Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of Piecemeal Degranulation and Vesicular Transport of MBP-1 in Liver-Infiltrating Mouse Eosinophils During Acute Experimental Schistosoma mansoni Infection

Eosinophils have been long associated with helminthic infections, although their functions in these diseases remain unclear. During schistosomiasis caused by the trematode Schistosoma mansoni, eosinophils are specifically recruited and migrate to sites of granulomatous responses where they degranulate. However, little is known about the mechanisms of eosinophil secretion during this disease. Here, we investigated the degranulation patterns, including the cellular mechanisms of major basic protein-1 (MBP-1) release, from inflammatory eosinophils in a mouse model of S. mansoni infection (acute phase). Fragments of the liver, a major target organ of this disease, were processed for histologic analyses (whole slide imaging), conventional transmission electron microscopy (TEM), and immunonanogold EM using a pre-embedding approach for precise localization of major basic protein 1 (MBP-1), a typical cationic protein stored pre-synthesized in eosinophil secretory (specific) granules. A well-characterized granulomatous inflammatory response with a high number of infiltrating eosinophils surrounding S. mansoni eggs was observed in the livers of infected mice. Moreover, significant elevations in the levels of plasma Th2 cytokines (IL-4, IL-13, and IL-10) and serum enzymes (alanine aminotransferase and aspartate aminotransferase) reflecting altered liver function were detected in response to the infection. TEM quantitative analyses revealed that while 19.1% of eosinophils were intact, most of them showed distinct degranulation processes: cytolysis (13.0%), classical and/or compound exocytosis identified by granule fusions (1.5%), and mainly piecemeal degranulation (PMD) (66.4%), which is mediated by vesicular trafficking. Immunonanogold EM showed a consistent labeling for MBP-1 associated with secretory granules. Most MBP-1-positive granules had PMD features (79.0 ± 4.8%). MBP-1 was also present extracellularly and on vesicles distributed in the cytoplasm and attached to/surrounding the surface of emptying granules. Our data demonstrated that liver-infiltrating mouse eosinophils are able to degranulate through different secretory processes during acute experimental S. mansoni infections with PMD being the predominant mechanism of eosinophil secretion. This means that a selective secretion of MBP-1 is occurring. Moreover, our study demonstrates, for the first time, a vesicular trafficking of MBP-1 within mouse eosinophils elicited by a helminth infection. Vesicle-mediated secretion of MBP-1 may be relevant for the rapid release of small concentrations of MBP-1 under cell activation.
Why the Energy Landscape of Barnase Is Hierarchical

We have used NMR and computational methods to characterize the dynamics of the ribonuclease barnase over a wide range of timescales in free and inhibitor-bound states. Using temperature- and denaturant-dependent measurements of chemical shift, we show that barnase undergoes frequent and highly populated hinge bending. Using relaxation dispersion, we characterize a slower and less populated motion with a rate of 750 ± 200 s−1, involving residues around the lip of the active site, which occurs in both free and bound states and therefore suggests conformational selection. Normal mode calculations characterize correlated hinge bending motions on a very rapid timescale. These three measurements are combined with previous measurements and molecular dynamics calculations on barnase to characterize its dynamic landscape on timescales from picoseconds to milliseconds and length scales from 0.1 to 2.5 nm. We show that barnase has two different large-scale fluctuations: one on a timescale of 10−9−10−6 s that has no free energy barrier and is a hinge bending that is determined by the architecture of the protein; and one on a timescale of milliseconds (i.e., 750 s−1) that has a significant free energy barrier and starts from a partially hinge-bent conformation. These two motions can be described as hierarchical, in that the more highly populated faster motion provides a platform for the slower (less probable) motion. The implications are discussed. The use of temperature and denaturant is suggested as a simple and general way to characterize motions on the intermediate ns-μs timescale.
Dysfunctional Breathing in Children and Adults With Asthma

Asthma occurs across the life course. Its optimal treatment includes the use of personalized management plans that recognize the importance of co-morbidities including so-called “dysfunctional breathing. ” Such symptoms can arise as a result of induced laryngeal obstruction (ILO) or alterations in the mechanics of normal breathing called breathing pattern disorders. Whilst these two types of breathing abnormalities might be related, studies tend to focus on only one of them and do not consider their relationship. Evidence for these problems amongst childhood asthmatics is largely anecdotal. They seem rare in early childhood. Both types are more frequently recognized in the second decade of life and girls are affected more often. These observations tantalizingly parallel epidemiological studies characterizing the increasing prevalence and severity of asthma that also occurs amongst females after puberty. Exercise ILO is more common amongst adolescents and young adults. It should be properly delineated as it might be causally related to specific treatable factors. More severe ILO occurring at rest and breathing pattern disorders are more likely to be occurring within a psychological paradigm. Dysfunctional breathing is associated with asthma morbidity through a number of potential mechanisms. These include anxiety induced breathing pattern disorders and the enhanced perception of subsequent symptoms, cooling and drying of the airways from hyperventilation induced hyperresponsiveness and a direct effect of emotional stimuli on airways constriction via cholinergic pathways. Hyperventilation is the most common breathing pattern disorder amongst adults. Although not validated for use in asthma, the Nijmegen questionnaire has been used to characterize this problem. Studies show higher scores amongst women, those with poorly controlled asthma and those with psychiatric problems. Evidence that treatment with breathing retraining techniques is effective in a primary care population including all types of asthmatics suggests the problem might be more ubiquitous than just these high-risk groups. Future challenges include the need for studies characterizing all types of dysfunctional breathing in pediatric and adult patient cohorts and clearly defined, age appropriate, interventional studies. Clinicians caring for asthmatics in all age groups need to be aware of these co-morbidities and routinely ask about symptoms that suggest these problems.
Tracking Economic Value of Products in Natural Settings: A Wireless EEG Study

Economic decision making refers to the process of individuals translating their preference into subjective value (SV). Little is known about the dynamics of the neural processes that underpin this form of value-based decision making and no studies have investigated these processes outside of controlled laboratory settings. The current study investigated the spatio-temporal dynamics that accompany economic valuation of products using mobile electroencephalography (EEG) and eye tracking techniques. Participants viewed and rated images of household products in a gallery setting while EEG and eye tracking data were collected wirelessly. A Becker-DeGroot-Marschak (BDM) auction task was subsequently used to quantify the individual’s willingness to pay (WTP) for each product. WTP was used to classify products into low, low medium, high medium and high economic value conditions. Eye movement related potentials (EMRP) were examined, and independent component analysis (ICA) was used to separate sources of activity from grand averaged EEG data. Four independent components (ICs) of EMRPs were modulated by WTP (i.e., SV) in the latency range of 150–250 ms. Of the four value-sensitive ICs, one IC displayed enhanced amplitude for all value conditions excluding low value, and another IC presented enhanced amplitude for low value products only. The remaining two value-sensitive ICs resolved inter-mediate levels of SV. Our study quantified, for the first time, the neural processes involved in economic value based decisions in a natural setting. Results suggest that multiple spatio-temporal brain activation patterns mediate the attention and aversion of products which could reflect an early valuation system. The EMRP parietal P200 component could reflect an attention allocation mechanism that separates the lowest-value products (IC7) from products of all other value (IC4), suggesting that low-value items are categorized early on as being aversive. While none of the ICs showed linear amplitude changes that parallel SV’s of products, results suggest that a combination of multiple components may sub-serve a fine-grained resolution of the SV of products.
Alteration of Brain Structure With Long-Term Abstinence of Methamphetamine by Voxel-Based Morphometry

Background: A large portion of previous studies that have demonstrated brain gray matter reduction in individuals who use methamphetamine (MA) have focused on short-term abstinence, but few studies have focused on the effects of long-term abstinence of methamphetamine on brain structures. Materials and Methods: Our study includes 40 healthy controls and 44 abstinent methamphetamine-dependent (AMD) subjects who have abstained for at least 14 months. For every AMD subject, the age when they first used MA, the total time of MA use, the frequency of MA use in the last month before abstinence, the duration of abstinence and the craving score were recorded. Here we used magnetic resonance imaging (MRI) to measure the gray matter volume (GMV) of each subject with voxel-based morphometry method. Two-sample t-test (AlphaSim corrected) was performed to obtain brain regions with different gray matter volume (GMV) between groups. In addition, partial correlation coefficients adjusted for age, years of education, smoking, and drinking were calculated in the AMD group to assess associations between the mean GMV values in significant clusters and variables of MA use and abstinence. Results: Compared with the healthy control group, AMD group showed increased gray matter volumes in the bilateral cerebellum and decreased volumes in the right calcarine and right cuneus. Moreover, GMV of left cerebellum are positively correlated with the duration of abstinence in the AMD group (p = 0.040, r = 0.626). Conclusions: The present study showed that the gray matter volume in some brain regions is abnormal in the AMD subjects with long-term abstinence. Changes in gray matter volume of visual and cognitive function regions suggested that these areas play important roles in the progress of MA addiction and abstinence. In addition, positive correlation between GMV of the left cerebellum crus and duration of abstinence suggested that prolonged abstinence is beneficial to cognitive function recovery.
Increased BOLD Signals in dlPFC Is Associated With Stronger Self-Control in Food-Related Decision-Making

Self-control is the ability to comply with a request, to postpone acting upon a desire object or goal, and to generate socially approved behavior in the absence of external monitors. Overeating is actually the failure in self-control while feeding. However, little is known about the brain function that allows individuals to consciously control their behavior in the context of food choice. To address this issue, we used functional MRI to measure brain activity among undergraduate young females. Forty-one undergraduate female students participated in the current study. Subjects underwent the food rating task, during which they rated each food item according to their subjective perception of its taste (from Dislike it very much to Like it very much), its long term effect on health (from very unhealthy to very healthy) and decision strength to eat it (from Strong no to Strong yes). Behavioral results indicate the positive correlation between taste rating and its corresponding decision strength to eat, no matter the food is high caloric or low. Moreover, health ratings of high caloric food was negatively correlated with DEBQ-emotional eating, and taste ratings of high caloric food was positively correlated with DEBQ-external eating. Whole brain analysis of fMRI data indicates that BOLD responses in dlPFC were positively correlated with successful self-control; BOLD responses in midcingulate cortex were positively correlated with failed self-control. This study provided direct evidence that dlPFC was involved in self-control in food-related choice.
Haemodynamic definitions and updated clinical classification of pulmonary hypertension

Since the 1st World Symposium on Pulmonary Hypertension (WSPH) in 1973, pulmonary hypertension (PH) has been arbitrarily defined as mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest, measured by right heart catheterisation. Recent data from normal subjects has shown that normal mPAP was 14.0±3.3 mmHg. Two standard deviations above this mean value would suggest mPAP >20 mmHg as above the upper limit of normal (above the 97.5th percentile). This definition is no longer arbitrary, but based on a scientific approach. However, this abnormal elevation of mPAP is not sufficient to define pulmonary vascular disease as it can be due to an increase in cardiac output or pulmonary arterial wedge pressure. Thus, this 6th WSPH Task Force proposes to include pulmonary vascular resistance ≥3 Wood Units in the definition of all forms of pre-capillary PH associated with mPAP >20 mmHg. Prospective trials are required to determine whether this PH population might benefit from specific management. Regarding clinical classification, the main Task Force changes were the inclusion in group 1 of a subgroup “pulmonary arterial hypertension (PAH) long-term responders to calcium channel blockers”, due to the specific prognostic and management of these patients, and a subgroup “PAH with overt features of venous/capillaries (pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis) involvement”, due to evidence suggesting a continuum between arterial, capillary and vein involvement in PAH. State of the art and research perspectives of haemodynamic definitions and clinical classification of pulmonary hypertension http://ow.ly/TJeR30mgWKj
Chasse, habitats et rythme des déplacements : réflexions à partir des campements magdaléniens de Champréveyres et Monruz (Neuchâtel, Suisse)

Les stations magdaleniennes de Champreveyres et Monruz, situees surla rive nord du lac de Neuchâtel, ont ete occupees durant la belle saison,essentiellement au printemps et au debut de l’ete. Le spectre faunique diversifieest domine par le cheval, qui represente respectivement 70 et 90 % du poids animal acquis dans chacun des gisements. Le cheval etant caracterisepar une distance de fuite elevee, il ne peut etre chasse a proximiteimmediate d’un lieu d’habitat. Les chasses ont donc du etre menees a unedistance relativement grande des camps residentiels. Le mode de chassepratique etait vraisemblablement de type a l’affut au sol. Il semble que lescampements ont ete installes sur les lieux memes de l’abattage, puisque,d’une part, le poids eleve des chevaux interdit qu’ils aient ete transportesentiers et, d’autre part, la representation des elements squelettiques demontreque les carcasses entieres sont presentes sur les sites. Les autresactivites techniques et domestiques attestees dans les campements, de memeque la chasse au petit gibier, ont probablement ete menees au cours del’occupation du site. Apres un sejour d’une a plusieurs semaines, le campementetait deplace de quelques kilometres sur un autre lieu d’abattagede gros gibier. Le nombre de cycles de combustion enregistre dans lesfoyers, de meme que la composition des assemblages lithiques, corroborentce modele de circulation. La frequente reoccupation des deux sites (environsix a Champreveyres et une vingtaine a Monruz) s’explique sans doute pardes conditions strategiques locales favorables a la chasse au cheval.
Club Cell Secretory Protein Deficiency Leads to Altered Lung Function

Rationale: CC16 (club cell secretory protein‐16), a member of the secretoglobin family, is one of the most abundant proteins in normal airway secretions and has been described as a serum biomarker for obstructive lung diseases. Objectives: To determine whether low CC16 is a marker for airway pathology or is implicated in the pathophysiology of progressive airway damage in these conditions. Methods: Using human data from the birth cohort of the Tucson Children's Respiratory Study, we examined the relation of circulating CC16 levels with pulmonary function and responses to bronchial methacholine challenge from childhood up to age 32 years. In wild‐type and CC16−/− mice, we set out to comprehensively examine pulmonary physiology, inflammation, and remodeling in the naive airway. Measurements and Main Results: We observed that Tucson Children's Respiratory Study participants in the lowest tertile of serum CC16 had significant deficits in their lung function and enhanced airway hyperresponsiveness to methacholine challenge from 11 years throughout young adult life. Similarly, CC16−/− mice had significant deficits in lung function and enhanced airway hyperresponsiveness to methacholine as compared with wild‐type mice, which were independent of inflammation and mucin production. As compared with wild‐type mice, CC16−/− mice had significantly elevated gene expression of procollagen type I, procollagen type III, and &agr;‐smooth muscle actin, areas of pronounced collagen deposition and significantly enhanced smooth muscle thickness. Conclusions: Our findings support clinical observations by providing evidence that lack of CC16 in the lung results in dramatically altered pulmonary function and structural alterations consistent with enhanced remodeling.
A Native Human Monoclonal Antibody Targeting HCMV gB (AD-2 Site I)

Hyperimmune globulin (HIG) has shown efficacy against human cytomegalovirus (HCMV) for both transplant and congenital transmission indications. Replicating that activity with a monoclonal antibody (mAb) offers the potential for improved consistency in manufacturing, lower infusion volume, and improved pharmacokinetics, as well as reduced risk of off-target reactivity leading to toxicity. HCMV pathology is linked to its broad cell tropism. The glycoprotein B (gB) envelope protein is important for infections in all cell types. Within gB, the antigenic determinant (AD)-2 Site I is qualitatively more highly-conserved than any other region of the virus. TRL345, a high affinity (Kd = 50 pM) native human mAb to this site, has shown efficacy in neutralizing the infection of fibroblasts, endothelial and epithelial cells, as well as specialized placental cells including trophoblast progenitor cells. It has also been shown to block the infection of placental fragments grown ex vivo, and to reduce syncytial spread in fibroblasts in vitro. Manufacturing and toxicology preparation for filing an IND (investigational new drug) application with the US Food and Drug Administration (FDA) are expected to be completed in mid-2019.
Diversified sources for human infections by Salmonella enterica serovar newport

Salmonella enterica Newport (S. Newport), with phylogenetic diversity feature, contributes to significant public health concerns. Our previous study suggested that S. Newport from multiple animal-borne routes, with distinct antibiotic resistant pattern, might transmit to human. However, their genetic information was lacking. As a complement to the earlier finding, we investigate the relationship between each other among the hosts, sources, genotype and antibiotic resistance in S. Newport. We used the multilocus sequence typing (MLST) in conjunction with minimum inhibitory concentration of 16 antibiotics of globally sampled 1842 S. Newport strains, including 282 newly contributed Chinese strains, to evaluate this association. Our analysis reveals that sequence types (STs) are significantly associated with different host sources, including livestock (ST45), birds (ST5), contaminated water and soil (ST118), reptiles (ST46) and seafood (ST31). Importantly, ST45 contained most of (344/553) the multi-drug resistance (MDR) strains, which were believed to be responsible for human MDR bacterial infections. Chinese isolates were detected to form two unique lineages of avian (ST808 group) and freshwater animal (ST2364 group) origin. Taken together, genotyping information of S. Newport could serve to improve Salmonella source-originated diagnostics and guide better selection of antibiotic therapy against Salmonella infections.
Volitional Preemptive Abdominal Contraction and Upper Extremity Muscle Latencies During D1 Flexion and Scaption Shoulder Exercises.

CONTEXT The abdominal-bracing maneuver, a volitional preemptive abdominal contraction (VPAC) strategy, is commonly used during resisted shoulder exercises. How VPAC affects shoulder-muscle function during resisted shoulder exercise is unknown. OBJECTIVE To identify the effects of VPAC on selected parascapular and glenohumeral muscles during specific shoulder exercises with or without resistance. DESIGN Cross-sectional study. SETTING Clinical biomechanics research laboratory. PATIENTS OR OTHER PARTICIPANTS Twenty-two asymptomatic volunteers between 18 and 40 years of age. INTERVENTION(S) Participants performed arm elevation in scaption and D1 shoulder-flexion (D1F) patterns with and without resistance and VPAC. MAIN OUTCOME MEASURE(S) Electromyography was used to test the muscle-contraction amplitudes and onset timing of the anterior deltoid, posterior deltoid, upper trapezius, lower trapezius, and serratus anterior. Muscle-response amplitudes were quantified using root mean square electromyography. Shoulder-muscle relative-onset timing was quantified in reference to kinematic elbow-movement initiation. RESULTS The VPAC increased serratus anterior amplitude during D1F ( P < .001) and scaption ( P < .001) and upper trapezius amplitude ( P < .001) in scaption. All muscle amplitudes increased with resistance. The VPAC decreased muscle-onset latencies for the anterior deltoid ( P < .001), posterior deltoid ( P = .008), upper trapezius ( P = .001), lower trapezius ( P = .006), and serratus anterior ( P = .001) during D1F. In addition, the VPAC decreased muscle-onset latencies for the anterior deltoid ( P < .001), posterior deltoid ( P = .007), upper trapezius ( P < .001), lower trapezius ( P < .001), and serratus anterior ( P < .001) during scaption. CONCLUSIONS The VPAC affected only the parascapular muscles that had the greatest scapular-stabilizing roles during the specific open chain movement we tested. It decreased latencies in all muscles. These neuromuscular changes may enhance the stability of the shoulder during D1F and scaption exercises.