Fluorescence lifetime imaging and spectroscopy as tools for nondestructive analysis of works of art.
A system for advanced fluorescence investigation of works of art has been assembled and integrated in a characterization procedure that allows one to localize and identify organic compounds that are present in artworks. At the beginning of the investigation, fluorescence lifetime imaging and spectroscopy address a selective microsampling of the artwork. Then analytical measurements of microsamples identify the chemical composition of the materials under investigation. Finally, on the basis of fluorescence lifetime and amplitude maps, analytical data are extended to the whole artwork. In such a way, information on the spatial distribution of organic materials can be inferred. These concepts have been successfully applied in an extensive campaign for analysis of Renaissance fresco paintings in Castiglione Olona, Italy. Residue of various types of glue and stucco left from a restoration carried out in the early 1970s was localized and classified. Insight into the technique used by the painter to make gilded reliefs was also obtained.


Mycobacterium chimaera Disseminated Infection.
The incidence and prevalence of nontuberculous mycobacterial disease is increasing due to enhanced clinician awareness and improved detection methods. The species identification using molecular microbiology techniques allows a better understanding of the differences in pathogenicity and treatment response. A 57-year-old man with a history of B-cell lymphoma in remission was transferred from the hematology department due to fever of unknown origin, night sweats and asthenia. The empirical antibiotic therapy was initiated with no clinical response, and he developed a subacute pneumonia, severe anemia and hepatosplenomegaly. After positive blood, bronchoalveolar lavage and bone marrow cultures, a disseminated Mycobacterium avium-intracellulare complex infection was diagnosed, and the patient began treatment with clarithromycin, rifabutin and ethambutol. Two weeks later, a fourth antibiotic was added, amikacin at first and then linezolid, with slow but gradual improvement. Due to amikacin-related severe kidney injury and linezolid-related severe myelosuppression, the fourth antibiotic was changed to moxifloxacin, which the patient tolerated. After 6 months of therapy, the sensitivity to the regimen was confirmed and the species was identified as Mycobacterium chimaera (MC), using the molecular genetic test GenoType NTM-DR. The blood and tissue cultures were negative after 4 months of therapy, and treatment was continued for 12 months. Although the infection was being treated successfully, the patient's B-cell lymphoma relapsed after 12 months and the patient died. This is a case report of a confirmed severe and disseminated MC infection in an immunocompromised patient using a molecular genetic test, successfully treated using a four-drug regimen.


A novel HECT-type E3 ubiquitin protein ligase NEDL1 enhances the p53-mediated apoptotic cell death in its catalytic activity-independent manner.
NEDL1 (NEDD4-like ubiquitin protein ligase-1) is a newly identified HECT-type E3 ubiquitin protein ligase highly expressed in favorable neuroblastomas as compared with unfavorable ones. In this study, we found that NEDL1 cooperates with p53 to induce apoptosis. During cisplatin (CDDP)-mediated apoptosis in neuroblastoma SH-SY5Y cells, p53 was induced to accumulate in association with an increase in expression levels of NEDL1. Enforced expression of NEDL1 resulted in a decrease in number of G418-resistant colonies in SH-SY5Y and U2OS cells bearing wild-type p53, whereas NEDL1 had undetectable effect on p53-deficient H1299 and SAOS-2 cells. Similarly, enforced expression of NEDL1 increased number of U2OS cells with sub-G1 DNA content. Co-immunoprecipitation and in vitro binding assays revealed that NEDL1 binds to the COOH-terminal region of p53. Luciferase reporter assay showed that NEDL1 has an ability to enhance the transcriptional activity of p53. Small interfering RNA-mediated knockdown of the endogenous NEDL1 conferred the resistance of U2OS cells to adriamycin. It is noteworthy that NEDL1 enhanced pro-apoptotic activity of p53 in its catalytic activity-independent manner. Taken together, our present findings suggest that functional interaction of NEDL1 with p53 might contribute to the induction of apoptosis in cancerous cells bearing wild-type p53.


Probiotic supplementation during pregnancy or infancy for the prevention of asthma and wheeze: systematic review and meta-analysis.
To evaluate the association of probiotic supplementation during pregnancy or infancy with childhood asthma and wheeze. Systematic review and meta-analysis of randomised controlled trials. Medline, Embase, and Central (Cochrane Library) databases from inception to August 2013, plus the World Health Organization's international clinical trials registry platform and relevant conference proceedings for the preceding five years. Included trials and relevant reviews were forward searched in Web of Science. Two reviewers independently identified randomised controlled trials evaluating probiotics administered to mothers during pregnancy or to infants during the first year of life. The primary outcome was doctor diagnosed asthma; secondary outcomes included wheeze and lower respiratory tract infection. We identified 20 eligible trials including 4866 children. Trials were heterogeneous in the type and duration of probiotic supplementation, and duration of follow-up. Only five trials conducted follow-up beyond participants' age of 6 years (median 24 months), and none were powered to detect asthma as the primary outcome. The overall rate of doctor diagnosed asthma was 10.7%; overall rates of incident wheeze and lower respiratory tract infection were 33.3% and 13.9%, respectively. Among 3257 infants enrolled in nine trials contributing asthma data, the risk ratio of doctor diagnosed asthma in participants randomised to receive probiotics was 0.99 (95% confidence interval 0.81 to 1.21, I(2)=0%). The risk ratio of incident wheeze was 0.97 (0.87 to 1.09, I(2)=0%, 9 trials, 1949 infants). Among 1364 infants enrolled in six trials, the risk ratio of lower respiratory tract infection after probiotic supplementation was 1.26 (0.99 to 1.61, I(2)=0%). We adjudicated most trials to be of high (ten trials) or unclear (nine trials) risk of bias, mainly due to attrition. We found no evidence to support a protective association between perinatal use of probiotics and doctor diagnosed asthma or childhood wheeze. Randomised controlled trials to date have not yielded sufficient evidence to recommend probiotics for the primary prevention of these disorders. Extended follow-up of existing trials, along with further clinical and basic research, are needed to accurately define the role of probiotics in the prevention of childhood asthma. PROSPERO (CRD42013004385).


Predation risk and the evolution of a vertebrate stress response: Parallel evolution of stress reactivity and sexual dimorphism.
Predation risk is often invoked to explain variation in stress responses. Yet, the answers to several key questions remain elusive, including the following: (1) how predation risk influences the evolution of stress phenotypes, (2) the relative importance of environmental versus genetic factors in stress reactivity and (3) sexual dimorphism in stress physiology. To address these questions, we explored variation in stress reactivity (ventilation frequency) in a post-Pleistocene radiation of live-bearing fish, where Bahamas mosquitofish (Gambusia hubbsi) inhabit isolated blue holes that differ in predation risk. Individuals of populations coexisting with predators exhibited similar, relatively low stress reactivity as compared to low-predation populations. We suggest that this dampened stress reactivity has evolved to reduce energy expenditure in environments with frequent and intense stressors, such as piscivorous fish. Importantly, the magnitude of stress responses exhibited by fish from high-predation sites in the wild changed very little after two generations of laboratory rearing in the absence of predators. By comparison, low-predation populations exhibited greater among-population variation and larger changes subsequent to laboratory rearing. These low-predation populations appear to have evolved more dampened stress responses in blue holes with lower food availability. Moreover, females showed a lower ventilation frequency, and this sexual dimorphism was stronger in high-predation populations. This may reflect a greater premium placed on energy efficiency in live-bearing females, especially under high-predation risk where females show higher fecundities. Altogether, by demonstrating parallel adaptive divergence in stress reactivity, we highlight how energetic trade-offs may mould the evolution of the vertebrate stress response under varying predation risk and resource availability.


kWIP: The k-mer weighted inner product, a de novo estimator of genetic similarity.
Modern genomics techniques generate overwhelming quantities of data. Extracting population genetic variation demands computationally efficient methods to determine genetic relatedness between individuals (or "samples") in an unbiased manner, preferably de novo. Rapid estimation of genetic relatedness directly from sequencing data has the potential to overcome reference genome bias, and to verify that individuals belong to the correct genetic lineage before conclusions are drawn using mislabelled, or misidentified samples. We present the k-mer Weighted Inner Product (kWIP), an assembly-, and alignment-free estimator of genetic similarity. kWIP combines a probabilistic data structure with a novel metric, the weighted inner product (WIP), to efficiently calculate pairwise similarity between sequencing runs from their k-mer counts. It produces a distance matrix, which can then be further analysed and visualised. Our method does not require prior knowledge of the underlying genomes and applications include establishing sample identity and detecting mix-up, non-obvious genomic variation, and population structure. We show that kWIP can reconstruct the true relatedness between samples from simulated populations. By re-analysing several published datasets we show that our results are consistent with marker-based analyses. kWIP is written in C++, licensed under the GNU GPL, and is available from https://github.com/kdmurray91/kwip.


Bacteremic meningitis is associated with inferior outcome in comparison to community acquired meningitis without bacteremia.
Meningitis associated with bacteremia is rare. Bacteremic form of meningitis occurred in 28 of 201 cases of community acquired meningitis (14%) in Slovakia within last 17 years. Bacteremic meningitis was associated with diabetes (21.4% vs. 7.5%, p=0.02) and with higher treatment failures (32.1% vs. 9.5%, p=0.01) and higher mortality (25% vs. 12.4%, NS). In univariate analysis comparing 28 cases of bacteremic community acquired bacterial meningitis (BCBM) to all CBM, no significant risk factor concerning underlying disease (cancer, ENT infection, alcohol abuses, trauma, splenectomy, etc.) or etiology was observed apart of diabetes mellitus, which was more common among bacteremic meningitis (21.4% vs. 7.5%, p=0.02). Mortality (25% vs. 12.4%, NS) insignificantly but therapy failure (32.1% vs. 9.5%, p=0.01) was significantly more frequently observed among meningitis with bacteremia. N. meningitis was the commonest causative agent (8 of 28 cases) followed by Str. pneumoniae (6), gram-negative bacteria (6), S. aureus (4) and H. influenzae (2).


Genome Sequences of Human Coronavirus OC43 and NL63, Associated with Respiratory Infections in Kilifi, Kenya.
Coding-complete genomes of two human coronavirus OC43 strains and one NL63 strain were obtained by metagenomic sequencing of clinical samples collected in 2017 and 2018 in Kilifi, Kenya. Maximum likelihood phylogenies showed that the OC43 strains were genetically dissimilar and that the NL63 strain was closely related to NL63 genotype B viruses.


Synergistic Adverse Effects of Azithromycin and Hydroxychloroquine on Human Cardiomyocytes at a Clinically Relevant Treatment Duration.
Adverse effects of drug combinations and their underlying mechanisms are highly relevant for safety evaluation, but often not fully studied. Hydroxychloroquine (HCQ) and azithromycin (AZM) were used as a combination therapy in the treatment of COVID-19 patients at the beginning of the pandemic, leading to higher complication rates in comparison to respective monotherapies. Here, we used human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to systematically investigate the effects of HCQ, AZM, and their combination on the structure and functionality of cardiomyocytes, and to better understand the underlying mechanisms. Our results demonstrate synergistic adverse effects of AZM and HCQ on electrophysiological and contractile function of iPSC-CMs. HCQ-induced prolongation of field potential duration (FPDc) was gradually increased during 7-day treatment period and was strongly enhanced by combination with AZM, although AZM alone slightly shortened FPDc in iPSC-CMs. Combined treatment with AZM and HCQ leads to higher cardiotoxicity, more severe structural disarrangement, more pronounced contractile dysfunctions, and more elevated conduction velocity, compared to respective monotreatments. Mechanistic insights underlying the synergistic effects of AZM and HCQ on iPSC-CM functionality are provided based on increased cellular accumulation of HCQ and AZM as well as increased Cx43- and Nav1.5-protein levels.


A tincture of hepcidin cures all: the potential for hepcidin therapeutics.
Iron overload as a result of blood transfusions and excessive intestinal iron absorption can be a complication of chronic anemias such as β-thalassemia. Inappropriately low levels of hepcidin, a negative regulator of iron absorption and recycling, underlie the pathophysiology of the intestinal hyperabsorption. In this issue of the JCI, Gardenghi et al. demonstrate that increasing hepcidin expression to induce iron deficiency in murine β-thalassemia not only mitigates the iron overload, but also the severity of the anemia. These data illustrate the therapeutic potential of modulating hepcidin expression in diseases associated with altered iron metabolism.


Using Smartphones and Wearable Devices to Monitor Behavioral Changes During COVID-19.
In the absence of a vaccine or effective treatment for COVID-19, countries have adopted nonpharmaceutical interventions (NPIs) such as social distancing and full lockdown. An objective and quantitative means of passively monitoring the impact and response of these interventions at a local level is needed. We aim to explore the utility of the recently developed open-source mobile health platform Remote Assessment of Disease and Relapse (RADAR)-base as a toolbox to rapidly test the effect and response to NPIs intended to limit the spread of COVID-19. We analyzed data extracted from smartphone and wearable devices, and managed by the RADAR-base from 1062 participants recruited in Italy, Spain, Denmark, the United Kingdom, and the Netherlands. We derived nine features on a daily basis including time spent at home, maximum distance travelled from home, the maximum number of Bluetooth-enabled nearby devices (as a proxy for physical distancing), step count, average heart rate, sleep duration, bedtime, phone unlock duration, and social app use duration. We performed Kruskal-Wallis tests followed by post hoc Dunn tests to assess differences in these features among baseline, prelockdown, and during lockdown periods. We also studied behavioral differences by age, gender, BMI, and educational background. We were able to quantify expected changes in time spent at home, distance travelled, and the number of nearby Bluetooth-enabled devices between prelockdown and during lockdown periods (P<.001 for all five countries). We saw reduced sociality as measured through mobility features and increased virtual sociality through phone use. People were more active on their phones (P<.001 for Italy, Spain, and the United Kingdom), spending more time using social media apps (P<.001 for Italy, Spain, the United Kingdom, and the Netherlands), particularly around major news events. Furthermore, participants had a lower heart rate (P<.001 for Italy and Spain; P=.02 for Denmark), went to bed later (P<.001 for Italy, Spain, the United Kingdom, and the Netherlands), and slept more (P<.001 for Italy, Spain, and the United Kingdom). We also found that young people had longer homestay than older people during the lockdown and fewer daily steps. Although there was no significant difference between the high and low BMI groups in time spent at home, the low BMI group walked more. RADAR-base, a freely deployable data collection platform leveraging data from wearables and mobile technologies, can be used to rapidly quantify and provide a holistic view of behavioral changes in response to public health interventions as a result of infectious outbreaks such as COVID-19. RADAR-base may be a viable approach to implementing an early warning system for passively assessing the local compliance to interventions in epidemics and pandemics, and could help countries ease out of lockdown.


[Effect of chronic craving for ethanol on accumulation of calcium ions in intracellular structures of rat myometrium].
In the experiments on the impregnant estrogenized rats the effect of chronic ethanol intake on Ca(2+)-accumulative mitochondrial systems and endoplasmatic systems of myometrium was estimated. It was defined that in chronic alcohol consumption the transport activity of mitochondria Ca(2+)-accumulative systems didn't prevail over endoplasmatic reticulum Ca(2+)-accumulative activity. Therewith mitochondria and endoplasmatic Ca(2+)-transport system was essentially disturbed. In the tested conditions Mg2+, ATP-dependent sensitivity of calcium pump to oxytocin inhibiting action was shown to disappear.


Intuitive t tests: lay use of statistical information.
Normatively, a statistical pairwise comparison is a function of the mean, standard deviation (SD), and sample size of the data. In our experiment, 203 undergraduates compared product pairs and judged their confidence thatone product was better than the other. We experimentally manipulated (within subjects) theaverage productratings, the number of raters (sample size), and the SD of the ratings. Each factor had two levels selected, so that the same change in statistical power resulted from moving from the low to the high level. We also manipulated (between subjects) whether subjects were given only the product rating data as summarized in a statistical format orthe summariesplus the raw ratings. Subjects gave the most weight to mean product ratings, less weight to sample size, and very little weight to SD. Providing subjects with raw data did not increase their use of sample size and SD, as predicted.


The contribution of children's time-specific and longitudinal expressive language skills on developmental trajectories of executive function.
To investigate whether children's early language skills support the development of executive functions (EFs), the current study used an epidemiological sample (N=1121) to determine whether two key language indicators, vocabulary and language complexity, were predictive of EF abilities over the preschool years. We examined vocabulary and language complexity both as time-varying covariates that predicted time-specific indicators of EF at 36 and 60 months of age and as time-invariant covariates that predicted children's EF at 60 months and change in EF from 36 to 60 months. We found that the rate of change in children's vocabulary between 15 and 36 months was associated with both the trajectory of EF from 36 to 60 months and the resulting abilities at 60 months. In contrast, children's language complexity had a time-specific association with EF only at 60 months. These findings suggest that children's early gains in vocabulary may be particularly relevant for emerging EF abilities.


Species concepts and malaria parasites: detecting a cryptic species of Plasmodium.
Species of malaria parasite (phylum Apicomplexa: genus Plasmodium) have traditionally been described using the similarity species concept (based primarily on differences in morphological or life-history characteristics). The biological species concept (reproductive isolation) and phylogenetic species concept (based on monophyly) have not been used before in defining species of Plasmodium. Plasmodium azurophilum, described from Anolis lizards in the eastern Caribbean, is actually a two-species cryptic complex. The parasites were studied from eight islands, from Puerto Rico in the north to Grenada in the south. Morphology of the two species is very similar (differences are indistinguishable to the eye), but one infects only erythrocytes and the other only white blood cells. Molecular data for the cytochrome b gene reveal that the two forms are reproductively isolated; distinct haplotypes are present on each island and are never shared between the erythrocyte-infecting and leucocyte-infecting species. Each forms a monophyletic lineage indicating that they diverged before becoming established in the anoles of the eastern Caribbean. This comparison of the similarity, biological and phylogenetic species concepts for malaria parasites reveals the limited value of using only similarity measures in defining protozoan species.


Chemical inhibition of Src family kinases affects major LPS-activated pathways in primary human macrophages.
Understanding the signalling mechanisms controlling inflammatory cytokine production is pivotal to the research of both acute and chronic immune disorders. Tyrosine phosphorylation is one of the earliest events to occur in response to an immune challenge yet the role of specific tyrosine kinases in inflammatory cytokine production has been difficult to ascribe due to conflicting literature. Here we show that the pyrazolo pyrimidine compound PP2, a selective inhibitor of Src family kinases (SFK), can inhibit LPS-induced TNF production as well as a number of other inflammatory cytokines. In addition, we show similar effects of PP2 on cytokine production when induced by other TLRs, (1, 2 and 5-8), indicating that SFK are important common regulators of TLR signalling. PP2 suppressed the activity of both TNF and IL-10 driven reporter genes, suggesting that this activity is mediated at the level of transcription. Interestingly, however, PP2 had no significant effect on the activation of NF-kappaB, or on p42/44 ERK, p46/54 JNK or p38 MAPK phosphorylation. In contrast, PP2 did inhibit AP-1 nuclear accumulation in response to LPS. Taken together, these findings show that the Src kinases are able to control inflammatory cytokine production at the transcriptional level independently of NF-kappaB, and highlight the role of the AP-1 family of transcription factors as downstream mediators of Src kinase action.


Prevalence and predictors of hepatic steatosis in adults with newly diagnosed chronic liver disease due to hepatitis C.
Obesity appears to be a risk factor for hepatic steatosis, which has been implicated in the development of hepatic fibrosis in patients with hepatitis C virus infection. We conducted the current study to examine whether obesity is associated with hepatic steatosis among patients with chronic hepatitis C identified from a population-based cohort. Study participants were persons with chronic hepatitis C who had had a liver biopsy, identified from a population-based study of persons with newly identified chronic liver disease conducted in gastroenterology practices. Data were collected through patient interviews, medical record abstraction, and review of previously performed liver biopsies. The outcome variable of interest was significant steatosis, defined as steatosis grade > or =2 determined from liver biopsy samples. Univariate and multivariate analyses were performed using logistic regression techniques. The analysis included 450 patients with chronic hepatitis C with available liver biopsy slides. Overall, only 15.8% of subjects had significant hepatic steatosis (grade > or =2), while 35.9% of obese subjects had significant steatosis. In multivariate analysis, significant fibrosis (defined as > or = grade 2) (odds ratio [OR], 3.43; 95% confidence interval [CI], 1.59-7.37), obesity (OR, 3.32; 95% CI, 1.84-5.98), genotype 3 (OR, 2.5; 95% CI, 1.09-5.75), and the presence of multiple metabolic comorbidities (OR, 1.91; 95% CI, 0.88-4.11) were independently associated with steatosis. In this unique United States cohort of patients with newly diagnosed chronic liver disease due to hepatitis C, obesity was independently associated with hepatic steatosis. The results of this study provide additional evidence that obesity worsens liver damage in patients with chronic hepatitis C, and suggest a role for weight loss as a treatment modality in these patients.


The spatial analysis of covariates in a study of environmental epidemiology.
Kanawha County, West Virginia, includes a deep river valley with a large population living in close proximity to many chemical manufacturing centres. One study of this area combined an epidemiologic survey of children attending Kanawha County schools with the measurement of the concentrations of 15 volatile organic compounds at each of the 75 elementary schools. Results have been reported by Ware et al. This paper further examines the associations of the concentrations of the ten individual volatile organic compounds related to chemical manufacturing processes with observed lower respiratory symptoms, generalizing the model of spatial variability and measurement error proposed by Donnelly et al. and using semi-variograms to assess the validity of model assumptions.


Mesoscale iron enrichment experiments 1993-2005: synthesis and future directions.
Since the mid-1980s, our understanding of nutrient limitation of oceanic primary production has radically changed. Mesoscale iron addition experiments (FeAXs) have unequivocally shown that iron supply limits production in one-third of the world ocean, where surface macronutrient concentrations are perennially high. The findings of these 12 FeAXs also reveal that iron supply exerts controls on the dynamics of plankton blooms, which in turn affect the biogeochemical cycles of carbon, nitrogen, silicon, and sulfur and ultimately influence the Earth climate system. However, extrapolation of the key results of FeAXs to regional and seasonal scales in some cases is limited because of differing modes of iron supply in FeAXs and in the modern and paleo-oceans. New research directions include quantification of the coupling of oceanic iron and carbon biogeochemistry.


Estimating regional effects of climate change and altered land use on biosphere carbon fluxes using distributed time delay neural networks with Bayesian regularized learning.
The ability to accurately predict changes of the carbon and energy balance on a regional scale is of great importance for assessing the effect of land use changes on carbon sequestration under future climate conditions. Here, a suite of land cover-specific Distributed Time Delay Neural Networks with a parameter adoption algorithm optimized through Bayesian regularization was used to model the statewide atmospheric exchange of CO2, water vapor, and energy in Oregon with its strong spatial gradients of climate and land cover. The network models were trained with eddy covariance data from 9 atmospheric flux towers. Compared to results derived with more common regression networks utilizing non-delayed input vectors, the performance of the DTDNN models was significantly improved with an average increase of the coefficients of determination of 64%. The optimized models were applied in combination with downscaled climate projections of the CMIP5 project to calculate future changes in the cycle of carbon, associated with a prescribed conversion of conventional grass-crops to hybrid poplar plantations for biofuel production in Oregon. The results show that under future RCP8.5 climate conditions the total statewide NEP increases by 0.87 TgC per decade until 2050 without any land use changes. With all non-forage grass completely converted to hybrid poplar the NEP averages 32.9 TgC in 2046-2050, an increase of 9%. Through comparisons with the results of a Bayesians inversion study, the results presented demonstrate that DTDNN models are a specifically well-suited approach to use the available data from flux networks to assess changes in biosphere-atmosphere exchange triggered by massive land use conversion superimposed on a changing climate.


Membrane potential-dependent inactivation of voltage-gated ion channels in alpha-cells inhibits glucagon secretion from human islets.
To document the properties of the voltage-gated ion channels in human pancreatic alpha-cells and their role in glucagon release. Glucagon release was measured from intact islets. [Ca(2+)](i) was recorded in cells showing spontaneous activity at 1 mmol/l glucose. Membrane currents and potential were measured by whole-cell patch-clamping in isolated alpha-cells identified by immunocytochemistry. Glucose inhibited glucagon secretion from human islets; maximal inhibition was observed at 6 mmol/l glucose. Glucagon secretion at 1 mmol/l glucose was inhibited by insulin but not by ZnCl(2). Glucose remained inhibitory in the presence of ZnCl(2) and after blockade of type-2 somatostatin receptors. Human alpha-cells are electrically active at 1 mmol/l glucose. Inhibition of K(ATP)-channels with tolbutamide depolarized alpha-cells by 10 mV and reduced the action potential amplitude. Human alpha-cells contain heteropodatoxin-sensitive A-type K(+)-channels, stromatoxin-sensitive delayed rectifying K(+)-channels, tetrodotoxin-sensitive Na(+)-currents, and low-threshold T-type, isradipine-sensitive L-type, and omega-agatoxin-sensitive P/Q-type Ca(2+)-channels. Glucagon secretion at 1 mmol/l glucose was inhibited by 40-70% by tetrodotoxin, heteropodatoxin-2, stromatoxin, omega-agatoxin, and isradipine. The [Ca(2+)](i) oscillations depend principally on Ca(2+)-influx via L-type Ca(2+)-channels. Capacitance measurements revealed a rapid (<50 ms) component of exocytosis. Exocytosis was negligible at voltages below -20 mV and peaked at 0 mV. Blocking P/Q-type Ca(2+)-currents abolished depolarization-evoked exocytosis. Human alpha-cells are electrically excitable, and blockade of any ion channel involved in action potential depolarization or repolarization results in inhibition of glucagon secretion. We propose that voltage-dependent inactivation of these channels underlies the inhibition of glucagon secretion by tolbutamide and glucose.


Low birthweight and preterm delivery, Scotland, 1981-84: effect of parents' occupation.
The relation between prematurity and parenteral occupation was examined in a national study of 252,147 liveborn babies delivered in Scotland between 1981 and 1984. Information about mothers' and fathers' work was routinely collected at the first antenatal visit, and birthweight and gestational age were recorded at delivery. Preterm delivery (less than 37 weeks' gestation) and low birthweight (less than 2500 g) were more frequent in the children of mothers and of fathers employed in manual rather than in non-manual jobs. The risk of preterm delivery and/or low birthweight was more than 50% higher in the children of women who worked with electrical, metal, or leather goods than in the children of other female manual workers. These findings were not explained by maternal age, gravidity, marital status, previous perinatal death, baby's sex, or father's social class. For male manual workers, only the children of ceramic workers had an increased risk of prematurity. The risk of a baby being small-for-gestational age (less than or equal to 5th gestation-specific birthweight percentile) varied little with mother's or father's occupation. Overall, the results suggest that parental occupational exposures do not have a pronounced effect on the risk of prematurity, and when there are adverse effects they are associated with maternal rather than paternal exposures.


Impaired brachial flow-mediated dilation is a predictor of a new-onset vascular event after stroke.
Brachial arterial flow-mediated dilation (FMD) is associated with an increased risk of vascular events. Our aim was to investigate the relationship between FMD measured in the acute phase of ischemic stroke and a new major adverse vascular event in a consecutive cohort of patients followed up for 48 months after an acute first-ever stroke. We measured FMD in 120 consecutive patients with acute ischemic stroke using high-resolution ultrasonography. FMD was calculated as the relationship between the basal diameter of the brachial artery before and after transient vascular occlusion. Intima-media thickness, extracranial carotid atherosclerosis, stroke severity National Institute of Health Stroke Scale, and modified Rankin Scale at 3 months were also evaluated. A vascular event was defined as any of the following: vascular disease (VD) death, nonfatal myocardial infarction (MI), nonfatal recurrent stroke (RS), claudication or peripheral arterial thrombosis (PVD), angioplasty or cardiac bypass graft surgery. There were 34 new major adverse vascular events in 32 of 120 patients (26.7%): 21 (61.8%) RS, 5 (14.7%) VD death, 5 (14.7%) MI, and 3 (8.8%) PVD. The presence of carotid artery plaque (81.3 vs. 46%; p < 0.0001), atrial fibrillation (37.5 vs. 14.8%; p = 0.007) and FMD (5.30 ± 7.48 vs. 10.54 ± 7.02; p = 0.001) were associated with new-onset vascular events. FMD ≤4.5% was an independent predictor of new-onset vascular events (hazards ratio 3.48; 95% confidence interval 1.26-9.63; p = 0.01). FMD is an independent predictor for a new-onset vascular event after first-ever ischemic stroke.


Resveratrol regulates the PTEN/AKT pathway through androgen receptor-dependent and -independent mechanisms in prostate cancer cell lines.
The tumor suppressor gene PTEN (phosphatase and tensin homolog deleted on chromosome 10) and the androgen receptor (AR) play important roles in tumor development and progression in prostate carcinogenesis. Among many functions, PTEN negatively regulates the cytoplasmic phosphatidylinositol-3-kinase/AKT anti-apoptotic pathway; and nuclear PTEN affects the cell cycle by also negatively regulating the MAPK pathway via cyclin D. Decreased PTEN expression is correlated with prostate cancer progression. Over-expression of AR and upregulation of AR transcriptional activity are often observed in the later stages of prostate cancer. Recent studies indicate that PTEN regulates AR activity and stability. However, the mechanism of how AR regulates PTEN has never been studied. Furthermore, resveratrol, a phytoalexin enriched in red grapes, strawberries and peanuts, has been shown to inhibit AR transcriptional activity in prostate cancer cells. In this study, we use prostate cancer cell lines to test the hypothesis that resveratrol inhibits cellular proliferation in both AR-dependent and -independent mechanisms. We show that resveratrol inhibits AR transcriptional activity in both androgen-dependent and -independent prostate cancer cells. Additionally, resveratrol stimulates PTEN expression through AR inhibition. In contrast, resveratrol directly binds epidermal growth factor receptor (EGFR) rapidly inhibiting EGFR phosphorylation, resulting in decreased AKT phosphorylation, in an AR-independent manner. Thus, resveratrol may act as potential adjunctive treatment for late-stage hormone refractory prostate cancer. More importantly, for the first time, our study demonstrates the mechanism by which AR regulates PTEN expression at the transcription level, indicating the direct link between a nuclear receptor and the PI3K/AKT pathway.


Sustained endothelial expression of HoxA5 in vivo impairs pathological angiogenesis and tumor progression.
HoxA5 is expressed in quiescent endothelial cells (EC), but absent in activated angiogenic EC. To examine the efficacy of targeting HoxA5 therapeutically to quell pathologic or tumor angiogenesis, we generated an inducible, transgenic mouse model of sustained HoxA5 expression in ECs. During pathologic angiogenesis, sustained HoxA5 regulates expression several angiogenic effector molecules, notably increased expression of TSP-2 and reduced expression of VEGF, thus leading to inhibition of pathological angiogenesis in tissues. To evaluate if this impressive reduction of vascularization could also impact tumor angiogenesis, HoxA5 mice were bred with a mouse model of de novo squamous carcinogenesis, e.g., K14-HPV16 mice. Activation of EC-HoxA5 significantly reduced infiltration by mast cells into neoplastic skin, an early hallmark of progression to dysplasia, reduced angiogenic vasculature, and blunted characteristics of tumor progression. To evaluate HoxA5 as a therapeutic, topical application of a HoxA5 transgene onto early neoplastic skin of K14-HPV16 mice similarly resulted in a significant impairment of angiogenic vasculature and progression to dysplasia to a similar extent as observed with genetic delivery of HoxA5. Together these data indicate that HoxA5 represents a novel molecule for restricting pathological and tumorigenic angiogenesis.


High levels of pigment epithelium-derived factor in diabetes impair wound healing through suppression of Wnt signaling.
Diabetic foot ulcer (DFU) caused by impaired wound healing is a common vascular complication of diabetes. The current study revealed that plasma levels of pigment epithelium-derived factor (PEDF) were elevated in type 2 diabetic patients with DFU and in db/db mice. To test whether elevated PEDF levels contribute to skin wound-healing delay in diabetes, endogenous PEDF was neutralized with an anti-PEDF antibody in db/db mice. Our results showed that neutralization of PEDF accelerated wound healing, increased angiogenesis in the wound skin, and improved the functions and numbers of endothelial progenitor cells (EPCs) in the diabetic mice. Further, PEDF-deficient mice showed higher baseline blood flow in the skin, higher density of cutaneous microvessels, increased skin thickness, improved numbers and functions of circulating EPCs, and accelerated wound healing compared with wild-type mice. Overexpression of PEDF suppressed the Wnt signaling pathway in the wound skin. Lithium chloride-induced Wnt signaling activation downstream of the PEDF interaction site attenuated the inhibitory effect of PEDF on EPCs and rescued the wound-healing deficiency in diabetic mice. Taken together, these results suggest that elevated circulating PEDF levels contribute to impaired wound healing in the process of angiogenesis and vasculogenesis through the inhibition of Wnt/β-catenin signaling.


Arrhythmogenic right ventricular dysplasia/cardiomyopathy: pathogenic desmosome mutations in index-patients predict outcome of family screening: Dutch arrhythmogenic right ventricular dysplasia/cardiomyopathy genotype-phenotype follow-up study.
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant inherited disease with incomplete penetrance and variable expression. Causative mutations in genes encoding 5 desmosomal proteins are found in ≈50% of ARVD/C index patients. Previous genotype-phenotype relation studies involved mainly overt ARVD/C index patients, so follow-up data on relatives are scarce. One hundred forty-nine ARVD/C index patients (111 male patients; age, 49±13 years) according to 2010 Task Force criteria and 302 relatives from 93 families (282 asymptomatic; 135 male patients; age, 44±13 years) were clinically and genetically characterized. DNA analysis comprised sequencing of plakophilin-2 (PKP2), desmocollin-2, desmoglein-2, desmoplakin, and plakoglobin and multiplex ligation-dependent probe amplification to identify large deletions in PKP2. Pathogenic mutations were found in 87 index patients (58%), mainly truncating PKP2 mutations, including 3 cases with multiple mutations. Multiplex ligation-dependent probe amplification revealed 3 PKP2 exon deletions. ARVD/C was diagnosed in 31% of initially asymptomatic mutation-carrying relatives and 5% of initially asymptomatic relatives of index patients without mutation. Prolonged terminal activation duration was observed more than negative T waves in V(1) to V(3), especially in mutation-carrying relatives <20 years of age. In 45% of screened families, ≥1 affected relatives were identified (90% with mutations). Pathogenic desmosomal gene mutations, mainly truncating PKP2 mutations, underlie ARVD/C in the majority (58%) of Dutch index patients and even 90% of familial cases. Additional multiplex ligation-dependent probe amplification analysis contributed to discovering pathogenic mutations underlying ARVD/C. Discovering pathogenic mutations in index patients enables those relatives who have a 6-fold increased risk of ARVD/C diagnosis to be identified. Prolonged terminal activation duration seems to be a first sign of ARVD/C in young asymptomatic relatives.


Gaining trust as well as respect in communicating to motivated audiences about science topics.
Expertise is a prerequisite for communicator credibility, entailing the knowledge and ability to be accurate. Trust also is essential to communicator credibility. Audiences view trustworthiness as the motivation to be truthful. Identifying whom to trust follows systematic principles. People decide quickly another's apparent intent: Who is friend or foe, on their side or not, or a cooperator or competitor. Those seemingly on their side are deemed warm (friendly, trustworthy). People then decide whether the other is competent to enact those intents. Perception of scientists, like other social perceptions, involves inferring both their apparent intent (warmth) and capability (competence). To illustrate, we polled adults online about typical American jobs, rated as American society views them, on warmth and competence dimensions, as well as relevant emotions. Ambivalently perceived high-competence but low-warmth, "envied" professions included lawyers, chief executive officers, engineers, accountants, scientists, and researchers. Being seen as competent but cold might not seem problematic until one recalls that communicator credibility requires not just status and expertise but also trustworthiness (warmth). Other research indicates the risk from being enviable. Turning to a case study of scientific communication, another online sample of adults described public attitudes toward climate scientists specifically. Although distrust is low, the apparent motive to gain research money is distrusted. The literature on climate science communicators agrees that the public trusts impartiality, not persuasive agendas. Overall, communicator credibility needs to address both expertise and trustworthiness. Scientists have earned audiences' respect, but not necessarily their trust. Discussing, teaching, and sharing information can earn trust to show scientists' trustworthy intentions.


Fibroblast growth factor receptor 2 (FGFR2) is required for corneal epithelial cell proliferation and differentiation during embryonic development.
Fibroblast growth factors (FGFs) play important roles in many aspects of embryonic development. During eye development, the lens and corneal epithelium are derived from the same surface ectodermal tissue. FGF receptor (FGFR)-signaling is essential for lens cell differentiation and survival, but its role in corneal development has not been fully investigated. In this study, we examined the corneal defects in Fgfr2 conditional knockout mice in which Cre expression is activated at lens induction stage by Pax6 P0 promoter. The cornea in LeCre, Fgfr2(loxP/loxP) mice (referred as Fgfr2(CKO)) was analyzed to assess changes in cell proliferation, differentiation and survival. We found that Fgfr2(CKO) cornea was much thinner in epithelial and stromal layer when compared to WT cornea. At embryonic day 12.5-13.5 (E12.5-13.5) shortly after the lens vesicle detaches from the overlying surface ectoderm, cell proliferation (judged by labeling indices of Ki-67, BrdU and phospho-histone H3) was significantly reduced in corneal epithelium in Fgfr2(CKO) mice. At later stage, cell differentiation markers for corneal epithelium and underlying stromal mesenchyme, keratin-12 and keratocan respectively, were not expressed in Fgfr2(CKO) cornea. Furthermore, Pax6, a transcription factor essential for eye development, was not present in the Fgfr2(CKO) mutant corneal epithelial at E16.5 but was expressed normally at E12.5, suggesting that FGFR2-signaling is required for maintaining Pax6 expression in this tissue. Interestingly, the role of FGFR2 in corneal epithelial development is independent of ERK1/2-signaling. In contrast to the lens, FGFR2 is not required for cell survival in cornea. This study demonstrates for the first time that FGFR2 plays an essential role in controlling cell proliferation and differentiation, and maintaining Pax6 levels in corneal epithelium via ERK-independent pathways during embryonic development.


Depression, cerebral atrophy, cognitive performance and incidence of dementia. Population study of 85-year-olds.
Hospital-based studies suggest that depression in old age relates to organic brain changes. To determine whether these findings are confirmed in a population-based sample. A population sample of non-demented 85-year-olds (227 mentally healthy and 62 with DSM-III-R depression were given a neuropsychiatric examination and computerised tomographic scans of the brain, and followed for three years. On the Mini-Mental State Examination, those with a low educational level with major depression performed worse than the mentally healthy; this distinction was not evident among those who had received higher education. Measures of brain atrophy were similar in depressed and mentally healthy individuals. The three-year incidence of dementia was increased in those with early-onset major depression. Higher education may protect against cognitive symptoms in depressed individuals. The association between depression and cerebral atrophy in the elderly is not very strong. The higher incidence of dementia in those with early-onset major depression may be due to a longer lifetime duration of depression, emphasising the importance of detecting and treating depression in the community.


Causal Model Comparison Shows That Human Representation Learning Is Not Bayesian.
How do we learn what features of our multidimensional environment are relevant in a given task? To study the computational process underlying this type of "representation learning," we propose a novel method of causal model comparison. Participants played a probabilistic learning task that required them to identify one relevant feature among several irrelevant ones. To compare between two models of this learning process, we ran each model alongside the participant during task performance, making predictions regarding the values underlying the participant's choices in real time. To test the validity of each model's predictions, we used the predicted values to try to perturb the participant's learning process: We crafted stimuli to either facilitate or hinder comparison between the most highly valued features. A model whose predictions coincide with the learned values in the participant's mind is expected to be effective in perturbing learning in this way, whereas a model whose predictions stray from the true learning process should not. Indeed, we show that in our task a reinforcement-learning model could help or hurt participants' learning, whereas a Bayesian ideal observer model could not. Beyond informing us about the notably suboptimal (but computationally more tractable) substrates of human representation learning, our manipulation suggests a sensitive method for model comparison, which allows us to change the course of people's learning in real time.


GSK3 beta mediates suppression of cyclin D2 expression by tumor suppressor PTEN.
PTEN, encoding a lipid phosphatase, is a tumor suppressor gene and is mutated in various types of cancers. It is reported to regulate G1 to S phase transition of the cell cycle by influencing the expression, protein stability and subcellular location of cyclin D1. Here, we provide evidence that PTEN modulates the transcription and protein stability of cyclin D2. Targeted deletion of Pten in mouse embryonic fibroblasts (MEFs) endowed cells with greater potential to overcome G1 arrest than wild-type MEFs and led to the elevated expression of cyclin D2, which was suppressed by the introduction of PTEN. We further defined a pathway involving GSK3beta and beta-catenin/TCF in PTEN-mediated suppression of cyclin D2 transcription. LiCl, an inhibitor of GSK3beta, abolished inhibitory effect of PTEN on cyclin D2 expression, and TCF members could directly bind to the promoter of cyclin D2 and regulate its transcription in a CREB-dependent manner. Our results indicate that the downregulation of cyclin D2 expression by PTEN is mediated by the GSK3beta/beta-catenin/TCF pathway in cooperation with CREB, and suggest a convergence from the PI-3 kinase/PTEN pathway and the Wnt pathway in modulation of cyclin D2 expression.


Tracking a Global Threat: a New Genotyping Method for Candida auris.
Over the past decade, Candida auris has emerged as an urgent threat to public health. Initially reported from cases of ear infections in Japan and Korea, C. auris has since been detected around the world. While whole-genome sequencing has been extensively used to trace the genetic relationships of the global emergence and local outbreaks, a recent report in mBio describes a targeted genotyping method as a rapid and inexpensive method for classifying C. auris isolates (T. de Groot, Y. Puts, I. Berrio, A. Chowdhary, and J. F. Meis, mBio 11:e02971-19, https://doi.org/10.1128/mBio.02971-19, 2020).


Effects of zeolite supplementation on parameters of intestinal barrier integrity, inflammation, redoxbiology and performance in aerobically trained subjects.
Zeolites are crystalline compounds with microporous structures of Si-tetrahedrons. In the gut, these silicates could act as adsorbents, ion-exchangers, catalysts, detergents or anti-diarrheic agents. This study evaluated whether zeolite supplementation affects biomarkers of intestinal wall permeability and parameters of oxidation and inflammation in aerobically trained individuals, and whether it could improve their performance. In a randomized, double-blinded, placebo controlled trial, 52 endurance trained men and women, similar in body fat, non-smokers, 20-50 years, received 1.85 g of zeolite per day for 12 weeks. Stool samples for determination of intestinal wall integrity biomarkers were collected. From blood, markers of redox biology, inflammation, and DNA damage were determined at the beginning and the end of the study. In addition, VO2max and maximum performance were evaluated at baseline and after 12 weeks of treatment. For statistical analyses a 2-factor ANOVA was used. At baseline both groups showed slightly increased stool zonulin concentrations above normal. After 12 weeks with zeolite zonulin was significantly (p < 0.05) decreased in the supplemented group. IL-10 increased tendentially (p < 0.1) in the zeolite group. There were no significant changes observed in the other measured parameters. Twelve weeks of zeolite supplementation exerted beneficial effects on intestinal wall integrity as indicated via decreased concentrations of the tight junction modulator zonulin. This was accompanied by mild anti-inflammatory effects in this cohort of aerobically trained subjects. Further research is needed to explore mechanistic explanations for the observations in this study.


Revision ACL reconstruction using autogenous patellar tendon graft.
This retrospective study examined revision anterior cruciate ligament reconstruction using a bone-tendon-bone autograft of the patellar ligament. We followed up 44 patients (mean age 27.9 years) for an average of 41.2 months. Clinical examination with the Lachmann and pivot shift tests showed clearly improved stability; KT-1000 arthrometer measurements had a mean difference of 3.5 mm in side-to-side comparison. The evaluated knee scores were significantly improved (P<0.01); the median Lysholm score was 85 and the median Tegner activity score 5.0 at follow-up. In the IKDC ranking system 75.0% of knees were rated normal or nearly normal (grades A and B). According to a modified Fairbank scale, progression of radiographic signs of osteoarthritis was noted in 36.4%. There was a significant difference (P<0.05) in progression of radiographic signs of osteoarthritis between patients with major (grades III, IV) versus minor (grades I, II) lesions of the articular cartilage surface and between knees with versus without extensive synovitis due to previous synthetic graft reconstruction (P<0.05). Revision anterior cruciate ligament reconstruction using an autogenous patellar tendon graft shows good results with improved knee function compared to the prerevision status and is in line with various operative techniques described in the literature. Progression of osteoarthritis must be expected in patients with major lesions of the articular cartilage surface and knees with long-term extensive synovitis due to previous anterior cruciate ligament reconstruction using synthetic grafts.


Elevated levels of endothelial cell-derived microparticles following short-term withdrawal of continuous positive airway pressure in patients with obstructive sleep apnea: data from a randomized controlled trial.
Obstructive sleep apnea has been associated with impaired endothelial function; however, the mechanisms underlying this association are not completely understood. Cell-derived microparticles may provide a link between obstructive sleep apnea and endothelial dysfunction. This randomized controlled trial aimed to examine the effect of a 2-week withdrawal of continuous positive airway pressure (CPAP) therapy on levels of circulating microparticles. Forty-one obstructive sleep apnea patients established on CPAP treatment were randomized to either CPAP withdrawal (subtherapeutic CPAP) or continuing therapeutic CPAP, for 2 weeks. Polysomnography was performed and circulating levels of microparticles were analyzed by flow cytometry at baseline and 2 weeks. CPAP withdrawal led to a recurrence of obstructive sleep apnea. Levels of CD62E+ endothelium-derived microparticles increased significantly in the CPAP withdrawal group compared to the continuing therapeutic CPAP group (median difference in change +32.4 per µl; 95% CI +7.3 to +64.1 per µl, p = 0.010). CPAP withdrawal was not associated with a statistically significant increase in granulocyte, leukocyte, and platelet-derived microparticles when compared with therapeutic CPAP. Short-term withdrawal of CPAP therapy leads to a significant increase in endothelium-derived microparticles, suggesting that microparticle formation may be causally linked to obstructive sleep apnea and may promote endothelial activation.


Metabolomics of the interaction between PPAR-alpha and age in the PPAR-alpha-null mouse.
Regulation between the fed and fasted states in mammals is partially controlled by peroxisome proliferator-activated receptor-alpha (PPAR-alpha). Expression of the receptor is high in the liver, heart and skeletal muscle, but decreases with age. A combined (1)H nuclear magnetic resonance (NMR) spectroscopy and gas chromatography-mass spectrometry metabolomic approach has been used to examine metabolism in the liver, heart, skeletal muscle and adipose tissue in PPAR-alpha-null mice and wild-type controls during ageing between 3 and 13 months. For the PPAR-alpha-null mouse, multivariate statistics highlighted hepatic steatosis, reductions in the concentrations of glucose and glycogen in both the liver and muscle tissue, and profound changes in lipid metabolism in each tissue, reflecting known expression targets of the PPAR-alpha receptor. Hepatic glycogen and glucose also decreased with age for both genotypes. These findings indicate the development of age-related hepatic steatosis in the PPAR-alpha-null mouse, with the normal metabolic changes associated with ageing exacerbating changes associated with genotype. Furthermore, the combined metabolomic and multivariate statistics approach provides a robust method for examining the interaction between age and genotype.


Improving Exposure Assessment Methodologies for Epidemiological Studies on Pesticides: Study Protocol.
Exposure to certain pesticides has been associated with several chronic diseases. However, to determine the role of pesticides in the causation of such diseases, an assessment of historical exposures is required. Exposure measurement data are rarely available; therefore, assessment of historical exposures is frequently based on surrogate self-reported information, which has inherent limitations. Understanding the performance of the applied surrogate measures in the exposure assessment of pesticides is therefore important to allow proper evaluation of the risks. The Improving Exposure Assessment Methodologies for Epidemiological Studies on Pesticides (IMPRESS) project aims to assess the reliability and external validity of the surrogate measures used to assign exposure within individuals or groups of individuals, which are frequently based on self-reported data on exposure determinants. IMPRESS will also evaluate the size of recall bias on the misclassification of exposure to pesticides; this in turn will affect epidemiological estimates of the effect of pesticides on human health. The IMPRESS project will recruit existing cohort participants from previous and ongoing research studies primarily of epidemiological origin from Malaysia, Uganda, and the United Kingdom. Consenting participants of each cohort will be reinterviewed using an amended version of the original questionnaire addressing pesticide use characteristics administered to that cohort. The format and relevant questions will be retained but some extraneous questions from the original (eg, relating to health) will be excluded for ethical and practical reasons. The reliability of pesticide exposure recall over different time periods (<2 years, 6-12 years, and >15 years) will then be evaluated. Where the original cohort study is still ongoing, participants will also be asked if they wish to take part in a new exposure biomonitoring survey, which involves them providing urine samples for pesticide metabolite analysis and completing questionnaire information regarding their work activities at the time of sampling. The participant's level of exposure to pesticides will be determined by analyzing the collected urine samples for selected pesticide metabolites. The biomonitoring measurement results will be used to assess the performance of algorithm-based exposure assessment methods used in epidemiological studies to estimate individual exposures during application and re-entry work. The project was funded in September 2017. Enrollment and sample collection was completed for Malaysia in 2019 and is on-going for Uganda and the United Kingdom. Sample and data analysis will proceed in 2020 and the first results are expected to be submitted for publication in 2021. The study will evaluate the consistency of questionnaire data and accuracy of current algorithms in assessing pesticide exposures. It will indicate where amendments can be made to better capture exposure data for future epidemiology studies and thus improve the reliability of exposure-disease associations. PRR1-10.2196/16448.


Separation methods that are capable of revealing blood-brain barrier permeability.
The objective of this review is to emphasize the application of separation science in evaluating the blood-brain barrier (BBB) permeability to drugs and bioactive agents. Several techniques have been utilized to quantitate the BBB permeability. These methods can be classified into two major categories: in vitro or in vivo. The in vivo methods used include brain homogenization, cerebrospinal fluid (CSF) sampling, voltametry, autoradiography, nuclear magnetic resonance (NMR) spectroscopy, positron emission tomography (PET), intracerebral microdialysis, and brain uptake index (BUI) determination. The in vitro methods include tissue culture and immobilized artificial membrane (IAM) technology. Separation methods have always played an important role as adjunct methods to the methods outlined above for the quantitation of BBB permeability and have been utilized the most with brain homogenization, in situ brain perfusion, CSF sampling, intracerebral microdialysis, in vitro tissue culture and IAM chromatography. However, the literature published to date indicates that the separation method has been used the most in conjunction with intracerebral microdialysis and CSF sampling methods. The major advantages of microdialysis sampling in BBB permeability studies is the possibility of online separation and quantitation as well as the need for only a small sample volume for such an analysis. Separation methods are preferred over non-separation methods in BBB permeability evaluation for two main reasons. First, when the selectivity of a determination method is insufficient, interfering substances must be separated from the analyte of interest prior to determination. Secondly, when large number of analytes is to be detected and quantitated by a single analytical procedure, the mixture must be separated to each individual component prior to determination. Chiral separation in particular can be essential to evaluate the stereo-selective permeation and distribution of agents into the brain. In conclusion, the usefulness of separation methods during BBB permeability evaluation is immense and more application of these methods is foreseen in the future.


Individual Variation in Adaptive Immune Responses and Risk of Hip Fracture-A NOREPOS Population-Based Cohort Study.
Immune-mediated bone loss significantly impacts fracture risk in patients with autoimmune disease, but to what extent individual variations in immune responses affect fracture risk on a population level is unknown. To examine how immune responses relate to risk of hip fracture, we looked at the individual variation in a post-vaccination skin test response that involves some of the immune pathways that also drive bone loss. From 1963 to 1975, the vast majority of the Norwegian adult population was examined as part of the compulsory nationwide Norwegian mass tuberculosis screening. These examinations included standardized tuberculin skin tests (TSTs). Our study population included young individuals (born 1940 to 1960 and aged 14 to 30 years at examination) who had all received Bacille Calmette-Guerin (BCG) vaccination after a negative TST at least 1 year prior and had no signs of tuberculosis upon clinical examination. The study population ultimately included 244,607 individuals, whose data were linked with a national database of all hospitalized hip fractures in Norway from 1994 to 2013. There were 3517 incident hip fractures during follow-up. Using a predefined Cox model, we found that men with a positive or a strong positive TST result had a 20% (hazard ratio [HR] = 1.20, 95% confidence interval [CI] 1.01-1.44) and 24% (HR = 1.24, 95% CI 1.03-1.49) increased risk of hip fracture, respectively, compared with men with a negative TST. This association was strengthened in sensitivity analyses. Total hip bone mineral density (BMD) was available for a limited subsample and similarly revealed a non-significantly reduced BMD among men with a positive TST. Interestingly, no such clear association was observed in women. An increased immune response after vaccination is associated with an increased risk of hip fracture decades later among men, possibly because of increased immune-mediated bone loss. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Combined molecular/continuum modeling reveals the role of friction during fast unfolding of coiled-coil proteins.
Coiled-coils are filamentous proteins that form the basic building block of important force-bearing cellular elements, such as intermediate filaments and myosin motors. In addition to their biological importance, coiled-coil proteins are increasingly used in new biomaterials including fibers, nanotubes, or hydrogels. Coiled-coils undergo a structural transition from an α-helical coil to an unfolded state upon extension, which allows them to sustain large strains and is critical for their biological function. By performing equilibrium and out-of-equilibrium all-atom molecular dynamics (MD) simulations of coiled-coils in explicit solvent, we show that two-state models based on Kramers' or Bell's theories fail to predict the rate of unfolding at high pulling rates. We further show that an atomistically informed continuum rod model accounting for phase transformations and for the hydrodynamic interactions with the solvent can reconcile two-state models with our MD results. Our results show that frictional forces, usually neglected in theories of fibrous protein unfolding, reduce the thermodynamic force acting on the interface, and thus control the dynamics of unfolding at different pulling rates. Our results may help interpret MD simulations at high pulling rates, and could be pertinent to cytoskeletal networks or protein-based artificial materials subjected to shocks or blasts.


Developments in subintimal angioplasty in the infrainguinal segment.
Since it was first described in 1990, subintimal angioplasty (SIA) has become an established percutaneous procedure for the treatment of symptomatic lower limb arterial occlusions. The concept of this technique is to create a dissection in the subintimal plane in order to cross an occluded intraluminal segment, then to re-enter the true lumen of the patent distal artery. Balloon dilatation of this subintimal channel results in a new extraluminal lumen that is free of atheromatous plaque. It is a safe and effective procedure with advantages over intraluminal angioplasty and open surgery, thereby increasing the scope of endovascular therapy to include complex infrapopliteal occlusions and high-risk patients with limb-threatening ischaemia who are unsuitable for surgical revascularization. It has good primary success rates, long-term outcomes and does not compromise future surgical revascularization, resulting in a paradigm shift in the management of lower limb ischemia with many centres adopting SIA as first-line therapy. This article aims to review the indications of SIA, variations and developments in the technique, outcomes and factors affecting patency, and complications associated with the procedure.


Potent anti-tumor response by targeting B cell maturation antigen (BCMA) in a mouse model of multiple myeloma.
Multiple myeloma (MM) is an aggressive incurable plasma cell malignancy with a median life expectancy of less than seven years. Antibody-based therapies have demonstrated substantial clinical benefit for patients with hematological malignancies, particular in B cell Non-Hodgkin's lymphoma. The lack of immunotherapies specifically targeting MM cells led us to develop a human-mouse chimeric antibody directed against the B cell maturation antigen (BCMA), which is almost exclusively expressed on plasma cells and multiple myeloma cells. The high affinity antibody blocks the binding of the native ligands APRIL and BAFF to BCMA. This finding is rationalized by the high resolution crystal structure of the Fab fragment in complex with the extracellular domain of BCMA. Most importantly, the antibody effectively depletes MM cells in vitro and in vivo and substantially prolongs tumor-free survival under therapeutic conditions in a xenograft mouse model. A BCMA-antibody-based therapy is therefore a promising option for the effective treatment of multiple myeloma and autoimmune diseases.


Accuracy and precision of the TAS analyser for near-patient INR testing by non-pathology staff in the community.
To assess the accuracy and precision of INR measurement by trained practice and district nursing staff using the Thrombolytic Assessment System (TAS) analyser. Seventeen nurses from four practices were trained to measure INR using the TAS analyser on citrated capillary blood samples. Quality control (QC) consisted of: daily internal QC using normal and abnormal commercial plasmas; monthly local external QC scheme using fresh citrated venous blood; and registration of all analysers in the NEQAS (national external quality assessment scheme) main users scheme. Analysis of internal QC results demonstrated satisfactory interanalyser and intra-analyser precision with no evidence of analytical drift in any of the four practice analysers over an eight month period. Local and national external QC results confirmed the interanalyser precision but INR was underestimated by the TAS analysers compared with the CA 1000 using either Diagen rabbit brain thromboplastin or Innovin, and with other NEQAS users. The TAS analyser has many features to commend it for use by nonpathology staff to determine INR. Local internal and external QC and entry into the NEQAS main users group are possible because the TAS analyses citrated plasma or blood. The TAS analyser underestimates INR when the geometric mean normal prothrombin time (GMNPT) is determined by conventional methods. A local correction factor can be introduced by adjusting the normal PT to give INR results comparable with the local laboratory. This is particularly desirable when INRs are measured using both near-patient and laboratory analytical systems on different occasions.


Remission from post-traumatic stress disorder in adults: a systematic review and meta-analysis of long term outcome studies.
Posttraumatic stress disorder (PTSD) is a frequent mental disorder associated with significant distress and high costs. We conducted the first systematic review and meta-analysis on spontaneous long-term remission rates, i. e., without specific treatment. Data sources were searches of databases, hand searches, and contact with authors. Remission estimates were obtained from observational prospective studies of PTSD without specific treatment. Remission was defined as the actual percentage of PTSD cases at baseline who are non-cases after a minimum of ten months. Forty-two studies with a total of 81,642 participants were included. The mean observation period was 40 months. Across all studies, an average of 44.0% of individuals with PTSD at baseline were non-cases at follow-up. Remission varied between 8 and 89%. In studies with the baseline within the first five months following trauma the remission rate was 51.7% as compared to 36.9% in studies with the baseline later than five months following trauma. Publications on PTSD related to natural disaster reported the highest mean of remission rate (60.0%), whereas those on PTSD related to physical disease reported the lowest mean of remission rate from PTSD (31.4%). When publications on natural disaster were used as a reference group, the only type of traumatic events to differ from natural disaster was physical disease. No other measured predictors were associated with remission from PTSD. Long-term remission from PTSD without specific treatment varies widely and is higher in studies with the baseline within five months following trauma.


Stream carbon and nitrogen supplements during leaf litter decomposition: contrasting patterns for two foundation species.
Leaf litter decomposition plays a major role in nutrient dynamics in forested streams. The chemical composition of litter affects its processing by microorganisms, which obtain nutrients from litter and from the water column. The balance of these fluxes is not well known, because they occur simultaneously and thus are difficult to quantify separately. Here, we examined C and N flow from streamwater and leaf litter to microbial biofilms during decomposition. We used isotopically enriched leaves ((13)C and (15)N) from two riparian foundation tree species: fast-decomposing Populus fremontii and slow-decomposing Populus angustifolia, which differed in their concentration of recalcitrant compounds. We adapted the isotope pool dilution method to estimate gross elemental fluxes into litter microbes. Three key findings emerged: litter type strongly affected biomass and stoichiometry of microbial assemblages growing on litter; the proportion of C and N in microorganisms derived from the streamwater, as opposed to the litter, did not differ between litter types, but increased throughout decomposition; gross immobilization of N from the streamwater was higher for P. fremontii compared to P. angustifolia, probably as a consequence of the higher microbial biomass on P. fremontii. In contrast, gross immobilization of C from the streamwater was higher for P. angustifolia, suggesting that dissolved organic C in streamwater was used as an additional energy source by microbial assemblages growing on slow-decomposing litter. These results indicate that biofilms on decomposing litter have specific element requirements driven by litter characteristics, which might have implications for whole-stream nutrient retention.


Hot spot formation and chemical reaction initiation in shocked HMX crystals with nanovoids: a large-scale reactive molecular dynamics study.
We report million-atom reactive molecular dynamic simulations of shock initiation of β-cyclotetramethylene tetranitramine (β-HMX) single crystals containing nanometer-scale spherical voids. Shock induced void collapse and subsequent hot spot formation as well as chemical reaction initiation are observed which depend on the void size and impact strength. For an impact velocity of 1 km s(-1) and a void radius of 4 nm, the void collapse process includes three stages; the dominant mechanism is the convergence of upstream molecules toward the centerline and the downstream surface of the void forming flowing molecules. Hot spot formation also undergoes three stages, and the principal mechanism is kinetic energy transforming to thermal energy due to the collision of flowing molecules on the downstream surface. The high temperature of the hot spot initiates a local chemical reaction, and the breakage of the N-NO2 bond plays the key role in the initial reaction mechanism. The impact strength and void size have noticeable effects on the shock dynamical process, resulting in a variation of the predominant mechanisms leading to void collapse and hot spot formation. Larger voids or stronger shocks result in more intense hot spots and, thus, more violent chemical reactions, promoting more reaction channels and generating more reaction products in a shorter duration. The reaction products are mainly concentrated in the developed hot spot, indicating that the chemical reactivity of the hmx crystal is greatly enhanced by void collapse. The detailed information derived from this study can aid a thorough understanding of the role of void collapse in hot spot formation and the chemical reaction initiation of explosives.


The relationship between child sexual abuse and academic achievement in a sample of adolescent psychiatric inpatients.
To examine the relationship between sexual abuse and academic achievement in an adolescent inpatient psychiatric population. Individual factors expected to influence this relationship were measured to explore the way they each interacted with sexual abuse and its relationship to academic achievement. Eighty-one adolescent psychiatric inpatients participated in the study (aged 12--18 years: M=16.0). Participants were administered tests of academic achievement (dependent variable) and intelligence, and completed a number of self-report measures of their experience of different types of maltreatment, their perception of the parenting they received, socio-economic status, substance abuse, and psychopathology. Hierarchical regression analysis revealed that intelligence was the main predictor of academic achievement (uniquely explaining 26% of the variance). A number of interaction effects were also significant indicating that intelligence, substance abuse, internalizing behavior problems, externalizing behavior problems all influenced the relationship between sexual abuse and academic achievement. Examining the impact of sexual abuse is complex because it is typically an experience embedded in a range of other risk factors, such as poverty, family dysfunction, and other types of maltreatment. This study demonstrated coexistence between sexual abuse and a number of other variables, including other maltreatment types and parental overprotection, underscoring the requirement for complex models of research that more accurately reflect the experience of abused children.


An integrative review of factors associated with telomere length and implications for biobehavioral research.
Although telomere shortening occurs as a natural part of aging, there is now a robust body of research that suggests that there is a relationship between psychosocial, environmental, and behavioral factors and changes in telomere length. These factors need to be considered when integrating telomere measurement in biobehavioral research studies. This article provides a brief summary of the known facts about telomere biology and an integrative review of current human research studies that assessed relationships between psychosocial, environmental, or behavioral factors and telomere length. An integrative review was conducted to examine human research studies that focused on psychosocial, environmental, and behavioral factors affecting telomere length and telomerase activity using the electronic databases PubMed/Medline and CINAHL from 2003 to the present. In addition to the known individual factors that are associated with telomere length, the results of the integrative review suggest that perceived stress, childhood adversities, major depressive disorder, educational attainment, physical activity, and sleep duration should also be measured. Multiple factors have been shown to affect telomere length. To advance understanding of the role of telomere length in health and disease risk, it will be important to further elucidate the mechanisms that contribute to telomere shortening.


Assessment of Clinical Alarms Influencing Nurses' Perceptions of Alarm Fatigue.
Excessive clinical alarms have inundated health care for years. Multiple governing bodies, organizations, and facilities have deemed alarm management a priority. Alarm management is a multifaceted problem that affects all health care organizations and clinical staff, especially those in critical care units. Ultimately, the lack of knowledge regarding nurses' perceptions to alarm management and alarm fatigue creates patient safety chiasms. The purpose of this quality improvement project was to understand nurses' perceptions of alarm fatigue (utilizing the Healthcare Technology Foundation's Clinical Alarms Committee Survey) while implementing interventions that improve patient safety. The design of this qualitative study is an electronically distributed survey to 31 nurses who work in critical care. The Healthcare Technology Foundation clinical alarms survey has 36 questions with various answering strategies distributed (with permission) via e-mail access by BlueQ through Creighton University. Twenty-six respondents (n = 26) completed the survey, with 42% being intensive care unit nurses and 58% being progressive care unit nurses. The majority of nurses (n = 23, 88%) agreed that nuisance alarms occur frequently and disrupt patient care (n = 25, 96%). A lack of standardized method was noted to alarm management and parameter changes. Multiple patterns emerged that initiated the need for further examination and improvement. Following the survey, themes emerged, and changes were implemented including the following: an alarm management policy was created, tools were provided to staff for easy usage, staff were educated using hands-on practice at an annual training summit, and sustainability was created through continuation of alarm management assessment and improvement.


Strengths and weaknesses of immunotherapy for advanced non-small-cell lung cancer: a meta-analysis of 12 randomized controlled trials.
Lung cancer is one of the leading causes of cancer death worldwide. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Immunotherapy has yielded no consistent benefit to date for those patients. Assessing the objective efficacy and safety of immunotherapy for advanced NSCLC patients will help to instruct the future development of immunotherapeutic drugs. We performed a meta-analysis of 12 randomized controlled trials including 3134 patients (1570 patients in the immunotherapy group and 1564 patients in the control group) with histologically confirmed stage IIIA, IIIB, or IV NSCLC. The analysis was executed with efficacy end points regarding overall survival (OS), progression-free survival (PFS), complete response (CR), partial response (PR), and total effective rate. Overall unstratified OS, PFS, PR, and total effective rate were significantly improved in advanced NSCLC patients in the immunotherapy group (P = 0.0007, 0.0004, 0.002, 0.003, respectively), whereas CR was not improved (P = 0.97). Subgroup analysis showed that monoclonal antibody (mAb) immunotherapy significantly improved the PFS, PR, and total effective rate and showed a trend of improving OS of advanced NSCLC patients compared with the control group, with one kind of adverse event being significantly dominant. Compared with the control group, the vaccine subgroup showed no significant difference with regard to serious adverse events, whereas cytokine immunotherapy significantly induced three kinds of serious adverse events. Immunotherapy works efficiently on advanced NSCLC patients. Of several immunotherapies, mAb therapy may be a potential immunotherapy for advanced NSCLC patients, and become a standard complementary therapeutic approach in the future if the issues concerning toxicity and allergenicity of mAbs have been overcome.


Underlying neurological mechanisms associated with symptomatic convergence insufficiency.
Convergence insufficiency (CI) is the most common binocular vision problem, associated with blurred/double vision, headaches, and sore eyes that are exacerbated when doing prolonged near work, such as reading. The Convergence Insufficiency Neuro-mechanism Adult Population Study (NCT03593031) investigates the mechanistic neural differences between 50 binocularly normal controls (BNC) and 50 symptomatic CI participants by examining the fast and slow fusional disparity vergence systems. The fast fusional system is preprogrammed and is assessed with convergence peak velocity. The slow fusional system optimizes vergence effort and is assessed by measuring the phoria adaptation magnitude and rate. For the fast fusional system, significant differences are observed between the BNC and CI groups for convergence peak velocity, final position amplitude, and functional imaging activity within the secondary visual cortex, right cuneus, and oculomotor vermis. For the slow fusional system, the phoria adaptation magnitude and rate, and the medial cuneus functional activity, are significantly different between the groups. Significant correlations are observed between vergence peak velocity and right cuneus functional activity (p = 0.002) and the rate of phoria adaptation and medial cuneus functional activity (p = 0.02). These results map the brain-behavior of vergence. Future therapeutic interventions may consider implementing procedures that increase cuneus activity for this debilitating disorder.


Obtaining History with a Language Barrier in the Emergency Department: Perhaps not a Barrier After All.
Patients with limited English proficiency may be at risk for incomplete history collection, potentially a patient safety issue. While federal law requires qualified medical interpreters be provided for these patients, little is known about the quality of information obtained in these encounters. Our study compared the medical histories obtained by physicians in the emergency department (ED) based on whether the patients primarily spoke English or Spanish. This was a prospective, observational study conducted at a single, urban, academic ED during a six-month time period. Resident and faculty physicians caring for adult patients with a chief complaint of chest or abdominal pain were eligible for participation. Patient encounters were directly observed by medical students who had been trained using simulated encounters. Observers documented which key historical data points were obtained by providers, including descriptions of pain (location, quality, severity, radiation, alleviating/aggravating factors), past medical/family/surgical history, and social history, in addition to the patient's language in providing history. Providers, interpreters, and observers were blinded to the nature of the study. We used chi-square analyses to examine differences in whether specific elements were collected based on the primary language of the patient. Encounters with 753 patients were observed: 105 Spanish speaking and 648 English speaking. Chi-square analyses found no statistically significant differences in any history questions between Spanish-speaking and English-speaking patients, with the exception that questions regarding alleviating factors were asked more often with Spanish-speaking patients (45%) than English-speaking patients (30%, p=.003). The average percentages of targeted history elements obtained in Spanish and English encounters were 60% and 57%, respectively. In this study at a large, urban, academic ED, the medical histories obtained by physicians were similar between English-speaking and Spanish-speaking patients. This suggests that the physicians sought to obtain medical histories at the same level of detail despite the language barrier. One limitation to consider is the Hawthorne effect; however, providers and observers were blinded to the nature of the study in an attempt to minimize the effect.


Complete genome sequence of Lactobacillus plantarum LZ206, a potential probiotic strain with antimicrobial activity against food-borne pathogenic microorganisms.
Lactobacilli strains have been considered as important candidates for manufacturing "natural food", due to their antimicrobial properties and generally regarded as safe (GRAS) status. Lactobacillus plantarum LZ206 is a potential probiotic strain isolated from raw cow milk, with antimicrobial activity against various pathogens, including Gram-positive bacteria (Staphylococcus aureus and Listeria monocytogenes), Gram-negtive bacteria (Escherichia coli and Salmonella enterica), and fungus Candida albicans. To better understand molecular base for its antimicrobial activity, entire genome of LZ206 was sequenced. It was revealed that genome of LZ206 contained a circular 3,212,951-bp chromosome, two circular plasmids and one predicted linear plasmid. A plantaricin gene cluster, which is responsible for bacteriocins biosynthesis and could be associated with its broad-spectrum antimicrobial activity, was identified based on comparative genomic analysis. Whole genome sequencing of L. plantarum LZ206 might facilitate its applications to protect food products from pathogens' contamination in the dairy industry.


The Brazilian health system: history, advances, and challenges.
Brazil is a country of continental dimensions with widespread regional and social inequalities. In this report, we examine the historical development and components of the Brazilian health system, focusing on the reform process during the past 40 years, including the creation of the Unified Health System. A defining characteristic of the contemporary health sector reform in Brazil is that it was driven by civil society rather than by governments, political parties, or international organisations. The advent of the Unified Health System increased access to health care for a substantial proportion of the Brazilian population, at a time when the system was becoming increasingly privatised. Much is still to be done if universal health care is to be achieved. Over the past 20 years, there have been other advances, including investments in human resources, science and technology, and primary care, and a substantial decentralisation process, widespread social participation, and growing public awareness of a right to health care. If the Brazilian health system is to overcome the challenges with which it is presently faced, strengthened political support is needed so that financing can be restructured and the roles of both the public and private sector can be redefined.


Investigating the Cellular Transcriptomic Response Induced by the Makona Variant of Ebola Virus in Differentiated THP-1 Cells.
Recent studies have shown that transcriptomic analysis of blood samples taken from patients with acute Ebola virus disease (EVD) during the 2013-2016 West African outbreak was suggestive that a severe inflammatory response took place in acutely ill patients. The significant knowledge gained from studying the Makona variant, a cause of the largest known EVD outbreak, may be applicable to other species of ebolavirus, and other variants of the Ebola virus (EBOV) species. To investigate the ability of Makona to initiate an inflammatory response in human macrophages and characterise the host response in a similar manner to previously characterised EBOV variants, the human monocytic cell line THP-1 was differentiated into macrophage-like cells and infected with Makona. RNA-Seq and quantitative proteomics were used to identify and quantify host mRNA and protein abundance during infection. Data from infection with Reston virus (RESTV) were used as comparators to investigate changes that may be specific to, or enhanced in, Makona infection in relation to a less pathogenic species of ebolavirus.. This study found demonstrable induction of the inflammatory response, and increase in the activation state of THP-1 macrophages infected with Makona. NFκB and inflammation-associated transcripts displayed significant changes in abundance, reflective of what was observed in human patients during the 2013-2016 EBOV outbreak in West Africa, and demonstrated that transcriptomic changes found in Makona-infected cells were similar to that observed in Reston virus infection and that have been described in previous studies of other variants of EBOV.


Gut-brain Axis and migraine headache: a comprehensive review.
The terminology "gut-brain axis "points out a bidirectional relationship between the GI system and the central nervous system (CNS). To date, several researches have shown that migraine is associated with some gastrointestinal (GI) disorders such as Helicobacter pylori (HP) infection, irritable bowel syndrome (IBS), and celiac disease (CD). The present review article aims to discuss the direct and indirect evidence suggesting relationships between migraine and the gut-brain axis. However, the mechanisms explaining how the gut and the brain may interact in patients with migraine are not entirely clear. Studies suggest that this interaction seems to be influenced by multiple factors such as inflammatory mediators (IL-1β, IL-6, IL-8, and TNF-α), gut microbiota profile, neuropeptides and serotonin pathway, stress hormones and nutritional substances. Neuropeptides including CGRP, SP, VIP, NPY are thought to have antimicrobial impact on a variety of the gut bacterial strains and thus speculated to be involved in the bidirectional relationship between the gut and the brain. According to the current knowledge, migraine headache in patients harboring HP might be improved following the bacteria eradication. Migraineurs with long headache history and high headache frequency have a higher chance of being diagnosed with IBS. IBS and migraine share some similarities and can alter gut microflora composition and thereby may affect the gut-brain axis and inflammatory status. Migraine has been also associated with CD and the condition should be searched particularly in patients with migraine with occipital and parieto-occipital calcification at brain neuroimaging. In those patients, gluten-free diet can also be effective in reducing migraine frequency. It has also been proposed that migraine may be improved by dietary approaches with beneficial effects on gut microbiota and gut-brain axis including appropriate consumption of fiber per day, adhering to a low glycemic index diet, supplementation with vitamin D, omega-3 and probiotics as well as weight loss dietary plans for overweight and obese patients.


Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome.
Wiskott-Aldrich syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP, a protein regulating the cytoskeleton. Hematopoietic stem/progenitor cell (HSPC) transplants can be curative, but, when matched donors are unavailable, infusion of autologous HSPCs modified ex vivo by gene therapy is an alternative approach. We used a lentiviral vector encoding functional WASP to genetically correct HSPCs from three WAS patients and reinfused the cells after a reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical scores. Vector integration analyses revealed highly polyclonal and multilineage haematopoiesis resulting from the gene-corrected HSPCs. Lentiviral gene therapy did not induce selection of integrations near oncogenes, and no aberrant clonal expansion was observed after 20 to 32 months. Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS.


Resolving the Role of Lipoxygenases in the Initiation and Execution of Ferroptosis.
Lipoxygenases (LOXs) have been implicated as central players in ferroptosis, a recently characterized cell death modality associated with the accumulation of lipid hydroperoxides: the products of LOX catalysis. To provide insight on their role, human embryonic kidney cells were transfected to overexpress each of the human isoforms associated with disease, 5-LOX, p12-LOX, and 15-LOX-1, which yielded stable cell lines that were demonstrably sensitized to ferroptosis. Interestingly, the cells could be rescued by less than half of a diverse collection of known LOX inhibitors. Furthermore, the cytoprotective compounds were similarly potent in each of the cell lines even though some were clearly isoform-selective LOX inhibitors. The cytoprotective compounds were subsequently demonstrated to be effective radical-trapping antioxidants, which protect lipids from autoxidation, the autocatalytic radical chain reaction that produces lipid hydroperoxides. From these data (and others reported herein), a picture emerges wherein LOX activity may contribute to the cellular pool of lipid hydroperoxides that initiate ferroptosis, but lipid autoxidation drives the cell death process.


Tree array quantum cascade laser.
A monolithic coupling scheme for mid-infrared quantum cascade laser arrays is investigated with respect to brightness enhancement. The tree-shaped resonator enables parallel coupling of six laser elements into a single element by means of several Y-junctions. Phase-locking is observed on the basis of far field analysis, and leads to in-phase emission on both sides of the device. The experimental results match calculated far field profiles and demonstrate a high level of modal control when driven far above threshold. Whereas optical power measurements confirm negligible coupling losses, the slope efficiency is below the theoretically expected value, which is attributed to modal competition. Additional evaluation of near fields and spectral characteristics provides background on the modal dynamics of the sophisticated cavity and reveals limitations to coherent beam combining. The findings pave the way to improved coupling efficiency and brightness scaling of a single facet emitting compact quantum cascade laser array.


Superior optical properties of homogeneous liquid crystal alignment on a tin (IV) oxide surface sequentially modulated via ion beam irradiation.
We first investigated the alignment characteristics of tin (IV) oxide (SnO(2)) thin films deposited by radio-frequency (RF) magnetron sputtering. This study demonstrates that liquid crystal (LC) molecules could be aligned homogeneously by controlling the Ion Beam (IB) irradiation energy densities. We also show that the pretilt angle of the LC molecules has a close relation with the surface energy. X-ray photoelectron spectroscopy (XPS) indicates that a non-stoichiometric SnO(2-x) surface converted by ion beam irradiation can horizontally align the LC molecules. The measured electro-optical (EO) characteristics showed high performance, comparable with those of rubbed and ion-beam irradiated polyimide (PI) layers.


Strain-induced ferroelectricity and lattice coupling in BaSnO3 and SrSnO3.
Perovskite stannates such as BaSnO3 and SrSnO3 exhibit promising photovoltaic properties, and hold promise for application in solar cell devices. However, the lack of ferroelectricity and the wide band gap in these materials limit their potential for photovoltaic applications. Here, by first-principles calculations, we demonstrate the realization of a primary ferroelectric polarization in non-ferroelectric BaSnO3 and SrSnO3 through strain engineering. In addition to the appearance of polarization, the band gaps of the materials are greatly narrowed when the paraelectric to ferroelectric phase transition takes place under compressive strain. Furthermore, an intriguing Q2 mode triggered by lattice coupling with the polar mode is found in the stannates subjected to a sufficient tensile strain and this mode has a significant effect on the band gap, which suggests another pathway to narrow the band gap through the electric field control of the Q2 mode. The fruitful electronic, structural, and energetic properties are discussed in detail to achieve a fundamental understanding of the strain-induced ferroelectricity, tunable band gap, and lattice couplings between the Q2 mode and different polar/rotational distortions in the perovskite stannates.