Miracle-dz/UniFAR-FTUs huggingface dataset:
The energetic consequences of loop 9 gating motions in acetylcholine receptor‐channels

Non technical summary Muscle cells have receptors that are activated by the neurotransmitter acetylcholine. The probability that these channels conduct ions across cell membranes increases dramatically when transmitter molecules are present at two binding sites, which are far from the region that regulates ionic conductance. In order to understand the molecular basis of receptor ‘gating’ we seek to learn how neurotransmitters and other small molecules activate this protein. We used single‐channel electrophysiology of receptors expressed in tissue‐cultured cells to study the effects of mutations at the C‐terminus of loop 9, a region near intra‐protein interfaces that are known to be important with regard to gating and assembly. We found that the mutation had modest but measurable effects on channel gating (mainly those in the epsilon subunit). We also found that mutations of loop 9 in the alpha subunit increase the kinetic heterogeneity of gating, which suggests that they alter the stability of the extracellular transmembrane domain interface.
Antagonism of the TRPv1 receptor partially corrects muscle metaboreflex overactivity in spontaneously hypertensive rats

Non‐technical summary The cardiovascular response to exercise is exaggerated in hypertension. This heightened circulatory responsiveness increases the risk of occurrence of an adverse cardiovascular event during and immediately following a bout of exercise. Accumulating evidence suggests the muscle metaboreflex, a chemically sensitive peripheral reflex originating in skeletal muscle, contributes significantly to this abnormal cardiovascular response to exercise. However, its role remains controversial. In addition, the receptor mechanisms underlying metaboreflex dysfunction in hypertension remain undetermined. To this end, the current investigation demonstrates that the metaboreflex is overactive in hypertensive rats eliciting exaggerated increases in sympathetic nerve activity and blood pressure. Importantly, the study shows, for the first time, that the metaboreflex dysfunction manifest in hypertension is mediated, in part, by activation of the skeletal muscle TRPv1 receptor. As such, the investigation identifies the muscle metaboreflex, specifically the TRPv1 receptor, as a potential target for the treatment of cardiovascular hyperexcitability during exercise in hypertension.
Analysis of multivariate repeated measures data with a Kronecker product structured covariance matrix

In this article we consider a set of t repeated measurements on p variables (or characteristics) on each of the n individuals. Thus, data on each individual is a p 2 t matrix. The n individuals themselves may be divided and randomly assigned to g groups. Analysis of these data using a MANOVA model, assuming that the data on an individual has a covariance matrix which is a Kronecker product of two positive definite matrices, is considered. The well-known Satterthwaite type approximation to the distribution of a quadratic form in normal variables is extended to the distribution of a multivariate quadratic form in multivariate normal variables. The multivariate tests using this approximation are developed for testing the usual hypotheses. Results are illustrated on a data set. A method for analysing unbalanced data is also discussed.
A novel method for spatially complex diffraction‐limited photoactivation and photobleaching in living cells

• For the contraction of a cardiac cell the liberation of calcium ions (Ca2+) from an intracellular Ca2+ storing compartment is required. • This release of Ca2+ ions occurs through groups (clusters) of Ca2+ release channels that can be activated by cellular signalling molecules such as Ca2+ itself or the messenger molecule inositol‐1,4,5‐trisphosphate (IP3). • Here we present a new technique that allows activation of individual release sites or groups of channels in a highly localized manner in living cells and the study of their structural and functional details with high precision.
Treatment of erythema migrans with doxycycline for 10 days versus 15 days.

BACKGROUND The efficacy of 10-day doxycycline treatment in patients with erythema migrans has been assessed in the United States but not in Europe. Experts disagree on the significance of post-Lyme borreliosis symptoms. METHODS In a noninferiority trial, the efficacies of 10 days and 15 days of oral doxycycline therapy were evaluated in adult European patients with erythema migrans. The prevalence of nonspecific symptoms was compared between patients with erythema migrans and 81 control subjects without a history of Lyme borreliosis. The efficacy of treatment, determined on the basis of clinical observations and microbiologic tests, was assessed at 14 days and at 2, 6, and 12 months. Nonspecific symptoms in patients and controls were compared at 6 months after enrollment. RESULTS A total of 117 patients (52%) were treated with doxycycline for 15 days, and 108 (48%) received doxycycline for 10 days. Twelve months after enrollment, 85 of 91 patients (93.4%) in the 15-day group and 79 of 86 (91.9%) in the 10-day group had complete response (difference, 1.6 percentage points; upper limit of the 95% confidence interval, 9.1 percentage points). At 6 months, the frequency of nonspecific symptoms in the patients was similar to that among controls. CONCLUSIONS The 10-day regimen of oral doxycycline was not inferior to the 15-day regimen among adult European patients with solitary erythema migrans. Six months after treatment, the frequency of nonspecific symptoms among erythema migrans patients was similar to that among control subjects. CLINICAL TRIALS REGISTRATION NCT00910715.
Megalin mediates transepithelial albumin clearance from the alveolar space of intact rabbit lungs

• Under physiological conditions the lung alveoli are impermeable to protein. • In patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) protein‐rich oedema fluid accumulates in the distal airspaces and leads to a life‐threatening impairment of alveolar gas exchange. • Albumin is a ligand of megalin, a member of the low‐density lipoprotein (LDL)‐receptor family. • We show that clearance of albumin from the distal air spaces is facilitated by active megalin‐mediated transport across the alveolar epithelium. • Understanding of protein clearance mechanisms in the lung may ultimately lead to novel therapeutic approaches for the treatment of ALI/ARDS.
Association between corticosteroids and infection, sepsis, and infectious death in pediatric acute myeloid leukemia (AML): results from the Canadian infections in AML research group.

BACKGROUND Infection continues to be a major problem for children with acute myeloid leukemia (AML). Objectives were to identify factors associated with infection, sepsis, and infectious deaths in children with newly diagnosed AML. METHODS We conducted a retrospective, population-based cohort study that included children ≤ 18 years of age with de novo, non-M3 AML diagnosed between January 1995 and December 2004, treated at 15 Canadian centers. Patients were monitored for infection from initiation of AML treatment until recovery from the last cycle of chemotherapy, conditioning for hematopoietic stem cell transplantation, relapse, persistent disease, or death (whichever occurred first). Consistent trained research associates abstracted all information from each site. RESULTS 341 patients were included. Median age was 7.1 years (interquartile range [IQR], 2.0-13.5) and 29 (8.5%) had Down syndrome. In sum, 26 (7.6%) experienced death as a first event. There were 1277 courses of chemotherapy administered in which sterile site microbiologically documented infection occurred in 313 courses (24.5%). Sepsis and infectious death occurred in 97 (7.6%) and 16 (1.3%) courses, respectively. The median days of corticosteroid administration was 2 per course (IQR, 0-6). In multiple regression analysis, duration of corticosteroid exposure was significantly associated with more microbiologically documented sterile site infection, bacteremia, fungal infection, and sepsis. The only factor significantly associated with infectious death was days of corticosteroid exposure (odds ratio, 1.05; 95% confidence interval, 1.02-1.08; P = .001). CONCLUSIONS In pediatric AML, infection, sepsis, and infectious death were associated with duration of corticosteroid exposure. Corticosteroids should be avoided when possible for this population.
Role of the Wnt‐Frizzled system in cardiac pathophysiology: a rapidly developing, poorly understood area with enormous potential

Abstract The Wnt‐Frizzled (Fzd) G‐protein‐coupled receptor system, involving 19 distinct Wnt ligands and 10 Fzd receptors, plays key roles in the development and functioning of many organ systems. There is increasing evidence that Wnt‐Fzd signalling is important in regulating cardiac function. Wnt‐Fzd signalling primarily involves a canonical pathway, with dishevelled‐1‐dependent nuclear translocation of β‐catenin that derepresses Wnt‐sensitive gene transcription, but can also include non‐canonical pathways via phospholipase‐C/Ca2+ mobilization and dishevelled‐protein activation of small GTPases. Wnt‐Fzd effects vary with specific ligand/receptor interactions and associated downstream pathways. This paper reviews the biochemistry and physiology of the Wnt‐Fzd complex, and presents current knowledge of Wnt signalling in cardiac remodelling processes such as hypertrophy and fibrosis, as well as disease states such as myocardial infarction (MI), heart failure and arrhythmias. Wnt signalling is activated during hypertrophy; inhibiting Wnt signalling by activating glycogen synthase kinase attenuates the hypertrophic response. Wnt signalling has complex and time‐dependent actions post‐MI, so that either beneficial or harmful effects might result from Wnt‐directed interventions. Stem cell biology, a promising area for therapeutic intervention, is highly regulated by Wnt signalling. The Wnt system regulates fibroblast function, and is prominently altered in arrhythmogenic ventricular cardiomyopathy, a familial disease involving excess deposition of fibroadipose tissue. Wnt signalling controls connexin43 expression, thereby contributing to the regulation of cardiac electrical stability and arrhythmia generation. Although much has been learned about Wnt‐Fzd signalling in hypertrophy and infarction, its role is poorly understood for a broad range of other heart disorders. Much more needs to be learned for its contributions to be fully appreciated, and to permit more effective exploitation of its enormous potential in therapeutic development.
Stroke-induced immunodepression: consequences, mechanisms and therapeutic implications

The clinical picture of stroke is not only characterized by neurological deficits but also by the high incidence of infectious complications, in particular pneumonia. The occurrence of pneumonia in stroke patients is associated with higher mortality, larger neurological deficits, longer hospitalization and increased costs for medical care. Immobilization and impaired protective reflexes are known to increase the risk of aspiration pneumonia. However, recent experimental and clinical evidence indicates that stroke-induced immunodepression is an independent risk factor that increases susceptibility to infections. This review provides an update on the mechanisms and consequences of stroke-induced immunodepression. The growing insight into these mechanisms may allow new immunomodulatory treatment approaches in stroke patients in the future. In the meantime, several trials on preventive antibacterial treatment to reduce the incidence of post-stroke infections have been conducted, which will be summarized in th.
β‐Adrenergic stimulation increases the intra‐sarcoplasmic reticulum Ca2+ threshold for Ca2+ wave generation

• In the heart, Ca2+ waves are arrhythmogenic spontaneous sarcoplasmic reticulum (SR) Ca2+ release events that arise when the Ca2+ content in the SR reaches a critical threshold level. • β‐Adrenergic signalling induces Ca2+ waves in cardiac myocytes, but it remains unclear if this is due to a decrease in the Ca2+ wave threshold or more simply due to an increase in SR Ca2+ content. • We used direct, dynamic measurement of SR Ca2+ levels to show that the Ca2+ wave threshold is unexpectedly increased during β‐adrenergic stimulation. • Our data show that the primary cause of Ca2+ waves following acute β‐adrenergic stimulation is the increase in SR Ca2+ content and not a decrease in the Ca2+ wave threshold. • We propose that the elevation of the Ca2+ wave threshold represents a protective mechanism against arrhythmogenic events during periods of β‐adrenergic stimulation.
Usability analysis for redesign of a Caribbean academic library web site: a case study

Purpose – This paper seeks to present a usability evaluation of the web site of the Main Library of the St Augustine Campus of the University of the West Indies (UWI) to get users and site visitors to identify the major strengths and weaknesses of the site and to incorporate the results and participant feedback into a redesign that reflects users' intuitions rather than those of the site developers and librarians.Design/methodology/approach – A combination of experimental and respondent research strategies was used to evaluate usability. These included survey questionnaires, focus groups, formal usability testing and card sort. In addition, both usability heuristics and ISO guidelines were used to assess effectiveness, learnability, usefulness and user satisfaction. Respondent strategies used a sample size of 529 participants for the self‐completion questionnaires and 16 participants in the focus group sessions. Experimental strategies combined observation of 21 individual participants and three groups of.
Piperine Congeners as Inhibitors of Vascular Smooth Muscle Cell Proliferation

Abstract Successful vascular healing after percutaneous coronary interventions is related to the inhibition of abnormal vascular smooth muscle cell proliferation and efficient re-endothelialization. In the search for vascular smooth muscle cell anti-proliferative agents from natural sources we identified piperine (1), the main pungent constituent of the fruits from Piper nigrum (black pepper). Piperine inhibited vascular smooth muscle cell proliferation with an IC50 of 21.6 µM, as quantified by a resazurin conversion assay. Investigations of ten piperamides isolated from black pepper fruits and 15 synthesized piperine derivatives resulted in the identification of three potent vascular smooth muscle cell proliferation inhibitors: the natural alkaloid pipertipine (4), and the two synthetic derivatives (2E,4E)-N,N-dibutyl-5-(3,5-dimethoxyphenyl)penta-2,4-dienamide (14) and (E)-N,N-dibutyl-3-(naphtho[2,3-d][1,3]dioxol-5-yl)acrylamide (20). They showed IC50 values of 3.38, 6.00, and 7.85 µM, respectively. Furthermore, the synthetic compound (2E,4E)-5-(4-fluorophenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one (12) was found to be cell type selective, by inhibiting vascular smooth muscle cell proliferation with an IC50 of 11.8 µM without influencing the growth of human endothelial cells.
Imperialine and Verticinone from Bulbs of Fritillaria wabuensis Inhibit Pro-inflammatory Mediators in LPS-stimulated RAW 264.7 Macrophages

Abstract The bulbs of plants belonging to the Fritillaria cirrhosa-group have been used as antitussive and expectorant herbs in traditional Chinese medicine for thousands of years. In this study, we isolated two isomers of verticinone and imperialine, steroidal alkaloids belonging to the cevanine group, from bulbs of Fritillaria wabuensis, which is a part of the Fritillaria cirrhosa group, and investigated their anti-inflammatory effects and relative mechanisms on lipopolysaccharide-stimulated RAW 264.7 macrophages. Our results clearly demonstrate that verticinone or imperialine could dose-dependently inhibit nitric oxide production and also suppress inducible nitric oxide synthase and cyclooxygenase-2 expressions. In addition, verticinone or imperialine suppress the production of pro-inflammatory cytokines in a dose dependent manner, such as tumor necrosis factor-α and interleukin-1β. The effect of verticinone and imperialine on the activation of nuclear factor-kappaB was also evaluated. The phosphorylation of nuclear factor-kappaB stimulated with LPS is also down-regulated by verticinone or imperialine in a concentration dependent manner, which coincided with the inhibition of phosphorylation forms of inhibitory kappaB-α, a crucial inhibitory factor of nuclear factor-kappaB. Generally, the anti-inflammatory effects and mechanisms of verticinone and imperialine are mediated by the inhibition of the nuclear factor-kappaB activation signaling pathway. According to the results of our researches, verticinone and imperialine may present great potentials to be developed as therapeutics for inflammatory diseases.
Sprint interval and endurance training are equally effective in increasing muscle microvascular density and eNOS content in sedentary males

Optimal vascular function is critical for health, and endurance training (ET) has previously been shown to be an effective method of improving this. Sprint interval training (SIT) has been proposed as a time efficient alternative to ET but its effect on skeletal muscle microvasculature has not been studied and no direct comparison with ET has been made. ET and SIT in this study were equally effective at decreasing arterial stiffness and increasing skeletal muscle capillarisation and eNOS content. The main results suggest that both training modes improve skeletal muscle microvascular and macrovascular function, with SIT being a time efficient alternative.
Chloride currents in cones modify feedback from horizontal cells to cones in goldfish retina

• The GABAergic pathway modulates feedback between retinal horizontal cells (HCs) and cone photoreceptors, but is not mediating negative feedback, as previously hypothesized. • Opening of GABA‐gated chloride channels in cone photoreceptors reduces the amplitude of feedback responses generated by HCs. • Activation of a different presynaptic chloride current, the calcium‐dependent chloride current, in individual cones has a similar effect on feedback as application of GABA. • Modulation of the strength of feedback from HCs seems to be a general consequence of activation of presynaptic chloride currents in cones. • This puts the functional role of these currents in a new perspective; GABA acts as a slow and global neuromodulator enhancing feedback in the light‐ and attenuating feedback in the dark‐adapted retina, whereas the calcium‐dependent chloride current modulates feedback fast and locally to tune the size of feedback to local light conditions.
Assessing the reliability and validity of a urinary incontinence scale after radical prostatectomy

Urinary incontinence (UI) is a major complication after a radical prostatectomy and this problem can last for over a year after surgery. There is a need for valid research instruments to assess the extent of this problem. The purpose of this study was to assess the reliability and validity of a urinary incontinence scale after radical prostatectomy (UISRP). Psychometric testing of the UISRP using a sample of 124 patients who had been diagnosed with prostate cancer and undergone radical prostatectomy was conducted to determine the quality of items, internal consistency reliability, test–retest reliability, construct validity and criterion-related validity. The final sample consisted of 102 patients (92·7%) in the data analysis. The results indicated that one factor was identified that accounted for 60·28% of the explained variance. The Cronbach's alpha coefficient was 0·90. Two-week test–retest reliability (ICC = 0·56; 95% CI = 0·26–0·72) was provided. Criterion-related validity was supported by correlation with the University of California, Los Angeles Prostate Cancer Index urinary function subscale (r = 0·74, p < 0·001) and a criterion variable measuring a 1-h pad test (r = 0·58, p < 0·001. The UISRP displays satisfactory reliability and validity for radical prostatectomy patients. The UISRP is a valuable research measure and can identify priority areas for nursing interventions designed to improve prostatectomy patients' outcomes.
Does epithelial sodium channel hyperactivity contribute to cystic fibrosis lung disease?

• Lung hydration and mucus clearance rates are set by a balance between CFTR‐mediated Cl− secretion and ENaC‐led Na+ absorption. In CF airways, CFTR is diminished, and ENaC is upregulated, leading to mucus dehydration and increased chance of infection. • Evidence for ENaC upregulation in CF airways includes electrophysiological evidence, increased ASL absorption rates, increased cleavage of CF ENaC and increased basolateral Na+/K+ ATPase activity in CF airways. • The mechanism of Na+ hyperabsorption in CF airways is unknown and it may be due to altered protein‐protein interactions and/or increased proteolysis of ENaC in CF airways. However, inhibition of ENaC is predicted to increase CF mucus hydration/clearance and thus, ENaC remains an important therapeutic target for the treatment of CF lung disease.
Improving the performance of Web access by bridging global ranking with local page popularity metrics

Considers the problem of improving the performance of Web access by proposing a reconstruction of the internal link structure of a Web site in order to match the quality of the pages (measured in terms of their link importance in the Web space – global ranking) with the popularity of the pages (measured in terms of their importance recognized by Web users – local metrics). Provides a set of simple algorithms for local reorganization of a Web site, which results in improving users’ access to quality pages in an easy and quick way.
Commercial Internet adoption in China: comparing the experience of small, medium and large businesses

Earlier research studies predicted that it would be small and medium‐sized businesses that were more likely to adopt and benefit from the use of the Internet because of their greater flexibility. Anecdotal evidence appears in the literature to support this claim; however, little systematic empirical research has been done among SMEs to test this speculation. A sample of 248 companies in Shanghai, China, was divided into small, medium and large groups. The statistical analysis indicates that there are significant differences between large and small companies. Large companies have benefited considerably more from the Internet than small companies not only in their increased sales (derived from the Internet) but also from cost savings. Although the whole sample confirms the main reason for establishing an Internet connection, to gain a competitive advantage, companies also think that the Internet does not work equally for all players.
An empirical study of the uptake of performance measurement by Internet retailers

Purpose – The purpose of this paper is twofold: to identify levels of uptake of performance measurement by small and medium‐sized retail companies selling goods online, and to determine key factors, which could explain any variation in use of performance indicators. The study is designed to explore these issues by this type of retailer as currently understanding is fairly limited.Design/methodology/approach – A quantitative mail questionnaire was used to survey UK retailers selling goods online. The questionnaire examined the uptake of performance measurement in conjunction with the business profile of each of the 252 responding companies.Findings – The results show great variation in levels and extent of uptake of performance measurement by online retailers in the UK. Company profile variables: size and operating format help to account for the variation in the number of indicators measured.Research limitations/implications – The sample frame has some limitations insofar as the study only focused on small.