Miracle-dz/UniFAR-FTUs huggingface dataset:
(–)‐Epicatechin enhances fatigue resistance and oxidative capacity in mouse muscle

Non‐technical summary During exercise, skeletal muscle performance depends in great part on the use of aerobic metabolism to supply the energetic demand of contractions. Endurance training increases the muscle aerobic capacity, which is not only associated with enhanced exercise performance, but also with a decreased risk of cardiovascular and metabolic diseases. Recently, it has been shown that regular use of small doses of dark chocolate may result in similar health benefits to exercise training. We show here that mice fed for 15 days with (–)‐epicatechin (present in dark chocolate) had improved exercise performance accompanied by: (1) an increased number of capillaries in the hindlimb muscle; and (2) an increased amount of muscle mitochondria as well as signalling for mitochondrial biogenesis. These results suggest that (–)‐epicatechin increases the capacity for muscle aerobic metabolism, thereby delaying the onset of fatigue. These findings may have potential application for clinical populations experiencing muscle fatigue.
Two‐pore domain K+ channels regulate membrane potential of isolated human articular chondrocytes

Non‐Technical Summary The debilitating condition of arthritis is caused by degeneration of the cartilage, a tissue that allows almost frictionless motion between the ends of bones in articulating joints such as the knee. The integrity of the cartilage is maintained by the metabolic activity of chondrocytes, the only type of cell found within the cartilage. An important factor in regulating the rate of metabolic activity of the chondrocytes is thought to be the magnitude of the electrical potential difference across the cell membrane, i.e. the ‘membrane potential’. This study identifies a type of ion channel, a so‐called ‘two‐pore potassium channel’, which was not previously known to be expressed in human chondrocytes. This ion channel importantly contributes to controlling chondrocyte membrane potential. Elucidation of the factors that control chondrocyte membrane potential is important for understanding the normal and pathophysiology of the chondrocytes, and consequently the health of the cartilage.
The role of in vivo Ca2+ signals acting on Ca2+–calmodulin‐dependent proteins for skeletal muscle plasticity

Abstract Skeletal muscle fibres are highly heterogeneous regarding size, metabolism and contractile function. They also show a large capacity for adaptations in response to alterations in the activation pattern. A major part of this activity‐dependent plasticity relies on transcriptional alterations controlled by intracellular Ca2+ signals. In this review we discuss how intracellular Ca2+ fluctuations induced by activation patterns likely to occur in vivo control muscle properties via effects on Ca2+–calmodulin‐dependent proteins. We focus on two such Ca2+ decoders: calcineurin and Ca2+–calmodulin‐dependent protein kinase II. Inherent Ca2+ transients during contractions differ rather little between slow‐ and fast‐twitch muscle fibres and this difference is unlikely to have any significant impact on the activity of Ca2+ decoders. The major exception to this is fatigue‐induced changes in Ca2+ transients that occur in fast‐twitch fibres exposed to high‐intensity activation typical of slow‐twitch motor units. In conclusion, the cascade from neural stimulation pattern to Ca2+‐dependent transcription is likely to be central in maintaining the fibre phenotypes in both fast‐ and slow‐twitch fibres. Moreover, changes in Ca2+ signalling (e.g. induced by endurance training) can result in altered muscle properties (e.g. increased mitochondrial biogenesis) and this plasticity involves other signalling pathways.
Pseudomonas aeruginosa biofilms in the respiratory tract of cystic fibrosis patients

The present study was undertaken to investigate the appearance and location of Pseudomonas aeruginosa in the cystic fibrosis (CF) lung and in sputum. Samples include preserved tissues of CF patients who died due to chronic P. aeruginosa lung infection prior to the advent of intensive antibiotic therapy, explanted lungs from 3 intensively treated chronically P. aeruginosa infected CF patients and routine sputum from 77 chronically P. aeruginosa infected CF patients. All samples were investigated microscopically using hematoxylin–eosin (HE), Gram and alcian‐blue stain, PNA FISH and immunofluorescence for alginate.
Chest wall dynamics during voluntary and induced cough in healthy volunteers

Non‐technical summary Cough is the commonest symptom for which people seek medical advice and has significant impact upon quality of life. Moreover ineffective coughing is associated with significant morbidity and mortality. A better understanding of cough mechanics is important for dealing with the complications of both excessive and impaired cough. This study investigates how the mechanical changes during coughing are influenced by the amount of air inhaled prior to coughing (operating volume), examining chest and abdominal motion, pressures and flow. We have shown that operating volume is the most important determinant of the flow achieved and volume expelled during single voluntary coughs and peals of voluntary coughs. Coughs within a peal appear to have a different motor pattern, producing similar pressures and flows but more rapidly than single coughs and therefore may be more efficient. Future studies investigating cough mechanics should control for the influence of operating volume.
Mechanism of auxiliary β‐subunit‐mediated membrane targeting of L‐type (CaV1.2) channels

Non‐technical summary Voltage‐dependent L‐type calcium (CaV1.2) channels are critical gateways for Ca2+ entry into excitable cells such as heart myocytes and neurons. This Ca2+ signal controls many essential physiological responses including triggering the heartbeat and regulating gene expression in nerve cells. CaV1.2 channels are multi‐subunit proteins, comprising α1C, β, and α2δ subunits, and must target to the cell surface to function. Association of a pore‐forming α1C and cytosolic β is necessary for targeting CaV1.2 channels to the cell surface through poorly understood mechanisms. Here, using a chimeric channel strategy, we provide data that suggest β binding to the α1C intracellular I–II loop causes a global rearrangement of intracellular domains, shifting a balance of power between export signals on the I–II loop and retention signals elsewhere on the channel. The results provide novel insights into the mechanism of a protein–protein interaction that is vital for forming functional CaV1.2 channels.
SAP97 directs NMDA receptor spine targeting and synaptic plasticity

Abstract SAP97 is a multidomain scaffold protein implicated in the forward trafficking and synaptic localization of NMDA‐ and AMPA‐type glutamate receptors. Alternative splicing of SAP97 transcripts gives rise to palmitoylated αSAP97 and L27‐domain containing βSAP97 isoforms that differentially regulate the subsynaptic localization of GluR1 subunits of AMPA receptors. Here, we examined whether SAP97 isoforms regulate the mechanisms underlying long‐term potentiation (LTP) and depression (LTD) and find that both α‐ and β‐forms of SAP97 impair LTP but enhance LTD via independent isoform‐specific mechanisms. Live imaging of α‐ and βSAP97 revealed that the altered synaptic plasticity was not due to activity‐dependent changes in SAP97 localization or exchange kinetics. However, by recording from pairs of synaptically coupled hippocampal neurons, we show that αSAP97 occludes LTP by enhancing the levels of postsynaptic AMPA receptors, while βSAP97 blocks LTP by reducing the synaptic localization of NMDA receptors. Examination of the surface pools of AMPA and NMDA receptors indicates that αSAP97 selectively regulates the synaptic pool of AMPA receptors, whereas βSAP97 regulates the extrasynaptic pools of both AMPA and NMDA receptors. Knockdown of βSAP97 increases the synaptic localization of both AMPA and NMDA receptors, showing that endogenous βSAP97 restricts glutamate receptor expression at excitatory synapses. This isoform‐dependent differential regulation of synaptic versus extrasynaptic pools of glutamate receptors will determine how many receptors are available for the induction and the expression of synaptic plasticity. Our data support a model wherein SAP97 isoforms can regulate the ability of synapses to undergo plasticity by controlling the surface distribution of AMPA and NMDA receptors.
Sexual dimorphism and oestrogen regulation of KCNE3 expression modulates the functional properties of KCNQ1 K+ channels

Non‐Technical Summary High levels of oestrogen are known to cause fluid retention in fertile females. It is thought that the increase in body fluid volume is necessary for proper implantation of the fertilised egg in the uterus. We show that the activity of a potassium ion channel, which drives salt and water movement across the cell membranes of the intestine, is inhibited by oestrogen and this effect is only found in females and is maximal during the peak phase of oestrogen in the oestrous cycle (when fertilization and implantation occur). These findings help us to understand the molecular mechanisms underlying the fluid retention effects of oestrogen in health and the potential adverse effects this response may have in exacerbating disease where fluid secretion is compromised such as in cystic fibrosis (the so‐called CF ‘gender gap’).
Losartan abolishes oxidative stress induced by intermittent hypoxia in humans

Non‐Technical Summary Intermittent hypoxia is known to increase oxidative stress and decrease nitric oxide metabolism. These two responses, which are involved in hypoxia‐induced hypertension, may be mediated by angiotensin II. Using a novel human experimental model, we show that blockade of the type 1 angiotensin II receptors by a medication called losartan prevented the increase in oxidative stress and the decrease in nitric oxide metabolism induced by 6 h of intermittent hypoxia. These results show that the upregulation of angiotensin II contributes to the overproduction of free radicals associated with intermittent hypoxia and help us better understand why blood pressure increases in medical disorders associated with intermittent hypoxia, such as obstructive sleep apnoea.
Oxidative stress and enhanced sympathetic vasoconstriction in contracting muscles of nitrate‐tolerant rats and humans

Non‐technical summary Activation of sympathetic nerves decreases blood flow to resting skeletal muscle, but this vasoconstrictor effect normally is blunted during exercise so that blood flow can increase to the working muscles. In rats and humans treated with nitroglycerin for 1 week, we show that overproduction of reactive oxygen species prevents the usual attenuation of sympathetic vasoconstriction in the working muscles, resulting in muscle ischaemia during exercise. Improved knowledge about the effect that reactive oxygen species has on muscle blood flow regulation may help us to better understand the decreased exercise tolerance that occurs with age as well as with chronic disease.
Lung function testing in preschool‐aged children with cystic fibrosis in the clinical setting

In cystic fibrosis (CF) lung function testing is a means of monitoring progression of lung disease. The preschool years have often been referred to as the “silent years” due to the previous lack suitable measures of lung function testing in this age group. This review outlines the various techniques of lung function testing in preschool children with CF in the clinical setting. This includes measures requiring tidal breathing including the forced oscillation technique, the interrupter technique, plethysmography, and multiple breath washout, as well as spirometry that requires respiratory maneuvers. We describe the feasibility and variability of different lung function methods used in preschoolers and report measurements made during tidal breathing have greater feasibility, although greater variability compared to spirometry. We also report associations with lung function and markers of CF lung disease. In the preschool age group measurements made during tidal breathing may be more appropriate in the clinic setting than those that require a higher degree of cooperation and specific respiratory maneuvers.maneuvers. Pediatr Pulmonol. 2010; 45:419–433. © 2010 Wiley‐Liss, Inc.
Peroxisome proliferator-activated receptors (PPARs) in dermatology

Since their discovery it has become clear that peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors involved in the genetic regulation of the lipid metabolism and energy homoeostasis. Subsequently, accumulating evidence suggests a role of PPARs in genomic pathways including the regulation of cell growth, apoptosis and differentiation. These findings indicate that PPARs and PPAR agonists play an important role in inflammatory responses and tumor promotion. Because of their diverse biologic activities on keratinocytes and other skin cells, PPARs represent a major research target for the understanding and treatment of many skin pathologies, such as hyperproliferative and inflammatory diseases. Overmore recent clinical trials identified PPARs as promising drug targets for the prevention and treatment of various diseases in the field of dermatology. The present review summerizes the current knowledge of PPAR functions in various skin disorders particularly those involving inflammation and epidermal hyperproliferation (a.e. psoriasis, atopic dermatitis, acne, scleroderma, skin malignancies).
Nitric oxide synthase inhibition prevents activity‐induced calcineurin–NFATc1 signalling and fast‐to‐slow skeletal muscle fibre type conversions

• Exercise is known to trigger skeletal muscle structural and functional adaptations. • Control of these adaptive alterations is a complex process involving multiple signalling pathways and levels of regulation. • The well‐characterized calcineurin–nuclear factor of activated T‐cells (NFATc1) signalling pathway is involved in the regulation of activity‐dependent alterations in skeletal muscle myosin heavy chain expression. Myosin heavy chain is a contractile protein that largely dictates a muscle's speed of contraction. • We show that a signalling molecule called nitric oxide may be regulating alterations in myosin heavy chain expression via activity‐modulated calcineurin–NFATc1 signalling. • These findings increase our understanding of how skeletal muscle adaptive alterations are regulated.
Understanding Consumer Intention with Respect to Purchase and Use of Pirated Software

Purpose – The purpose of this paper is to study factors that influence consumers' intention to purchase and use of pirated software.Design/methodology/approach – This study tests the impact of five factors (procedural fairness, reciprocal fairness, distributive fairness, subjective norm, and attitude) on intention towards software piracy by 289 consumers' in Malaysia. Survey questions from prior studies were adopted and customized, and the model was analyzed using partial least squares and structural equation modeling tool (Smart‐PLS 2.0 M3). Findings – The results indicated that a significant and positive relationship exists between reciprocal fairness, procedural fairness, subjective norm, attitude, and consumers' intention towards software piracy.Research limitations/implications – This study was restricted to consumers within one country (Malaysia). Additional studies across other countries are encouraged. This research can help businesses better improve the ways to reduce software piracy rates. They g.
Rapid diagnostic test-based management of malaria: an effectiveness study in Papua New Guinean infants with Plasmodium falciparum and Plasmodium vivax malaria.

BACKGROUND In malaria-endemic areas it is recommended that febrile children be tested for malaria by rapid diagnostic test (RDT) or blood slide (BS) and receive effective malaria treatment only if results are positive. However, RDTs are known to perform less well for Plasmodium vivax. We evaluated the safety of withholding antimalarial drugs from young Papua New Guinean children with negative RDT results in areas with high levels of both Plasmodium falciparum and P. vivax infections. METHODS Longitudinal prospective study of children aged 3-27 months visiting outpatient clinics for fever. RDT was administered at first visit. RDT and microscopy were performed if children returned because of persistent symptoms. Outcomes were rates of reattendance and occurrence of severe illnesses. RESULTS Of 5670 febrile episodes, 3942 (70%) involved a negative RDT result. In 133 cases (3.4%), the children reattended the clinic within 7 days for fever, of whom 29 (0.7%) were parasitemic by RDT or microscopy. Of children who reattended, 24 (0.7%) presented with a severe illness: 2 had lower respiratory tract infections (LRTIs) with low-density P. vivax on BS; 2 received a diagnosis of P. vivax malaria on the basis of RDT but BSs were negative; 16 had LRTIs; 3 had alternative diagnoses. Of these 24, 22 were cured at day 28. Two children died of illnesses other than malaria and were RDT and BS negative at the initial and subsequent visits. CONCLUSION Treatment for malaria based on RDT results is safe and feasible even in infants living in areas with moderate to high endemicity for both P. falciparum and P. vivax infections.
Sellar Reconstruction and Rates of Delayed Cerebrospinal Fluid Leak after Endoscopic Pituitary Surgery

Abstract Objectives Delayed cerebrospinal fluid (CSF) leaks are a complication in transsphenoidal surgery, potentially causing morbidity and longer hospital stays. Sella reconstruction can limit this complication, but is it necessary in all patients? Design Retrospective review. Setting Single-surgeon team (2005–2012) addresses this trend toward graded reconstruction. Participants A total of 264 consecutive patients with pituitary adenomas underwent endoscopic transsphenoidal resections. Sellar defects sizable to accommodate a fat graft were reconstructed. Main outcomes Delayed CSF leak and autograft harvesting. Results Overall, 235 (89%) had reconstruction with autograft (abdominal fat, septal bone/cartilage) and biological glue. Delayed CSF leak was 1.9%: 1.7%, and 3.4% for reconstructed and nonreconstructed sellar defects, respectively (p = 0.44). Complications included one reoperation for leak, two developed meningitis, and autograft harvesting resulted in abdominal hematoma in 0.9% and wound infection in 0.4%. Conclusion In our patients, delayed CSF leaks likely resulted from missed intraoperative CSF leaks or postoperative changes. Universal sellar reconstruction can preemptively treat missed leaks and provide a barrier for postoperative changes. When delayed CSF leaks occurred, sellar reconstruction often allowed for conservative treatment (i.e., lumbar drain) without repeat surgery. We found universal reconstruction provides a low risk of delayed CSF leak with minimal complications.
Doença renal crônica: importância do diagnóstico precoce, encaminhamento imediato e abordagem interdisciplinar estruturada para melhora do desfecho em pacientes ainda não submetidos à diálise

At present, chronic kidney disease (CKD) is broadly defined on the basis of changes in the glomerular filtration rate and/or the presence of parenchymal damage present for at least 3 months. Although the diagnosis of CKD is now quite straightforward, the proportion of patients with end-stage renal disease seen by a nephrologist for the first time immediately before the initiation of dialysis is still unacceptable. Early diagnosis and immediate nephrology referral are key steps in management because enable predialysis education, allow implementation of preventive measures that delay or even halt progression of CKD to end stage renal disease, as well as decrease initial morbidity and mortality. In this review, we discuss the complexity of CKD and the multiplicity of interventions currently recommended in its secondary prevention, different models of healthcare delivery, and examine the rational and outcomes of patients followed in interdisciplinary care clinics.
Vitamin D3 decreases parathyroid hormone in HIV-infected youth being treated with tenofovir: a randomized, placebo-controlled trial.

BACKGROUND The study goal was to determine the effect of vitamin D (VITD) supplementation on tubular reabsorption of phosphate (TRP), parathyroid hormone (PTH), bone alkaline phosphatase (BAP), and C-telopeptide (CTX) in youth infected with human immunodeficiency virus (HIV) receiving and not receiving combination antiretroviral therapy (cART) containing tenofovir disoproxil fumarate (TDF). METHODS This randomized, double-blind, placebo-controlled multicenter trial enrolled HIV-infected youth 18-25 years based on stable treatment with cART containing TDF (n = 118) or no TDF (noTDF; n = 85), and randomized within those groups to vitamin D3, 50 000 IU (n = 102) or placebo (n = 101), administered at 0, 4, and 8 weeks. Outcomes included change in TRP, PTH, BAP, and CTX from baseline to week 12 by TDF/noTDF; and VITD/placebo. RESULTS At baseline, VITD and placebo groups were similar except those on TDF had lower TRP and higher PTH and CTX. At week 12, 95% in the VITD group had sufficient serum 25-hydroxy vitamin D (25-OHD; ≥20 ng/mL), increased from 48% at baseline, without change in placebo (P < .001). PTH decreased in the TDF group receiving VITD (P = .031) but not in the noTDF group receiving VITD, or either placebo group. The decrease in PTH with VITD in those on TDF occurred with insufficient and sufficient baseline 25-OHD (mean PTH change, -7.9 and -6.2 pg/mL; P = .031 and .053, respectively). CONCLUSIONS In youth on TDF, vitamin D3 supplementation decreased PTH, regardless of baseline 25-OHD concentration. CLINICAL TRIALS REGISTRATION NCT00490412.
Rod, M‐cone and M/S‐cone inputs to hyperpolarizing bipolar cells in the mouse retina

Non‐technical summary ON and OFF pathways are major information processing channels of the visual system, and they begin at the retinal bipolar cell level. Here we show a systematic study correlating light response characteristics and cell morphology of OFF (hyperpolarizing) bipolar cells (HBCs) in the mouse retina. Results from this study provide a description of how rods, M‐cones and M/S‐cones mediate responses in three major types of HBCs, and how synapses in the OFF pathway are interconnected to serve various visual tasks.
Cardiac output and sympathetic vasoconstrictor responses during upright tilt to presyncope in healthy humans

Key points • Syncope is a common clinical condition occurring even in healthy people without manifest cardiovascular disease; we determined the role of cardiac output and sympathetic vasoconstriction in neurally mediated (pre)syncope. • Our data showed that a moderate fall in cardiac output with coincident vasodilatation occurred in the majority (64%) of the presyncopal subjects, while a marked fall in cardiac output, driven predominantly by a decrease in heart rate, with no changes in total peripheral resistance at presyncope, occurred in a smaller (36%) subset. • Sympathetic withdrawal occurred late, after the onset of hypotension. • Sympathetic vasoconstriction and baroreflex sensitivity during symptom‐free upright posture were well preserved and, thus, an intrinsic impairment of sympathetic neural control and vasomotor responsiveness was not the cause of neurally mediated (pre)syncope in this population. • These results help us better understand the mechanisms for syncope in humans.
Clinical use of dornase alfa is associated with a slower rate of FEV1 decline in cystic fibrosis

Randomized controlled trials of dornase alfa have shown forced expiratory volume in 1 sec (FEV1) to improve in patients with cystic fibrosis (CF) but have not assessed change in the rate of lung function decline. We assessed the relationship of dornase alfa use and FEV1 decline using the Epidemiologic Study of Cystic Fibrosis (ESCF).