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Background: Sporadic parathyroid adenoma (PA) is the most common cause of hyperparathyroidism, yet the mechanisms involved in its pathogenesis remain incompletely understood. Methods: Surgically removed PA samples, along with normal parathyroid gland (PG) tissues that were incidentally dissected during total thyroidectomy, were analysed using single‐cell RNA‐sequencing with the 10× Genomics Chromium Droplet platform and Cell Ranger software. Gene set variation analysis was conducted to characterise hallmark pathway gene signatures, and single‐cell regulatory network inference and clustering were utilised to analyse transcription factor regulons. Immunohistochemistry and immunofluorescence were performed to validate cellular components of PA tissues. siRNA knockdown and gene overexpression, alongside quantitative polymerase chain reaction, Western blotting and cell proliferation assays, were conducted for functional investigations. Results: There was a pervasive increase in gene transcription in PA cells (PACs) compared with PG cells. This is associated with high expression of histone‐lysine N‐methyltransferase 2A (KMT2A). High KMT2A levels potentially contribute to promoting PAC proliferation through upregulation of the proto‐oncogene CCND2, which is mediated by the transcription factors signal transducer and activator of transcription 3 (STAT3) and GATA binding protein 3 (GATA3). PA tissues are heavily infiltrated with myeloid cells, while fibroblasts, endothelial cells and macrophages in PA tissues are commonly enriched with proinflammatory gene signatures relative to their counterparts in PG tissues. Conclusions: We revealed the previously underappreciated involvement of the KMT2A‒STAT3/GATA3‒CCND2 axis and chronic inflammation in the pathogenesis of PA. These findings underscore the therapeutic promise of KMT2A inhibition and anti‐inflammatory strategies, highlighting the need for future investigations to translate these molecular insights into practical applications. Highlights: Single‐cell RNA‐sequencing reveals a transcriptome catalogue comparing sporadic parathyroid adenomas (PAs) with normal parathyroid glands.PA cells show a pervasive increase in gene expression linked to KMT2A upregulation.KMT2A‐mediated STAT3 and GATA3 upregulation is key to promoting PA cell proliferation via cyclin D2.PAs exhibit a proinflammatory microenvironment, suggesting a potential role of chronic inflammation in PA pathogenesis. [ABSTRACT FROM AUTHOR]

Summary: Background: Stricturing Crohn's disease (CD) occurs most commonly in the terminal ileum and poses a clinical problem. Cross‐sectional imaging modalities such as intestinal ultrasound (IUS), computed tomography enterography (CTE), and magnetic resonance enterography (MRE) allow for assessment of the entire bowel wall and associated peri‐enteric findings. Radiologic definitions of strictures have been developed for CTE and MRE; their reliability and responsiveness are being evaluated in index development programs. A comprehensive assessment strategy for strictures using IUS is needed. Aims: To provide a detailed summary of definitions, diagnosis and monitoring of strictures on IUS as well as technical aspects of image acquisition. Methods: We searched four databases up to 6 January 2024. Two‐stage screening was done in duplicate. We assessed risk of bias using QUADAS‐2. Results: There were 56 studies eligible for inclusion. Definitions for strictures on IUS are heterogeneous, but the overall accuracy for diagnosis of strictures is high. The capability of IUS for characterising inflammation versus fibrosis in strictures is not accurate enough to be used in clinical practice or trials. We summarise definitions for improvement of strictures on IUS, and discuss parameters for image acquisition and standardisation. Conclusions: This systematic review is the first step for a structured program to develop a stricture IUS index for CD. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this investigation was to assess the effect of visceral adipose tissue volume (VA) on reader efficacy in diagnosing and characterizing small bowel Crohn's disease using lower exposure CT enterography (CTE). Secondarily, we investigated the effect of lower exposure and VA on reader diagnostic confidence. Methods: Prospective paired investigation of 256 CTE, 129 with Crohn's disease, were reconstructed at 100% and simulated 50% and 30% exposure. The senior author provided the disease classification for the 129 patients with Crohn's disease. Patient VA was measured, and exams were evaluated by six readers for presence or absence of Crohn's disease and phenotype using a 0–10‐point scale. Logistic regression models assessed the effect of VA on sensitivity and specificity. Results: The effect of VA on sensitivity was significantly reduced at 30% exposure (odds radio [OR]: 1.00) compared to 100% exposure (OR: 1.12) (p = 0.048). There was no statistically significant difference among the exposures with respect to the effect of visceral fat on specificity (p = 0.159). The study readers' probability of agreement with the senior author on disease classification was 60%, 56%, and 53% at 100%, 50%, and 30% exposure, respectively (p = 0.004). When detecting low severity Crohn's disease, readers' mean sensitivity was 83%, 75%, and 74% at 100%, 50%, and 30% exposure, respectively (p = 0.002). In low severity disease, sensitivity also tended to increase as visceral fat increased (ORs per 1000 cm3 increase in visceral fat: 1.32, 1.31, and 1.18, p = 0.010, 0.016, and 0.100, at 100%, 50%, and 30% exposure). Conclusions: While the interaction is complex, VA plays a role in detecting and characterizing small bowel Crohn's disease when exposure is altered, particularly in low severity disease. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to develop a novel pathway linking genetic data with routinely collected data for people with epilepsy, and to analyze the influence of rare, deleterious genetic variants on epilepsy outcomes. Methods: We linked whole‐exome sequencing (WES) data with routinely collected primary and secondary care data and natural language processing (NLP)‐derived seizure frequency information for people with epilepsy within the Secure Anonymised Information Linkage Databank. The study participants were adults who had consented to participate in the Swansea Neurology Biobank, Wales, between 2016 and 2018. DNA sequencing was carried out as part of the Epi25 collaboration. For each individual, we calculated the total number and cumulative burden of rare and predicted deleterious genetic variants and the total of rare and deleterious variants in epilepsy and drug metabolism genes. We compared these measures with the following outcomes: (1) no unscheduled hospital admissions versus unscheduled admissions for epilepsy, (2) antiseizure medication (ASM) monotherapy versus polytherapy, and (3) at least 1 year of seizure freedom versus <1 year of seizure freedom. Results: We linked genetic data for 107 individuals with epilepsy (52% female) to electronic health records. Twenty‐six percent had unscheduled hospital admissions, and 70% were prescribed ASM polytherapy. Seizure frequency information was linked for 100 individuals, and 10 were seizure‐free. There was no significant difference between the outcome groups in terms of the exome‐wide and gene‐based burden of rare and deleterious genetic variants. Significance: We successfully uploaded, annotated, and linked genetic sequence data and NLP‐derived seizure frequency data to anonymized health care records in this proof‐of‐concept study. We did not detect a genetic influence on real‐world epilepsy outcomes, but our study was limited by a small sample size. Future studies will require larger (WES) data to establish genetic variant contribution to epilepsy outcomes. [ABSTRACT FROM AUTHOR]

Background: Limited data exist on pregnant women living with HIV exposed to cabotegravir + rilpivirine (CAB + RPV). Outcomes in pregnant participants exposed to CAB + RPV, and pharmacokinetic washout data in those exposed to CAB + RPV long‐acting (LA) with live births, are presented. Methods: Women exposed to one or more doses of CAB + RPV (oral/LA) from ViiV Healthcare‐sponsored phase 2b/3/3b clinical trials and the compassionate use programme who became pregnant were included. Upon pregnancy in the trial programme, CAB + RPV was discontinued, an alternative antiretroviral regimen was initiated, and quarterly pharmacokinetic sampling for 52 weeks post‐last injection was obtained. CAB + RPV continuation or alternative antiretroviral regimen initiation was decided by pregnant compassionate use programme participants and their treating physicians. Results: As of 31 March 2021, 25 pregnancies following CAB + RPV exposure at conception were reported (five oral, 20 LA), including four who conceived during pharmacokinetic washout following treatment discontinuation. There were eight elective abortions, six miscarriages (five in first trimester), one ectopic pregnancy, and 10 live births (one oral, nine LA), including one infant born with congenital ptosis. Among participants exposed to CAB + RPV LA at conception with live births, plasma CAB and RPV washout concentrations during pregnancy were within the range of those observed in non‐pregnant women. Conclusion: In this first analysis of pregnancy outcomes following CAB + RPV exposure at conception, 10 live births, including one with congenital anomaly, were reported. Plasma CAB and RPV washout concentrations during pregnancy were within the range of those in non‐pregnant women. Pregnancy surveillance within ViiV Healthcare‐sponsored clinical trials is ongoing, with dedicated pregnancy studies planned. [ABSTRACT FROM AUTHOR]

Herein, we compare the different experimental regimes used to induce testicular heat stress and summarise their impact on sperm production and male fertility. Irrespective of the protocol used, scrotal heat stress causes loss of sperm production. This is first seen 1–2 weeks post heat stress, peaking 4–5 weeks thereafter. The higher the temperature, or the longer the duration of heat, the more pronounced germ cell loss becomes, within extreme cases this leads to azoospermia. The second, and often underappreciated impact of testicular hyperthermia is the production of poor‐quality spermatozoa. Typically, those cells that survive hyperthermia develop into morphologically abnormal and poorly motile spermatozoa. While both apoptotic and non‐apoptotic pathways are known to contribute to hyperthermic germ cell loss, the mechanisms leading to formation of poor‐quality sperm remain unclear. Mechanistically, it is unlikely that testicular hyperthermia affects messenger RNA (mRNA) abundance, as a comparison of four different mammalian studies shows no consistent single gene changes. Using available evidence, we propose two novel models to explain how testicular hyperthermia impairs sperm formation. Our first model suggests aberrant alternative splicing, while the second model proposes a loss of RNA repression. Importantly, neither model requires consistent changes in RNA species. [ABSTRACT FROM AUTHOR]

New Findings: What is the topic of this review?The emerging condition of long COVID, its epidemiology, pathophysiological impacts on patients of different backgrounds, physiological mechanisms emerging as explanations of the condition, and treatment strategies being trialled. The review leads from a Physiological Society online conference on this topic.What advances does it highlight?Progress in understanding the pathophysiology and cellular mechanisms underlying Long COVID and potential therapeutic and management strategies. Long COVID, the prolonged illness and fatigue suffered by a small proportion of those infected with SARS‐CoV‐2, is placing an increasing burden on individuals and society. A Physiological Society virtual meeting in February 2022 brought clinicians and researchers together to discuss the current understanding of long COVID mechanisms, risk factors and recovery. This review highlights the themes arising from that meeting. It considers the nature of long COVID, exploring its links with other post‐viral illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome, and highlights how long COVID research can help us better support those suffering from all post‐viral syndromes. Long COVID research started particularly swiftly in populations routinely monitoring their physical performance – namely the military and elite athletes. The review highlights how the high degree of diagnosis, intervention and monitoring of success in these active populations can suggest management strategies for the wider population. We then consider how a key component of performance monitoring in active populations, cardiopulmonary exercise training, has revealed long COVID‐related changes in physiology – including alterations in peripheral muscle function, ventilatory inefficiency and autonomic dysfunction. The nature and impact of dysautonomia are further discussed in relation to postural orthostatic tachycardia syndrome, fatigue and treatment strategies that aim to combat sympathetic overactivation by stimulating the vagus nerve. We then interrogate the mechanisms that underlie long COVID symptoms, with a focus on impaired oxygen delivery due to micro‐clotting and disruption of cellular energy metabolism, before considering treatment strategies that indirectly or directly tackle these mechanisms. These include remote inspiratory muscle training and integrated care pathways that combine rehabilitation and drug interventions with research into long COVID healthcare access across different populations. Overall, this review showcases how physiological research reveals the changes that occur in long COVID and how different therapeutic strategies are being developed and tested to combat this condition. [ABSTRACT FROM AUTHOR]

Summary: Background: Anti‐drug antibodies are associated with treatment failure to anti‐TNF agents in patients with inflammatory bowel disease (IBD). Aim: To assess whether immunogenicity to a patient's first anti‐TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence Methods: We conducted a UK‐wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti‐TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti‐TNF agent, defined at any timepoint as an anti‐TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab. Results: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27–3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46–4.80, p < 0.001). For each 10‐fold increase in anti‐infliximab and anti‐adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38–2.17, p < 0.001) and 1.99 (95%CI 1.34–2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39–4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti‐TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure. Conclusion: Irrespective of drug sequence, immunogenicity to the first anti‐TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure. [ABSTRACT FROM AUTHOR]

Aim: To characterize cabotegravir population pharmacokinetics using data from phase 1, 2 and 3 studies and evaluate the association of intrinsic and extrinsic factors with pharmacokinetic variability. Methods: Analyses were implemented in NONMEM and R. Concentrations below the quantitation limit were modelled with likelihood‐based approaches. Covariate relationships were evaluated using forward addition (P <.01) and backward elimination (P <.001) approaches. The impact of each covariate on trough and peak concentrations was evaluated through simulations. External validation was performed using prediction‐corrected visual predictive checks. Results: The model‐building dataset included 23 926 plasma concentrations from 1647 adult HIV‐1‐infected (72%) and uninfected (28%) subjects in 16 studies at seven dose levels (oral 10‐60 mg, long‐acting [LA] intramuscular injection 200‐800 mg). A two‐compartment model with first‐order oral and LA absorption and elimination adequately described the data. Clearances and volumes were scaled to body weight. Estimated relative bioavailability of oral to LA was 75.6%. Race and age were not significant covariates. LA absorption rate constant (KALA) was 50.9% lower in females and 47.8% higher if the LA dose was given as two split injections. KALA decreased with increasing BMI and decreasing needle length. Clearance was 17.4% higher in current smokers. The impact of any covariate was ≤32% on trough and peak concentrations following LA administration. The final model adequately predicted 5097 plasma concentrations from 647 subjects who were not included in the model‐building dataset. Conclusions: A cabotegravir population pharmacokinetic model was developed that can be used to inform dosing strategies and future study design. No dose adjustment based on subject covariates is recommended. [ABSTRACT FROM AUTHOR]

Focal cortical dysplasia (FCD) is one of the most common malformations causing refractory epilepsy. Dysregulation of glutamatergic systems plays a critical role in the hyperexcitability of dysplastic neurons in FCD lesions. The pharmacoresistant nature of epilepsy associated with FCD may be due to a lack of well‐tolerated and precise antiepileptic drugs that can target glutamate receptors. Here, for the first time in human FCD brain slices, we show that the established, noncompetitive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor antagonist, perampanel has potent antiepileptic action. Moreover, we demonstrate that this effect is due to a reduction in burst firing behavior in human FCD microcircuits. These data support a potential role for the treatment of refractory epilepsy associated with FCD in human patients. [ABSTRACT FROM AUTHOR]

The adoption of 2D transition metal dichalcogenide (TMD) based optoelectronic devices is limited by Fermi level pinning effects and consequent large contact resistances upon contacting TMDs with bulk metal electrodes. A potential solution for near‐ideal Schottky–Mott behavior and concomitant Schottky barrier height control is proposed by contacting TMDs and (semi‐)metals in van der Waals heterostructures. However, measurement approaches to directly assess interface parameters relevant to the Schottky–Mott rule on a local scale are still lacking. In the present work, a heterostructure of monolayer tungsten diselenide (WSe2) with monolayer graphene (1LG) and bilayer graphene (2LG) is investigated on a bottom‐gate substrate. Kelvin probe force microscopy and tip‐enhanced photoluminescence measurements at different electrostatic doping induced Fermi levels in graphene enable decoupling and quantification of contributions from the interface dipole and electrode work function. These are used to locally probe Schottky barrier characteristics with below 32 nm lateral resolution, demonstrating that the WSe2/1LG junction operates at the Schottky–Mott limit (S ≈ 1). At the WSe2/2LG junction, a reduction of the interface dipole is directly related to changes in excitonic emission properties. These are attributed to charge transfer modulation across the interface, critical for obtaining high‐performance transfer characteristics in transistors and related devices. [ABSTRACT FROM AUTHOR]

This paper details 3 years of cadmium telluride (CdTe) photovoltaic performance onboard the AlSat‐1N CubeSat in low earth orbit. These are the first CdTe solar cells to yield I–V measurements from space and help to strengthen the argument for further development of this technology for space application. The data have been collected over some 17 000 orbits by the CubeSat with the cells showing no signs of delamination, no deterioration in short circuit current or series resistance. The latter indicating that the aluminium‐doped zinc oxide transparent front electrode performance remained stable over the duration. Effects of temperature on open circuit voltage (Voc) were observed with a calculated temperature coefficient for Voc of −0.19%/°C. Light soaking effects were also observed to increase the Voc. The fill factor decreased over the duration of the mission with a major contribution being a decrease in shunt resistance of all four of the cells. The decrease in shunt resistance is speculated to result from gold diffusion from the rear contacts into the absorber and through to the front interface. This has likely resulted in the formation of a deep trap state within the CdTe and micro shunts formed between the rear and front contact. Further development of this technology should therefore utilise more stable back contacting methodologies more commonly employed for terrestrial CdTe modules. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to assess the effect of obesity and iterative reconstruction on the ability to reduce exposure by studying the accuracy for detection of low‐contrast low‐attenuation (LCLA) liver lesions on computed tomography (CT) using a phantom model. Methods: A phantom with four unique LCLA liver lesions (5‐ to 15‐mm spheres, –24 to –6 HU relative to 90‐HU background) was scanned without ("thin" phantom) and with ("obese" phantom) a 5‐cm thick fat‐attenuation ring at 150 mAs (thin phantom) and 450 mAs (obese phantom) standard exposures and at 33% and 67% exposure reductions. Images were reconstructed using standard filtered back projection (FBP) and with iterative reconstruction (Adaptive Model‐Based Iterative Reconstruction strength 3, ADMIRE). A noninferiority analysis of lesion detection was performed. Results: Mean area under the curve (AUC) values for lesion detection were significantly higher for the thin phantom than for the obese phantom regardless of exposure level (P < 0.05) for both FBP and ADMIRE. At 33% exposure reduction, AUC was noninferior for both FBP and ADMIRE strength 3 (P < 0.0001). At 67% exposure reduction, AUC remained noninferior for the thin phantom (P < 0.0035), but was no longer noninferior for the obese phantom (P ≥ 0.7353). There were no statistically significant differences in AUC between FBP and ADMIRE at any exposure level for either phantom. Conclusions: Accuracy for lesion detection was not only significantly lower in the obese phantom at all relative exposures, but detection accuracy decreased sooner while reducing the exposure in the obese phantom. There was no significant difference in lesion detection between FBP and ADMIRE at equivalent exposure levels for either phantom. [ABSTRACT FROM AUTHOR]

Background: Electromyogram (EMG) burst duration can provide additional diagnostic information when investigating hyperkinetic movement disorders, particularly when a functional movement disorder is suspected. It is generally accepted that EMG bursts <50 milliseconds are pathological. Objective: To reassess minimum physiological EMG burst duration. Methods: Surface EMG was recorded from face, trunk, and limb muscles in controls (n = 60; ages 19–85). Participants were instructed to generate the briefest possible ballistic movements involving each muscle (40 repetitions) or, in muscles spanning joints, to generate rapid rhythmic alternating movements (20–30 seconds), or both. Results: We found no effect of age on EMG burst duration. However, EMG burst duration varied significantly between body regions. Rhythmic EMG bursts were shorter than ballistic bursts but only significantly so for lower limbs (P < 0.001). EMG bursts of duration <50 milliseconds were frequently observed, particularly in appendicular muscles. Conclusion: We present normal reference data for minimum EMG burst duration, which may assist clinical interpretation when investigating hyperkinetic movement disorders. [ABSTRACT FROM AUTHOR]

Early stage oxidation of a dilute‐depleted uranium‐molybdenum alloy was analysed in situ under ultra‐high vacuum conditions by AES and XPS. At the equivalent of less than 300 ns at 1‐atm O2, U‐5Mo oxidizes to form stoichiometric UO2. No molybdenum oxidation is observed. After an oxygen dose of approximately 39 L, the oxide layer approached a limiting thickness of approximately 2.4 nm. The oxidation kinetics followed a logarithmic rate law, with the best fit to the experimental data for the oxide thickness, d, being given by d = 1.26 log(0.12t + 0.56). Changes in oxygen KLL and 1s peak positions associated with transformation from chemisorbed oxygen to metal oxide were observed at similar oxygen doses of 2.3 and 2.6 L O2 by AES and XPS, respectively, which opens up the possibility of using well‐characterized XPS chemical information to inform Auger peak shifts. [ABSTRACT FROM AUTHOR]

Abstract: In many languages, overt case marking hides ϕ‐features from agreement probes. In some languages, such as Hindi, this effect is absolute. But in Adıyaman Kurmanji, our focus here, the effect is partial: the number feature of third‐person oblique subjects can be registered on the verb. We account for the difference by saying that overtly case‐marked nominals are in fact agreed with in the syntax, but the actual transfer of ϕ‐feature values happens at PF, where it is sensitive to postsyntactic operations like Fusion. All and only heads that fuse with case (a K head) can feed valuation and thus be realized on the agreement probe. Adıyaman Kurmanji is a language where number fuses with K and this feeds agreement, resulting in partial agreement with overtly case‐marked nominals (in number but not person), whereas Hindi is not. The possibility of object agreement in these languages is, we claim, the result of Multiple Agree, which creates complex feature bundles on agreement probes that are only partially realized morphologically at PF. We further support our theory by applying it to Icelandic and Faroese, languages that are often thought not to have agreement with oblique subjects but that may allow agreement in very specific situations, which our theory elucidates. [ABSTRACT FROM AUTHOR]

Summary: Focal status epilepticus in POLG‐related mitochondrial disease is highly refractory to pharmacological agents, including general anesthesia. We report the challenges in managing a previously healthy teenager who presented with de novo epilepsia partialis continua and metabolic stroke resulting from the homozygous p.Ala467Thr POLG mutation, the most common pathogenic variant identified in the Caucasian population. We applied transcranial direct current stimulation (tDCS; 2 mA; 20 min) daily as an adjunctive therapy because her focal seizures failed to respond to five antiepileptic drugs at maximal doses. The electrical and clinical seizures stopped after 3 days of tDCS. The second course of tDCS was administered for 14 days when the focal seizures re‐emerged a month later. The patient tolerated the procedure well. Following 4 months of hospitalization and prolonged community rehabilitation, our patient has now returned to full‐time education with support, and there is no report of cognitive deficit. We have demonstrated the safety and efficacy of tDCS in treating refractory focal motor seizures caused by mitochondrial disease. [ABSTRACT FROM AUTHOR]

Increased interest in the fractionation of Sn isotopes has led to the development of several techniques for preparing cassiterite (SnO2, the primary ore of Sn) for isotopic analysis. Two distinct methods have been applied in recent isotopic studies of cassiterite: (a) reduction to tin metal with potassium cyanide ( KCN) at high temperature (800 °C), with subsequent dissolution in HCl, and (b) reduction to a Sn solution with hydriodic acid ( HI) at low temperature (100 °C). This study compares the effectiveness and accuracy of these two methods and contributes additional methodological details. The KCN method consistently yielded more Sn (> 70% in comparison with < 5%), does not appear to fractionate Sn isotopes at high temperatures over a 2-hour period and produced consistent Sn isotope values at flux mass ratios of ≥ 4:1 (flux to mineral) with a minimum reduction time of 40 min. By means of a distillation experiment, it was demonstrated that HI could volatilise Sn, explaining the consistently low yields by this method. Furthermore, the distillation generated Sn vapour, which is up to 0.38‰ per mass unit different from the starting material, the largest induced Sn fractionation reported to date. Accordingly, the HI method is not recommended for cassiterite preparation for Sn isotopic analysis. [ABSTRACT FROM AUTHOR]

Application of the new quantitative elastohydrodynamics to the concentrated contacts operating within refrigerant compressors will require the accurate description of the viscosity of the lubricant that is diluted by the refrigerant. This article presents extensive viscosity measurements on polyolester and polyvinylether oils and their mixtures with low mass fractions (2-23%) of refrigerants R134a and R410a. Pressures up to 400 MPa and temperatures to 100°C were reached. Correlations are presented to predict the viscosity and pressure-viscosity coefficients at arbitrary temperatures and pressures and concentrations. Pressure-viscosity coefficients are compared with those derived from film thickness measurements using one of the popular definitions for the coefficient. Where comparisons can be made, the film-derived pressure-viscosity coefficients were mostly inaccurate. Part of the problem has been the lack of a single well-accepted and rigorous definition of the pressure-viscosity coefficient and the lack of an accurate film thickness formula that employs that definition. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Key points Optic nerve axons get less excitable with warming., F-fibre latency does not shorten at temperatures above 30°C., Action potential amplitude falls when the Na+-pump is blocked, an effect speeded by warming., Diuretics reduce the rate of action potential fall in the presence of ouabain., Our data are consistent with electroneutral entry of Na+ occurring in axons and contributing to setting the resting potential., Abstract Raising the temperature of optic nerve from room temperature to near physiological has effects on the threshold, refractoriness and superexcitability of the shortest latency (fast, F) nerve fibres, consistent with hyperpolarization. The temperature dependence of peak impulse latency was weakened at temperatures above 30°C suggesting a temperature-sensitive process that slows impulse propagation. The amplitude of the supramaximal compound action potential gets larger on warming, whereas in the presence of bumetanide and amiloride (blockers of electroneutral Na+ movement), the action potential amplitude consistently falls. This suggests a warming-induced hyperpolarization that is reduced by blocking electroneutral Na+ movement. In the presence of ouabain, the action potential collapses. This collapse is speeded by warming, and exposure to bumetanide and amiloride slows the temperature-dependent amplitude decline, consistent with a warming-induced increase in electroneutral Na+ entry. Blocking electroneutral Na+ movement is predicted to be useful in the treatment of temperature-dependent symptoms under conditions with reduced safety factor (Uhthoff's phenomenon) and provide a route to neuroprotection. [ABSTRACT FROM AUTHOR]

The flow behavior and viscosity of TAGs containing oleic and stearic acids were examined in the liquid phase as well as at temperatures close to the onset of crystallization by means of a temperature-controlled rheometer. Gelling and crystallization transitions were unambiguously identified by singularities in the viscosity versus temperature curves of the TAGs. An additional transition between the gelling and onset of crystallization temperatures, attributed to the reorganization of the gel, was observed in the symmetrical TAGs only. The effect of the cooling rate, ranging between 0.1 and 5 °C/min, was investigated. The flow behavior of the studied TAGs was shown to be strongly determined by structural parameters (symmetry, degree of unsaturation). The flow behavior was also affected significantly by the cooling rate, suggesting that to certain extents the flow behavior determined by structural parameters could be changed by manipulating the cooling rate. The study confirmed that TAG crystallization is initiated by and depends, at least in part, on complex molecular short range order transformations occurring in the melt. The findings of the study may be valuable for evaluating systems and equipment that are involved in the storage, handling and processing of materials incorporating these TAGs. [ABSTRACT FROM AUTHOR]

This work describes progress towards achieving a flexible, high specific power and low‐cost photovoltaic (PV) for emerging large area space applications. The study reports the highest conversion efficiency of 15.3% AM1.5G for a CdTe device on ultra‐thin cerium‐doped cover glass, the standard protective material for extra‐terrestrial PVs. The deposition technique used for all of the semiconductor layers comprising the device structure was atmospheric pressure metal organic chemical vapour deposition. Improvements to the device structure over those previously reported led to a Voc of 788 mV and a relatively low series resistance of 3.3 Ω·cm2. These were largely achieved by the introduction of a post‐growth air anneal and a refinement of the front contact bus bars, respectively. The aluminium‐doped zinc oxide transparent conductive oxide, being the first layer applied to the cover glass, was subject to thermal shock cycling +80 to (−) 196°C to test the adhesion under the extreme conditions likely to be encountered for space application. Scotch Tape testing and sheet resistance measurements before and after the thermal shock testing demonstrated that the aluminium‐doped zinc oxide remained well adhered to the cover glass and its electrical performance unchanged. [ABSTRACT FROM AUTHOR]

Ivacaftor is a novel cystic fibrosis (CF) transmembrane conductance regulator (CFTR) potentiator that improves the pulmonary function for patients with CF bearing a G551D CFTR-protein mutation. Because ivacaftor is highly bound (>97%) to plasma proteins, there is the strong possibility that co-administered CF drugs may compete for the same plasma protein binding sites and impact the free drug concentration. This, in turn, could lead to drastic changes in the in vivo efficacy of ivacaftor and therapeutic outcomes. This biochemical study compares the binding affinity of ivacaftor and co-administered CF drugs for human serum albumin (HSA) and α1-acid glycoprotein (AGP) using surface plasmon resonance and fluorimetric binding assays that measure the displacement of site-selective probes. Because of their ability to strongly compete for the ivacaftor binding sites on HSA and AGP, drug-drug interactions between ivacaftor are to be expected with ducosate, montelukast, ibuprofen, dicloxacillin, omeprazole, and loratadine. The significance of these plasma protein drug-drug interactions is also interpreted in terms of molecular docking simulations. This in vitro study provides valuable insights into the plasma protein drug-drug interactions of ivacaftor with co-administered CF drugs. The data may prove useful in future clinical trials for a staggered treatment that aims to maximize the effective free drug concentration and clinical efficacy of ivacaftor. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction The effects of age, height, and gender on magnetic central and peripheral motor conduction times (CMCT, PMCT) were analyzed using a multiple regression model. Methods Motor evoked potentials were recorded in 91 healthy volunteers. Magnetic stimulation was performed over the primary motor cortex (cortical latency) and over the cervical and lumbar spines (spinal latency). The spinal latency was taken as an estimate of PMCT and was subtracted from cortical latency to yield CMCT. Results Lower limb CMCT correlated significantly with height only; there were no significant predictors for upper limb CMCT. Upper and lower limb PMCT correlated with both age and height. Conclusions This is among the largest studies of CMCT in normal subjects. The multiple regression model unifies previously reported simple regression analyses, reconciles past discrepancies, and allows normal ranges to be individualized. Muscle Nerve 51:706-712, 2015 [ABSTRACT FROM AUTHOR]

A major assumption of brain-machine interface research is that patients with disconnected neural pathways can still volitionally recall precise motor commands that could be decoded for naturalistic prosthetic control. However, the disconnected condition of these patients also blocks kinaesthetic feedback from the periphery, which has been shown to regulate centrally generated output responsible for accurate motor control. Here, we tested how well motor commands are generated in the absence of kinaesthetic feedback by decoding hand movements from human scalp electroencephalography in three conditions: unimpaired movement, imagined movement, and movement attempted during temporary disconnection of peripheral afferent and efferent nerves by ischemic nerve block. Our results suggest that the recall of cortical motor commands is impoverished in the absence of kinaesthetic feedback, challenging the possibility of precise naturalistic cortical prosthetic control. Hum Brain Mapp 36:643-654, 2015. © 2014 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The sperm anterior head plasma membrane (APM) is the site where sperm first bind to the zona pellucida (ZP). This binding reaches the maximum following the sperm capacitation process. To gain a better understanding of the sperm-ZP binding mechanisms, we compared protein profiles obtained from mass spectrometry of APM vesicles isolated from non-capacitated and capacitated sperm. The results revealed that ZP-binding proteins were the most abundant group of proteins, with a number of them showing increased levels in capacitated sperm. Blue native gel electrophoresis and far-western blotting revealed presence of high molecular weight (HMW) protein complexes in APM vesicles of both non-capacitated and capacitated sperm, but the complexes (∼750-1300 kDa) from capacitated sperm possessed much higher binding capacity to pig ZP3 glycoprotein. Proteomic analyses indicated that a number of proteins known for their acrosome localization, including zonadhesin, proacrosin/acrosin and ACRBP, were components of capacitated APM HMW complexes, with zonadhesin being the most enriched protein. Our immunofluorescence results further demonstrated that a fraction of these acrosomal proteins was transported to the surface of live acrosome-intact sperm during capacitation. Co-immunoprecipitation indicated that zonadhesin, proacrosin/acrosin and ACRBP interacted with each other and they may traffic as a complex from the acrosome to the sperm surface. Finally, the significance of zonadhesin in the binding of APM HMW complexes to pig ZP3 was demonstrated; the binding ability was decreased following treatment of the complexes with anti-zonadhesin antibody. Our results suggested that acrosomal proteins, especially zonadhesin, played roles in the initial sperm-ZP binding during capacitation. J. Cell. Physiol. 230: 449-463, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The phase composition of triacylglycerols (TAG) is determined by chemical structure and is greatly affected by kinetics. Positional isomerism and unsaturation are two key structural elements that govern, for a large part, the phase behavior of TAG during crystallization. Polymorphism, thermal properties, and microstructure of dioleoyl-stearoyl isomers (OSO, SOO) were investigated at different cooling rates with XRD, DSC and PLM techniques, respectively. The physical properties of the symmetrical TAG were found to predictably vary with cooling rate; whereas, the properties of the asymmetrical TAG remained relatively constant. This was explained to be mainly due to the extra steric hindrance caused by asymmetry and the disturbances introduced at the 'terrace' level via methyl-end group interactions. The findings underscore the intricate contribution of saturation and symmetry to the phase trajectories of diunsaturated TAG. The knowledge gained will help understand the behavior of more complex materials and can be used for the manipulation of fat structures at different length scales and direct the manufacture of novel food systems and other relevant materials. Graphical abstract: [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Importin α proteins function as adaptors to connect a cargo protein and importin β1 in the classical nuclear import pathway. Here we measure for the first time the stoichiometry of importins α2, α3, α4, and β1 in primary cells corresponding to 2 successive stages of rat spermatogenesis: meiotic spermatocytes and haploid round spermatids. Importin α2 levels were more than 2-fold higher in spermatocytes than in spermatids, while importins α4 and β1 levels did not differ significantly. We performed a comprehensive proteomics analysis to identify binding proteins in spermatocytes and spermatids using recombinant importin α2 and α4 proteins. Among the 100 candidate partners, 42 contained a strong classical nuclear localization signal (cNLS; score of>6 by cNLS Mapper), while 8 nuclear proteins lacked any cNLS. hi addition, we developed a new strategy to predict which cargoes bind to importin α through the conserved C-terminal acidic domain (ARM repeats 9-10), and provided functional validation of a predicted importin α C-terminal binding segment in Senataxin and Smarca4. Evaluation of this set of candidate binding partners from spermatogenic cells using several bioinformatics approaches provides new evidence that individual importin as may serve unique and nonredundant roles in mediating cellular differentiation. [ABSTRACT FROM AUTHOR]

Positional isomerism in triacylglycerols (TAG), present in a molecular ensemble arising from genetic, environmental or processing-induced changes, can result in significant differences in the macroscopic physico-chemical functionality of crystallized networks of the ensemble. The differences in phase behavior induced by positional isomerism and levels of unsaturation of pure oleoyl-distearoyl TAG (SOS, SSO) were detailed at different length scales. The effect of cooling rate on the polymorphism, thermal properties and microstructure were systematically investigated between 0.1 and 5 °C/min. The symmetrical SOS presented a complex polymorphism and microstructure, which varied predictively with cooling rate. The crystal phases and transitions observed for this TAG are similar to those of cocoa butter. In contrast, the cooling rate had limited effect on the phase behavior of the asymmetrical SSO. The differences between the crystallization of SSO and SOS induced by kinetics are related to the kinked oleic acid at the outer position in the SSO molecule and favorable end group structure for SOS. The fundamental understanding gained from such model systems can be used in many industrial formulations, particularly foods. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Mild cognitive impairment in Parkinson's disease (PD) is common and predicts those at risk of dementia. Cholinergic dysfunction may contribute to its pathophysiology and can be assessed using short latency afferent inhibition. Methods Twenty-two patients with PD (11 cognitively normal; 11 with mild cognitive impairment) and 22 controls participated. Short latency afferent inhibition was measured by conditioning motor evoked potentials, which were elicited by transcranial magnetic stimulation of the motor cortex with electrical stimuli delivered to the contralateral median nerve at varying interstimulus intervals. Results There was no significant difference between cognitively normal PD and controls for short latency afferent inhibition (62.8±30.3% vs. 55.7±21.7%; P=0.447). The PD-mild cognitive impairment group had significantly less inhibition (88.4±25.8%) than both cognitively normal PD ( P=0.021) and controls ( P=0.01). Conclusions Cholinergic dysfunction occurs early in those with PD-mild cognitive impairment. Short latency afferent inhibition may be a useful biomarker of increased risk of dementia in PD patients. © 2013 Movement Disorder Society [ABSTRACT FROM AUTHOR]

This study utilizes sensitive, modern isothermal titration calorimetric methods to characterize the microscopic thermodynamic parameters that drive the binding of basic drugs to α-1-acid glycoprotein (AGP) and thereby rationalize the thermodynamic data in relation to docking models and crystallographic structures of the drug-AGP complexes. The binding of basic compounds from the tricyclic antidepressant series, together with miaserine, chlorpromazine, disopyramide and cimetidine, all displayed an exothermically driven binding interaction with AGP. The impact of protonation/deprotonation events, ionic strength, temperature and the individual selectivity of the A and F1*S AGP variants on drug-binding thermodynamics was characterized. A correlation plot of the thermodynamic parameters for all of the test compounds revealed that an enthalpy-entropy compensation is in effect. The exothermic binding energetics of the test compounds were driven by a combination of favorable (negative) enthalpic (∆ Hº) and favorable (positive) entropic (∆ Sº) contributions to the Gibbs free energy (∆ Gº). Collectively, the data imply that the free energies that drive drug binding to AGP and its relationship to drug serum residency evolve from the complex interplay of enthalpic and entropic forces from interactions with explicit combinations of hydrophobic and polar side-chain sub-domains within the multi-lobed AGP ligand binding cavity.Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]