Miracle-dz/UniFAR-FTUs huggingface dataset:
Ethinyl oestradiol administration in women suppresses synthesis of collagen in tendon in response to exercise

Women are at greater risk than men of sustaining certain kinds of injury and diseases of collagen‐rich tissues. To determine whether a high level of oestradiol has an acute influence on collagen synthesis in tendons at rest and in response to exercise, one‐legged kicking exercise was performed for 60 min at 67% of maximum power by healthy, young oral contraceptive (OC) users when circulating synthetic (ethinyl) oestradiol was high (n= 11, HE‐OC) and compared to similar women who had never used OCs when circulating endogenous oestrogen was low (n= 12, LE‐NOC). Interstitial fluid was collected 24 h post‐exercise through microdialysis catheters placed anterior to the patellar tendon in both legs and subsequently analysed for the amino‐terminal propeptide of type I collagen (PINP), a marker of tendon collagen synthesis. To determine the long‐term effect of OC usage, patellar tendon cross‐sectional area (CSA) was measured by magnetic resonance imaging (MRI). A lower exercise‐induced increase in tendon collagen synthesis was observed in HE‐OC than in LE‐NOC (ΔPINP (mean ±s.e.m.) 1.5 ± 5.3 versus 24.2 ± 9.4 ng ml−1, P < 0.05). Furthermore, serum and the interstitial peritendinous tissue concentrations of insulin‐like growth factor I (IGF‐I) and IGF‐binding proteins showed a reduced bioavailability in HE‐OC compared with results in LE‐NOC. No difference in patellar tendon CSA was observed between groups. In conclusion, the selective increase in tendon collagen synthesis in LE‐NOC but not HE‐OC 24 h post‐exercise is consistent with the hypothesis that oestradiol inhibits exercise‐induced collagen synthesis in human tendon. The mechanism behind this is either a direct effect of oestradiol, or an indirect effect via a reduction in levels of free IGF‐I. However, the data did not indicate any long‐term effect on tendon size associated with chronic OC use.
Spike Ca2+ influx upmodulates the spike afterdepolarization and bursting via intracellular inhibition of KV7/M channels

In principal brain neurons, activation of Ca2+ channels during an action potential, or spike, causes Ca2+ entry into the cytosol within a millisecond. This in turn causes rapid activation of large conductance Ca2+‐gated channels, which enhances repolarization and abbreviates the spike. Here we describe another remarkable consequence of spike Ca2+ entry: enhancement of the spike afterdepolarization. This action is also mediated by intracellular modulation of a particular class of K+ channels, namely by inhibition of KV7 (KCNQ) channels. These channels generate the subthreshold, non‐inactivating M‐type K+ current, whose activation curtails the spike afterdepolarization. Inhibition of KV7/M by spike Ca2+ entry allows the spike afterdepolarization to grow and can convert solitary spikes into high‐frequency bursts of action potentials. Through this novel intracellular modulatory action, Ca2+ spike entry regulates the discharge mode and the signalling capacity of principal brain neurons.
Preferential motor unit loss in the SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis

The present study investigated motor unit (MU) loss in a murine model of familial amyotrophic lateral sclerosis (ALS). The fast‐twitch tibialis anterior (TA) and medial gastrocnemius (MG) muscles of transgenic SOD1G93A and SOD1WT mice were studied during the presymptomatic phase of disease progression at 60 days of age. Whole muscle maximum isometric twitch and tetanic forces were 80% lower (P < 0.01) in the TA muscles of SOD1G93A compared to SOD1WT mice. Enumeration of total MU numbers within TA muscles showed a 60% reduction (P < 0.01) within SOD1G93A mice (38 ± 7) compared with SOD1WT controls (95 ± 12); this was attributed to a lower proportion of the most forceful fast‐fatigable (FF) MU in SOD1G93A mice, as seen by a significant (P < 0.01) leftward shift in the cumulative frequency histogram of single MU forces. Similar patterns of MU loss and corresponding decreases in isometric twitch force were observed in the MG. Immunocytochemical analyses of the entire cross‐sectional area (CSA) of serial sections of TA muscles stained with anti‐neural cell adhesion molecule (NCAM) and various monoclonal antibodies for myosin heavy chain (MHC) isoforms showed respective 65% (P < 0.01) and 28% (P < 0.05) decreases in the number of innervated IIB and IID/X muscle fibres in SOD1G93A, which paralleled the 60% decrease (P < 0.01) in the force generating capacity of individual fibres. The loss of fast MUs was partially compensated by activity‐dependent fast‐to‐slower fibre type transitions, as determined by increases (P < 0.04) in the CSA and proportion of IIA fibres (from 4% to 14%) and IID/X fibres (from 31% to 39%), and decreases (P < 0.001) in the CSA and proportion of type IIB fibres (from 65% to 44%). We conclude that preferential loss of IIB fibres is incomplete at 60 days of age, and is consistent with a selective albeit gradual loss of FF MUs that is not fully compensated by sprouting of the remaining motoneurons that innervate type IIA or IID/X muscle fibres. Our findings indicate that disease progression in fast‐twitch muscles of SOD1G93A mice involves parallel processes: (1) gradual selective motor axon die‐back of the FF motor units that contain large type IIB muscle fibres, and of fatigue‐intermediate motor units that innervate type IID/X muscle fibres, and (2) activity‐dependent conversion of motor units to those innervated by smaller motor axons innervating type IIA fatigue‐resistant muscle fibres.
‘Pressure–flow‘‐triggered intracellular Ca2+ transients in rat cardiac myocytes: possible mechanisms and role of mitochondria

Cardiac myocytes, in the intact heart, are exposed to shear/fluid forces during each cardiac cycle. Here we describe a novel Ca2+ signalling pathway, generated by ‘pressurized flows’ (PFs) of solutions, resulting in the activation of slowly developing (∼300 ms) Ca2+ transients lasting ∼1700 ms at room temperature. Though subsequent PFs (applied some 10–30 s later) produced much smaller or undetectable responses, such transients could be reactivated following caffeine‐ or KCl‐induced Ca2+ releases, suggesting that a small, but replenishable, Ca2+ pool serves as the source for their activation. PF‐triggered Ca2+ transients could be activated in Ca2+‐free solutions or in solutions that block voltage‐gated Ca2+ channels, stretch‐activated channels (SACs), or the Na+–Ca2+ exchanger (NCX), using Cd2+, Gd3+, or Ni2+, respectively. PF‐triggered Ca2+ transients were significantly smaller in quiescent than in electrically paced myocytes. Paced Ca2+ transients activated at the peak of PF‐triggered Ca2+ transients were not significantly smaller than those produced normally, suggesting functionally separate Ca2+ pools for paced and PF‐triggered transients. Suppression of nitric oxide (NO) or IP3 signalling pathways did not alter the PF‐triggered Ca2+ transients. On the other hand, mitochondrial metabolic uncoupler FCCP, in the presence of oligomycin (to prevent ATP depletion), reversibly suppressed PF‐triggered Ca2+ transients, as did the mitochondrial Ca2+ uniporter (mCU) blocker, Ru360. Reducing agent DTT and reactive oxygen species (ROS) scavenger tempol, as well as mitochondrial NCX (mNCX) blocker CGP‐37157, inhibited PF‐triggered Ca2+ transients. In rhod‐2 AM‐loaded and permeabilized cells, confocal imaging of mitochondrial Ca2+ showed a transient increase in Ca2+ on caffeine exposure and a decrease in mitochondrial Ca2+ on application of PF pulses of solution. These signals were strongly suppressed by either Na+‐free or CGP‐37157‐containing solutions, implicating mNCX in mediating the Ca2+ release process. We conclude that subjecting rat cardiac myocytes to pressurized flow pulses of solutions triggers the release of Ca2+ from a store that appears to access mitochondrial Ca2+.
Temporal changes in the involvement of pyruvate dehydrogenase complex in muscle lactate accumulation during lipopolysaccharide infusion in rats

A characteristic manifestation of sepsis is muscle lactate accumulation. This study examined any putative (causative) association between pyruvate dehydrogenase complex (PDC) inhibition and lactate accumulation in the extensor digitorum longus (EDL) muscle of rats infused with lipopolysaccharide (LPS), and explored the involvement of increased transcription of muscle‐specific pyruvate dehydrogenase kinase (PDK) isoenzymes. Conscious, male Sprague–Dawley rats were infused i.v. with saline (0.4 ml h−1, control) or LPS (150 μg kg−1 h−1) for 2 h, 6 h or 24 h (n= 6–8). Muscle lactate concentration was elevated after 2, 6 and 24 h LPS infusion. Muscle PDC activity was the same at 2 h and 6 h, but was 65% lower after 24 h of LPS infusion (P < 0.01), when there was a 47% decrease in acetylcarnitine concentration (P < 0.05), and a 24‐fold increase in PDK4 mRNA expression (P < 0.001). These changes were preceded by marked increases in tumour necrosis factor‐α and interleukin‐6 mRNA expression at 2 h. The findings indicate that the early (2 and 6 h) elevation in muscle lactate concentration during LPS infusion was not attributable to limited muscle oxygen availability or ATP production (evidenced by unchanged ATP and phosphocreatine (PCr) concentrations) or to PDC inhibition, whereas after 24 h, muscle lactate accumulation appears to have resulted from PDC activation status limiting pyruvate flux, most probably due to cytokine‐mediated up‐regulation of PDK4 transcription.
Sestd1 Encodes a Developmentally Dynamic Synapse Protein That Complexes With BCR Rac1-GAP to Regulate Forebrain Dendrite, Spine and Synapse Formation.

SEC14 and Spectrin domain-1 (Sestd1) is a synapse protein that exhibits a striking shift from the presynaptic to postsynaptic space as neurons mature postnatally in the mouse hippocampus. Hippocampal pyramidal neurons from mice with global genetic deletion of Sestd1 have reduced dendrite arbors, spines, and excitatory synapses. Electrophysiologically this correlates with cell-autonomous reductions in both AMPAand NMDA-excitatory postsynaptic currents in individual hippocampal neurons from which Sestd1 has been deleted in vivo. These neurodevelopmental and functional deficits are associated with increased activation of the Rho family GTPases Rac1 and RhoA. Co-immunoprecipitation and mass spectrometry reveal that the Breakpoint Cluster Region protein, a Rho GTPase activating protein (GAP), forms complexes with Sestd1 in brain tissue. This complements earlier findings that Sestd1 can also partner with other Rho family GAPs and guanine nucleotide exchange factors. Our findings demonstrate that Sestd1 is a developmentally dynamic synaptic regulator of Rho GTPases that contributes to dendrite and excitatory synapse formation within differentiating pyramidal neurons of the forebrain.
Nuclear pore disassembly from endoplasmic reticulum membranes promotes Ca2+ signalling competency

The functionality of the endoplasmic reticulum (ER) as a Ca2+ storage organelle is supported by families of Ca2+ pumps, buffers and channels that regulate Ca2+ fluxes between the ER lumen and cytosol. Although many studies have identified heterogeneities in Ca2+ fluxes throughout the ER, the question of how differential functionality of Ca2+ channels is regulated within proximal regions of the same organelle is unresolved. Here, we studied the in vivo dynamics of an ER subdomain known as annulate lamellae (AL), a cytoplasmic nucleoporin‐containing organelle widely used in vitro to study the mechanics of nuclear envelope breakdown. We show that nuclear pore complexes (NPCs) within AL suppress local Ca2+ signalling activity, an inhibitory influence relieved by heterogeneous dissociation of nucleoporins to yield NPC‐denuded ER domains competent at Ca2+ signalling. Consequently, we propose a novel generalized role for AL – reversible attenuation of resident protein activity – such that regulated AL (dis)assembly via a kinase/phosphatase cycle allows cells to support rapid gain/loss‐of‐function transitions in cellular physiology.
Low expression of Kv7/M channels facilitates intrinsic and network bursting in the developing rat hippocampus

Early in development, network activity in the hippocampus is characterized by recurrent synchronous bursts, whose cellular correlates are giant depolarizing potentials (GDPs). The propensity for generating GDPs is attributed to GABAergic synaptic transmission being depolarizing and excitatory in neonatal neurons. However, developmental regulation of intrinsic conductances may also influence GDPs generation. A likely candidate is the non‐inactivating, low‐threshold, muscarinic‐sensitive K+ current (M current; Im), which down‐regulates intrinsic bursting activity in adult hippocampal pyramidal neurons. Western blot analysis of homogenates of the CA3 hippocampal region showed that expression of the Kv7.2 subunit, one of the constituents of neuronal M channels, is weak in neonatal neurons, and markedly increases after the first postnatal week. Likewise, the density of Im was very low in neonatal CA3 pyramidal cells and increased later on. Spontaneously occurring intrinsic bursts in neonatal neurons were longer and more robust, and recurred more regularly, than in juvenile neurons. The Im blocker linopirdine only mildly affected intrinsic bursting in neonatal neurons, but strongly facilitated and regularized it in juvenile neurons. We conclude that the low expression of Kv7/M channels and the depolarizing action of GABA early after birth enhance intrinsic bursting and neuronal synchronization leading to generation of GDPs within the hippocampal network.
α‐Adrenergic and neuropeptide Y Y1 receptor control of collateral circuit conductance: influence of exercise training

This study evaluated the role of α‐adrenergic receptor‐ and neuropeptide Y (NPY) Y1 receptor‐mediated vasoconstriction in the collateral circuit of the hind limb. Animals were evaluated either the same day (Acute) or 3 weeks following occlusion of the femoral artery; the 3‐week animals were in turn limited to cage activity (Sed) or given daily exercise (Trained). Collateral‐dependent blood flows (BFs) were measured during exercise with microspheres before and after α‐receptor inhibition (phentolamine) and then NPY Y1 receptor inhibition (BIBP 3226) at the same running speed. Blood pressures (BPs) were measured above (caudal artery) and below (distal femoral artery) the collateral circuit. Arterial BPs were reduced by α‐inhibition (50–60 mmHg) to ∼75 mmHg, but not further by NPY Y1 receptor inhibition. Effective experimental sympatholysis was verified by 50–100% increases (P < 0.001) in conductance of active muscles not affected by femoral occlusion with receptor inhibition. In the absence of receptor inhibition, vascular conductance of the collateral circuit was minimal in the Acute group (0.13 ± 0.02), increased over time in the Sed group (0.41 ± 0.03; P < 0.001), and increased further in the Trained group (0.53 ± 0.03; P < 0.02). Combined receptor inhibition increased collateral circuit conductances (P < 0.005), most in the Acute group (116 ± 37%; P < 0.02), as compared to the Sed (41 ± 6.6%; P < 0.001) and Trained (31 ± 5.6%; P < 0.001) groups. Thus, while the sympathetic influence of the collateral circuit remained in the Sed and Trained animals, it became less influential with time post‐occlusion. Collateral conductances were collectively greater (P < 0.01) in the Trained as compared to Sed group, irrespective of the presence or absence of receptor inhibition. Conductances of the active ischaemic calf muscle, with combined receptor inhibition, were suboptimal in the Acute group, but increased in Sed and Trained animals to exceptionally high values (e.g. red fibre section of the gastrocnemius: ∼7 ml min−1 (100 g)−1 mmHg−1). Thus, occlusion of the femoral artery promulgated vascular adaptations, even in vessels that are not part of the collateral circuit. The presence of active sympathetic control of the collateral circuit, even with exercise training, raises the potential for reductions in collateral BF below that possible by the structure of the collateral circuit. However, even with release of this sympathetic vasoconstriction, conductance of the collateral circuit was significantly greater with exercise training, probably due to the network of structurally larger collateral vessels.
What is competence? A new model for diagnostic radiographers: Part 2

Abstract Purpose: The aim of this study was to establish a model of competence for newly qualified diagnostic radiographers which incorporated the notion of ‘fitness' from the perspective of a number of key stakeholders. The research is published in two parts. Part 1, published in the last issue, described the background to the study, its methods and the results. Part 2 discusses the findings and considers the implications for professional practice and research. Methods: An expert panel was surveyed using the Delphi technique. The panel was asked to provide a statement that described the primary role of diagnostic radiographers and also to state the associated roles and responsibilities which would be expected of a new qualifier in their first post. In view of the lack of clarity concerning the expectations of new radiographers, a clear interpretation was needed on the term ‘first post'. In addition, the panel was asked to predict changes in the provision of health care and in society which may have an impact on the future role of radiographers. Results: A primary role statement was developed which placed more emphasis on the needs of the patient than on technology. The associated roles and responsibilities were named statements of competence and were organized into nine categories. Variations were noted in the interpretation of the term ‘first post', with the majority of the panel agreeing that qualification and competence were not synonymous. The panel returned a wide range of predictions concerning the future role of radiographers, which, by the final round had been condensed to 33 statements. Conclusion: A model of competence was developed incorporating a range of knowledge, skills and attributes which could be used as a starting point for making judgements on the scope of practice: the range of roles and duties from which the competence of the newly qualified can be inferred. More than 50% of the competences could be classified as multiprofessional, lending support for the need to develop a curriculum which integrates the needs of a number of professional disciplines. The research highlighted that there are unclear boundaries around the area of qualification, in which new qualifiers continue to be supported. Regarding the future role, the panel predicted that changes in technology would have the most important impact and that the scope of practice for radiographers will continue to expand.
In vitro characterization of HCN channel kinetics and frequency dependence in myocytes predicts biological pacemaker functionality

The pacemaker current, mediated by hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels, contributes to the initiation and regulation of cardiac rhythm. Previous experiments creating HCN‐based biological pacemakers in vivo found that an engineered HCN2/HCN1 chimeric channel (HCN212) resulted in significantly faster rates than HCN2, interrupted by 1–5 s pauses. To elucidate the mechanisms underlying the differences in HCN212 and HCN2 in vivo functionality as biological pacemakers, we studied newborn rat ventricular myocytes over‐expressing either HCN2 or HCN212 channels. The HCN2‐ and HCN212‐over‐expressing myocytes manifest similar voltage dependence, current density and sensitivity to saturating cAMP concentrations, but HCN212 has faster activation/deactivation kinetics. Compared with HCN2, myocytes expressing HCN212 exhibit a faster spontaneous rate and greater incidence of irregular rhythms (i.e. periods of rapid spontaneous rate followed by pauses). To explore these rhythm differences further, we imposed consecutive pacing and found that activation kinetics of the two channels are slower at faster pacing frequencies. As a result, time‐dependent HCN current flowing during diastole decreases for both constructs during a train of stimuli at a rapid frequency, with the effect more pronounced for HCN2. In addition, the slower deactivation kinetics of HCN2 contributes to more pronounced instantaneous current at a slower frequency. As a result of the frequency dependence of both instantaneous and time‐dependent current, HCN2 exhibits more robust negative feedback than HCN212, contributing to the maintenance of a stable pacing rhythm. These results illustrate the benefit of screening HCN constructs in spontaneously active myocyte cultures and may provide the basis for future optimization of HCN‐based biological pacemakers.
Psychological morbidity and health‐related quality of life in patients with differing awareness of cancer diagnosis: a cross‐sectional study

Concealment of cancer diagnosis from patients is not rare worldwide and physicians in mainland China are in fact discouraged from disclosing a cancer diagnosis to cancer patients. Preventing worsened psychological morbidity is at the core of the argument for nondisclosure. The purpose of this study was to quantify anxiety, depression, and distress among patients with various degrees of awareness of their cancer diagnosis. Quality of life was also measured.
Effective Medical Resources Searching Using an Ontology-Driven Medical Information Retrieval System: H1N1 case study

Purpose – As international users increase rapidly, multilingual systems have become a very important service for global users. The purpose of this paper is to design and implement an ontology‐driven medical information retrieval (OMIR) system by building a medical ontology based on the Centers for Disease Control and Prevention's (CDC) medical records.Design/methodology/approach – A traditional cataloging scheme is used as a navigation menu in the CDC system. This traditional cataloging scheme is transformed to a unique medical ontology for global users in the OMIR system. An experimental study was conducted on both an ontology‐driven medical information system (OMIR) and the CDC system.Findings – The medical ontology can be used to filter out unsuitable resources based on semantic relationships. In addition, the recommended resources can be categorized and provide the patron with different languages to access resources. The OMIR system provides better relevancy and shorter search times compared with alte.