Miracle-dz/UniFAR-FTUs huggingface dataset:
Evidence for a differential interaction of brivaracetam and levetiracetam with the synaptic vesicle 2A protein

Brivaracetam (BRV) and levetiracetam (LEV) are effective antiepileptic drugs that bind selectively to the synaptic vesicle 2A (SV2A) protein. However, BRV differs from LEV in that it exhibits more potent and complete seizure suppression in animal models including in amygdala‐kindled mice, where BRV afforded nearly complete seizure suppression. This raises the possibility that aside from potency differences, BRV and LEV may interact differently with the SV2A protein, which is not apparent in radioligand‐binding competition studies. In this study, we used a recently identified SV2A allosteric modulator, UCB1244283, that appears to induce conformational changes in SV2A, to probe the binding properties of labeled BRV and LEV.
Link utility and traffic aware energy saving in software defined networks

Software Defined Networking (SDN) is an emerging network paradigm that gains increasing attention both from academia and industry. Energy saving aspects of network protocols, being studied for different network technologies, have also recently been addressed in SDN. In this paper, we address the traffic and energy aware routing problem in SDN and propose link utility based heuristic algorithms, namely NSP and NMU, that are not only general in their applicability but also balance the trade-off between energy saving and performance. We propose an IP formulation for traffic and energy aware routing problem based on link utility information, and evaluate the algorithms using real traces of low, medium and high traffic volumes and network topologies. NSP and NMU are shown to outperform the existing solutions in terms of average path length and achieve up to 37% energy saving.
Analysis of Substrate Specificity of the RuvC Holliday Junction Resolvase with Synthetic Holliday Junctions*

The Escherichia coli RuvC protein endonucleolytically resolves Holliday junctions, which are formed as intermediates during genetic recombination and recombination repair. Previous studies using model Holliday junctions suggested that a certain size of central core of homology and a specific sequence in the junction were required for efficient cleavage by RuvC, although not for binding. To determine the minimum length of sequence homology required for RuvC cleavage, we made a series of synthetic Holliday junctions with various lengths of homologous sequence in the core region. It was demonstrated that a monomobile junction possessing only 2 base pairs of the homology core was efficiently cleaved by RuvC. To study the sequence specificity for cleavage, we made 16 bimobile junctions, which differed only in the homologous core sequence. Among them, 6 junctions were efficiently cleaved. Cleavage occurred by introduction of nicks symmetrically at the 3′-side of thymine in all cases. However, the nucleotide bases at the 3′-side of the thymines were not always identical between the two strands nicked. These results suggest that RuvC recognizes mainly topological symmetry of the Holliday junction but not the sequence symmetry per se, that the thymine residue at the cleavage site plays an important role for RuvC-mediated resolution, and that a long homologous core sequence is not essential for cleavage.
Impairment of Human Ether-à-Go-Go-related Gene (HERG) K+ Channel Function by Hypoglycemia and Hyperglycemia

Hyperglycemia and hypoglycemia both can cause prolongation of the Q-T interval and ventricular arrhythmias. Here we studied modulation of human ether-à-go-go-related gene (HERG) K+ channel, the major molecular component of delayed rectifier K+current responsible for cardiac repolarization, by glucose in HEK293 cells using whole-cell patch clamp techniques. We found that both hyperglycemia (extracellular glucose concentration [Glu] o = 10 or 20 mm) and hypoglycemia ([Glu] o = 2.5, 1, or 0 mm) impaired HERG function by reducing HERG current (IHERG) density, as compared with normoglycemia ([Glu] o = 5 mm). Complete inhibition of glucose metabolism (glycolysis and oxidative phosphorylation) by 2-deoxy-d-glucose mimicked the effects of hypoglycemia, but inhibition of glycolysis or oxidative phosphorylation alone did not cause IHERG depression. Depletion of intracellular ATP mimicked the effects of hypoglycemia, and replacement of ATP by GTP or non-hydrolysable ATP failed to prevent the effects. Inhibition of oxidative phosphorylation by NaCN or application of antioxidants vitamin E or superoxide dismutase mimetic (Mn(III) tetrakis(4-benzoic acid) porphyrin chloride) abrogated and incubation with xanthine/xanthine oxidase mimicked the effects of hyperglycemia. Hyperglycemia or xanthine/xanthine oxidase markedly increased intracellular levels of reactive oxygen species, as measured by 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate (CM-H2DCFDA) fluorescence dye, and this increase was prevented by NaCN, vitamin E, or Mn(III) tetrakis(4-benzoic acid) porphyrin chloride. We conclude that ATP, derived from either glycolysis or oxidative phosphorylation, is critical for normal HERG function; depression of IHERG in hypoglycemia results from underproduction of ATP and in hyperglycemia from overproduction of reactive oxygen species. Impairment of HERG function might contribute to Q-T prolongation caused by hypoglycemia and hyperglycemia.
Computer mouse position as a determinant of posture, muscular load and perceived exertion.

OBJECTIVES This study concerned the influence of 6 positions of the computer mouse on the work table on posture, muscular load, and perceived exertion during text editing. METHODS An optoelectronic 3-dimensional motion analysis system was used to register the postures of 10 men and 10 women using video display units. Muscular load was also registered (with electromyography), as was perceived exertion (with rating scales). RESULTS A neutral posture with a relaxed and supported arm showed the least perceived exertion, and the electromyographic results showed low activity in both trapezius muscles in this position. Short operators (all women) showed a numerically higher activity in the 4 examined muscles than the tall operators (all men, except 1). This finding could be related to lower muscle force among women and to anthropometric differences, which also influence biomechanic load moments. Narrow-shouldered operators (8 women and 1 man) and short operators worked with larger outward rotation and abduction of the shoulder in a position of the mouse lateral to the keyboard than the broad-shouldered (7 men and 2 women) and tall operators did. Arm support markedly reduced muscle load in the neck-shoulder region among the operators. CONCLUSIONS The operators using video display units in this study preferred to use the mouse on a table in a close to relaxed, neutral posture of the arm in combination with arm support. Short and narrow-shouldered operators worked in more strenuous postures of the arm when the mouse was located lateral to the keyboard.
Identification of a Specific Region in the E1 Fusion Protein Involved in Zinc Inhibition of Semliki Forest Virus Fusion

ABSTRACT The enveloped alphaviruses infect cells via a low-pH-triggered membrane fusion reaction mediated by the viral transmembrane protein E1. During fusion, E1 inserts into the target membrane and refolds to a hairpin-like postfusion conformation in which domain III (DIII) and the juxtamembrane stem pack against a central core trimer. Although zinc has previously been shown to cause a striking block in alphavirus fusion with liposome target membranes, the mechanism of zinc's effect on the E1 fusion protein is not understood. Here we developed a cell culture system to study zinc inhibition of fusion and infection of the alphavirus Semliki Forest virus (SFV). Inclusion of 2 mM ZnCl2 in the pH 5.75 fusion buffer caused a decrease of ∼5 logs in SFV fusion at the plasma membrane. Fusion was also inhibited by nickel, a chemically related transition metal. Selection for SFV zinc resistance identified a key histidine residue, H333 on E1 DIII, while other conserved E1 histidine residues were not involved. An H333N mutation conferred resistance to both zinc and nickel, with properties in keeping with the known pH-dependent chelation of these metals by histidine. Biochemical studies demonstrated that zinc strongly inhibits formation of the postfusion E1 trimer in wild-type SFV but not in an H333 mutant. Together our results suggest that zinc acts by blocking the fold-back of DIII via its interaction with H333.
The mediating effect of ambidextrous knowledge strategy between social capital and innovation of cultural tourism clusters firms

Purpose This paper aims to analyze the extent to which social capital (SC) spurs innovation in firms located within tourism clusters. Specifically, the study focuses on the mediating role of ambidextrous knowledge strategy (AKS) on the relationship between SC and innovation. Design/methodology/approach A structural model is used on a sample of 215 firms of the hospitality and tourism industry located in World Heritage Cities of Spain. Data analysis is carried out using partial least squares. Findings The combination of bonding and bridging capital yields higher innovation performance through AKS. Research limitations/implications This analysis does not take into account the full set of confounding factors that influence innovation. The factors captured by this study significantly explain heterogeneity in the intensity of innovation among the studied firms. Practical Implications The main recommendation is that firms located in cultural tourism clusters (CTCs) do not restrict the focus on either local or outside relations only but pursue a strategy based on the combination of internal and external relations. This will enable ambidextrous knowledge strategies and better innovation performance. Originality/value There are numerous studies on the relation between some dimensions of SC, some knowledge strategies and some types of innovation. The value added of the present study is the articulation of complementarities among these dimensions. In particular, this study integrates bonding and bridging dimensions of SC, exploration and exploitation of knowledge and incremental and radical innovation. In addition, the paper provides an empirical identification of World Heritage Cities of Spain as CTCs.
Occurrence of the Asn45Ser mutation in the GPIX gene in a Belgian patient with Bernard Soulier syndrome

Bernard Soulier Syndrome (BSS) is a rare inherited bleeding disorder caused by a defect in the glycoprotein (GP)Ib/IX/V complex. A patient with a bleeding problem was diagnosed as having BSS based on the prolonged bleeding time, the absence of ristocetin induced platelet aggregations, thrombocytopenia and the presence of giant platelets. Analysis of the platelets of the propositus, a 39-year-old Belgian female, by flow cytometry revealed a decreased expression of the GPIb/IX polypeptides. Western blotting confirmed these results and showed moreover that there was a decreased disulfide bridge formation between GPIb f and GPIb g . After sequence analysis of the GPIb f , GPIb g and GPIX genes, only a mutation in the GPIX gene at position 1826 (A M G) was identified, changing Asn45 M Ser. Restriction analysis with Fnu 4H1 demonstrated that the patient was homozygous for this mutation. As this Asn45 M Ser mutation in the GPIX gene was already found in four unrelated families, i.e. in a British, Austrian, Swedish and Finnish one, the occurrence of this mutation in a Belgian patient supports the hypothesis of Koskela et al . (1999) that the Asn45Ser mutation in GPIX appears to be an ancient mutation shared by northern and central European populations. Our present observation of a decreased disulfide bridge formation between GPIb f and GPIb g shows that GPIX is not only needed for the correct assembly of the complex but might also be needed for the disulfide bridge formation between GPIb f and GPIb g .
Population pharmacokinetics of tacrolimus and CYP3A5, MDR1 and IL‐10 polymorphisms in adult liver transplant patients

Background and objective: Tacrolimus, an immunosuppressant widely used after liver transplantation, is characterized by a large inter‐individual variability in its pharmacokinetics. The aim of this study was to perform population pharmacokinetic analysis of oral tacrolimus in liver transplant recipients and clarify the potential role of CYP3A5, MDR1 and IL‐10 genetic polymorphisms in the variability of population pharmacokinetic parameters.
Patient Pain in Primary Care: Factors That Influence Physician Diagnosis

BACKGROUND The accurate recognition of patient pain is a crucial, but sometimes difficult, task in medical care. This study explored factors related to the physician’s diagnosis of pain in primary care patients. METHODS New adult patients were prospectively randomized to care by primary care providers at a university medical center clinic. Study participants were interviewed prior to the initial visit, and their level of self-reported pain was measured with the Visual Analog Pain Scale and the Medical Outcomes Study Short Form-36. The medical encounter was videotaped in its entirety and later analyzed using the Davis Observation Code to characterize physician practice style. Patient satisfaction was measured immediately after the visit. A review of the medical record was used to assess physician recognition of patient pain. RESULTS For all patients (N = 509), as the amount of pain increased, the percentage of patients having pain diagnosed by the physician also increased. Female patients reported a greater amount of pain than male patients. When women were in severe pain, they were more likely than men to have their pain accurately recognized by their physician. The correct diagnosis of pain was not significantly related to patient satisfaction. Physician practice styles emphasizing technically oriented activities and health behavior discussions were strongly predictive of the physician diagnosing patient pain. CONCLUSIONS The diagnosis of pain is influenced by the severity of patient pain, patient gender, and physician practice style. If the routine use of pain assessment tools is found to be effective in improving physician recognition and treatment of patients’ pain, then application of these tools in patient care settings should be encouraged.
Technique‐associated outcomes in horses following large colon resection

OBJECTIVE To compare survival and complications in horses undergoing large colon resection with either sutured end-to-end or stapled functional end-to-end anastomoses. STUDY DESIGN Retrospective cohort study. ANIMALS Twenty-six client-owned horses with gastrointestinal disease. METHODS Retrospective data were retrieved from the medical records of 26 horses undergoing colectomy, including 14 horses with sutured end-to-end and 12 horses with stapled functional end-to-end anastomoses, between 2003 and 2016. Records were evaluated for signalment, medical and surgical treatments, and survival to hospital discharge. Long-term follow-up was obtained through owner contact. Continuous variables were compared with Mann-Whitney tests. Fisher's exact testing was used to compare survival to hospital discharge. Survival time was compared by constructing Kaplan-Meier survival curves and performing log-rank curve comparison testing. RESULTS Mean age of horses undergoing colectomy was 13 years. Reason for colectomy was prophylaxis (12) or salvage (14). Mean surgical time was 169 minutes. Mean hospitalization time was 9 days, which did not differ with anastomosis type (P = .62). Nine of 12 horses undergoing stapled functional end-to-end anastomosis and 12 of 14 horses undergoing sutured end-to-end anastomosis survived to hospital discharge (P = .63). Survival time did not differ with anastomosis technique (P = .35). CONCLUSION Short- and long-term survival outcomes are not different between sutured end-to-end or stapled functional end-to-end anastomoses in horses undergoing colectomy.
The Intradermal Anatomy of the Inframammary Fold

&NA; The anatomy of the inframammary fold has been a subject of controversy. This report describes the anatomic location and the histologic structure of the inframammary fold on the basis of caderveric dissections and microscopic examination. Ten breast cadaver dissections were performed on female cadavers (ages 35 to 72). Twenty specimens after en bloc resections of the inframammary fold and subcutaneous tissue, including the pectoralis muscle, were harvested. Specimens were examined for gross collagen structure by using India ink to highlight the collagenous aspects of the subcutaneous soft‐tissue networks. The inframammary fold skin and dermis from the contralateral breast and control samples of skin and dermis from the upper chest and the abdomen were collected for microscopic studies. These samples were stained with Sirius red and examined microscopically by polarized light. On histologic examination, regular arrays of collagen were found running parallel with the inframammary fold, and the control sections showed random patterns of collagen deposition. On gross examination, a condensation of the superficial fascial system was observed. This formed a zone of adherence between the skin and the underlying pectoralis fascia. The conclusion of this study is that the inframammary fold is an intrinsic dermal structure consisting of regular arrays of collagen held in place by a zone of adherence that is a specialized area of the superficial fascial system. The clinical significance of this study is that the intradermal structure of the inframammary fold should be preserved in any breast procedure for natural aesthetic results. (Plast. Reconstr. Surg. 102: 1030, 1998.)
Specific cesium transport via the Escherichia coli Kup (TrkD) K+ uptake system

Escherichia coli cells which contain a functional Kup (formerly TrkD) system took up Cs+ with a moderate rate and affinity. Kup is a separate K+ uptake system with relatively little discrimination in the transport of the cations K+, Rb+, and Cs+. Regardless of the presence or absence of Kup, K+-replete cells took up Cs+ primarily by a very low affinity mode, proportional to the ratio of the Cs+ and K+ concentrations in the medium.
Radiotherapy beyond cancer: target localization in real-time MRI and treatment planning for cardiac radiosurgery.

PURPOSE Atrial fibrillation (AFib) is the most common cardiac arrhythmia that affects millions of patients world-wide. AFib is usually treated with minimally invasive, time consuming catheter ablation techniques. While recently noninvasive radiosurgery to the pulmonary vein antrum (PVA) in the left atrium has been proposed for AFib treatment, precise target location during treatment is challenging due to complex respiratory and cardiac motion. A MRI linear accelerator (MRI-Linac) could solve the problems of motion tracking and compensation using real-time image guidance. In this study, the authors quantified target motion ranges on cardiac magnetic resonance imaging (MRI) and analyzed the dosimetric benefits of margin reduction assuming real-time motion compensation was applied. METHODS For the imaging study, six human subjects underwent real-time cardiac MRI under free breathing. The target motion was analyzed retrospectively using a template matching algorithm. The planning study was conducted on a CT of an AFib patient with a centrally located esophagus undergoing catheter ablation, representing an ideal case for cardiac radiosurgery. The target definition was similar to the ablation lesions at the PVA created during catheter treatment. Safety margins of 0 mm (perfect tracking) to 8 mm (untracked respiratory motion) were added to the target, defining the planning target volume (PTV). For each margin, a 30 Gy single fraction IMRT plan was generated. Additionally, the influence of 1 and 3 T magnetic fields on the treatment beam delivery was simulated using Monte Carlo calculations to determine the dosimetric impact of MRI guidance for two different Linac positions. RESULTS Real-time cardiac MRI showed mean respiratory target motion of 10.2 mm (superior-inferior), 2.4 mm (anterior-posterior), and 2 mm (left-right). The planning study showed that increasing safety margins to encompass untracked respiratory motion leads to overlapping structures even in the ideal scenario, compromising either normal tissue dose constraints or PTV coverage. The magnetic field caused a slight increase in the PTV dose with the in-line MRI-Linac configuration. CONCLUSIONS The authors' results indicate that real-time tracking and motion compensation are mandatory for cardiac radiosurgery and MRI-guidance is feasible, opening the possibility of treating cardiac arrhythmia patients completely noninvasively.
Effect of lead on erythrocytic antioxidant defence, lipid peroxide level and thiol groups in calves.

Fifteen crossbred male calves were exposed to lead for a period of 28 days orally at the dose rate of 7.5 mg of lead acetate as 0.75 per cent solution kg(-1)body weight to study its effect on erythrocytic antioxidant defense, lipid peroxide level and thiol groups. Five calves were given no treatment and served as unexposed controls. Blood samples were collected before exposure to lead and thereafter at weekly intervals (ie. on day 7, 14, 21 and 28). Erythrocyte haemolysate (10 per cent) was prepared and analysed for lipid peroxide level, activity of Superoxide dismutase (SOD) and catalase. Total, protein-bound and non protein-bound thiol groups were also measured. Exposure to lead significantly (P < 0.05) reduced the erythrocytic SOD activity by day 7 and it remained lower until day 21 followed by a marginal increase on day 28. Catalase activity declined after an initial compensatory rise on day 7. Erythrocytic lipid peroxide level was recorded to be significantly (P < 0.05) higher by day 21 and 28 of exposure. Total, protein-bound and non protein-bound -SH content of erythrocytes declined. It was concluded that oral exposure of lead reduced the erythrocytic thiol content and antioxidant defence indicating possible role of free radicals in pathogenesis of lead toxicity.
Whole Body Deletion of AMP-activated Protein Kinase β2 Reduces Muscle AMPK Activity and Exercise Capacity*

AMP-activated protein kinase (AMPK) β subunits (β1 and β2) provide scaffolds for binding α and γ subunits and contain a carbohydrate-binding module important for regulating enzyme activity. We generated C57Bl/6 mice with germline deletion of AMPK β2 (β2 KO) and examined AMPK expression and activity, exercise capacity, metabolic control during muscle contractions, aminoimidazole carboxamide ribonucleotide (AICAR) sensitivity, and susceptibility to obesity-induced insulin resistance. We find that β2 KO mice are viable and breed normally. β2 KO mice had a reduction in skeletal muscle AMPK α1 and α2 expression despite up-regulation of the β1 isoform. Heart AMPK α2 expression was also reduced but this did not affect resting AMPK α1 or α2 activities. AMPK α1 and α2 activities were not changed in liver, fat, or hypothalamus. AICAR-stimulated glucose uptake but not fatty acid oxidation was impaired in β2 KO mice. During treadmill running β2 KO mice had reduced maximal and endurance exercise capacity, which was associated with lower muscle and heart AMPK activity and reduced levels of muscle and liver glycogen. Reductions in exercise capacity of β2 KO mice were not due to lower muscle mitochondrial content or defects in contraction-stimulated glucose uptake or fatty acid oxidation. When challenged with a high-fat diet β2 KO mice gained more weight and were more susceptible to the development of hyperinsulinemia and glucose intolerance. In summary these data show that deletion of AMPK β2 reduces AMPK activity in skeletal muscle resulting in impaired exercise capacity and the worsening of diet-induced obesity and glucose intolerance.