Miracle-dz/UniFAR-FTUs huggingface dataset:
Dominance of the lurcher mutation in heteromeric kainate and AMPA receptor channels

Homomeric glutamate receptor (GluR) channels become spontaneously active when the last alanine residue within the invariant SYTANLAAF‐motif in the third membrane segment is substituted by threonine. The same mutation in the orphan GluRδ2 channel is responsible for neurodegeneration in ‘Lurcher’ (Lc) mice. Since most native GluRs are composed of different subunits, we investigated the effect of an Lc‐mutated subunit in heteromeric kainate and AMPA receptors expressed in HEK293 cells. Kainate receptor KA2 subunits, either wild type or carrying the Lc mutation (KA2Lc), are retained inside the cell but are surface‐expressed when assembled with GluR6 sununits. Importantly, KA2Lc dominates the gating of KA2Lc/GluR6WT channels, as revealed by spontaneous activation and by slowed desensitization and deactivation kinetics of ligand‐activated whole‐cell currents. Moreover, the AMPA receptor subunit GluR‐BLc(Q) which forms spontaneously active homomeric channels with rectifying current‐voltage relationships, dominates the gating of heteromeric GluR‐BLc(Q)/GluR‐A(R) channels. The spontaneous currents of these heteromeric AMPAR channels show linear current–voltage relationships, and the ligand‐activated whole‐cell currents display slower deactivation and desensitization kinetics than the respective wild‐type channels. For heteromeric Lc‐mutated kainate and AMPA receptors, the effects on kinetics were reduced relative to the homomeric Lc‐mutated forms. Thus, an Lc‐mutated subunit can potentially influence heteromeric channel function in vivo, and the severity of the phenotype will critically depend on the levels of homomeric GluRLc and heteromeric GluRLc/GluRWT channels.
Neonatal Appendicitis (Part 1): A Review of 52 cases with Abdominal Manifestation

Although no age is free from the risk of appendicitis, it is extremely uncommon in newborns. Credit of describing the first neonatal case is disputed between Diess (1908) [1] and Albrecht (1905). [2] Although Lillenthal reported a survivor of scrotal appendicitis in 1908, [2] 45 years elapsed before Meigher and Lucas [1] in 1952 documented the first survivor of abdominal disease. Another 35 years passed before proving as to what Sir Zachery Cope remarked as “No age” really extends into prenatal period. Martin Glen (1986) [3] and Narasimharao et al. (1987) [4] recorded antenatal appendicitis. A further 15 years went before hearing about the first successful laparoscopic appendicectomy in neonate by Efrati et al. [5] Intrigued by the tardy progress, Athena looked for a review article to dwell more on this subject. Although Karaman et.al [2] summarized 141 cases collected over a century (1901 2000), Athena is disappointed that the entity has largely remained anecdotal and almost all the published reports are individual case reports or at the best a small series. Therefore, she decided to critically analyze the published data to solve certain unanswered questions.
Gaining Control of Cellular Traffic Accounting by Spurious TCP Retransmission

Packet retransmission is a fundamental TCP mechanism that ensures reliable data transfer between two end nodes. Interestingly, when it comes to cellular data accounting, TCP retransmissions create an important policy issue giving rise to a tension between ISPs accounting for network resource consumption, and users only being aware of the application layer data. Regardless of the policies, we find that TCP retransmissions can be easily abused to manipulate the current practice of cellular
Análisis cinemático de las exigencias en futbolistas de categoría benjamín mediante un dispositivo inercial (WIMU PROTM)

espanolObjetivo: Los objetivos de este trabajo fueron examinar (i) las exigencias cinematicas en entrenamientos y partidos de competicion oficial, (ii) diferencias en dichas exigencias entre partidos y entrenamientos y (iii) diferencias entre puestos especificos en jugadores de futbol de categoria benjamin. Participantes: 11 jugadores benjamines participaron en esta investigacion (edad: 9.81 ± 0.62 anos; altura: 135.81 ± 5.81 cm y masa corporal: 35.16 ± 6.32 kg). Metodo: Se registraron ocho sesiones de entrenamiento y cuatro partidos de competicion oficial del campeonato Primera Benjamin de la temporada 2016-2017 organizado por la Federacion de Futbol de la Region de Murcia (FFRM). El registro de los datos de los sujetos participantes en la investigacion se realizo mediante un dispositivo inercial WIMU PROTM y el analisis de los datos se realizo con el software S PROTM (RealTrack Systems, Almeria, Espana). Resultados: Los principales datos obtenidos no establecieron diferencias significativas entre las variables analizadas durante los entrenamientos y partidos, excepto en las variables aceleraciones/minuto (p EnglishObjective: The aim of this study was to examine (i) the kinematical demands in training and official matches, (ii) differences between training and matches in kinematical load and (iii) differences between specific role positions in base football players. Participants. 11 players under-10 participated in this research (age: 9.81 ± 0.62 years, height: 135.81 ± 5.81 cm and body mass: 35.16 ± 6.32 kg). Method: Eight training sessions and four official matches of First U-10 championship 2016-2017 season organized by the Region of Murcia Football Federation (FFRM) were registered. The data of the footballers participating in the research were recorded using an inertial device called WIMU PROTM and the data analysis was performed using S PROTM software (RealTrack Systems, Almeria, Spain). Results: The main results obtained did not establish significant differences in the different variables analyzed between training and matches, except in accelerations/minute (p
Membrane anchoring of the autoantigen GAD65 to microvesicles in pancreatic beta-cells by palmitoylation in the NH2-terminal domain

Pancreatic beta-cells and gamma-aminobutyric acid (GABA)-secreting neurons both express the enzyme glutamic acid decarboxylase (GAD) which is a major target of autoantibodies associated with beta-cell destruction and impairment of GABA-ergic neurotransmitter pathways. The predominant form of GAD in pancreatic beta-cells, GAD65, is synthesized as a soluble hydrophilic molecule, which is modified to become firmly membrane anchored. Here we show by immunogold electron microscopy that GAD65 is localized to the membrane of small vesicles which are identical in size to small synaptic-like microvesicles in pancreatic beta-cells. The NH2-terminal domain of GAD65 is the site of a two-step modification, the last of which results in a firm membrane anchoring that involves posttranslational hydroxylamine sensitive palmitoylation. GAD65 can be released from the membrane by an apparent enzyme activity in islets, suggesting that the membrane anchoring step is reversible and potentially regulated. The hydrophobic modifications and consequent membrane anchoring of GAD65 to microvesicles that store its product GABA may be of functional importance and, moreover, significant for its selective role as an autoantigen.
Self-Stabilizing k-out-of-ℓ exclusion on tree networks

In this paper, we address the problem of k-out-of-ℓ exclusion, a generalization of the mutual exclusion problem, in which there are ℓ units of a shared resource, and any process can request up to k units (1 ≤ k ≤ ℓ). We propose the first deterministic self-stabilizing distributed k-out-of-ℓ exclusion protocol in message-passing systems for asynchronous oriented tree networks which assumes bounded local memory for each process.
Culture-Level Dimensions of Social Axioms and Their Correlates across 41 Cultures

Leung and colleagues have revealed a five-dimensional structure of social axioms across individuals from five cultural groups. The present research was designed to reveal the culture level factor structure of social axioms and its correlates across 41 nations. An ecological factor analysis on the 60 items of the Social Axioms Survey extracted two factors: Dynamic Externality correlates with value measures tapping collectivism, hierarchy, and conservatism and with national indices indicative of lower social development. Societal Cynicism is less strongly and broadly correlated with previous values measures or other national indices and seems to define a novel cultural syndrome. Its national correlates suggest that it taps the cognitive component of a cultural constellation labeled maleficence, a cultural syndrome associated with a general mistrust of social systems and other people. Discussion focused on the meaning of these national level factors of beliefs and on their relationships with individual level factors of belief derived from the same data set.
Integrated Computational Approach for Virtual Hit Identification against Ebola Viral Proteins VP35 and VP40

The Ebola virus (EBOV) has been recognised for nearly 40 years, with the most recent EBOV outbreak being in West Africa, where it created a humanitarian crisis. Mortalities reported up to 30 March 2016 totalled 11,307. However, up until now, EBOV drugs have been far from achieving regulatory (FDA) approval. It is therefore essential to identify parent compounds that have the potential to be developed into effective drugs. Studies on Ebola viral proteins have shown that some can elicit an immunological response in mice, and these are now considered essential components of a vaccine designed to protect against Ebola haemorrhagic fever. The current study focuses on chemoinformatic approaches to identify virtual hits against Ebola viral proteins (VP35 and VP40), including protein binding site prediction, drug-likeness, pharmacokinetic and pharmacodynamic properties, metabolic site prediction, and molecular docking. Retrospective validation was performed using a database of non-active compounds, and early enrichment of EBOV actives at different false positive rates was calculated. Homology modelling and subsequent superimposition of binding site residues on other strains of EBOV were carried out to check residual conformations, and hence to confirm the efficacy of potential compounds. As a mechanism for artefactual inhibition of proteins through non-specific compounds, virtual hits were assessed for their aggregator potential compared with previously reported aggregators. These systematic studies have indicated that a few compounds may be effective inhibitors of EBOV replication and therefore might have the potential to be developed as anti-EBOV drugs after subsequent testing and validation in experiments in vivo.
Methotrexate reduces HbA1c concentration but does not produce chronic accumulation of ZMP in patients with rheumatoid or psoriatic arthritis

Objectives: The mechanism by which methotrexate (MTX) improves glucose homeostasis in patients with rheumatoid (RA) and psoriatic arthritis (PsA) remains undetermined. Animal studies indicate a role for intracellular accumulation of 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranosyl 5ʹ-monophosphate (ZMP) but this has not been directly demonstrated in humans. We explored whether accumulation of ZMP is associated with improvements in glucose homeostasis during MTX therapy. Method: MTX-naïve, non-diabetic RA (n = 16) and PsA (n = 10) patients received uninterrupted MTX treatment for 6 months. To evaluate whether ZMP accumulated during MTX therapy, we measured the concentration of ZMP in erythrocytes and the concentration of its dephosphorylated derivative 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) in urine using liquid chromatography mass spectrometry (LC-MS/MS). To assess glucose homeostasis, we determined the concentration of glycated haemoglobin (HbA1c) and homeostasis model assessment of insulin resistance [HOMA-IR: fasting glucose (mmol/L) × fasting insulin (μU/mL)/22.5]. Results: Erythrocyte ZMP and urinary AICAR concentrations did not increase during 6 months of MTX therapy. HbA1c concentration was reduced from 5.80 ± 0.29% at baseline to 5.51 ± 0.32% at 6 months (p < 0.001), while HOMA-IR remained unaltered. Reduction in HbA1c concentration was not associated with increased ZMP or AICAR concentrations. Conclusions: MTX therapy probably does not produce a chronic increase in erythrocyte ZMP or urinary AICAR concentrations. Collectively, our data do not support the hypothesis that MTX improves glucose homeostasis through chronic accumulation of ZMP.
Clinical spectrum and prevalence of neurologic events provoked by tilt table testing.

BACKGROUND Motor activity occurring during neurocardiogenic syncope can mimic true neurologic events. OBJECTIVE To assess the prevalence and type of apparent neurologic events associated with tilt table testing. METHODS The records of consecutive patients undergoing tilt table testing for the evaluation of syncope were reviewed. Patients underwent a 70 degrees upright tilt for 40 minutes, followed by a 20-minute tilt while receiving isoproterenol hydrochloride. The results of tilt table tests were considered positive when clinical symptoms were reproduced in association with a decline in blood pressure. Clinical variables and neurologic events were analyzed. RESULTS Tilt table tests were performed on 694 patients during the study period, and the results were positive in 222 of them. Eighteen patients (8%) had apparent neurologic events during tilt table testing. Eleven patients (5%) had apparent tonic-clonic seizure-like activity, and 7 patients (3%) had non-tonic-clonic neurologic events, including focal seizures (n = 3), dysarthria or aphasia (n = 2), unilateral extremity dysesthesia (n = 1), and reproduction of temporal lobe epilepsy symptoms (n = 1). The patients with tonic-clonic seizure-like activity had a significantly lower systolic blood pressure reading at the termination of tilt table testing than all other patients whose tilt table test results were positive (P =.04). The heart rate at the time of test termination was significantly lower in the patients with tonic-clonic seizure-like activity and non-tonic-clonic neurologic events (P<.01) than in those with positive test results and no provoked neurologic events, and asystole was provoked more frequently in these 2 patient populations (P =.03). CONCLUSIONS Neurologic events are common during episodes of neurocardiogenic syncope, and this diagnosis should be considered in the evaluation of unexplained seizure-like activity.
Efavirenz in an Obese HIV-Infected Patient – a Report and An In Vitro–In Vivo Extrapolation Model Indicate Risk of Underdosing

Here, we report suboptimal efavirenz exposure in an obese patient treated with the standard 600 mg dose. Tripling the dose allowed attainment of therapeutic efavirenz concentrations. We developed an in vitro–in vivo extrapolation model to quantify dose requirements in obese individuals. Obesity represents a risk factor for antiretroviral therapy underdosing.
Empirical testing of forecast update procedure for seasonal products

Updating of forecasts is essential for successful collaborative forecasting, especially for seasonal products. This paper discusses the results of a theoretical simulation and an empirical test of a proposed time-series forecast updating procedure. It involves a two-stage longitudinal case study of a toy supply chain. The theoretical simulation involves historical weekly consumer demand data for 122 toy products. The empirical test is then carried out in real-time with 291 toy products. The results show that the proposed forecast updating procedure: 1) reduced forecast errors of the annual consumer demand, 2) determined timing for the commitment to subsequent replenishment during the selling seasons within acceptable forecast uncertainty, and 3) facilitated collaborative forecasting with more accurate forecast updates. However, during the empirical test, the forecast updating procedure provided less forecast accuracy improvement and it needed a longer time to achieve relatively acceptable forecast uncertainty.
Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV infection

Objective:To assess the safety and efficacy of two, single-tablet regimens for the initial treatment of HIV infection. Design:Phase 2, randomized, double-blind, double-dummy, multicenter, active-controlled study. Methods:Antiretroviral treatment-naive adults with a screening HIV-1 RNA at least 5000 copies/ml and a CD4 cell count more than 50 cells/μl were randomized 2: 1 to receive fixed-dose combination tablets of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF; N = 48) or efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF; n = 23) for 48 weeks. The primary endpoint was proportion of participants with HIV-1 RNA less than 50 copies/ml at week 24. Results:Participants receiving EVG/COBI/FTC/TDF exhibited a more rapid decline in HIV-1 RNA and a greater proportion suppressed viral load to less than 50 copies/ml than participants receiving EFV/FTC/TDF. Both EVG/COBI/FTC/TDF and EFV/FTC/TDF resulted in high rates of viral suppression and increases in CD4 cell count. Ninety and 83% of participants suppressed HIV-1 RNA to less than 50 copies/ml both at the 24-week and 48-week visits for EVG/COBI/FTC/TDF and EFV/FTC/TDF, respectively. Once-daily administration of EVG/COBI/FTC/TDF provided a mean EVG trough concentration 10-fold over its protein binding-adjusted IC95 across study visits. EVG/FTC/TDF/GS-9350 was generally well tolerated with a lower rate of drug-related central nervous system (17%) and psychiatric (10%) adverse events versus EFV/FTC/TDF (26 and 44%, respectively). Decreases in estimated glomerular filtration rate occurred within the first few weeks of dosing in participants receiving EVG/COBI/FTC/TDF, remained within the normal range and did not progress at week 24 or 48; no participant experienced a clinical adverse event or discontinued study drug due to changes in serum creatinine or renal function. Conclusion:Once-daily EVG/COBI/FTC/TDF achieved and maintained a high rate of virologic suppression with fewer central nervous system and psychiatric adverse events compared to a current standard-of-care regimen of EFV/FTC/TDF.
Increased serum TRAIL and DR5 levels correlated with lung function and inflammation in stable COPD patients

Background Chronic obstructive pulmonary disease (COPD) is associated with abnormal systemic inflammation, and apoptosis is one of the pathogenic mechanisms of COPD. Several studies have suggested that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors were not only involved in diseases associated with apoptosis but also in inflammatory diseases. However, limited data about the possible relationship between COPD and TRAIL/TRAIL-receptors are available. Objective To evaluate the potential relationship between TRAIL/TRAIL-receptors and COPD. Methods Serum levels of TRAIL, decoy receptor 5 (DR5), C-reactive protein, and tumor necrosis factor-α were analyzed using multiplex enzyme-linked immunosorbent assay kits. Then, serum levels of TRAIL and DR5 in 57 COPD patients with 35 healthy controls were compared and correlated with lung function and systemic inflammation. Results Mean levels of serum TRAIL and DR5 were significantly higher in COPD patients than those in controls (50.17±17.70 versus 42.09±15.49 pg/mL, P=0.029; 48.15±22.88 versus 38.94±10.95 pg/mL, P=0.032, respectively). Serum levels of TRAIL and DR5 correlated inversely with forced expiratory volume in 1 second % predicted, an index of lung function in COPD (r=-0.354, P=0.007 for TRAIL; r=−0.394, P=0.002 for DR5) in all participants (r=-0.291, P=0.005 for TRAIL; r=−0.315, P=0.002 for DR5), while DR5 correlated positively with C-reactive protein (r=0.240, P=0.021 for total subjects) and TRAIL correlated positively with tumor necrosis factor-α (r=0.371, P=0.005 for COPD; r=0.349, P=0.001 for total subjects). Conclusion Our results suggested that circulating TRAIL and DR5 increased in COPD patients and were associated with lung function and systemic inflammation in COPD. Future studies are needed to verify whether and how TRAIL and its receptors play roles in COPD.
Tweeting back: predicting new cases of back pain with mass social media data

BACKGROUND Back pain is a global health problem. Recent research has shown that risk factors that are proximal to the onset of back pain might be important targets for preventive interventions. Rapid communication through social media might be useful for delivering timely interventions that target proximal risk factors. Identifying individuals who are likely to discuss back pain on Twitter could provide useful information to guide online interventions. METHODS We used a case-crossover study design for a sample of 742 028 tweets about back pain to quantify the risks associated with a new tweet about back pain. RESULTS The odds of tweeting about back pain just after tweeting about selected physical, psychological, and general health factors were 1.83 (95% confidence interval [CI], 1.80-1.85), 1.85 (95% CI: 1.83-1.88), and 1.29 (95% CI, 1.27-1.30), respectively. CONCLUSION These findings give directions for future research that could use social media for innovative public health interventions.
Exercise stress echocardiography is superior to rest echocardiography in predicting left ventricular reverse remodelling and functional improvement after cardiac resynchronization therapy.

AIMS Cardiac resynchronization therapy (CRT) improves functional capacity and survival in heart failure. However, one-third of patients fail to respond to CRT. Resting left ventricular (LV) dyssynchrony assessed by echocardiography (ECHO) showed discordant results in identifying CRT responders. LV dyssynchrony can totally change during exercise. Aim of this study was to evaluate whether exercise dyssynchrony could select responders to CRT. METHODS AND RESULTS Sixty-four patients scheduled for CRT implantation performed bicycle exercise ECHO in semi-supine position on an exercise tilting table before and 6 months after CRT implantation. Tissue Doppler imaging (TDI) was acquired both at rest and during exercise to detect LV mechanical dyssynchrony. Predictive values for CRT response were 70% for rest TDI and 89% for exercise TDI (P = 0.01). Exercise LV dyssynchrony was the only parameter independently associated with follow-up improvement of rest ejection fraction and LV volume during multivariable analysis (P < 0.001). Functional improvement at 6-min walking test was statistically higher in patients with exercise dyssynchrony (P = 0.005), and not different considering rest dyssynchrony (P = 0.30). CONCLUSION Exercise intraventricular dyssynchrony assessed by exercise TDI ECHO is a strong independent predictor of CRT response. It could be used to select candidates for CRT, thus reducing ineffective implantations of biventricular pacemakers.