Transgenic mice overexpressing leptin accumulate adipose mass at an older, but not younger, age.
Sensitivity to leptin is associated with a normal regulation of the adipose mass, whereas decreased leptin sensitivity results in elevated adipose tissue stores. To address whether the effects of chronic hyperleptinemia are sustained with age, we generated transgenic mice that overexpress leptin under the control of the fat specific aP2 promoter/enhancer. At 6-9 weeks of age, transgenic mice overexpressed 5-fold more human leptin than endogenous mouse levels and had consistently low body weights, with reduced brown and white fat depots characterized by adipocytes either devoid of or containing minute lipid droplets. However, at 33-37 weeks, despite continuous secretion of human leptin, the transgenic mice showed a rebound effect characterized by an increase in body weight, accumulation of adipose mass, and lipid-filled adipocytes. Thus, this mouse model exhibits a two-stage phenotype, with respect to fat accumulation. In addition, plasma glucose, triglycerides, and cholesterol levels were markedly depressed in young, but not older, transgenic mice. A detrimental consequence of early hyperleptinemia was a failure of the transgenic mice to acclimatize to the cold, as a result of depleted fat stores within their brown adipocytes. Cold exposure was tolerated after a 2-week high-fat diet or at an older age when fat depots had naturally accumulated. Treatment of the older transgenic mice with large doses of leptin stimulated weight loss, demonstrating that the leptin pathway still responds to pharmacological levels of leptin. Overall, these studies show that moderate hyperleptinemia in normal mice results in a sensitivity of the adipose mass to leptin at a younger (but not older) age. The mechanisms that lead to the accumulation of fat at an older age remain largely unknown, and this hyperleptinemic mouse model will allow the uncovering of at least some of these mechanisms.


Time delay measurement for linac based treatment delivery in synchronized respiratory gating radiotherapy.
A time delay in a respiratory gating system could cause an unexpected phase mismatch for synchronized gating radiotherapy. This study presents a method of identifying and measuring the time delay in a gating system. Various port films were taken for a motion phantom at different gating window levels with a very narrow window size. The time delay for the gating system was determined by comparing the motion curve (the position of a moving object versus the gating time) measured in the port films to the motion curve determined by the video cameras. The measured time delay for a linac-based gating system was 0.17+/-0.03 s. This time delay could induce target missing if it was not properly taken into account for the synchronized gating radiotherapy. Measurement/verification of the time delay should be considered as an important part of the accepting/commissioning test before the clinical use of the gating system.


Evolutionary dynamics and temporal/geographical correlates of recombination in the human enterovirus echovirus types 9, 11, and 30.
The relationship between virus evolution and recombination in species B human enteroviruses was investigated through large-scale genetic analysis of echovirus type 9 (E9) and E11 isolates (n = 85 and 116) from 16 European, African, and Asian countries between 1995 and 2008. Cluster 1 E9 isolates and genotype D5 and A E11 isolates showed evidence of frequent recombination between the VP1 and 3Dpol regions, the latter falling into 23 (E9) and 43 (E11) clades interspersed phylogenetically with 46 3Dpol clades of E30 and with those of other species B serotypes. Remarkably, only 2 of the 112 3Dpol clades were shared by more than one serotype (E11 and E30), demonstrating an extremely large and genetically heterogeneous recombination pool of species B nonstructural-region variants. The likelihood of recombination increased with geographical separation and time, and both were correlated with VP1 divergence, whose substitution rates allowed recombination half-lives of 1.3, 9.8, and 3.1 years, respectively, for E9, E11, and E30 to be calculated. These marked differences in recombination dynamics matched epidemiological patterns of periodic epidemic cycles of 2 to 3 (E9) and 5 to 6 (E30) years and the longer-term endemic pattern of E11 infections. Phylotemporal analysis using a Bayesian Markov chain Monte Carlo method, which placed recombination events within the evolutionary reconstruction of VP1, showed a close relationship with VP1 lineage expansion, with defined recombination events that correlated with their epidemiological periodicity. Whether recombination events contribute directly to changes in transmissibility that drive epidemic behavior or occur stochastically during periodic population bottlenecks is an unresolved issue vital to future understanding of enterovirus molecular epidemiology and pathogenesis.


Further application of hyperbaric oxygen in prostate cancer.
Hyperbaric oxygen therapy (HBOT) has been used as an adjuvant treatment for multiple pathological states, which involves hypoxic conditions. Over the past 50 years, HBOT has been recommended and used in a wide variety of medical conditions, clinically in the treatment of ischemic or nonhealing wounds and radiation-injured tissue, and in the treatment of malignancy. The mechanism of this treatment is providing oxygen under pressure which is higher than the atmosphere thus increasing tissue oxygen concentration. When cells get enough oxygen in the microenvironment, they become active and replicate effectively. Prostate cancer is the second most common cancer and the fifth leading cause of cancer death among male around the world. It is estimated that more than 29,000 men died from metastatic prostate cancer in 2014. With the development of the prostate-specific antigen-based screening technology, prostate cancer incidence has increased markedly over time. According to the survey, the morbidity and mortality of prostate cancer have surpassed bladder cancer and renal carcinoma, becoming the most common cancer in urology in Chinese adults. Nowadays, the main solution to deal with prostate cancer is still the surgical ways, including laparoscopic radical prostatectomy and robot-assisted radical prostatectomy. Nevertheless, the complications of the surgical treatment have not been completely avoided. HBOT has gained great clinical recognition over the decade. It has been demonstrated that HBOT has considerable effects on carcinoma, especially on decreasing complications and improving mortality. So, it is important to combine the HBOT with patients who suffer from prostate cancer. This review illuminates the effect and underlying mechanism of the HBOT in prostate cancer for further clinical application.


On moment closures for population dynamics in continuous space.
A first-order moment closure, the mean-field assumption that organisms encounter one another in proportion to their spatial average densities, lies at the heart of much theoretical ecology. This assumption ignores all spatial information and, at the very least, needs to be replaced by a second-order closure to gain understanding of ecological dynamics in spatially structured populations. We describe a number of conditions that a second-order closure should satisfy and use these conditions to evaluate some closures currently available in the literature. Two conditions are particularly helpful in discriminating among the alternatives: that the closure should be positive, and that the dynamics should be unaltered when identical individuals are given different labels. On this basis, a class of closures we refer to as 'power-2' turns out to provide a good compromise between positivity and dynamical invariance under relabelling.


Simulating Surfactant-Iron Oxide Interfaces: From Density Functional Theory to Molecular Dynamics.
Understanding the behavior of surfactant molecules on iron oxide surfaces is important for many industrial applications. Molecular dynamics (MD) simulations of such systems have been limited by the absence of a force field (FF), which accurately describes the molecule-surface interactions. In this study, interaction energies from density functional theory (DFT) + U calculations with a van der Waals functional are used to parameterize a classical FF for MD simulations of amide surfactants on iron oxide surfaces. The original FF, which was derived using mixing rules and surface Lennard-Jones (LJ) parameters developed for nonpolar molecules, was shown to significantly underestimate the adsorption energy and overestimate the equilibrium adsorption distance compared to DFT. Conversely, the optimized FF showed excellent agreement with the interaction energies obtained from DFT calculations for a wide range of surface coverages and molecular conformations near to and adsorbed on α-Fe2O3(0001). This was facilitated through the use of a Morse potential for strong chemisorption interactions, modified LJ parameters for weaker physisorption interactions, and adjusted partial charges for the electrostatic interactions. The original FF and optimized FF were compared in classical nonequilibrium molecular dynamics simulations of amide molecules confined between iron oxide surfaces. When the optimized FF was employed, the amide molecules were pulled closer to the surface and the orientation of the headgroups was more similar to that observed in the DFT calculations. The optimized FF proposed here facilitates classical MD simulations of anhydrous amide-iron oxide interfaces in which the interactions are representative of accurate DFT calculations.


Layer-by-layer thin films and microcapsules for biosensors and controlled release.
We present an overview of the preparation and properties of layer-by-layer (LbL) deposited thin films and microcapsules in relation to their use in the development of biosensors and controlled release systems. Enzyme biosensors can be constructed by immobilizing enzymes on the surface of electrodes by LbL deposition without loss of their catalytic activity. In addition to synthetic polymers, binding proteins, such as avidin and lectin, are also used for constructing LbL films through avidin-biotin and lectin-sugar interactions. The performance characteristics of LbL film-based biosensors can be tuned by controlling the number of layers and by the choice of film components. The permeability of polyelectrolyte LbL films to ions and molecules is discussed in relation to the use of the films for eliminating interference in biosensors. The possible use of polysaccharide LbL film-coated electrodes for the construction of biosensors is highlighted, and examples of LbL film- and microcapsule-based optical sensors are described. We then focus on the use of LbL films and microcapsules as vehicles for controlled release, in particular on recent progress in the controlled release of insulin from LbL films and microcapsules. LbL films composed of insulin and polymers are sensitive to environmental pH, and release insulin in response to pH changes, suggesting that insulin LbL films can be used in the development of orally administered insulin. The construction of glucose-dependent insulin release systems using LbL insulin microcapsules functionalized with phenylboronic acid, lectin, and glucose oxidase is also examined.


Modelling the distribution in Hawaii of Angiostrongylus cantonensis (rat lungworm) in its gastropod hosts.
Angiostrongylus cantonensis (rat lungworm), a parasitic nematode, is expanding its distribution. Human infection, known as angiostrongyliasis, may manifest as eosinophilic meningitis, an emerging infectious disease. The range and incidence of this disease are expanding throughout the tropics and subtropics. Recently, the Hawaiian Islands have experienced an increase in reported cases. This study addresses factors affecting the parasite's distribution and projects its potential future distribution, using Hawaii as a model for its global expansion. Specimens of 37 snail species from the Hawaiian Islands were screened for the parasite using PCR. It was present on five of the six largest islands. The data were used to generate habitat suitability models for A. cantonensis, based on temperature and precipitation, to predict its potential further spread within the archipelago. The best current climate model predicted suitable habitat on all islands, with greater suitability in regions with higher precipitation and temperatures. Projections under climate change (to 2100) indicated increased suitability in regions with estimated increased precipitation and temperatures, suitable habitat occurring increasingly at higher elevations. Analogously, climate change could facilitate the spread of A. cantonensis from its current tropical/subtropical range into more temperate regions of the world, as is beginning to be seen in the continental USA.


Brain Connectivity Changes after Osteopathic Manipulative Treatment: A Randomized Manual Placebo-Controlled Trial.
The effects of osteopathic manipulative treatment (OMT) on functional brain connectivity in healthy adults is missing in the literature. To make up for this lack, we applied advanced network analysis methods to analyze resting state functional magnetic resonance imaging (fMRI) data, after OMT and Placebo treatment (P) in 30 healthy asymptomatic young participants randomized into OMT and placebo groups (OMTg; Pg). fMRI brain activity measures, performed before (T0), immediately after (T1) and three days after (T2) OMT or P were used for inferring treatment effects on brain circuit functional organization. Repeated measures ANOVA and post-hoc analysis demonstrated that Right Precentral Gyrus (F (2, 32) = 5.995, p < 0.005) was more influential over the information flow immediately after the OMT, while decreased betweenness centrality in Left Caudate (F (2, 32) = 6.496, p < 0.005) was observable three days after. Clustering coefficient showed a distinct time-point and group effect. At T1, reduced neighborhood connectivity was observed after OMT in the Left Amygdala (L-Amyg) (F (2, 32) = 7.269, p < 0.005) and Left Middle Temporal Gyrus (F (2, 32) = 6.452, p < 0.005), whereas at T2 the L-Amyg and Vermis-III (F (2, 32) = 6.772, p < 0.005) increased functional interactions. Data demonstrated functional connectivity re-arrangement after OMT.


Shift work, fetal development and course of pregnancy.
Information on 1475 mothers of infants with selected structural malformations and an equal number of mothers of "normal" babies was analyzed for a possible relationship between shift work and adverse pregnancy outcome or a complicated course of pregnancy. The primary data were obtained from the Finnish Register of Congenital Malformations supplemented by special interviews on the mothers' work conditions. No signs of a teratogenic risk were observed. The relationship between course of pregnancy and outcomes other than malformations was determined from the noncase mothers' experience. Threatened abortion and pregnancy-induced hypertension were not associated with rotating shift work alone, but in a noisy work environment moderate risks could not be ruled out. Rotating shift work was associated with a slight excess of babies small for their gestational age independently of noise exposure. The results suggest that further studies on the effects of different work schedules on pregnancy are worth consideration.


Opportunities and challenges of Integral Projection Models for modelling host-parasite dynamics.
Epidemiological dynamics are shaped by and may in turn shape host demography. These feedbacks can result in hard to predict patterns of disease incidence. Mathematical models that integrate infection and demography are consequently a key tool for informing expectations for disease burden and identifying effective measures for control. A major challenge is capturing the details of infection within individuals and quantifying their downstream impacts to understand population-scale outcomes. For example, parasite loads and antibody titres may vary over the course of an infection and contribute to differences in transmission at the scale of the population. To date, to capture these subtleties, models have mostly relied on complex mechanistic frameworks, discrete categorization and/or agent-based approaches. Integral Projection Models (IPMs) allow variance in individual trajectories of quantitative traits and their population-level outcomes to be captured in ways that directly reflect statistical models of trait-fate relationships. Given increasing data availability, and advances in modelling, there is considerable potential for extending this framework to traits of relevance for infectious disease dynamics. Here, we provide an overview of host and parasite natural history contexts where IPMs could strengthen inference of population dynamics, with examples of host species ranging from mice to sheep to humans, and parasites ranging from viruses to worms. We discuss models of both parasite and host traits, provide two case studies and conclude by reviewing potential for both ecological and evolutionary research.


Comparative efficacy of bone anabolic therapies in women with postmenopausal osteoporosis: A systematic review and network meta-analysis of randomized controlled trials.
To systematically evaluate the effects of bone anabolic therapies (BATs) - specifically, drug therapy with teriparatide, abaloparatide or romosozumab - on fractures, bone mineral density (BMD), and bone metabolites in postmenopausal osteoporosis. Six computerized engines were searched through to November 2018. We selected randomized controlled trials (RCTs) evaluating the effect of BATs on postmenopausal osteoporosis and with at least 6 months of follow-up. Controls were placebo, no treatment, or bisphosphonates. Primary outcomes were vertebral and non-vertebral fractures. Secondary outcomes were: BMD determined by dual energy X-ray absorptiometry at total hip, lumbar spine, and femoral neck; N-terminal propeptide of type I procollagen (PINP); C-terminal telopeptide of type I collagen (CTX); and severe adverse events (SAE). We followed the PRISMA guidelines for reporting, and used version 2 of the Cochrane risk-of-bias tool. Frequentist network meta-analyses were performed per outcome. Effects for dichotomous and continuous outcomes were expressed as relative risks and mean differences and their 95% confidence intervals. We used p-scores to rank best treatments per outcome. Sixteen RCTs (n = 18,940) were evaluated. Mean ages ranged between 61 and 74 years, and follow-up times between 6 and 30 months. Four RCTs (n = 971) excluded patients with previous fractures. In contrast to placebo/no treatment, all BATs significantly reduced the risk of vertebral fractures, but no intervention significantly reduced the risk of non-vertebral fractures; abaloparatide ranked better than other interventions for both fracture types (p-scores: 0.95, and 0.89, respectively). All BATs significantly increased BMD at all locations in comparison with placebo/no treatment; romosozumab consistently ranked better than other interventions at all BMD locations (p-scores >0.86). Teriparatide ranked better than other interventions for increasing PINP. No differences in SAE were observed among treatments. Abaloparatide, romosozumab, and teriparatide are the best treatments, respectively, to reduce vertebral/non-vertebral fractures, increase BMD, and increase bone formation.


Effects of nationwide training of multiprofessional trauma teams in norwegian hospitals.
Norway has 50 trauma hospitals serving a geographically disperse population (4.6 million) and many have low trauma case loads. We showed that personnel find functioning as a team especially challenging, and developed a 1-day training course, arranged locally at each hospital, focused on team training in communication, leadership, and cooperation during simulated patient treatment. This study evaluates the effects of training on participants' knowledge, confidence, and perceived trauma team performance, controlling for hospital size and the participants' previous experience. Anonymous, written questionnaires were answered by 4,203 participants (28% physicians, 55% nurses) in 44 hospitals before and immediately after training courses, and by 1,368 trauma team members in 26 of the hospitals 6 months after their last training course. Outcome measures were knowledge and confidence concerning the respondent's own role, and evaluation of trauma team performance in live trauma resuscitations. There was a significant increase in self-reported knowledge and confidence among all participants. Community hospitals and participants without recent trauma experience had the lowest preintervention scores, but reached levels comparable to participants at the other hospitals after training. The effects increased after 6 months, with trauma team performance evaluated as having improved, even by team members who had not participated in the training. Practical team training in hospitals improved the participants' perceived knowledge and confidence, which continued to increase for 6 months after training independent of participants' experience level, suggesting that small hospitals may reach levels comparable to major hospitals.


Next-generation tissue-engineered heart valves with repair, remodelling and regeneration capacity.
Valvular heart disease is a major cause of morbidity and mortality worldwide. Surgical valve repair or replacement has been the standard of care for patients with valvular heart disease for many decades, but transcatheter heart valve therapy has revolutionized the field in the past 15 years. However, despite the tremendous technical evolution of transcatheter heart valves, to date, the clinically available heart valve prostheses for surgical and transcatheter replacement have considerable limitations. The design of next-generation tissue-engineered heart valves (TEHVs) with repair, remodelling and regenerative capacity can address these limitations, and TEHVs could become a promising therapeutic alternative for patients with valvular disease. In this Review, we present a comprehensive overview of current clinically adopted heart valve replacement options, with a focus on transcatheter prostheses. We discuss the various concepts of heart valve tissue engineering underlying the design of next-generation TEHVs, focusing on off-the-shelf technologies. We also summarize the latest preclinical and clinical evidence for the use of these TEHVs and describe the current scientific, regulatory and clinical challenges associated with the safe and broad clinical translation of this technology.


Late life depression: a comparison of risk factors and symptoms according to age of onset in community dwelling older adults.
It has been reported that late onset depression is more frequently associated with acquired organic pathology and that patients are less likely to report a family history of depression. Differences in phenomenology according to age of onset have been described although these have not been consistently replicated. The majority of these studies have been in hospital populations. The aim of this study is to address this question in a sample of community dwelling older adults. 89 subjects with GMS-AGECAT depression were identified from a sample of 1231 community dwelling adults aged 65 years and over. Subjects were analysed across a range of aetiological and phenomenological variables according to age of onset of first depressive episode. Subjects with late onset depression (≥ 60) were significantly less likely to report a family history of depression, were less likely to report previous hospitalisation for depression and had greater cognitive impairment. Late onset subjects were also less likely to report feelings of guilt or thoughts that life was not worth living in the previous month. While we found that patients with late onset depression differed from early onset patients according to certain aetiological risk factors, we did not find a distinctive profile of depressive symptomatology which might be considered clinically useful at an individual level. These findings are consistent with studies based in hospital populations.


Intracardiac extension of intravenous leiomyoma.
Intravenous leiomyoma with intracaval and intracardiac extension is a rare benign neoplasm affecting women. We report a case in which an intravenous leiomyoma originated from the right iliac vein and extended through the inferior vena cava into the right atrium. The correct diagnosis was made intraoperatively, after resection of the intracardiac extension of the tumor, which was 28 cm in length. At the 2nd stage of the operation, a right common iliac venotomy enabled the removal of all residual tumor from the inferior vena cava.


αvβ6 integrin may be a potential prognostic biomarker in interstitial lung disease.
Idiopathic pulmonary fibrosis (IPF) and fibrotic nonspecific interstitial pneumonitis are progressive interstitial lung diseases (ILDs) with limited treatment options and poor survival. However, the rate of disease progression is variable, implying there may be different endotypes of disease. We hypothesised that immunophenotyping biopsies from ILD patients might reveal distinct endotypes of progressive fibrotic disease, which may facilitate stratification when undertaking clinical trials of novel therapies for IPF.43 paraffin-embedded, formalin-fixed lung tissue sections were immunostained for five molecules implicated in the pathogenesis of the fibrosis: α-smooth muscle actin (αSMA), αvβ6 integrin, pro-surfactant protein C (SP-C), hepatocyte growth factor (HGF) and tenascin-C (TenC). Levels of immunostaining and numbers of fibroblastic foci were quantified using operator-dependent and -independent methods. The relationship of all these markers to overall survival was analysed.Staining revealed high levels of αSMA, αvβ6 integrin, pro-SP-C, HGF and TenC, and fibroblastic foci. Immunostaining varied across samples for all molecules but only the extent of αvβ6 integrin immunostaining was associated with increased mortality. There was no association with the other markers measured.Our data suggest high levels of αvβ6 integrin may identify a specific endotype of progressive fibrotic lung disease.


Three new mononuclear tri-spin lanthanide-nitronyl nitroxide radical compounds: syntheses, structures and magnetic properties.
Based on the nitronyl nitroxide radical, 2-(4-(methoxycarbonyl)phenyl)-4,4,5,5-tetramethylimidazolin-1-oxyl-3-oxide (1, NITPhCOOMe), and three mononuclear tri-spin compounds [Ln(hfac)3(NITPhCOOMe)2] (Ln = Gd (2), Tb (3), Dy (4); hfac = hexafluoroacetylacetonate) are successfully synthesized and fully characterized. Compounds 2 and 4 are isostructural and crystallize in the C2/c space group, while compound 3 crystallizes in the P2₁/c space group. For compounds 2-4, the central metal ions are all eight-coordinate in distorted triangular dodecahedral LnO8 coordination geometry (D(2d) symmetry) completed by three bischelate hfac(-) ligands and two monodentate radicals. Magnetic studies show that radical 1 undertakes the transition from the paramagnetic state to 3D antiferromagnetic ordering at 4.2 K. In addition, compound 3 exhibits field-induced single-molecule magnet (SMM) behavior.


Trapped intermediate state of plant pyruvate phosphate dikinase indicates substeps in catalytic swiveling domain mechanism.
Pyruvate phosphate dikinase (PPDK) is an essential enzyme of both the C4 photosynthetic pathway and cellular energy metabolism of some bacteria and unicellular protists. In C4 plants, it catalyzes the ATP- and Pi -dependent formation of phosphoenolpyruvate (PEP) while in bacteria and protozoa the ATP-forming direction is used. PPDK is composed out of three distinct domains and exhibits one of the largest single domain movements known today during its catalytic cycle. However, little information about potential intermediate steps of this movement was available. A recent study resolved a discrete intermediate step of PPDK's swiveling movement, shedding light on the details of this intriguing mechanism. Here we present an additional structural intermediate that possibly represents another crucial step in the catalytic cycle of PPDK, providing means to get a more detailed understanding of PPDK's mode of function.


Phospholipid synthesis participates in the regulation of diacylglycerol required for membrane trafficking at the Golgi complex.
The lipid metabolite diacylglycerol (DAG) is required for transport carrier biogenesis at the Golgi, although how cells regulate its levels is not well understood. Phospholipid synthesis involves highly regulated pathways that consume DAG and can contribute to its regulation. Here we altered phosphatidylcholine (PC) and phosphatidylinositol synthesis for a short period of time in CHO cells to evaluate the changes in DAG and its effects in membrane trafficking at the Golgi. We found that cellular DAG rapidly increased when PC synthesis was inhibited at the non-permissive temperature for the rate-limiting step of PC synthesis in CHO-MT58 cells. DAG also increased when choline and inositol were not supplied. The major phospholipid classes and triacylglycerol remained unaltered for both experimental approaches. The analysis of Golgi ultrastructure and membrane trafficking showed that 1) the accumulation of the budding vesicular profiles induced by propanolol was prevented by inhibition of PC synthesis, 2) the density of KDEL receptor-containing punctated structures at the endoplasmic reticulum-Golgi interface correlated with the amount of DAG, and 3) the post-Golgi transport of the yellow fluorescent temperature-sensitive G protein of stomatitis virus and the secretion of a secretory form of HRP were both reduced when DAG was lowered. We confirmed that DAG-consuming reactions of lipid synthesis were present in Golgi-enriched fractions. We conclude that phospholipid synthesis pathways play a significant role to regulate the DAG required in Golgi-dependent membrane trafficking.


Expression and prognostic impact of lncRNAs in acute myeloid leukemia.
Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides, located within the intergenic stretches or overlapping antisense transcripts of protein coding genes. LncRNAs are involved in numerous biological roles including imprinting, epigenetic regulation, apoptosis, and cell cycle. To determine whether lncRNAs are associated with clinical features and recurrent mutations in older patients (aged ≥60 y) with cytogenetically normal (CN) acute myeloid leukemia (AML), we evaluated lncRNA expression in 148 untreated older CN-AML cases using a custom microarray platform. An independent set of 71 untreated older patients with CN-AML was used to validate the outcome scores using RNA sequencing. Distinctive lncRNA profiles were found associated with selected mutations, such as internal tandem duplications in the FLT3 gene (FLT3-ITD) and mutations in the NPM1, CEBPA, IDH2, ASXL1, and RUNX1 genes. Using the lncRNAs most associated with event-free survival in a training cohort of 148 older patients with CN-AML, we derived a lncRNA score composed of 48 lncRNAs. Patients with an unfavorable compared with favorable lncRNA score had a lower complete response (CR) rate [P < 0.001, odds ratio = 0.14, 54% vs. 89%], shorter disease-free survival (DFS) [P < 0.001, hazard ratio (HR) = 2.88] and overall survival (OS) (P < 0.001, HR = 2.95). The validation set analyses confirmed these results (CR, P = 0.03; DFS, P = 0.009; OS, P = 0.009). Multivariable analyses for CR, DFS, and OS identified the lncRNA score as an independent marker for outcome. In conclusion, lncRNA expression in AML is closely associated with recurrent mutations. A small subset of lncRNAs is correlated strongly with treatment response and survival.


Measurement of Coherent π^{+} Production in Low Energy Neutrino-Carbon Scattering.
We report the first measurement of the flux-averaged cross section for charged current coherent π^{+} production on carbon for neutrino energies less than 1.5 GeV, and with a restriction on the final state phase space volume in the T2K near detector, ND280. Comparisons are made with predictions from the Rein-Sehgal coherent production model and the model by Alvarez-Ruso et al., the latter representing the first implementation of an instance of the new class of microscopic coherent models in a neutrino interaction Monte Carlo event generator. We observe a clear event excess above background, disagreeing with the null results reported by K2K and SciBooNE in a similar neutrino energy region. The measured flux-averaged cross sections are below those predicted by both the Rein-Sehgal and Alvarez-Ruso et al.


Be honest and help me prepare for the future: What people with interstitial lung disease want from education in pulmonary rehabilitation.
Pulmonary rehabilitation (PR) is recommended for people with interstitial lung disease (ILD); however, the educational content of PR was not designed for this group. This study explored the perspectives of patients and ILD clinicians regarding the educational content of PR for ILD. A qualitative study using individual semi-structured interviews was undertaken. Transcripts were coded independently by two investigators and themes established by consensus. Participants were 18 people with ILD (9 idiopathic pulmonary fibrosis, diffusing capacity for carbon monoxide 54 (20)% predicted) and 14 clinicians from 5 countries and 5 disciplines. Major themes from patient interviews were the importance of knowing what the future might bring and the need for honesty from clinicians. Most were happy to attend standard PR education sessions but wanted ILD-specific content. Patients wanted information about end-of-life planning and most were happy to discuss it in a group. Among clinicians, there was no consensus regarding whether prognosis should be discussed in PR. Most clinicians supported discussion of advanced care planning, however, some thought it should not be discussed in a group. We conclude that people with ILD have specific educational needs that may not be met in the current PR format. Patients and clinicians have some discordant views about programme content.


Effect of short- and long-term administration of lithium on the release of endogenous 5-HT in the hippocampus of the rat in vivo and in vitro.
The present study determined the effect of short- (3 days) and long- (21 days) term treatment with lithium on the release of 5-hydroxytryptamine (5-HT) form the hippocampus of the rat, measured both in vivo using microdialysis and in vitro using incubated slices. In the in vivo experiments (on the chloral hydrate-anaesthetized rat) electrical stimulation of the dorsal raphe nucleus for 20 min evoked an increase of 5-HT in dialysates of hippocampus, which both lasted for the duration of the stimulus and was frequency-dependent (2-10 Hz). Electrical stimulation of the dorsal raphe nucleus, at low stimulation pulse frequencies (2 and 3 Hz), released 3-4 fold more 5-HT in rats treated for 3 days with lithium chloride (3 mmol/kg s.c. twice daily), compared to controls. However, the effect of stimulation of the dorsal raphe nucleus was not altered in rats receiving lithium in the diet for 21 days. Basal levels of 5-HT in hippocampal dialysates for rats receiving long- but not short-term treatment with lithium, were significantly lower than controls. In agreement with the in vivo experiments, the in vitro experiments showed that depolarization (high potassium)-evoked release of endogenous 5-HT from slices of hippocampus of rats treated with short- but not long-term administration of lithium was enhanced compared to controls. These experiments provide direct biochemical evidence that short-term treatment with lithium increases depolarization-evoked release of endogenous 5-HT in the hippocampus, an effect which may be related to the rapid antidepressant actions of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)


Prospective double-blinded study of abdominal-pelvic computed tomography guided by the region of tenderness: estimation of detection of acute pathology and radiation exposure reduction.
Computed tomography (CT) is increasingly used for emergency department (ED) patients with abdominal tenderness. CT-related radiation contributes to 2% of US cancers. We hypothesized that in the ED patient with nontraumatic abdominal tenderness, the tender region accurately delineates acute pathology. z axis-restricted CT guided by this region could detect pathology while reducing radiation dose. This was a prospective double-blinded observational trial with informed consent and was institutional review board-approved and registered with ClinicalTrials.gov. A convenience sample of ED patients undergoing abdominal CT was recruited, excluding pregnant women, patients with altered mental status or abdominal sensation, preverbal children, and patients with abdominal trauma or surgery in the previous month. Before standard CT, physicians demarcated the tender region with labels invisible to radiologists on abdominal windows. Radiologists blinded to the tender region recorded cephalad-caudad limits of pathology on CT. Personnel blinded to pathology location recorded label positions on lung windows. Two hypothetical CT strategies were then explored: CT restricted to the tender region and CT from the cephalad skin marker to the lower caudad limit of the usual CT. The percentage of the pathologic region contained within the extent of the 2 hypothetical z axis restricted CTs was calculated. z axis reduction, which is linearly related to radiation reduction, from the restricted CTs was determined. One hundred two subjects were enrolled, 93 with complete data for analysis. Fifty-one subjects had acute pathology on CT. CT limited to the tender region would reduce z axis (radiation exposure) by 69% (95% confidence interval [CI] 60% to 78%). All acute pathology was included within these boundaries in 17 of the 51 abnormal cases (33%; 95% CI 22% to 47%). CT from the cephalad marker through the caudad abdomen and pelvis would reduce z axis (radiation exposure) by 38% (95% CI 29% to 48%). All acute pathology was included within these boundaries in 36 of 51 abnormal cases (71%; 95% CI 57% to 81%). With both strategies 1 and 2, the pathologic region was at least partially included within the CT region in the majority of cases (84% and 92%, respectively). CT with z axis restriction based on abdominal tenderness could reduce radiation exposure but with a potentially unacceptably high rate of misdiagnosis, using our current methods. Further prospective study may be warranted to determine the diagnostic utility of partially visualized pathology.


Association Between IL-18 and Carotid Intima-Media Thickness in Patients with Type II Diabetic Nephropathy.
BACKGROUND We specifically designed this study to determine the relationship between levels of IL-8 and carotid intima-media thickness (cIMT) in patients with type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS A total of 149 diabetic patients at different stages of diabetic nephropathy and 72 matched controls were recruited in this study. A wide range of parameters were measured: IL-18 (by ELISA), urinary albumin excretion rates (UAER), and carotid intima-media thickness (cIMT, by pulse wave velocity [PWV]). All the diabetic patients were treated by alprostadil. RESULTS ELISA indicated that the level of IL-18 in the patient group was significantly higher compared with that in the control group. The level of IL-18 apparently increased in the higher cIMT group in T2DM patients. Serum IL-18 levels were positively correlated with cIMT in patients with T2DM, the level of IL-18 was negatively correlated with cIMT, and IL-18 levels were positively correlated to age. Moreover, IMT was positively correlated with hemoglobin A1C (HbA1C) and IL-18 levels were significantly associated with cIMT (all P<0.05). CONCLUSIONS IL-18 levels were positively correlated with atherosclerotic burden in patients with T2DM and it may be considered as a significant therapeutic target.


Statin shapes inflamed tumor microenvironment and enhances immune checkpoint blockade in non-small cell lung cancer.
Immune checkpoint blockade (ICB) therapy has achieved breakthroughs in the treatment of advanced non-small cell lung cancer (NSCLC). Nevertheless, the low response due to immuno-cold (i.e., tumors with limited tumor-infiltrating lymphocytes) tumor microenvironment (TME) largely limits the application of ICB therapy. Based on the glycolytic/cholesterol synthesis axis, a stratification framework for EGFR-WT NSCLC was developed to summarize the metabolic features of immuno-cold and immuno-hot tumors. The cholesterol subgroup displays the worst prognosis in immuno-cold NSCLC, with significant enrichment of the cholesterol gene signature, indicating that targeting cholesterol synthesis is essential for the therapy for immuno-cold NSCLC. Statin, the inhibitor for cholesterol synthesis, can suppress the aggressiveness of NSCLC in vitro and in vivo and can also drastically reverse the phenotype of immuno-cold to an inflamed phenotype in vivo. This change led to a higher response to ICB therapy. Moreover, both our in-house data and meta-analysis further support that statin can significantly enhance ICB efficacy. In terms of preliminary mechanisms, statin could transcriptionally inhibit PD-L1 expression and induce ferroptosis in NSCLC cells. Overall, we reveal the significance of cholesterol synthesis in NSCLC and demonstrate the improved therapeutic efficacy of ICB in combination with statin. These findings could provide a clinical insight to treat NSCLC patients with immuno-cold tumors.


[Cholesterol: blood level and control by Swiss physicians].
The high coronary heart disease morbidity and mortality and the economic costs have led to intensive prevention efforts in Switzerland, where the management of multiple risk factors plays a prominent role. An important risk factor is hypercholesterolemia, one of the main causes in the development of human atherosclerosis. However, the eminence of this risk factor is not yet sufficiently established in the awareness of many physicians. Inappropriate public discussions of the problem have caused confusion among patients and physicians. Therefore, the purpose of the Cholesterin Informations Program of the Swiss Heart Foundation is to work out a far-reaching and objective information strategy for experts and the general population, based on scientific knowledge, as a contribution to promoting the health of the Swiss population.


Analysis of optical trapping and propulsion of Rayleigh particles using Airy beam.
The radiation forces and trajectories of Rayleigh dielectric particles induced by one-dimensional Airy beam were numerically analyzed. Results show that the Airy beam drags particles into the optical intensity peaks, and guides particles vertically along parabolic trajectories. Viscosity of surrounding medium significantly affects the trajectories. Random Brownian force affects the trajectories. Meanwhile, trapping potential depths and minimum trapping particle radii in different potential wells were also discussed. The trapping stability could be improved by increasing either the input peak intensity or the particle radius.


Sub-strains of Drosophila Canton-S differ markedly in their locomotor behavior.
We collected five sub-strains of the standard laboratory wild-type Drosophila melanogaster Canton Special (CS) and analyzed their walking behavior in Buridan's paradigm using the CeTrAn software. According to twelve different aspects of their behavior, the sub-strains fit into three groups. The group separation appeared not to be correlated with the origin of the stocks. We conclude that founder effects but not laboratory selection likely influenced the gene pool of the sub-strains. The flies' stripe fixation was the parameter that varied most. Our results suggest that differences in the genome of laboratory stocks can render comparisons between nominally identical wild-type stocks meaningless. A single source for control strains may settle this problem.


Two Years of Relationship-Focused Mentoring for First Nations, Métis, and Inuit Adolescents: Promoting Positive Mental Health.
First Nations, Métis, and Inuit (FNMI) youth are disproportionately affected by a range of negative health outcomes including poor emotional and psychosocial well-being. At the same time, there is increasing awareness of culturally-specific protective factors for these youth, such as cultural connectedness and identity. This article reports the findings of a mixed-methods, exploratory longitudinal study on the effects of a culturally-relevant school-based mentoring program for FNMI youth that focuses on promoting mental well-being and the development of cultural identity. Participants included a cohort of FNMI adolescents whom we tracked across the transition from elementary to secondary school. We utilized data from annual surveys (n = 105) and a subset of youth whom we interviewed (n = 28). Quantitative analyses compared youth who participated in 1 or 2 years of mentoring programs with those who did not participate. At Wave 3, the 2-year mentoring group demonstrated better mental health and improved cultural identity, accounting for Wave 1 functioning. These results were maintained when sex and school climate were accounted for in the models. Sex did not emerge as a significant moderator; however, post hoc analyses with simple slopes indicated that the mentoring program benefited girls more than boys for both outcomes. Interview data were coded and themed through a multi-phase process, and revealed that the mentoring program helped participants develop their intrapersonal and interpersonal skills, and enhanced their cultural and healthy relationships knowledge base. Collectively, the quantitative and qualitative components of this study identify multiple years of culturally-relevant mentoring as a promising approach for promoting well-being among FNMI youth.


Medicinal chemistry of the anti-diabetic effects of momordica charantia: active constituents and modes of actions.
Diabetes mellitus (DM) is one of the oldest known human disease currently affecting more than 200 million people worldwide. Diabetes mellitus is derived from two Greek words meaning siphon and sugar. In DM, patients have high blood level of glucose and this passes out with urine. This is because the endocrine pancreas does not produce either or not enough insulin or the insulin which is produced is not exerting its biochemical effect (or insulin resistance) effectively. Insulin is a major metabolic hormone which has numerous functions in the body and one main role is to stimulate glucose uptake into body's cells where it is utilized to provide energy. The disease is classified into type 1 and type 2 DM. Type 1 DM develops when the insulin producing β cells have been destroyed and are unable to produce insulin. This is very common in children and is treated with insulin. Type 2 DM (T2DM) develops when the body is unable to produce an adequate amount of insulin or the insulin which is provided does not work efficiently. This is due to life style habits including unhealthy diet, obesity, lack of exercise and hereditary and environmental factors. Some symptoms of DM include excess urination, constant thirst, lethargy, weight loss, itching, decreased digestive enzyme secretion, slow wound healing and other related symptoms. If left untreated, DM can result in severe long-term complications such as kidney and heart failure, stroke, blindness, nerve damage, exocrine glands insufficiency and other forms of complications. T2DM can be treated and controlled by prescribed drugs, regular exercise, diet (including some plant-based food) and general change in life style habits. This review is concerned with the role of plant-based medicine to treat DM. One such plant is Momordica charantia which is grown in tropical countries worldwide and it has been used as a traditional herbal medicine for thousands of years although its origin in unknown. This review examines the medicinal chemistry and use(s) of M. charantia and its various extracts and compounds, their biochemical properties and how they act as anti-diabetic (hypoglycemic) drugs and the various mechanisms by which they exert their beneficial effects in controlling and treating DM.


Improved glycemic control with proximal intestinal bypass and weight loss following gastrectomy in non-obese diabetic gastric cancer patients.
The aim of this study was to assess whether gastrectomy influences glycemic control in non-obese diabetic gastric cancer patients and to identify factors related to glucose metabolism after gastrectomy. We retrospectively analyzed changes in glucose metabolism in 238 non-obese (body mass index < 30 kg/m2) patients with type II diabetes who underwent distal gastrectomy with either gastroduodenostomy (n = 91) or gastrojejunostomy (n = 147) for stage I gastric cancer. We collected demographics, diabetes-related features, surgery-related features, and changes in glucose metabolism during follow-up. The effect of surgery on the course of diabetes was evaluated at different time points according to fasting blood glucose levels and use of diabetes-related medication. Preoperatively, the mean body mass index was 24.3 ± 2.3. Weight, body mass index and fasting blood glucose of all patients were significantly lower compared to preoperative levels at all time points. Weight loss after 6 months and the percentage of patients whose weight loss ratio was higher than 10% after one year were greater in the gastrojejunostomy group than the gastroduodenostomy group. Overall, 88 (37%) patients showed improvement in their diabetes course at one month after surgery; 152 (64%) showed improvement after 2 years. Duration of diabetes, weight loss, and reconstruction type were associated with improvement in diabetes at different time points. At 6 months and thereafter, the percentage of patients with an improved diabetes course was highest in the gastrojejunostomy plus higher than 10% weight loss group. Although weight loss may be associated with adverse effects of gastrectomy, postoperative weight loss in an acceptable range is a useful measure of the better glycemic control for the group of diabetic patients. Selecting gastrojejunostomy during gastrectomy and inducing acceptable weight loss after gastrectomy could be beneficial to the non-obese diabetic gastric cancer patients for improved glycemic control.


NetSurfP-2.0: Improved prediction of protein structural features by integrated deep learning.
The ability to predict local structural features of a protein from the primary sequence is of paramount importance for unraveling its function in absence of experimental structural information. Two main factors affect the utility of potential prediction tools: their accuracy must enable extraction of reliable structural information on the proteins of interest, and their runtime must be low to keep pace with sequencing data being generated at a constantly increasing speed. Here, we present NetSurfP-2.0, a novel tool that can predict the most important local structural features with unprecedented accuracy and runtime. NetSurfP-2.0 is sequence-based and uses an architecture composed of convolutional and long short-term memory neural networks trained on solved protein structures. Using a single integrated model, NetSurfP-2.0 predicts solvent accessibility, secondary structure, structural disorder, and backbone dihedral angles for each residue of the input sequences. We assessed the accuracy of NetSurfP-2.0 on several independent test datasets and found it to consistently produce state-of-the-art predictions for each of its output features. We observe a correlation of 80% between predictions and experimental data for solvent accessibility, and a precision of 85% on secondary structure 3-class predictions. In addition to improved accuracy, the processing time has been optimized to allow predicting more than 1000 proteins in less than 2 hours, and complete proteomes in less than 1 day.


Thermally assisted quantum annealing of a 16-qubit problem.
Efforts to develop useful quantum computers have been blocked primarily by environmental noise. Quantum annealing is a scheme of quantum computation that is predicted to be more robust against noise, because despite the thermal environment mixing the system's state in the energy basis, the system partially retains coherence in the computational basis, and hence is able to establish well-defined eigenstates. Here we examine the environment's effect on quantum annealing using 16 qubits of a superconducting quantum processor. For a problem instance with an isolated small-gap anticrossing between the lowest two energy levels, we experimentally demonstrate that, even with annealing times eight orders of magnitude longer than the predicted single-qubit decoherence time, the probabilities of performing a successful computation are similar to those expected for a fully coherent system. Moreover, for the problem studied, we show that quantum annealing can take advantage of a thermal environment to achieve a speedup factor of up to 1,000 over a closed system.


Potential effects of ongoing and proposed hydropower development on terrestrial biological diversity in the Indian Himalaya.
Indian Himalayan basins are earmarked for widespread dam building, but aggregate effects of these dams on terrestrial ecosystems are unknown. We mapped distribution of 292 dams (under construction and proposed) and projected effects of these dams on terrestrial ecosystems under different scenarios of land-cover loss. We analyzed land-cover data of the Himalayan valleys, where dams are located. We estimated dam density on fifth- through seventh-order rivers and compared these estimates with current global figures. We used a species-area relation model (SAR) to predict short- and long-term species extinctions driven by deforestation. We used scatter plots and correlation studies to analyze distribution patterns of species and dams and to reveal potential overlap between species-rich areas and dam sites. We investigated effects of disturbance on community structure of undisturbed forests. Nearly 90% of Indian Himalayan valleys would be affected by dam building and 27% of these dams would affect dense forests. Our model projected that 54,117 ha of forests would be submerged and 114,361 ha would be damaged by dam-related activities. A dam density of 0.3247/1000 km(2) would be nearly 62 times greater than current average global figures; the average of 1 dam for every 32 km of river channel would be 1.5 times higher than figures reported for U.S. rivers. Our results show that most dams would be located in species-rich areas of the Himalaya. The SAR model projected that by 2025, deforestation due to dam building would likely result in extinction of 22 angiosperm and 7 vertebrate taxa. Disturbance due to dam building would likely reduce tree species richness by 35%, tree density by 42%, and tree basal cover by 30% in dense forests. These results, combined with relatively weak national environmental impact assessment and implementation, point toward significant loss of species if all proposed dams in the Indian Himalaya are constructed.


Ulnar Tunnel Syndrome, Radial Tunnel Syndrome, Anterior Interosseous Nerve Syndrome, and Pronator Syndrome.
In addition to the more common carpal tunnel and cubital tunnel syndromes, orthopaedic surgeons must recognize and manage other potential sites of peripheral nerve compression. The distal ulnar nerve may become compressed as it travels through the wrist, which is known as ulnar tunnel or Guyon canal syndrome. The posterior interosseous nerve may become entrapped in the proximal forearm as it travels through the radial tunnel, which results in a pain syndrome without motor weakness. The median nerve may become entrapped in the proximal forearm, which can result in a variety of symptoms. Spontaneous neuropathy of the anterior interosseous nerve of the median nerve can be observed without external compression. Electrodiagnostic and imaging studies may aid surgeons in the diagnosis of these syndromes; however, a thorough physical examination is paramount to localize compressed segments of these nerves. An understanding of the anatomy of each of these nerve areas allows practitioners to appreciate a patient's clinical findings and helps guide surgical decompression.


Idiopathic scoliosis: managing pain before and after spinal surgery.
Idiopathic scoliosis surgery is performed to correct a curvature of the spine. This is a painful surgical procedure which is carried out on otherwise healthy young people. This article reports on a small evaluation project which focused on young people's opinions and experiences of their pain information needs, pain management and pain assessment. Nine young people completed written activity sheets before and after scoliosis surgery. Most of the information provided on the activity sheets involved positive comments about the surgical experience although some indicated that the management of pain continued to be a challenge after spinal surgery. The project has highlighted that there is more work to be done to ensure that young people are prepared for surgery and they are helped to convey their experiences of pain to health professionals during their treatment and recovery.


Magnetic fields and seasonality of affective illness: implications for therapy.
Seasonal affective disorder is characterized by recurrent winter depression associated with hypersomnia, overeating, and carbohydrate craving. The severe form of winter depression affects about 5% of the general population and is believed to be caused by light deficiency. About 70%-80% of patients with winter depression experience attenuation of symptoms when exposed to bright light therapy. Hypotheses pertaining to the pathogenesis of winter depression implicate the effects of light on different characteristics of circadian rhythms. One of the environmental factors which may be implicated, in addition to light, in the pathophysiology of winter depression is the geomagnetic field. There is strong indication that the pineal gland is a magnetosensitive system and that changes in the ambient magnetic field alter melatonin secretion and synchronize the circadian rhythms. In man, shielding of the ambient magnetic field significantly desynchronizes circadian rhythms which could be gradually resynchronized after application of magnetic fields. The strength of the environmental magnetic field diminishes during the winter months, leading to increased susceptibility for desynchronization of circadian rhythms. Thus, since the acute application of magnetic fields in experimental animals resembles that of acute exposure to light with respect to melatonin secretion (i.e., suppression of melatonin secretion), magnetic treatment might be beneficial for patients with winter depression. In addition, since the environmental light and magnetic fields, which undergo diurnal and seasonal variations, influence the activity of the pineal gland, we propose that a synergistic effect of light and magnetic therapy in patients with winter depression would be more physiological and, therefore, superior to phototherapy alone.(ABSTRACT TRUNCATED AT 250 WORDS)


Cellular reprogramming: a new approach to modelling Parkinson's disease.
iPSCs (induced pluripotent stem cells) offer an unparalleled opportunity to generate and study physiologically relevant cell types in culture. iPSCs can be generated by reprogramming almost any somatic cell type using pluripotency factors such as Oct4, SOX2, Nanog and Klf4. By reprogramming cells from patients carrying disease-associated mutations, and subsequent differentiation into the cell type of interest, researchers now have the opportunity to study disease-specific cell types which were previously inaccessible. In the case of PD (Parkinson's disease), reprogramming is advancing rapidly, and cell lines have been generated from patients carrying mutations in several disease-associated genes, including SNCA (α-synuclein), PARK2 (parkin), PINK1 (phosphatase and tensin homologue deleted on chromosome 10-induced putative kinase 1), PARK7 (DJ-1) and LRRK2 (leucine-rich repeat kinase 2), as well as idiopathic cases. Functional dopaminergic neurons have been differentiated from these cells and their physiology has been compared with control neurons. Human dopaminergic neurons had been previously inaccessible until post-mortem, when the disease is generally highly progressed into pathology. In comparison, iPSCs provide a living cell model with the potential to study early molecular changes which accumulate in cells and ultimately result in neurodegeneration. Although clear phenotypes have not yet been unambiguously identified in patient-derived dopaminergic neurons, there are suggested aberrations in cellular pathways involved in neurodegeneration. Overall, these cells offer a unique opportunity to study dopaminergic neurons carrying a 'Parkinsonian genome'. The present review discusses the advances in cellular reprogramming technologies and studies that have been carried out on PD-derived iPSCs and differentiated dopaminergic neurons.


A plausible accelerating function of intermediate states in cancer metastasis.
Epithelial-to-mesenchymal transition (EMT) is a fundamental cellular process and plays an essential role in development, tissue regeneration, and cancer metastasis. Interestingly, EMT is not a binary process but instead proceeds with multiple partial intermediate states. However, the functions of these intermediate states are not fully understood. Here, we focus on a general question about how the number of partial EMT states affects cell transformation. First, by fitting a hidden Markov model of EMT with experimental data, we propose a statistical mechanism for EMT in which many unobservable microstates may exist within one of the observable macrostates. Furthermore, we find that increasing the number of intermediate states can accelerate the EMT process and that adding parallel paths or transition layers may accelerate the process even further. Last, a stabilized intermediate state traps cells in one partial EMT state. This work advances our understanding of the dynamics and functions of EMT plasticity during cancer metastasis.


Liquid chromatography-tandem mass spectrometry analysis allows the simultaneous characterization of C-glycosyl and O-glycosyl flavonoids in stingless bee honeys.
The analysis of the phytochemicals present in stingless bee honey samples has been a difficult task due to the small amounts of samples available and to the complexity of the phytochemical composition that often combines flavonoid glycosides and aglycones. Honey samples produced in Venezuela from Melipona species were analyzed using a combination of solid-phase extraction and HPLC-DAD-MSn/ESI methodologies with specific study of the fragment ions produced from flavonoid glycosides. The analyses revealed that flavonoid glycosides were the main constituents. The honey samples analyzed contained a consistent flavonoid pattern composed of flavone-C-glycosides, flavonol-O-glycosides and flavonoid aglycones. The HPLC-DAD-MSn/ESI analysis and the study of the fragment ions obtained allowed the characterization and quantification for the first time of five apigenin-di-C-glycosides, and ten quercetin, kaempferol and isorhamnetin O-glycosides (di- and tri- glycosides), and the aglycones pinobanksin, quercetin, kaempferol and isorhamnetin in the different samples. This is the first report of flavonoid-C-glycosides in honey. The results show that the content of flavonoid-glycosides (mean values of 2712 μg/100 g) in stingless bee honeys is considerably higher than the content of flavonoid aglycones (mean values of 315 μg/100 g). This differs from previous studies on Apis mellifera honeys that consistently showed much higher aglycone content and smaller flavonoid glycoside content. The occurrence of relevant amounts of flavonoid glycosides, and particularly C-glycosides, in stingless bee honeys could be associated with their putative anticataract properties.


Laparoscopic Revision of Nissen to Partial Fundoplication 20 Years After Initial Surgery as an Infant.
We report a case of a 21-year-old male who presented with adult-onset dysphagia after previous Nissen fundoplication initially created at age 10.5 months. The patient first presented one year ago to a different hospital, where he underwent extensive workup for his symptomatology. Physiologic tests performed were esophagogastroduodenoscopy (EGD), abdominal ultrasound, hepatobiliary iminodiacetic acid scan, esophageal manometry, and lactulose breath test. The EGD identified stricture at the level of the gastroesophageal junction. The other studies did not reveal other physiologic causes for his symptoms. The patient then presented to our institution, at which time a repeat EGD showed evidence of tight Nissen fundoplication. The patient subsequently underwent laparoscopic exploration, which revealed that the fundoplication had was partially disrupted, herniated, and twisted causing a long-segment distal stricture. To alleviate the patient's presenting symptom of dysphagia as well as prevent possible future reflux, it was decided to convert repair the hernia and revise the Nissen into a partial fundoplication. This was successfully accomplished laparoscopically with subsequent resolution of the patient's symptoms.


Adrenal crisis in a 14-year-old boy 12 years after hematopoietic stem cell transplantation.
We report on a boy of Albanian descent with the history of juvenile myelomonocytic leukemia (JMML). JMML was diagnosed at the age of 17 months and treated by hematopoietic stem cell transplantation (HSCT). At the age of 14.3 years, about 12 years after HSCT, he was hospitalized with an adrenal crisis. Hormone findings were consistent with primary adrenal insufficiency. Autoimmune adrenalitis was confirmed by positive autoantibodies against 21-hydroxylase and adrenal tissue. Since autoimmune Hashimoto thyroiditis was already known from the age of 9 years, we assume that both diseases are part of the spectrum of autoimmune polyglandular syndrome (APS) type 2. APS type 2 is a rare endocrine disease characterized by Addison's disease along with autoimmune thyroid disease and/or type 1 diabetes. Endocrine sequelae after hematopoietic stem cell transplantation (HSCT) are common and can develop over a long period.Primary adrenal insufficiency after HSCT is absolutely rare.The combination of adrenal autoimmune disease and Hashimoto thyroiditis is consistent with autoimmune polyglandular syndrome type 2.


Identifying the gaps: Armenian health care legislation and human rights in patient care protections.
Since the collapse of the Soviet Union, the Republic of Armenia has undergone an extensive legislative overhaul. Although a number of developments have aimed to improve the quality and accessibility of Armenia's health care system, a host of factors has prevented the country from fully introducing measures to ensure respect for human rights in patient care. In particular, inadequate health care financing continues to oblige patients to make both formal and informal payments to obtain basic medical care and services. More generally, a lack of oversight and monitoring mechanisms has obstructed the implementation of Armenia's commitments to human rights in several international agreements. Within the framework of a broader project on promoting human rights in patient care, research was carried out to examine Armenia's health care legislation with the aim of identifying gaps in comparison with international and regional standards. This research was designed using the 14 rights enshrined in the European Charter on Patient Rights as guiding principles, along with domestic legal acts relevant to the rights of health care providers. The gaps analysis revealed numerous problems with Armenian legislation governing the relationships between stakeholders in health care service delivery. It also identified several practical inconsistencies with the international legal instruments ratified by the Armenian government. These legislative shortcomings are illustrated by highlighting key health-related rights violations experienced by patients and their health care providers, and by indicating opportunities for improved rights protections. A full list of human rights relevant to patient care and recommendations for promoting them in the Armenian context is provided in Tables 1 and 2. A number of initiatives must be undertaken in order to promote the full spectrum of human rights in patient care in Armenia. This section highlights certain recommendations flowing from the findings of the gap analysis, including further work needed to make pain relief medication more accessible to patients with chronic or terminal illness. New initiatives are also suggested, such as the establishment of an independent body of medical professionals and ethicists mandated to resolve disputes between patients and providers, and other efforts intended to ensure that the rights of patients and providers alike are upheld and respected.


Primary forests are irreplaceable for sustaining tropical biodiversity.
Human-driven land-use changes increasingly threaten biodiversity, particularly in tropical forests where both species diversity and human pressures on natural environments are high. The rapid conversion of tropical forests for agriculture, timber production and other uses has generated vast, human-dominated landscapes with potentially dire consequences for tropical biodiversity. Today, few truly undisturbed tropical forests exist, whereas those degraded by repeated logging and fires, as well as secondary and plantation forests, are rapidly expanding. Here we provide a global assessment of the impact of disturbance and land conversion on biodiversity in tropical forests using a meta-analysis of 138 studies. We analysed 2,220 pairwise comparisons of biodiversity values in primary forests (with little or no human disturbance) and disturbed forests. We found that biodiversity values were substantially lower in degraded forests, but that this varied considerably by geographic region, taxonomic group, ecological metric and disturbance type. Even after partly accounting for confounding colonization and succession effects due to the composition of surrounding habitats, isolation and time since disturbance, we find that most forms of forest degradation have an overwhelmingly detrimental effect on tropical biodiversity. Our results clearly indicate that when it comes to maintaining tropical biodiversity, there is no substitute for primary forests.


Linearized optical single sideband Mach-Zehnder electro-optic modulator for radio over fiber systems.
We propose a linearized optical single sideband Mach-Zehnder electro-optic modulator (MZ-EOM) for radio over fiber systems. This proposed modulator utilizes a dual-electrode MZ-EOM biased at quandrature, the two electrodes are fed with asymmetrical RF power through an 180? hybrid coupler and the two optical ports of MZ-EOM are bi-directionally injected by the same optical source, but with different optical power. Using such a modulator, third order nonlinear distortion is significantly suppressed and relative spurious free dynamic range is improved by 10 and 20 dB compared to dual-parallel linearized MZ-EOM and conventional MZ-EOM, respectively.


The influence of poverty and rabies knowledge on healthcare seeking behaviors and dog ownership, Cameroon.
Rabies is a fatal encephalitis caused by lyssaviruses, with most human cases worldwide resulting from rabid dog bites. Although effective animal and human vaccines have been available for over 100 years, control efforts have not been adequately implemented on the global scale and rabies remains one of the greatest global zoonotic threats to human health. We conducted a knowledge, attitudes and practices survey in Northern Cameroon to describe dog ownership characteristics, rates of dog bites, and post-bite healthcare seeking behaviors. The survey was performed in four rural Cameroonian communities. A structured community-based questionnaire was conducted over a 20-day period in April 2010, and focused on socio-economic factors correlated with gaps in rabies knowledge. Information pertaining to socio-demographics, as well as attitudes and practices with regard to animal bites and bite treatment practices were recorded. Characteristics of dog ownership such as dog confinement, resources provided to dogs, and dog vaccination status were examined. Human to dog ratios were compared on a linear scale to poverty scores by community. When applicable, 2-tailed Chi-square tests or Fisher's exact tests were calculated to determine relationships between variables. We also used One-way Analysis of Variance (ANOVA) to identify associations between rabies knowledge and wealth with dog ownership, dog vaccination, and human healthcare seeking behaviors. Independent variables were evaluated using multivariate logistic regression analysis. A total of 208 households were enrolled. Respondents were predominantly male (68.3%), with a median age of 43.6 years. Eighty-four households (39.9%) reported owning a total of 141 dogs (human dog ratio 10.4:1). The majority of dogs (61%) were allowed to roam freely. A history of rabies vaccination was reported for 30.8% of owned dogs. Respondents reported 11 bites during the two years preceding the survey (annual bite incidence was 2.6% [95% CI 1.4%- 4.6%]). Only one person (9.1%) received rabies post-exposure prophylaxis (PEP), and none described symptoms of clinical illness consistent with rabies. Respondents who indicated that they would seek medical care and PEP after a dog bite had higher average wealth and rabies knowledge index scores (p = 0.01 and 0.04, respectively). Respondents who indicated that they would seek care from a traditional healer had significantly lower wealth scores, but not significantly different knowledge scores (p < 0.01 and p = 0.49, respectively). In the communities evaluated, the majority of dogs were allowed to roam freely and had no history of rabies vaccination; factors that favor enzootic transmission of canine rabies virus. We also identified a strong relationship between poverty and dog ownership. Bite events were relatively common among respondents, and very few victims reported utilizing health services to treat wounds. Increased wealth and knowledge were significantly associated with increased likelihood that a respondent would seek medical care and post-exposure prophylaxis. These findings indicate the need for educational outreach to raise awareness of dog rabies and proper prevention measures.


Results of laparoscopic cryoablation in the treatment of small renal masses.
Study of clinical outcome in renal cryoablation. Laparoscopic cryoablation (LCA) is emerging as a reliable treatment option for small renal masses (SRMs) particularly in elderly patients. Our aim was to study the results of cryoablation for small renal masses in our cohort of patients. We retrospectively studied all patients who underwent LCA for SRMs between September 2005 and July 2008. All patients were discussed in our multidisciplinary meeting prior to cryoablation. Our LCA protocol included two freeze-thaw cycles, achieving a core temperature of -70°C and a peripheral temperature of at least -40°C. Follow-up included serum creatinine measurements and pre- and postcontrast CT scans at 3, 6, 12, 18, and 24 months and yearly thereafter. Paired samples t-test was used to study statistical difference. Twenty-two patients underwent LCA with a mean (range) age of 68 (39-81 years) years. The mean (range) tumor size was 29 (19-45 mm) mm. Two patients required blood transfusions, one patient developed pneumonia, and another patient developed a small area of skin necrosis at the cryoneedle entry site. The average (range) hospital stay was 4 (2-14 days) days. Twenty-one patients have had CT follow-up at a mean (range) of 24 (4-42 months) months. Three of the 21 tumors showed central enhancement on follow-up CT scans, consistent with treatment failure. Laparoscopic cryoablation is a safe treatment option for SRM in a selected group of patients.


Multi-state recognition pathway of the intrinsically disordered protein kinase inhibitor by protein kinase A.
In the nucleus, the spatiotemporal regulation of the catalytic subunit of cAMP-dependent protein kinase A (PKA-C) is orchestrated by an intrinsically disordered protein kinase inhibitor, PKI, which recruits the CRM1/RanGTP nuclear exporting complex. How the PKA-C/PKI complex assembles and recognizes CRM1/RanGTP is not well understood. Using NMR, SAXS, fluorescence, metadynamics, and Markov model analysis, we determined the multi-state recognition pathway for PKI. After a fast binding step in which PKA-C selects PKI's most competent conformations, PKI folds upon binding through a slow conformational rearrangement within the enzyme's binding pocket. The high-affinity and pseudo-substrate regions of PKI become more structured and the transient interactions with the kinase augment the helical content of the nuclear export sequence, which is then poised to recruit the CRM1/RanGTP complex for nuclear translocation. The multistate binding mechanism featured by PKA-C/PKI complex represents a paradigm on how disordered, ancillary proteins (or protein domains) are able to operate multiple functions such as inhibiting the kinase while recruiting other regulatory proteins for nuclear export.


Calibrating and adjusting expectations in life: A grounded theory on how elderly persons with somatic health problems maintain control and balance in life and optimize well-being.
This study aims at exploring the main concern for elderly individuals with somatic health problems and what they do to manage this. In total, 14 individuals (mean=74.2 years; range=68-86 years) of both gender including hospitalized and outpatient persons participated in the study. Open interviews were conducted and analyzed according to grounded theory, an inductive theory-generating method. The main concern for the elderly individuals with somatic health problems was identified as their striving to maintain control and balance in life. The analysis ended up in a substantive theory explaining how elderly individuals with somatic disease were calibrating and adjusting their expectations in life in order to adapt to their reduced energy level, health problems, and aging. By adjusting the expectations to their actual abilities, the elderly can maintain a sense of that they still have the control over their lives and create stability. The ongoing adjustment process is facilitated by different strategies and result despite lower expectations in subjective well-being. The facilitating strategies are utilizing the network of important others, enjoying cultural heritage, being occupied with interests, having a mission to fulfill, improving the situation by limiting boundaries and, finally, creating meaning in everyday life. The main concern of the elderly with somatic health problems was to maintain control and balance in life. The emerging theory explains how elderly people with somatic health problems calibrate their expectations of life in order to adjust to reduced energy, health problems, and aging. This process is facilitated by different strategies and result despite lower expectation in subjective well-being.


Two-pore Channels (TPC2s) and Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) at Lysosomal-Sarcoplasmic Reticular Junctions Contribute to Acute and Chronic β-Adrenoceptor Signaling in the Heart.
Ca(2+)-permeable type 2 two-pore channels (TPC2) are lysosomal proteins required for nicotinic acid adenine dinucleotide phosphate (NAADP)-evoked Ca(2+) release in many diverse cell types. Here, we investigate the importance of TPC2 proteins for the physiology and pathophysiology of the heart. NAADP-AM failed to enhance Ca(2+) responses in cardiac myocytes from Tpcn2(-/-) mice, unlike myocytes from wild-type (WT) mice. Ca(2+)/calmodulin-dependent protein kinase II inhibitors suppressed actions of NAADP in myocytes. Ca(2+) transients and contractions accompanying action potentials were increased by isoproterenol in myocytes from WT mice, but these effects of β-adrenoreceptor stimulation were reduced in myocytes from Tpcn2(-/-) mice. Increases in amplitude of L-type Ca(2+) currents evoked by isoproterenol remained unchanged in myocytes from Tpcn2(-/-) mice showing no loss of β-adrenoceptors or coupling mechanisms. Whole hearts from Tpcn2(-/-) mice also showed reduced inotropic effects of isoproterenol and a reduced tendency for arrhythmias following acute β-adrenoreceptor stimulation. Hearts from Tpcn2(-/-) mice chronically exposed to isoproterenol showed less cardiac hypertrophy and increased threshold for arrhythmogenesis compared with WT controls. Electron microscopy showed that lysosomes form close contacts with the sarcoplasmic reticulum (separation ∼ 25 nm). We propose that Ca(2+)-signaling nanodomains between lysosomes and sarcoplasmic reticulum dependent on NAADP and TPC2 comprise an important element in β-adrenoreceptor signal transduction in cardiac myocytes. In summary, our observations define a role for NAADP and TPC2 at lysosomal/sarcoplasmic reticulum junctions as unexpected but major contributors in the acute actions of β-adrenergic signaling in the heart and also in stress pathways linking chronic stimulation of β-adrenoceptors to hypertrophy and associated arrhythmias.


Microencapsulated Immunoassays for Detection of Cytokines in Human Blood.
Cytokines are produced by leukocytes in blood and may be used as indicators of malignancies or infections. The objective of this study was to develop a strategy for immunosensing cytokines in whole, unprocessed human blood. Microfluidic droplet generation was employed to fabricate ∼400 μm diameter microcapsules with a hydrogel shell and an aqueous core containing sensing microbeads. The hydrogel shell was composed of poly(ethylene glycol) forming a thin (∼10 μm) immunoisolation layer protecting antibody-modified microbeads inside the capsule from immune cells on the outside. The microbeads were functionalized with antibodies against cytokines of interest: interferon (IFN)-γ and tumor necrosis factor (TNF)-α. While nonfouling, a hydrogel shell was permeable to cytokine molecules; these molecules were captured on microbeads and were detected with fluorescently labeled secondary antibodies. Calibration of encapsulated immunoassays with known concentrations of cytokines revealed a limit of detection of 14.8 and 14.4 pM for IFN-γ and TNF-α, respectively. We also demonstrated the concept of multi-cytokine detection by fabricating distinct populations of capsules carrying either anti-IFN-γ or anti-TNF-α microbeads and dispensing these capsules into a solution containing both cytokine types. Importantly, when placed into whole blood for 16 h, microcapsules were free of leukocytes, effectively protecting sensing beads from the blood components. To further demonstrate utility of this strategy, encapsulated microbeads were used for detection of IFN-γ in blood of patients with latent tuberculosis infection (LTBI) and unexposed healthy controls. When compared to gold standard technology (interferon gamma release assay or IGRA), our encapsulated immunoassay accurately predicted LTBI diagnosis in 11 out of 14 patients. Overall, encapsulation of immunoassays represents a promising strategy for keeping sensing elements operational in a highly fouling complex environment such as blood.


Noise robustness of persistent homology on greyscale images, across filtrations and signatures.
Topological data analysis is a recent and fast growing field that approaches the analysis of datasets using techniques from (algebraic) topology. Its main tool, persistent homology (PH), has seen a notable increase in applications in the last decade. Often cited as the most favourable property of PH and the main reason for practical success are the stability theorems that give theoretical results about noise robustness, since real data is typically contaminated with noise or measurement errors. However, little attention has been paid to what these stability theorems mean in practice. To gain some insight into this question, we evaluate the noise robustness of PH on the MNIST dataset of greyscale images. More precisely, we investigate to what extent PH changes under typical forms of image noise, and quantify the loss of performance in classifying the MNIST handwritten digits when noise is added to the data. The results show that the sensitivity to noise of PH is influenced by the choice of filtrations and persistence signatures (respectively the input and output of PH), and in particular, that PH features are often not robust to noise in a classification task.


Allogeneic stem cell transplantation as initial salvage for patients with acute myeloid leukemia refractory to high-dose cytarabine-based induction chemotherapy.
Outcomes of patients with acute myeloid leukemia (AML) who are refractory to high-dose Cytarabine (HiDAC)-based induction are dismal. Allogeneic hematopoietic stem cell transplantation (AHSCT) as initial salvage may be effective and potentially superior to conventional salvage chemotherapy. Eighteen percent (285 of 1597) of AML patients were primary refractory to HiDAC-based regimens at the MD Anderson Cancer Center between 1995 and 2009. AHSCT was the initial salvage in 28 cases. These patients were compared against 149 patients who received salvage chemotherapy, but never received AHSCT. Patients receiving salvage chemotherapy were older, had higher bone marrow blasts percentage, and higher incidence of unfavorable cytogenetics (P < 0.001). Median time from induction to AHSCT was 76 days. Objective response was achieved in 23 of 28 patients (82%) undergoing AHSCT. The incidence of grade III/IV acute and chronic graft versus-host-disease was 11% and 29%, respectively. Median follow up for living patients is 80 months. Median overall survival (OS) was 15.7 months and 2.9 months for AHSCT and chemotherapy, respectively (P < 0.001); the 3-year OS rates were 39% and 2%, respectively. ASHCT as initial salvage therapy was identified as an independent prognostic factor for survival in multivariate analysis (HR = 3.03; P < 0.001). Initial salvage therapy with AHSCT in patients with primary HiDAC refractory AML is feasible and may yield superior outcomes to salvage chemotherapy.


Chloroquine resistance before and after its withdrawal in Kenya.
The spread of resistance to chloroquine (CQ) led to its withdrawal from use in most countries in sub-Saharan Africa in the 1990s. In Malawi, this withdrawal was followed by a rapid reduction in the frequency of resistance to the point where the drug is now considered to be effective once again, just nine years after its withdrawal. In this report, the polymorphisms of markers associated with CQ-resistance against Plasmodium falciparum isolates from coastal Kenya (Kilifi) were investigated, from 1993, prior to the withdrawal of CQ, to 2006, seven years after its withdrawal. Changes to those that occurred in the dihydrofolate reductase gene (dhfr) that confers resistance to the replacement drug, pyrimethamine/sulphadoxine were also compared. Mutations associated with CQ resistance, at codons 76 of pfcrt, at 86 of pfmdr1, and at codons 51, 59 and 164 of dhfr were analysed using PCR-restriction enzyme methods. In total, 406, 240 and 323 isolates were genotyped for pfcrt-76, pfmdr1-86 and dhfr, respectively. From 1993 to 2006, the frequency of the pfcrt-76 mutant significantly decreased from around 95% to 60%, while the frequency of pfmdr1-86 did not decline, remaining around 75%. Though the frequency of dhfr mutants was already high (around 80%) at the start of the study, this frequency increased to above 95% during the study period. Mutation at codon 164 of dhfr was analysed in 2006 samples, and none of them had this mutation. In accord with the study in Malawi, a reduction in resistance to CQ following official withdrawal in 1999 was found, but unlike Malawi, the decline of resistance to CQ in Kilifi was much slower. It is estimated that, at current rates of decline, it will take 13 more years for the clinical efficacy of CQ to be restored in Kilifi. In addition, CQ resistance was declining before the drug's official withdrawal, suggesting that, prior to the official ban, the use of CQ had decreased, probably due to its poor clinical effectiveness.


Melatonin in septic shock: some recent concepts.
Melatonin is a versatile molecule, synthesized not only in the pineal gland, but also in many other organs. Melatonin plays an important physiologic role in sleep and circadian rhythm regulation, immunoregulation, antioxidant and mitochondrial-protective functions, reproductive control, and regulation of mood. Melatonin has also been reported as effective in combating various bacterial and viral infections. Melatonin is an effective anti-inflammatory agent in various animal models of inflammation and sepsis, and its anti-inflammatory action has been attributed to inhibition of nitric oxide synthase with consequent reduction of peroxynitrite formation, to the stimulation of various antioxidant enzymes thus contributing to enhance the antioxidant defense, and to protective effects on mitochondrial function and in preventing apoptosis. In a number of animal models of septic shock, as well as in patients with septic disease, melatonin reportedly exerts beneficial effects to arrest cellular damage and multiorgan failure. The significance of these actions in septic shock and its potential usefulness in the treatment of multiorgan failure are discussed.


Long-Term Conditions in Older People are Linked with Loneliness, but a Sense of Coherence Buffers the Adverse Effects on Quality of Life: A Cross-Sectional Study.
The impact of disability, long-term conditions, rurality, living alone, and being a carer on health has some evidence base, but the extent to which a strong sense of coherence (SoC), a factor hypothesised to promote wellbeing, may moderate these associations is unknown. A model of physical, environmental and social factors on quality of life was tested, with particular emphasis on whether a strong SoC buffered (mitigated) these determinants of quality of life. A cross-sectional postal survey was undertaken of a random sample of 1471 respondents aged over 65 years, across a population of rural individuals. Physical, environmental, and psychological variables were assessed against quality of life using ANOVA and a generalised linear model including the interaction effects of SoC. ANOVA demonstrated that age, gender, long-term conditions or disability (LTC-D), living alone, >20 hours unpaid care for others per week, SoC, and loneliness, were associated with lower quality of life (p<0.01). There were strong correlations (p>0.01), between age and LTC-D, living alone, and poor SoC. Living alone was correlated with emotional and social loneliness; but those with higher SoC were less likely to experience loneliness. In an adjusted generalised linear model, significant associations with a lower quality of life were observed from: LTC-D, emotional loneliness and social loneliness (B= -0.44, -0.30, and -0.39, respectively, all p<0.001). The only interaction with SoC that was statistically significant (at p<0.05) was LTC-D. A stronger sense of coherence buffered the negative effects of long-term condition/disability on quality of life. The physical, environmental and social factors examined, identified LTC-D and loneliness to be the strongest factors associated with poor quality of life. SoC somewhat buffered the adverse effect of LTC-D on quality of life, but did not do so for loneliness.


Understanding how domestic health policy is integrated into foreign policy in South Africa: a case for accelerating access to antiretroviral medicines.
South Africa, as an emerging middle-income country, is becoming increasingly influential in global health diplomacy (GHD). However, little empirical research has been conducted to inform arguments for the integration of domestic health into foreign policy by state and non-state actors. This study seeks to address this knowledge gap. It takes the form of an empirical case study which analyses how South Africa integrates domestic health into its foreign policy, using the lens of access to antiretroviral (ARV) medicines. To explore state and non-state actors' perceptions regarding how domestic health policy is integrated into foreign policy. The ultimate goal of this study was to achieve better insights into the health and foreign policy processes at the national level. Employing qualitative approaches, we examined changes in the South African and global AIDS policy environment. Purposive sampling was used to select key informants, a sample of state and non-state actors who participated in in-depth interviews. Secondary data were collected through a systematic literature review of documents retrieved from five electronic databases, including review of key policy documents. Qualitative data were analysed for content. This content was coded, and the codes were collated into tentative categories and sub-categories using Atlas.ti v.7 software. The findings of this work illustrate the interplay among social, political, economic and institutional conditions in determining the success of this integration process. Our study shows that a series of national and external developments, stakeholders, and advocacy efforts and collaboration created these integrative processes. South Africa's domestic HIV/AIDS constituencies, in partnership with the global advocacy movement, catalysed the mobilization of support for universal access to ARV treatment nationally and globally, and the promotion of access to healthcare as a human right. Transnational networks may influence government's decision making by providing information and moving issues up the agenda.


The SCARECROW gene regulates an asymmetric cell division that is essential for generating the radial organization of the Arabidopsis root.
In the Arabidopsis root meristem, initial cells undergo asymmetric divisions to generate the cell lineages of the root. The scarecrow mutation results in roots that are missing one cell layer owing to the disruption of an asymmetric division that normally generates cortex and endodermis. Tissue-specific markers indicate that a heterogeneous cell type is formed in the mutant. The deduced amino acid sequence of SCARECROW (SCR) suggests that it is a member of a novel family of putative transcription factors. SCR is expressed in the cortex/endodermal initial cells and in the endodermal cell lineage. Tissue-specific expression is regulated at the transcriptional level. These results indicate a key role for SCR in regulating the radial organization of the root.


All members of the MHC multigene family respond to thyroid hormone in a highly tissue-specific manner.
In mammals different isoforms of myosin heavy chain are encoded by the members of a multigene family. The expression of each gene of this family is regulated in a tissue- and developmental stage-specific manner as well as by hormonal and various pathological stimuli. In this study the molecular basis of isoform switches induced in myosin heavy chain by thyroid hormone was investigated. The expression of the myosin heavy chain gene family was analyzed in seven different muscles of adult rats subjected to hypo- or hyperthyroidism with complementary DNA probes specific for six different myosin heavy chain genes. The results demonstrate that all six genes are responsive to thyroid hormone. More interestingly, the same myosin heavy chain gene can be regulated by thyroid hormone in highly different modes, even in opposite directions, depending on the tissue in which it is expressed. Furthermore, the skeletal embryonic and neonatal myosin heavy chain genes, so far considered specific to these two developmental stages, can be reinduced by hypothyroidism in specific adult muscles.


Interferometric quantum spectroscopy with undetected photons via distinguishability modulation.
Quantum spectroscopy with undetected photons (QSUP) utilizing the quantum entanglement of parametrically down-converted photons has emerged as a new spectroscopic platform. Here, we demonstrate a high-resolution and remote-measurement QSUP, where light-matter interactions and photon detections are performed in spectrally and spatially different regions. A dual-stimulated parametric down-conversion scheme with an optical frequency-comb pump and ultra-narrow coherent seed beam in an idler mode is used to generate path-entangled pairs of the undetected idler and measured frequency-comb signal photons. To demonstrate the frequency resolution of this scheme, a Fabry-Pérot cavity with a narrow bandwidth is used as a sample that modulates the distinguishability of one-photon-added coherent idler beams, which directly affects the interference fringe visibility of the entangled signal photons. We thus anticipate that the remote QSUP whose frequency resolution is determined by the linewidth of the coherent seed laser will enable the development of quantum spectroscopy featuring high resolution.