Miracle-dz/UniFAR-FTUs huggingface dataset:
In silico assessment of genetic variation in KCNA5 reveals multiple mechanisms of human atrial arrhythmogenesis

A recent experimental study investigating patients with lone atrial fibrillation identified six novel mutations in the KCNA5 gene. The mutants exhibited both gain- and loss-of-function of the atrial specific ultra-rapid delayed rectifier K+ current, IKur. The aim of this study is to elucidate and quantify the functional impact of these KCNA5 mutations on atrial electrical activity. A multi-scale model of the human atria was updated to incorporate detailed experimental data on IKur from both wild-type and mutants. The effects of the mutations on human atrial action potential and rate dependence were investigated at the cellular level. In tissue, we assessed the effects of the mutations on the vulnerability to unidirectional conduction patterns and dynamics of re-entrant excitation waves. Gain-of-function mutations shortened the action potential duration in single cells, and stabilised and accelerated re-entrant excitation in tissue. Loss-of-function mutations had heterogeneous effects on action potential duration and promoted early-after-depolarisations following beta-adrenergic stimulation. In the tissue model, loss-of-function mutations facilitated breakdown of excitation waves at more physiological excitation rates than the wild-type, and the generation of early-after-depolarisations promoted unidirectional patterns of excitation. Gain- and loss-of-function IKur mutations produced multiple mechanisms of atrial arrhythmogenesis, with significant differences between the two groups of mutations. This study provides new insights into understanding the mechanisms by which mutant IKur contributes to atrial arrhythmias. In addition, as IKur is an atrial-specific channel and a number of IKur-selective blockers have been developed as anti-AF agents, this study also helps to understand some contradictory results on both pro- and anti-arrhythmic effects of blocking IKur.
Spikelets in Pyramidal Neurons: Action Potentials Initiated in the Axon Initial Segment That Do Not Activate the Soma

Spikelets are small spike-like depolarizations that can be measured in somatic intracellular recordings. Their origin in pyramidal neurons remains controversial. To explain spikelet generation, we propose a novel single-cell mechanism: somato-dendritic input generates action potentials at the axon initial segment that may fail to activate the soma and manifest as somatic spikelets. Using mathematical analysis and numerical simulations of compartmental neuron models, we identified four key factors controlling spikelet generation: (1) difference in firing threshold, (2) impedance mismatch, and (3) electrotonic separation between the soma and the axon initial segment, as well as (4) input amplitude. Because spikelets involve forward propagation of action potentials along the axon while they avoid full depolarization of the somato-dendritic compartments, we conjecture that this mode of operation saves energy and regulates dendritic plasticity while still allowing for a read-out of results of neuronal computations.
An internet-based prospective study of body size and time-to-pregnancy.

BACKGROUND Recent studies have shown that both female and male obesity may delay time-to-pregnancy (TTP). Little is known about central adiposity or weight gain and fecundability in women. METHODS We examined the association between anthropometric factors and TTP among 1651 Danish women participating in an internet-based prospective cohort study of pregnancy planners (2007-2008). We categorized body mass index (BMI = kg/m(2)) as underweight (<20), normal weight (20-24), overweight (25-29), obese (30-34) and very obese (> or =35). We used discrete-time Cox regression to estimate fecundability ratios (FRs) and 95% confidence intervals (CI), controlling for potential confounders. RESULTS We found longer TTPs for overweight (FR = 0.83, 95% CI = 0.70-1.00), obese (FR = 0.75, 95% CI = 0.58-0.97), and very obese (FR = 0.61, 95% CI = 0.42-0.88) women, compared with normal weight women. After further control for waist circumference, FRs for overweight, obese, and very obese women were 0.72 (95% CI = 0.58-0.90), 0.60 (95% CI = 0.42-0.85) and 0.48 (95% CI = 0.31-0.74), respectively. Underweight was associated with reduced fecundability among nulliparous women (FR = 0.82, 95% CI = 0.63-1.06) and increased fecundability among parous women (FR = 1.61, 95% CI = 1.08-2.39). Male BMI was not materially associated with TTP after control for female BMI. Compared with women who maintained a stable weight since age 17 (-5 to 4 kg), women who gained > or =15 kg had longer TTPs (FR = 0.72, 95% CI = 0.59-0.88) after adjustment for BMI at age 17. Associations of waist circumference and waist-to-hip ratio with TTP depended on adjustment for female BMI: null associations were observed before adjustment for BMI and weakly positive associations were observed after adjustment for BMI. CONCLUSIONS Our results confirm previous studies showing reduced fertility in overweight and obese women. The association between underweight and fecundability varied by parity.
Deep Back-Projection Networks for Super-Resolution

The feed-forward architectures of recently proposed deep super-resolution networks learn representations of low-resolution inputs, and the non-linear mapping from those to high-resolution output. However, this approach does not fully address the mutual dependencies of low- and high-resolution images. We propose Deep Back-Projection Networks (DBPN), that exploit iterative up- and downsampling layers, providing an error feedback mechanism for projection errors at each stage. We construct mutually-connected up- and down-sampling stages each of which represents different types of image degradation and high-resolution components. We show that extending this idea to allow concatenation of features across up- and downsampling stages (Dense DBPN) allows us to reconstruct further improve super-resolution, yielding superior results and in particular establishing new state of the art results for large scaling factors such as 8Ã— across multiple data sets.
KCa3.1 upregulation preserves endothelium‐dependent vasorelaxation during aging and oxidative stress

Endothelial oxidative stress develops with aging and reactive oxygen species impair endothelium‐dependent relaxation (EDR) by decreasing nitric oxide (NO) availability. Endothelial KCa3.1, which contributes to EDR, is upregulated by H2O2. We investigated whether KCa3.1 upregulation compensates for diminished EDR to NO during aging‐related oxidative stress. Previous studies identified that the levels of ceramide synthase 5 (CerS5), sphingosine, and sphingosine 1‐phosphate were increased in aged wild‐type and CerS2 mice. In primary mouse aortic endothelial cells (MAECs) from aged wild‐type and CerS2 null mice, superoxide dismutase (SOD) was upregulated, and catalase and glutathione peroxidase 1 (GPX1) were downregulated, when compared to MAECs from young and age‐matched wild‐type mice. Increased H2O2 levels induced Fyn and extracellular signal‐regulated kinases (ERKs) phosphorylation and KCa3.1 upregulation. Catalase/GPX1 double knockout (catalase−/−/GPX1−/−) upregulated KCa3.1 in MAECs. NO production was decreased in aged wild‐type, CerS2 null, and catalase−/−/GPX1−/− MAECs. However, KCa3.1 activation‐induced, NG‐nitro‐l‐arginine‐, and indomethacin‐resistant EDR was increased without a change in acetylcholine‐induced EDR in aortic rings from aged wild‐type, CerS2 null, and catalase−/−/GPX1−/− mice. CerS5 transfection or exogenous application of sphingosine or sphingosine 1‐phosphate induced similar changes in levels of the antioxidant enzymes and upregulated KCa3.1. Our findings suggest that, during aging‐related oxidative stress, SOD upregulation and downregulation of catalase and GPX1, which occur upon altering the sphingolipid composition or acyl chain length, generate H2O2 and thereby upregulate KCa3.1 expression and function via a H2O2/Fyn‐mediated pathway. Altogether, enhanced KCa3.1 activity may compensate for decreased NO signaling during vascular aging.
Ether‐à‐go‐go K+ channels: effective modulators of neuronal excitability

Mammalian ether‐à‐go‐go (EAG) channels are voltage‐gated K+ channels. They are encoded by the KCNH gene family and divided into three subfamilies, eag (Kv10), erg (eag‐related gene; Kv11) and elk (eag‐like; Kv12). All EAG channel subtypes are expressed in the brain where they effectively modulate neuronal excitability. This Topical Review describes the biophysical properties of each of the EAG channel subtypes, their function in neurons and the neurological diseases induced by EAG channel mutations. In contrast to the function of erg currents in the heart, where they contribute to repolarization of the cardiac action potential, erg currents in neurons are involved in the maintenance of the resting potential, setting of action potential threshold and frequency accommodation. They can even support high frequency firing by preventing a depolarization‐induced Na+ channel block. EAG channels are modulated differentially, e.g. eag channels by intracellular Ca2+, erg channels by extracellular K+ and GPCRs, and elk channels by changes in pH. So far, only currents mediated by erg channels have been recorded in neurons with the help of selective blockers. Neuronal eag and elk currents have not been isolated due to the lack of suitable channel blockers. However, findings in KO mice indicate a physiological role of eag1 currents in synaptic transmission and an involvement of elk2 currents in cognitive performance. Human eag1 and eag2 gain‐of‐function mutations underlie syndromes associated with epileptic seizures.
Design of novel efficient adder and subtractor for quantum‐dot cellular automata

Quantum‐dot cellular automata (QCA) is one of the new emerging technologies being investigated as an alternative to complementary metal oxide semiconductor technology. This paper proposes optimized one‐bit full adder (FA) for implementation in QCA. The fault effects at the proposed FA outputs due to the missing cell defects are analyzed, and the test vectors for detection of all faults are identified. Also, the efficient designs of one‐bit full subtractor (FS), one‐bit FA/FS and four‐bit carry flow adder (CFA) are presented using the proposed FA. These structures are designed and simulated using QCADesigner software. The proposed designs are compared with other previous works. In comparison with the best previous design, the proposed FA has 25% and 26% improvement in cells count and area, respectively, and it is faster. For the proposed FS, FA/FS and CFA, the obtained results confirm that these designs are more efficient in terms of area, cell count and delay. Therefore, the implementation of these designs may lead to the efficient use of the calculative unit in various applications, which may be used as a basic building block of a general purpose nanoprocessor. Copyright © 2014 John Wiley & Sons, Ltd.
The TAM receptor Tyro3 regulates myelination in the central nervous system

Myelin is an essential component of the mammalian nervous system, facilitating rapid conduction of electrical impulses by axons, as well as providing trophic support to neurons. Within the central nervous system, the oligodendrocyte is the specialized neural cell responsible for producing myelin by a process that is thought to be regulated by both activity dependent and independent mechanisms but in incompletely understood ways. We have previously identified that the protein Gas6, a ligand for a family of tyrosine kinase receptors known as the TAM (Tyro3, Axl, and Mertk) receptors, directly increases oligodendrocyte induced myelination in vitro. Gas6 can bind to and activate all three TAM receptors, but the high level of expression of Tyro3 on oligodendrocytes makes this receptor the principal candidate for transducing the pro‐myelinating effect of Gas6. In this study, we establish that in the absence of Tyro3, the pro‐myelinating effect of Gas6 is lost, that developmental myelination is delayed and that the myelin produced is thinner than normal. We show that this effect is specific to the myelination process and not due to changes in the proliferation or differentiation of oligodendrocyte precursor cells. We have further demonstrated that the reduction in myelination is due to the loss of Tyro3 on oligodendrocytes, and this effect may be mediated by activation of Erk1. Collectively, our findings indicate the critical importance of Tyro3 in potentiating central nervous system myelination. GLIA 2017 GLIA 2017;65:581–591
Investigation of cesium adsorption on soil and sediment samples from Fukushima Prefecture by sequential extraction and EXAFS technique

Previous studies have shown that radiocesium (mainly 137 Cs) was retained at the very surface of soils in Fukushima Prefecture. Clay minerals and micas are assumed as the main sorbents for cesium (Cs) in Fukushima, but direct evidence is lacking for this hypothesis. In this study, radiocesium in the natural sample (soil and sediment) from Fukushima Prefecture was investigated through sequential extraction experiment (modified BCR method), which showed that more than 94% of 137 Cs was fixed in the residual phase. The results indicated that most of Cs occurred in the interlayer of phyllosilicate minerals. Furthermore, Cs LIII-edge extended X-ray absorption fine structure (EXAFS) showed that the Cs species adsorbed on the natural samples were very similar to those adsorbed on clay minerals and micas. This finding provided the direct evidence on the significant contribution of clay minerals or micas to Cs retention in soils from Fukushima Prefecture.
Pregnancy decision-making in women with multiple sclerosis treated with natalizumab II : Maternal risks

Objective To assess the risk of disease reactivation during pregnancy after natalizumab suspension in women with multiple sclerosis (MS). Methods Data of all pregnancies occurring between 2009 and 2015 in patients with MS treated with natalizumab and referring to 19 participating sites were collected and compared with those of pregnancies in untreated patients and patients treated with injectable immunomodulatory agents through a 2-factor repeated measures analysis. Predictors of disease activity were assessed through stepwise multivariable logistic regression models. Results A total of 92 pregnancies were tracked in 83 women receiving natalizumab. Among these pregnancies, 74 in 70 women resulted in live births, with a postpartum follow-up of at least 1 year, and were compared with 350 previously published pregnancies. Relapse rate during and after pregnancy was higher in women treated with natalizumab (p < 0.001). In multivariable analysis, longer natalizumab washout period was the only predictor of relapse occurrence during pregnancy (p = 0.001). Relapses in the postpartum year were related to relapses during pregnancy (p = 0.019) and early reintroduction of disease-modifying drugs (DMD; p = 0.021). Disability progression occurred in 16.2% of patients and was reduced by early reintroduction of DMD (p = 0.024). Conclusions Taken as a whole, our findings indicate that the combination of avoiding natalizumab washout and the early resumption of DMD after delivery could be the best option in the perspective of maternal risk. This approach must take into account possible fetal risks that need to be discussed with the mother and require further investigation. Classification of evidence This study provides Class IV evidence that in women with MS, the risk of relapses during pregnancy is higher in those who had been using natalizumab as compared to those who had been using interferon-β or no treatment. RELATED ARTICLE
Müller glial cell reactivation in Xenopus models of retinal degeneration

A striking aspect of tissue regeneration is its uneven distribution among different animal classes, both in terms of modalities and efficiency. The retina does not escape the rule, exhibiting extraordinary self‐repair properties in anamniote species but extremely limited ones in mammals. Among cellular sources prone to contribute to retinal regeneration are Müller glial cells, which in teleosts have been known for a decade to re‐acquire a stem/progenitor state and regenerate retinal neurons following injury. As their regenerative potential was hitherto unexplored in amphibians, we tackled this issue using two Xenopus retinal injury paradigms we implemented: a mechanical needle poke injury and a transgenic model allowing for conditional photoreceptor cell ablation. These models revealed that Müller cells are indeed able to proliferate and replace lost cells following damage/degeneration in the retina. Interestingly, the extent of cell cycle re‐entry appears dependent on the age of the animal, with a refractory period in early tadpole stages. Our findings pave the way for future studies aimed at identifying the molecular cues that either sustain or constrain the recruitment of Müller glia, an issue of utmost importance to set up therapeutic strategies for eye regenerative medicine.
Sale of antibiotics without a prescription at community pharmacies in urban China: a multicentre cross-sectional survey

Objectives To quantify sales of antibiotics without a medical prescription and to assess the quality of pharmacy services in relation to the antibiotics sold in community pharmacies in urban China. Methods A multicentre cross-sectional survey of community pharmacies was undertaken in 2015 using the simulated client method. Two clinical case scenarios (paediatric diarrhoea and adult acute upper respiratory infection) were presented at systematically sampled community pharmacies in Eastern (Nanjing), Central (Changsha) and Western China (Xi'an). Results Of 256 pharmacies, antibiotics were obtained without a prescription from 55.9% (95% CI: 49.5%-62.0%) when paediatric diarrhoea was simulated and from 77.7% (95% CI: 72.1%-82.7%) when adult respiratory infection was simulated. Of the pharmacies where antibiotics were dispensed, 83.9% and 66.3% dispensed after the simulated clients requested or insisted in the case of paediatric diarrhoea and adult respiratory infection, respectively. Significant differences ( P < 0.001, χ 2 test) in inappropriate antibiotic dispensing were found among cities, with 57.7%, 37.3% and 73.7% in the case of paediatric diarrhoea and 60.8%, 80.7% and 96.1% in adult respiratory infection in Nanjing, Changsha and Xi'an, respectively. Pharmacists were available in only 14.8% (95% CI: 10.7%-19.8%) of the pharmacies. The performance of pharmacy staff regarding the provision of information and advice was unsatisfactory. Conclusions Antibiotics were easily obtained without a prescription in community pharmacies in urban China. Measures to enhance the enforcement of prescription-only regulations and training programmes for pharmacy staff to promote the appropriate use of antibiotics are warranted.
Subpectoral Implantation of Internal Pulse Generators for Deep Brain Stimulation: Technical Note for Improved Cosmetic Outcomes.

BACKGROUND Deep brain stimulation is increasingly used to treat a variety of disorders. As the prevalence of this technology increases, greater demands are placed on neurosurgical practitioners to improve cosmetic results, maximize patient comfort, and minimize complication rates. We have increasingly employed subpectoral implantation of internal pulse generators (IPGs) to improve patient satisfaction. OBJECTIVE To determine the complication rates of subpectorally placed IPGs as compared to those placed in a subcutaneous location. METHODS We reviewed a series of 301 patients from a single institution. Complication rates including infection, hematoma, and lead fracture were recorded. Rates were compared for subcutaneously and subpectorally located devices. RESULTS Of the records reviewed, we found 301 patients who underwent 308 procedures for initial IPG implantation. Of these, 275 were subpectoral IPG implantation, 19 were infraclavicular subcutaneous implantation, and 14 were subcutaneous implantation in the abdomen. A total of 6 IPG pocket infections occurred, 2 subpectoral and 4 infraclavicular subcutaneous. Of the IPG infections, 2 of the infraclavicular subcutaneous devices had associated erosions. Two patients had their devices relocated from a subpectoral pocket to a subcutaneous pocket in the abdomen due to discomfort. Two patients in the subpectoral group suffered from hematoma requiring evacuation. Two patients in the infraclavicular subcutaneous group had lead fracture occur. CONCLUSIONS Subpectoral implantation of deep brain stimulation IPGs is a viable alternative with a low complication rate. This technique may offer a lower rate of infection and wound erosion.
Is There a Relationship Between Body Mass Index and Fluoroscopy Time During Cervical Interlaminar Epidural Steroid Injections?

Background The challenge of obtaining medical imaging in individuals with higher body mass index (BMI) is described, but there is minimal data regarding the relationship between BMI and fluoroscopy time during cervical interlaminar epidural steroid injection (CIESI). Objective To determine the relationship between BMI and fluoroscopy time during CIESI. Methods Retrospective cohort study of patients who underwent fluoroscopically guided CIESI between January 2014 and February 2015 at an academic pain medicine center. Fluoroscopy time data were collected. Comparisons based on analysis of variance were made between patients with normal (<25.0 kg/m 2 ), overweight (25.0-29.9 kg/m 2 ), and obese (≥30.0 kg/m 2 ) BMI. Results Of 399 procedure encounters, 366 had documented BMI and fluoroscopy time data and were included for analysis. Mean age (± SD) in this cohort was 53 ± 13 years, including 189 females (52%) and 205 first-time injections. Mean fluoroscopy time for all injections was 18 ± 10 seconds. Separated by categorical BMI class, the mean fluoroscopy time was 18 ± 9 seconds for normal weight patients, 17 ± 10 seconds for overweight patients, and 20 ± 11 seconds for obese patients, respectively. Post hoc analysis showed that fluoroscopy time was significantly longer only in obese compared with overweight patients ( P = 0.02). Trainee involvement and first-time vs repeat injection did not significantly alter fluoroscopy time ( P = 0.17 and P = 0.12, respectively). Conclusions The findings of this study indicate that BMI does not appear to have a clinically significant impact on fluoroscopy time during cervical interlaminar epidural steroid injection procedures. Future study is needed to directly quantify radiation exposure in patients and practitioners, as well as the associated health risk.
Revised global model of thermosphere winds using satellite and ground‐based observations

Thermospheric wind data obtained from the Atmosphere Explorer E and Dynamics Explorer 2 satellites have been combined with wind data for the lower and upper thermosphere from ground-based incoherent scatter radar and Fabry-Perot optical interferometers to generate a revision (HWM90) of the HWM87 empirical model and extend its applicability to 100 km. Comparison of the various data sets with the aid of the model shows in general remarkable agreement, particularly at mid and low latitudes. The ground-based data allow modeling of seasonal/diurnal variations, which are most distinct at mid latitudes. While solar activity variations are now included, they are found to be small and not always very clearly delineated by the current data. They are most obvious at the higher latitudes. The model describes the transition from predominately diurnal variations in the upper thermosphere to semidiurnal variations in the lower thermosphere and a transition from summer to winter flow above 140 km to winter to summer flow below. Significant altitude gradients in the wind are found to extend to 300 km at some local times and pose complications for interpretation of Fabry-Perot observations.