Miracle-dz/UniFAR-FTUs huggingface dataset:
The Cytotoxicity of Epsilon Toxin from Clostridium perfringens on Lymphocytes Is Mediated by MAL Protein Expression

Epsilon toxin (Etx) from Clostridium perfringens is a pore-forming protein that crosses the blood-brain barrier, binds to myelin, and, hence, has been suggested to be a putative agent for the onset of multiple sclerosis, a demyelinating neuroinflammatory disease. Recently, myelin and lymphocyte (MAL) protein has been identified to be a key protein in the cytotoxic effect of Etx; however, the association of Etx with the immune system remains a central question. ABSTRACT Epsilon toxin (Etx) from Clostridium perfringens is a pore-forming protein that crosses the blood-brain barrier, binds to myelin, and, hence, has been suggested to be a putative agent for the onset of multiple sclerosis, a demyelinating neuroinflammatory disease. Recently, myelin and lymphocyte (MAL) protein has been identified to be a key protein in the cytotoxic effect of Etx; however, the association of Etx with the immune system remains a central question. Here, we show that Etx selectively recognizes and kills only human cell lines expressing MAL protein through a direct Etx-MAL protein interaction. Experiments on lymphocytic cell lines revealed that MAL protein-expressing T cells, but not B cells, are sensitive to Etx and reveal that the toxin may be used as a molecular tool to distinguish subpopulations of lymphocytes. The overall results open the door to investigation of the role of Etx and Clostridium perfringens on inflammatory and autoimmune diseases like multiple sclerosis.
Do postconcussive symptoms from traumatic brain injury in combat veterans predict risk for receiving opioid therapy for chronic pain?

ABSTRACT Objectives: Opioid therapy is contraindicated in patients with traumatic brain injury (TBI) with neuropsychological impairment, yet guidelines do not consistently predict practice. We evaluated independent risk for initiation of opioid therapy among combat veterans with chronic pain diagnoses and persistent postconcussive symptoms. Methods: We assembled a retrospective cohort of 53 124 Iraq and Afghanistan veterans in Veterans Affairs (VA) healthcare between October 2007 and March 2015 who received chronic pain diagnoses, completed a Comprehensive TBI Evaluation (CTBIE) and had not received opioid therapy in the prior year. Primary exposure variables were self-reported severe or very severe Emotional, Vestibular, Cognitive and Somatic/Sensory symptoms measured using the Neurobehavioral Symptom Inventory. Outcome measures were initiation of short-term and long-term opioid therapy within the year following CTBIE. Results: Self-reported severe and very severe postconcussive symptoms predicted initiation of long-term and short-term opioid use for chronic pain in both unadjusted and adjusted analyses. In adjusted analyses, all four postconcussive symptom domains significantly predicted initiation of long-term opioid therapy, with Emotional symptoms being the strongest predictor [ARR = 1.68 (1.52, 1.86)]. Conclusions: Increased opioid prescribing in veterans with self-reported severe persistent postconcussive symptoms indicates a need to educate prescribers and make non-opioid pain management options available for veterans with TBI and neuropsychological sequelae.
Social Crises: Signatures of Complexity in a Fast-Growing Economy

Social systems are always exposed to critical processes in which their organization, or part of it, is questioned by the society that demands solutions through different critical saliences. The traditional approach to such social crises has mainly focused on their anticipation and management, implying that the focus is on trying to deal with crises once they occur, rather than delving in their essential characteristics that seemingly depend on the adaptive nature of the system and the increase in its internal complexity. To address this issue, we propose a dual approach that utilizes both qualitative (documentary analysis) and quantitative methods (online social network analysis) in order to delve into the relationship between the complexity of the social system, its adaptation, and critical episodes. Our analysis shows how an explosive economic growth affects a social system, increasing its complexity. This complexity produces different demands from the system itself. These demands manifest signatures of complexity such as a heterogeneous and rich social structure, which emerges during moments when the society acts strongly.
Recommendation with Multi-Source Heterogeneous Information

Network embedding has been recently used in social network recommendations by embedding low-dimensional representations of network items for recommendation. However, existing item recommendation models in social networks suffer from two limitations. First, these models partially use item information and mostly ignore important contextual information in social networks such as textual content and social tag information. Second, network embedding and item recommendations are learned in two independent steps without any interaction. To this end, we in this paper consider item recommendations based on heterogeneous information sources. Specifically, we combine item structure, textual content and tag information for recommendation. To model the multi-source heterogeneous information, we use two coupled neural networks to capture the deep network representations of items, based on which a new recommendation model Collaborative multi-source Deep Network Embedding (CDNE for short) is proposed to learn different latent representations. Experimental results on two real-world data sets demonstrate that CDNE can use network representation learning to boost the recommendation performance.
Self-Adaptive Double Bootstrapped DDPG

Deep Deterministic Policy Gradient (DDPG) algorithm has been successful for state-of-the-art performance in high-dimensional continuous control tasks. However, due to the complexity and randomness of the environment, DDPG tends to suffer from inefficient exploration and unstable training. In this work, we propose Self-Adaptive Double Bootstrapped DDPG (SOUP), an algorithm that extends DDPG to bootstrapped actor-critic architecture. SOUP improves the efficiency of exploration by multiple actor heads capturing more potential actions and multiple critic heads evaluating more reasonable Q-values collaboratively. The crux of double bootstrapped architecture is to tackle the fluctuations in performance, caused by multiple heads of spotty capacity varying throughout training. To alleviate the instability, a self-adaptive confidence mechanism is introduced to dynamically adjust the weights of bootstrapped heads and enhance the ensemble performance effectively and efficiently. We demonstrate that SOUP achieves faster learning by at least 45% while improving cumulative reward and stability substantially in comparison to vanilla DDPG on OpenAI Gym's MuJoCo environments.
MiR-663, a MicroRNA Linked with Inflammation and Cancer That Is under the Influence of Resveratrol

Resveratrol (trans-3,5,4′-trihydroxystilbene, RSV) is a non-flavonoid dietary polyphenol with antioxidant, anti-inflammatory and anti-cancer properties that is primarily found in red berries. While RSV displays many beneficial effects in vitro, its actual effects in vivo or in animal models remain passionately debated. Recent publications suggest that RSV pleiotropic effects could arise from its capability to regulate the expression and activity of microRNAs, short regulators themselves capable of regulating up to several hundreds of target genes. In particular, RSV increases microRNA miR-663 expression in different human cell lines, suggesting that at least some of its multiple beneficial properties are through the modulation of expression of this microRNA. Indeed, the expression of microRNA miR-663 is reduced in certain cancers where miR-663 is considered to act as a tumor suppressor gene, as well as in other pathologies such as cardiovascular disorders. Target of miR-663 include genes involved in tumor initiation and/or progression as well as genes involved in pathologies associated with chronic inflammation. Here, we review the direct and indirect effects of RSV on the expression of miR-663 and its target transcripts, with emphasise on TGFβ1, and their expected health benefits, and argue that elucidating the molecular effects of different classes of natural compounds on the expression of microRNAs should help to identify new therapeutic targets and design new treatments.
HPLC Separation of 2-Ethyl-5(6)-methylpyrazine and Its Electroantennogram and Alarm Activities on Fire Ants (Solenopsis invicta Buren)

2-Ethyl-3,6-dimethylpyrazine (EDMP) was an alarm pheromone component isolated from the mandibular gland of the red imported fire ant, Solenopsis invicta Buren. Several pyrazine analogues have been previously found to elicit significant alarm responses in S. invicta workers. This study aimed to separate the commercially available 2-ethyl-5(6)-methylpyrazine (EMP), i.e., a mixture of 2-ethyl-6-methylpyrazine (2E6MP) and 2-ethyl-5-methylpyrazine (2E5MP), and to examine both electroantennogram (EAG) and behavioral responses of S. invicta workers to EMP and the purified isomers. HPLC separations were achieved using a polysaccharide chiral stationary phase (Chiralpak AD-H) column with both mobile phases: Cyclohexane/isopropanol, and hexane/isopropanol. A ratio of 99:1 was selected for the separation of EMP at semipreparative level. The structures of the isomers obtained through the cyclohexane/isopropanol mobile phase were confirmed by detailed analyses of 2D-HSQC- and -HMBC-NMR data. The two isomers showed differential methine C–H correlations evidenced by 2D-HMBC-NMR spectra. The two concentrated fractions obtained through hexane/isopropanol mobile phase were subjected to EAG test and behavioral bioassay on S. invicta workers. The two HPLC−purified isomers, 2E6MP and 2E5MP, and their mixture (1:1) at same dose elicited similar EAG and alarm responses, indicating that these two isomers are equally active. The 2D-NMR−spectroscopic characterization, and electrophysiological and alarm activities of 2E6MP and 2E5MP were reported here for the first time.
Stratification for Constraint-Based Multi-Objective Combinatorial Optimization

New constraint-based algorithms have been recently proposed to solve Multi-Objective Combinatorial Optimization (MOCO) problems. These new methods are based on Minimal Correction Subsets (MCSs) or P-minimal models and have shown to be successful at solving MOCO instances when the constraint set is hard to satisfy. However, if the constraints are easy to satisfy, constraint-based tools usually do not perform as well as stochastic methods. For solving such instances, algorithms should focus on dealing with the objective functions. This paper proposes the integration of stratification techniques in constraint-based algorithms for MOCO. Moreover, it also shows how to diversify the stratification among the several objective criteria in order to better approximate the Pareto front of MOCO problems. An extensive experimental evaluation on publicly available MOCO instances shows that the new algorithm is competitive with stochastic methods and it is much more effective than existing constraint-based methods.
Impaired chronic pain‐like behaviour and altered opioidergic system in the TASTPM mouse model of Alzheimer's disease

Chronic pain conditions, especially osteoarthritis (OA), are as common in individuals with Alzheimer's disease (AD) as in the general elderly population, which results in detrimental impact on patient's quality of life. However, alteration in perception of pain in AD coupled with deteriorating ability to communicate pain sensations often result in under‐diagnosis and inappropriate management of pain. Therefore, a better understanding of mechanisms in chronic pain processing in AD is needed. Here, we explored the development and progression of OA pain and the effect of analgesics in a transgenic mouse model of AD.
SegBot: A Generic Neural Text Segmentation Model with Pointer Network

Text segmentation is a fundamental task in natural language processing that comes in two levels of granularity: (i) segmenting a document into a sequence of topical segments (topic segmentation), and (ii) segmenting a sentence into a sequence of elementary discourse units (EDU segmentation). Traditional solutions to the two tasks heavily rely on carefully designed features. The recently proposed neural models do not need manual feature engineering, but they either suffer from sparse boundary tags or they cannot well handle the issue of variable size output vocabulary. We propose a generic end-to-end segmentation model called SegBot. SegBot uses a bidirectional recurrent neural network to encode input text sequence. The model then uses another recurrent neural network together with a pointer network to select text boundaries in the input sequence. In this way, SegBot does not require hand-crafted features. More importantly, our model inherently handles the issue of variable size output vocabulary and the issue of sparse boundary tags. In our experiments, SegBot outperforms state-of-the-art models on both topic and EDU segmentation tasks.
Accuracy of Diffusion-weighted Magnetic Resonance Imaging in Detecting Mucosal Healing and Treatment Response, and in Predicting Surgery, in Crohn’s Disease

Background and Aims The Nancy score is a luminal Crohn's disease [CD] activity index applied in diffusion-weighted magnetic resonance imaging [DW-MRI]. We assessed the accuracy of the Nancy score in detecting mucosal healing and treatment response, and in predicting surgery. Methods This was a retrospective, single-centre study of all patients with active CD and serial DW-MRI before and after treatment initiation with a biologic drug, between January 2010 and September 2016. The gold standard was endoscopy. The association between the Nancy score and the cumulative probability of intestinal resection during follow-up was tested combining Kaplan-Meier curves and log-rank testing. Results A total of 96 patients were included; 20 had concomitantly undergone endoscopy. The Nancy score correlated well with the Crohn's Disease Endoscopic Index of Severity [r = 0.60 for the total score and r = 0.63 for the segmental score]. A total Nancy score <6 and a segmental Nancy score <2 detected mucosal healing with an area under the receiver operating characteristic curve [AUROC] of 0.82 (95% confidence interval [CI] 0.69-0.94, p <0.0001) and 0.80 [95% CI 0.73-0.87, p <0.0001], respectively. The Nancy score was highly sensitive to changes [Guyatt's responsiveness indices: 1.18 for the total score and 0.85 for the segmental score]. Mucosal healing on DW-MRI after treatment initiation was associated with a lower cumulative probability of intestinal surgery (p = 0.0251, median [interquartile range: IQR] follow-up 2.2 [1.6-3.7] years). Conclusions In CD, the Nancy score accurately detects mucosal healing and treatment response, the latter associated with a lower likelihood of intestinal resection.
Recognition of conserved antigens by Th17 cells provides broad protection against pulmonary Haemophilus influenzae infection

Significance Nontypeable Haemophilus influenzae (NTHi) is a major cause of community acquired pneumonia and exacerbation of chronic obstructive pulmonary disease. Current effort in NTHi vaccine development has focused on generating antibody responses to surface antigens and has had limited success, largely because of antigenic diversity among the numerous circulating NTHi strains. In this study, we have uncovered Th17 responses as the immune mechanism of cross-protection and identified Th17 antigens that are conserved and induce protection against NTHi lung infection, thus making a critical first step toward development of a broadly protective “universal” vaccine—the Holy Grail of vaccine development against respiratory pathogens. Nontypeable Haemophilus influenzae (NTHi) is a major cause of community acquired pneumonia and exacerbation of chronic obstructive pulmonary disease. A current effort in NTHi vaccine development has focused on generating humoral responses and has been greatly impeded by antigenic variation among the numerous circulating NTHi strains. In this study, we showed that pulmonary immunization of mice with killed NTHi generated broad protection against lung infection by different strains. While passive transfer of immune antibodies protected only against the homologous strain, transfer of immune T cells conferred protection against both homologous and heterologous strains. Further characterization revealed a strong Th17 response that was cross-reactive with different NTHi strains. Responding Th17 cells recognized both cytosolic and membrane-associated antigens, while immune antibodies preferentially responded to surface antigens and were highly strain specific. We further identified several conserved proteins recognized by lung Th17 cells during NTHi infection. Two proteins yielding the strongest responses were tested as vaccine candidates by immunization of mice with purified proteins plus an adjuvant. Immunization induced antigen-specific Th17 cells that recognized different strains and, upon adoptive transfer, conferred protection. Furthermore, immunized mice were protected against challenge with not only NTHi strains but also a fully virulent, encapsulated strain. Together, these results show that the immune mechanism of cross-protection against pneumonia involves Th17 cells, which respond to a broad spectrum of antigens, including those that are highly conserved among NTHi strains. These mechanistic insights suggest that inclusion of Th17 antigens in subunit vaccines offers the advantage of inducing broad protection and complements the current antibody-based approaches.
Performance of Osteoporosis Self-Assessment Tool (OST) in Predicting Osteoporosis—A Review

Bone health screening plays a vital role in the early diagnosis and treatment of osteoporosis to prevent fragility fractures among the elderly and high-risk individuals. Dual-energy X-ray absorptiometry (DXA), which detects bone mineral density, is the gold standard in diagnosing osteoporosis but is not suitable for screening. Therefore, many screening tools have been developed to identify individuals at risk for osteoporosis and prioritize them for DXA scanning. The Osteoporosis Self-assessment Tool (OST) is among the first tools established to predict osteoporosis in postmenopausal women. It can identify the population at risk for osteoporosis, but its performance varies according to ethnicity, gender, and age. Thus, these factors should be considered to ensure the optimal use of OST worldwide. Overall, OST is a simple and economical screening tool to predict osteoporosis and it can help to optimize the use of DXA.
Oscillation Criteria for Delay and Advanced Differential Equations with Nonmonotone Arguments

We study the oscillatory behavior of differential equations with nonmonotone deviating arguments and nonnegative coefficients. New oscillation criteria, involving and , are obtained based on an iterative method. Examples, numerically solved in MATLAB, are given to illustrate the applicability and strength of the obtained conditions over known ones.
Efficacy of omalizumab 150 mg/month as a maintenance dose in patients with severe chronic spontaneous urticaria showing a prompt and complete response to the drug

Christian Lupinek Valérie Siroux Rachel Nadif Jocelyne Just Jean Bousquet Rudolf Valenta Thomas A. Platts-Mills Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands The Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, Inserm, CNRS, Institute for Advanced Biosciences (IAB), U1209 Joint Research Center, University Grenoble Alpes, Grenoble, France INSERM U1168, VIMA: Aging and Chronic Diseases. Epidemiological and Public Health Approaches, Villejuif, France UMR-S 1168, Univ Versailles St-Quentin-en-Yvelines, Montigny le Bretonneux, France Assistance Publique-Hôpitaux de Paris, Allergology Department, Hôpital Armand-Trousseau, Paris, France Université Paris, Paris, France University Hospital, Montpellier, France Asthma and Allergic Diseases Center, University of Virginia Health System, Charlottesville, Virginia
Lung Deposition of the Dry Powder Fixed Combination Beclometasone Dipropionate Plus Formoterol Fumarate Using NEXThaler® Device in Healthy Subjects, Asthmatic Patients, and COPD Patients

Abstract Background: This study evaluated the lung deposition and the distribution pattern in the airways of a fixed combination of beclometasone dipropionate (BDP) and formoterol fumarate (FF) (100/6 μg) delivered as an extrafine dry powder formulation (mass median aerodynamic diameter, MMAD (μm) BDP = 1.5; FF = 1.4) through the NEXThaler® device in healthy subjects, asthmatics, and patients with COPD. Methods: Healthy subjects (n = 10), asthmatic patients (n = 9; 30%≤FEV1 < 80%), and COPD patients (n = 9; FEV1/FVC ≤70%, 30%≤FEV1 < 50%) completed this open-label, single administration (inhalation of four actuations) parallel group study. After inhalation of 99mTc-radiolabeled BDP/FF combination (radiolabeled BDP + unlabeled FF), the drug deposition was assessed using a gamma-scintigraphy technique. Patients' lung function was assessed. Results: No significant difference in drug deposition was observed between the three study groups. Mean lung deposition, extrathoracic deposition, and amount exhaled ranged, respectively, between 54.9% and 56.2%, between 41.8% and 43.2%, and between 1.6% and 3.3% of BDP emitted dose (71.7 ± 2.5 μg) for the three study groups. The central to peripheral ratio (reflecting the lung distribution pattern) ranged between 1.23 and 2.02 for the three study groups, indicating a distribution of the drug throughout the airways, including periphery. The study treatment produced a forced expiratory volume in one second (FEV1) increase over time, reaching a maximum improvement generally within 1–4 hours. Conclusions: The fixed extrafine dry powder combination BDP/FF (100/6 μg) administered through the DPI NEXThaler® achieved similar intrapulmonary deposition in healthy subjects, in asthmatic patients, and COPD patients (approximately 55% of emitted dose) irrespective of the underlying lung disease with a negligible amount of exhaled particles. The study showed high reliability of the device, reproducible dosing, and distribution throughout the lungs. The results supported the concept of efficient delivery of the combination to the target pulmonary regions, thanks to the extrafine formulation. FEV1 profile confirmed a relevant pharmacodynamic effect of the product.