.58, 95% CI 1.60–4.17) was associated with increased risk of cardiovascular death, HCV infection (AHR 2.55, 95% CI 1.52–4.26) with cancer mortality risk, and HCV (AHR 1.92, 95% CI 1.03–3.60) and alcohol use disorder (AHR 5.44, 95% CI 2.95–10.05) with liver-related mortality risk.

Conclusions:
Patients with OUD in a general healthcare system demonstrated alarmingly high morbidity and mortality, which challenges healthcare systems to find innovative ways to identify and treat patients with substance use disorder.
Attentional Avoidance is Associated With Increased Pain Sensitivity in Patients With Chronic Posttraumatic Pain and Comorbid Posttraumatic Stress
Authors: Harvold Mathea , MacLeod Colin , Vaegter Henrik B. 
Published: April 2017

Objectives:
Posttraumatic stress disorder (PTSD) is common in chronic posttraumatic pain. Theoretical models suggest that attentional biases (AB) contribute to the development and maintenance of chronic pain and PTSD; however, the influence of AB on clinical and heat pain sensitivity in chronic posttraumatic pain patients is unknown. This study investigated AB for linguistic pain-related stimuli and trauma-related stimuli, and clinical and thermal sensitivity in patients with chronic posttraumatic pain with and without PTSD.

Materials and Methods:
In total, 34 patients with chronic posttraumatic cervical pain performed the visual attentional probe task assessing patterns of selective attentional responding to trauma cues and to pain cues. The task used short (500 ms) and long (1250 ms) stimulus exposure durations to ensure sensitivity to both the orienting and maintenance of attention. Heat pain threshold was assessed at the nonpainful hand. Clinical pain intensity, psychological distress (anxiety, depression, and disability), and PTSD symptomatology were assessed with questionnaires.

Results:
The Pain/PTSD group (N=14) demonstrated increased clinical and heat pain sensitivity as well as psychological distress compared with the Pain/No-PTSD group (N=20; P<0.05). AB scores were significantly different between groups (P=0.04). Irrespective of stimulus exposure duration, the Pain/PTSD group demonstrated attentional bias away from trauma and pain cues (avoidance), whereas the Pain/No-PTSD group demonstrated attentional bias toward pain cues (vigilance). Attentional avoidance of pain cues was associated with increased pain intensity and heat pain sensitivity (P<0.02).

Discussion:
These results suggest that attentional avoidance is associated with increased chronic posttraumatic pain. The causal contribution of attentional avoidance to pain outcomes remains unclear.
Triggering Receptor Expressed on Myeloid Cells 2, a Novel Regulator of Immunocyte Phenotypes, Confers Neuroprotection by Relieving Neuroinflammation
Authors: Zhai Qian , Li Feng , Chen Xiyao , Jia Ji , Sun Sisi , Zhou Dandan , Ma Lei , Jiang Tao , Bai Fuhai , Xiong Lize , Wang Qiang 
Published: April 2017

Abstract

Background
Microglia can not only detrimentally augment secondary injury but also potentially promote recovery. However, the mechanism underlying the regulation of microglial phenotypes after stroke remains unclear.

Methods
Mice were subjected to middle cerebral artery occlusion for 60 min. At 3 days after reperfusion, the effects of activation and suppression of triggering receptor expressed on myeloid cells 2 on immunocyte phenotypes (n = 5), neurobehavioral scores (n = 7), infarct volumes (n = 8), and neuronal apoptosis (n = 7) were analyzed. In vitro, cultured microglia were exposed to oxygen–glucose deprivation for 4 h. Inflammatory cytokines, cellular viability (n = 8), neuronal apoptosis (n = 7), and triggering receptor expressed on myeloid cells 2 expression (n = 5) were evaluated in the presence or absence of triggering receptor expressed on myeloid cell-specific small interfering RNA or triggering receptor expressed on myeloid cells 2 overexpression lentivirus.

Results
Triggering receptor expressed on myeloid cells 2 expression in the ischemic penumbra peaked at 3 days after ischemia–reperfusion injury (4.4 ± 0.1-fold, P = 0.0004) and was enhanced in interleukin-4/interleukin-13–treated microglia in vitro (1.7 ± 0.2-fold, P = 0.0119). After oxygen–glucose deprivation, triggering receptor expressed on myeloid cells 2 conferred neuroprotection by regulating the phenotypic conversion of microglia and inflammatory cytokine release. Intraperitoneal administration of triggering receptor expressed on myeloid cells 2 agonist heat shock protein 60 or unilateral delivery of a recombinant triggering receptor expressed on myeloid cells 2 lentivirus into the cerebral ventricle induced a significant neuroprotective effect in mice (apoptotic neurons decreased to 31.3 ± 7.6%; infarct volume decreased to 44.9 ± 5.3%). All values are presented as the mean ± SD.

Conclusions
Activation or up-regulation of triggering receptor expressed on myeloid cells 2 promoted the phenotypic conversion of microglia and decreased the number of apoptotic neurons. Our study suggests that triggering receptor expressed on myeloid cells 2 is a novel regulator of microglial phenotypes and may be a potential therapeutic target for stroke.
Short-course Regimens of Liposomal Amphotericin B for the Treatment of Mediterranean Visceral Leishmaniasis in Children
Authors: Krepis Panagiotis , Argyri Ioanna , Krepi Adamantia , Syrmou Areti , Spyridis Nikos , Tsolia Maria 
Published: April 2017

Background:
Visceral leishmaniasis (VL) remains an important public health problem in endemic regions. Current antileishmanial agents share several limitations including potentially serious side effects and the risk of clinical failure.

Objectives:
Aim of this study was to examine the effectiveness and safety of short-course liposomal amphotericin B (L-AmB) regimens in the treatment of childhood VL in our area.

Methods:
The cases of 43 VL patients (20 males; 23 females; mean age: 4.6 years) treated at a tertiary children’s hospital over an 11-year period were retrospectively reviewed. Diagnosis was confirmed with identification of Leishmania spp. in bone marrow samples and/or a positive serologic test. All patients were treated with 5 different L-AmB regimens at a dose of 18–22 mg/kg.

Results:
Initial response to treatment was attained in all patients (100%), while definitive cure at 6 months was achieved in 98% of patients. Adverse effects were recorded in 14 children and consisted mostly of infusion reactions and electrolyte disorders. Self-limiting nephrotoxicity was observed in 3 patients including a 12-year-old girl in whom acute kidney injury was developed. In addition, ventricular arrhythmias developed in a 13-year-old boy necessitating drug discontinuation. Although side effects were more frequent with the 2-day regimen, the difference with regard to toxicity between dosing regimens was not significant.

Conclusions:
Short-course L-AmB regimens are effective and safe for the treatment of childhood VL in our area. Our findings suggest that large L-AmB doses can possibly account for a higher rate of adverse events including nephrotoxicity.
Altered neural responses to heat pain in drug-naive patients with Parkinson disease
Authors: Forkmann Katarina , Grashorn Wiebke , Schmidt Katharina , Fründt Odette , Buhmann Carsten , Bingel Ulrike 
Published: April 2017

AbstractPain is a frequent but still neglected nonmotor symptom of Parkinson disease (PD). However, neural mechanisms underlying pain in PD are poorly understood. Here, we explored whether the high prevalence of pain in PD might be related to dysfunctional descending pain control. Using functional magnetic resonance imaging we explored neural responses during the anticipation and processing of heat pain in 21 PD patients (Hoehn and Yahr I-III) and 23 healthy controls (HC). Parkinson disease patients were naive to dopaminergic medication to avoid confounding drug effects. Fifteen heat pain stimuli were applied to the participants' forearm. Intensity and unpleasantness ratings were provided for each stimulus. Subjective pain perception was comparable for PD patients and HC. Neural processing, however, differed between groups: PD patients showed lower activity in several descending pain modulation regions (dorsal anterior cingulate cortex [dACC], subgenual anterior cingulate cortex, and dorsolateral prefrontal cortex [DLPFC]) and lower functional connectivity between dACC and DLPFC during pain anticipation. Parkinson disease symptom severity was negatively correlated with dACC-DLPFC connectivity indicating impaired functional coupling of pain modulatory regions with disease progression. During pain perception PD patients showed higher midcingulate cortex activity compared with HC, which also scaled with PD severity. Interestingly, dACC-DLPFC connectivity during pain anticipation was negatively associated with midcingulate cortex activity during the receipt of pain in PD patients. This study indicates altered neural processing during the anticipation and receipt of experimental pain in drug-naive PD patients. It provides first evidence for a progressive decline in descending pain modulation in PD, which might be related to the high prevalence of pain in later stages of PD.
p16INK4a, Cytokeratin 7, and Ki-67 as Potential Markers for Low-Grade Cervical Intraepithelial Neoplasia Progression
Authors: da Costa Larissa Bastos Eloy , Triglia Renata De Marchi , Andrade Liliana A. Lucci De Angelo 
Published: April 2017

Summary

Objective
The aim of this study was to evaluate p16INK4a, cytokeratin 7 (CK7), and Ki-67 immunoexpressions in low-grade squamous intraepithelial lesion (LSIL), looking for differences among cases that progress to high-grade squamous intraepithelial lesion, maintain LSIL, or regress.

Materials and Methods
Sixty-six LSIL biopsies were studied. In the follow-up, a second biopsy showed 28.7% regression, 37.9% LSIL, and 33.4% progressed to high-grade squamous intraepithelial lesion. Immunostaining for these markers were performed in the first biopsy. A qualitative evaluation method was used, as well as histomorphometry, using ImageJ software. Pearson χ2, Mann-Whitney, Kruskal-Wallis, and Fisher tests were used to compare the groups (P ≤ .05). A cutoff point was assessed through receiver operating characteristic curve positive cell ratio, for each marker, as progression predictors.

Results
The mean age of patients with and without progression was 33 and 27 years (P = .006), respectively. The qualitative evaluation indicated a tendency of progression, but without statistical significance. However, through histomorphometry, the receiver operating characteristic curve analysis showed cutoff points of 0.396, 0.345, and 0.026 for p16INK4a, CK7, and Ki-67 ratios, respectively, as predictors of progression (P = .003, .03, and .002, respectively). In a logistic regression analysis, p16INK4a, CK7, and Ki-67 positive cell ratio showed a significant correlation with progression (P = .036, .012, and .006, respectively).

Conclusions
p16INK4a, CK7, and Ki-67 may represent useful biomarkers that can identify LSIL lesions that need particular attention.