Jamaica's disappearing forests: physical and human aspects.
Jamaica is a small island that is losing its forest cover at a rapid rate. Due to the dependency of its largely poor population on the many services and functions its forests provide, this loss threatens to have substantial socioeconomic and ecological consequences for the country. Despite these basic facts, the problem of Jamaican deforestation has received very little attention from the scientific community. This article presents results of an island-wide, satellite-based study of forest change for Jamaica for the period 1987-1992, which was supplemented by a field trip to the island in 1999 to assess the overall accuracy of the estimate. Landsat MSS images, which are available only up until 1992, have proved to be an invaluable and cost-effective resource for mapping forest change in the tropics, particularly in large areas. A supervised classification indicates that Jamaica experienced an average annual deforestation rate of 3.9% for this period, a figure higher than existing estimates based on partial ground surveys but lower than the FAO's 1990 Tropical Forest Assessment of 5.3% for 1981-1990. Deforestation estimates for Jamaica's 14 parishes are also presented, based on the integration of satellite-derived forest classification maps with a parish administrative boundaries map of the island in a GIS. A correlation analysis between parish deforestation estimates and socioeconomic and land use/quality indicators derived from official sources suggests that deforestation is occurring most rapidly in highly populated areas possessing large numbers of small farmers who live and work under resource-poor conditions. By providing a sense of the magnitude of and main forest loss hotspots, it is hoped that these national and subnational level forest estimates will draw scientific attention to the problem of deforestation on the island. In addition, the socioeconomic analysis may provide policy-makers and planners with some sense of the relative contribution of underlying driving process in this deforestation as a first step toward the creation of effective social programs to combat the problem.


Myosin Vs organize actin cables in fission yeast.
Myosin V motors are believed to contribute to cell polarization by carrying cargoes along actin tracks. In Schizosaccharomyces pombe, Myosin Vs transport secretory vesicles along actin cables, which are dynamic actin bundles assembled by the formin For3 at cell poles. How these flexible structures are able to extend longitudinally in the cell through the dense cytoplasm is unknown. Here we show that in myosin V (myo52 myo51) null cells, actin cables are curled, bundled, and fail to extend into the cell interior. They also exhibit reduced retrograde flow, suggesting that formin-mediated actin assembly is impaired. Myo52 may contribute to actin cable organization by delivering actin regulators to cell poles, as myoV defects are partially suppressed by diverting cargoes toward cell tips onto microtubules with a kinesin 7-Myo52 tail chimera. In addition, Myo52 motor activity may pull on cables to provide the tension necessary for their extension and efficient assembly, as artificially tethering actin cables to the nuclear envelope via a Myo52 motor domain restores actin cable extension and retrograde flow in myoV mutants. Together these in vivo data reveal elements of a self-organizing system in which the motors shape their own tracks by transporting cargoes and exerting physical pulling forces.


Internalizing Mental Disorders and Accelerated Cellular Aging Among Perinatally HIV-Infected Youth in Uganda.
Introduction: Internalizing mental disorders (IMDs) in HIV+ children and adolescents are associated with impaired quality of life and non-adherence to anti-retroviral treatment. Telomere length is a biomarker of cellular aging, and shorter telomere length has been associated with IMDs. However, the nature of this association has yet to be elucidated. Objective: We determined the longitudinal association between IMDs and relative telomere length (rTL) and the influence of chronic stress among Ugandan perinatally HIV-infected youth (PHIY). Methods: IMDs (depressive disorders, anxiety disorders, and post-traumatic stress disorder) and IMDs were assessed using the locally adapted Child and Adolescent Symptom Inventory-5. In 368 PHIY with any IMD and 368 age- and sex-matched PHIY controls without any psychiatric disorder, rTL was assessed using quantitative polymerase chain reaction. Hierarchical cluster analysis was used to generate the three chronic stress classes (mild, moderate, and severe). t-tests were used to assess the difference between baseline and 12 month rTL and the mean difference in rTL between cases and controls both at baseline and at 12 months. Linear regression analysis was used to model the effects of chronic stress on the association between IMDs and rTL, controlling for age and sex. Results: We observed longer rTL among cases of IMDs compared with controls (p < 0.001). We also observed a statistically significant reduction in rTL between baseline and 12 months in the combined sample of cases and controls (p < 0.001). The same statistical difference was observed when cases and controls were individually analyzed (p < 0.001). We found no significant difference in rTL between cases and controls at 12 months (p = 0.117). We found no significant influence of chronic stress on the association between IMDs and rTL at both baseline and 12 months. Conclusion: rTL is longer among cases of IMDs compared with age- and sex-matched controls. We observed a significant attrition in rTL over 12 months, which seems to be driven by the presence of any IMDs. There is a need for future longitudinal and experimental studies to understand the mechanisms driving our findings.


Galaxy HiCExplorer: a web server for reproducible Hi-C data analysis, quality control and visualization.
Galaxy HiCExplorer is a web server that facilitates the study of the 3D conformation of chromatin by allowing Hi-C data processing, analysis and visualization. With the Galaxy HiCExplorer web server, users with little bioinformatic background can perform every step of the analysis in one workflow: mapping of the raw sequence data, creation of Hi-C contact matrices, quality assessment, correction of contact matrices and identification of topological associated domains (TADs) and A/B compartments. Users can create publication ready plots of the contact matrix, A/B compartments, and TADs on a selected genomic locus, along with additional information like gene tracks or ChIP-seq signals. Galaxy HiCExplorer is freely usable at: https://hicexplorer.usegalaxy.eu and is available as a Docker container: https://github.com/deeptools/docker-galaxy-hicexplorer.


Critical role of connexin 43 in secondary expansion of traumatic spinal cord injury.
Spinal cord injury (SCI) is often complicated by secondary injury as a result of the innate inflammatory response to tissue trauma and swelling. Previous studies have shown that excessive ATP release from peritraumatic regions contributes to the inflammatory response to SCI by activation of low-affinity P2X7 receptors. Because connexin hemichannels constitute an important route for astrocytic ATP release, we here evaluated the impact on post-traumatic ATP release of deletion of connexins (Cx30/Cx43) in astrocytes. In vivo bioluminescence imaging showed a significant reduction in ATP release after weight-drop injury in mice with deletion of Cx43 compared with Cx43-expressing littermates, both on a Cx30 knockout background. Moreover, astrogliosis and microglia activation were reduced in peritraumatic areas of those mice lacking Cx43; motor recovery was also significantly improved, and the traumatic lesion was smaller. Combined, these observations are consistent with a contribution by astrocytic hemichannels to post-traumatic ATP release that aggravates secondary injury and restrains functional recovery after experimental spinal cord injury. Connexins may thereby constitute a new therapeutic target in spinal cord injury.


B-cell depletion attenuates serological biomarkers of fibrosis and myofibroblast activation in IgG4-related disease.
Fibrosis is a predominant feature of IgG4-related disease (IgG4-RD). B-cell depletion induces a prompt clinical and immunological response in patients with IgG4-RD, but the effects of this intervention on fibrosis in IgG4-RD are unknown. We used the enhanced liver fibrosis (ELF) score to address the impact of rituximab on fibroblast activation. The ELF score is an algorithm based on serum concentrations of procollagen-III aminoterminal propeptide, tissue inhibitor of matrix metalloproteinase-1 and hyaluronic acid. Ten patients with active, untreated IgG4-RD were enrolled. ELF scores were measured and correlated with the IgG4-RD Responder Index, serum IgG4, circulating plasmablasts and imaging studies. Through immunohistochemical stains for CD3, CD20, IgG4 and α-smooth muscle actin, we assessed the extent of the lymphoplasmacytic infiltration and the degree of fibroblast activation in one patient with tissue biopsies before and after rituximab. The ELF score was increased in patients with IgG4-RD compared with healthy controls (8.3±1.4 vs 6.2±0.9; p=0.002) and correlated with the number of organs involved (R(2)=0.41; p=0.04). Rituximab induced significant reductions in the ELF score, the number of circulating plasmablasts and the IgG4-RD Responder Index (p<0.05 for all three parameters). Rituximab reduced both the lymphoplasmacytic infiltrate and myofibroblast activation. IgG4-RD relapse coincided with recurrent increases in the ELF score, indicating reactivation of collagen deposition. The ELF score may be a clinically useful indicator of active fibrosis and the extent of disease in IgG4-RD. B-cell depletion has the potential to halt continued collagen deposition by attenuating the secretory phenotype of myofibroblasts in IgG4-RD lesions.


A paternal methyl donor-rich diet altered cognitive and neural functions in offspring mice.
Dietary intake of methyl donors, such as folic acid and methionine, shows considerable intra-individual variation in human populations. While it is recognized that maternal departures from the optimum of dietary methyl donor intake can increase the risk for mental health issues and neurological disorders in offspring, it has not been explored whether paternal dietary methyl donor intake influences behavioral and cognitive functions in the next generation. Here, we report that elevated paternal dietary methyl donor intake in a mouse model, transiently applied prior to mating, resulted in offspring animals (methyl donor-rich diet (MD) F1 mice) with deficits in hippocampus-dependent learning and memory, impaired hippocampal synaptic plasticity and reduced hippocampal theta oscillations. Gene expression analyses revealed altered expression of the methionine adenosyltransferase Mat2a and BK channel subunit Kcnmb2, which was associated with changes in Kcnmb2 promoter methylation in MD F1 mice. Hippocampal overexpression of Kcnmb2 in MD F1 mice ameliorated altered spatial learning and memory, supporting a role of this BK channel subunit in the MD F1 behavioral phenotype. Behavioral and gene expression changes did not extend into the F2 offspring generation. Together, our data indicate that paternal dietary factors influence cognitive and neural functions in the offspring generation.


Robotic-arm assisted total hip arthroplasty results in smaller acetabular cup size in relation to the femoral head size: a matched-pair controlled study.
To compare the acetabular component size relative to the patient's native femoral head size between conventional THA (CTHA) approach and robotic-arm assisted THA (RTHA) to infer which of these techniques preserved more acetabular bone. Patients were included if they had primary osteoarthritis (OA) and underwent total hip replacement between June 2008 and March 2014. Patients were excluded if they had missing or rotated postoperative anteroposterior radiographs. RTHA patients were matched to a control group of CTHA patients, in terms of preoperative native femoral head size, age, gender, body mass index (BMI) and approach. Acetabular cup size relative to femoral head size was used as a surrogate for amount of bone resected. We compared the groups according to 2 measures describing acetabular cup diameter (c) in relation to femoral head diameter (f): (i) c-f, the difference between cup diameter and femoral head diameter and (ii) (c-f)/f, the same difference as a fraction of femoral head diameter. 57 matched pairs were included in each group. There were no significant differences between groups for demographic measures, femoral head diameter, or acetabular cup diameter (p>0.05). However, measures (i) and (ii) did differ significantly between the groups, with lower values in the RTHA group (p<0.02). Using acetabular cup size relative to femoral head size as an approximate surrogate measure of acetabular bone resection may suggest greater preservation of bone stock using RTHA compared to CTHA. Further studies are needed to validate the relationship between acetabular cup size and bone loss in THA.


EPHB4 and survival of colorectal cancer patients.
The family of receptor tyrosine kinases EPH and their Ephrin ligands regulate cell proliferation, migration, and attachment. An important role in colorectal carcinogenesis is emerging for some of its members. In this study, we evaluate the role of EPHB4 in colorectal cancer and its value as a prognostic marker. EPHB4 levels were assessed by immunohistochemical staining of tissue microarrays of 137 colorectal tumors and aberrant hypermethylation of the EPHB4 promoter was investigated using methylation-specific PCR. We found that EPHB4 expression is frequently reduced or lost in colorectal tumors. Patients with low EPHB4 tumor levels had significantly shorter survival than patients in the high EPHB4 group (median survival, 1.8 and >9 years, respectively; P < 0.01, log-rank test), and this finding was validated using an independent set of 125 tumor samples. In addition, we show that EPHB4 promoter hypermethylation is a common mechanism of EPHB4 inactivation. Moreover, reintroduction of EPHB4 resulted in a significant reduction in the clonogenic potential of EPHB4-deficient cells, whereas abrogation of EPHB4 in cells with high levels of this receptor lead to a significant increase in clonogenicity. In summary, we identified EPHB4 as a useful prognostic marker for colorectal cancer. In addition, we provide mechanistic evidence showing that promoter methylation regulates EPHB4 transcription and functional evidence that EPHB4 can regulate the long-term clonogenic potential of colorectal tumor cells, revealing EPHB4 as a potential new tumor suppressor gene in colorectal cancer.


Comparison of sodium content of meals served by independent takeaways using standard versus reduced holed salt shakers: cross-sectional study.
Takeaway food has a relatively poor nutritional profile. Providing takeaway outlets with reduced-holed salt shakers is one method thought to reduce salt use in takeaways, but effects have not been formally tested. We aimed to determine if there was a difference in sodium content of standard fish and chip meals served by Fish & Chip Shops that use standard (17 holes) versus reduced-holed (5 holes) salt shakers, taking advantage of natural variations in salt shakers used. We conducted a cross-sectional study of all Fish & Chip Shops in two local government areas (n = 65), where servers added salt to meals as standard practice, and salt shaker used could be identified (n = 61). Standard fish and chip meals were purchased from each shop by incognito researchers and the purchase price and type of salt shaker used noted. Sodium content of full meals and their component parts (fish, chips, and fish batter) was determined using flame photometry. Differences in absolute and relative sodium content of meals and component parts between shops using reduced-holed versus standard salt-shakers were compared using linear regression before and after adjustment for purchase price and area. Reduced-holed salt shakers were used in 29 of 61 (47.5 %) included shops. There was no difference in absolute sodium content of meals purchased from shops using standard versus reduced-holed shakers (mean = 1147 mg [equivalent to 2.9 g salt]; SD = 424 mg; p > 0.05). Relative sodium content was significantly lower in meals from shops using reduced-holed (mean = 142.5 mg/100 g [equivalent to 0.4 g salt/100 g]; SD = 39.0 mg/100 g) versus standard shakers (mean = 182.0 mg/100 g; [equivalent to 0.5 g salt/100 g]; SD = 68.3 mg/100 g; p = 0.008). This was driven by differences in the sodium content of chips and was extinguished by adjustment for purchase price and area. Price was inversely associated with relative sodium content (p < 0.05). Using reduced-holed salt shakers in Fish & Chip Shops is associated with lower relative sodium content of fish and chip meals. This is driven by differences in sodium content of chips, making our results relevant to the wide range of takeaways serving chips. Shops serving higher priced meals, which may reflect a more affluent customer base, may be more likely to use reduced-holed shakers.


Evaluation of a shared autoimmune disease-associated polymorphism of TRAF6 in systemic sclerosis and giant cell arteritis.
We evaluated whether a single-nucleotide polymorphism (SNP) of the TRAF6 gene previously associated with systemic lupus erythematosus and rheumatoid arthritis may be a common risk factor for systemic sclerosis (SSc) and giant cell arteritis (GCA). A total of 1185 patients with SSc, 479 patients with biopsy-proven GCA, and 1442 unrelated healthy controls of white Spanish origin were genotyped for the rs540386 variant using a specifically designed TaqMan(©) allele discrimination assay. No significant associations of this SNP with global SSc or GCA were found. This was also the case when the potential associations of the TRAF6 polymorphism with the main clinical phenotypes of the 2 diseases (e.g., limited cutaneous and diffuse cutaneous SSc, or presence of polymyalgia rheumatica and visual ischemic manifestations in GCA) were assessed. Our data do not support a role of the rs540386 TRAF6 variant as a key component of the genetic network underlying SSc and GCA.


Relationship between sleep quality and quantity and weight loss in women participating in a weight-loss intervention trial.
Evidence suggests that individuals who report fewer total hours of sleep are more likely to be overweight or obese. Few studies have prospectively evaluated weight-loss success in relation to reported sleep quality and quantity. This analysis sought to determine the association between sleep characteristics and weight loss in overweight or obese women enrolled in a randomized clinical trial of a weight-loss program. We hypothesized that in overweight/obese women, significant weight loss would be demonstrated more frequently in women who report a better Pittsburgh Sleep Quality Index (PSQI) Global Score or sleep >7 h/night as compared to women who report a worse PSQI score or sleep ≤7 h/night. Women of ages 45.5 ± 10.4 (mean ± SD) years and BMI of 33.9 ± 3.3 (n = 245) were randomized and completed PSQI at baseline and 6 months; 198 had weight change assessed through 24 months. At baseline, 52.7% reported PSQI scores above the clinical cutoff of 5. Better subjective sleep quality increased the likelihood of weight-loss success by 33% (relative risk (RR), 0.67; 95% confidence interval (CI), 0.52-0.86), as did sleeping >7 h/night. A worse Global Score at 6 months was associated with a 28% lower likelihood of continued successful weight loss at 18 months, but unassociated by 24 months. These results suggest that sleep quality and quantity may contribute to weight loss in intervention-based studies designed to promote weight control in overweight/obese adult women.


On the ups and downs of emotion: testing between conceptual-metaphor and polarity accounts of emotional valence-spatial location interactions.
In the past decade, many studies have focused on the relationship between emotional valence and vertical spatial positions from a processing perspective. Lakoff and Johnson's (1980) work on conceptual metaphor has traditionally motivated these investigations, but recent work (Lakens in J Exp Psychol: Learn, Mem Cogn, 38: 726-736, 2012) has suggested that polarity-based perspectives offer an alternative account of response time patterns. We contrasted the predictions of these two theories using a new facial emotion recognition task, in which participants made speeded responses to happy or sad faces on a display, with the spatial location of those faces being manipulated. In three experiments (two-alternative forced choice tasks and a go/no-go task), we found a pattern of responses consistent with a polarity-based account, but inconsistent with key predictions of the conceptual-metaphor account. Overall, congruency effects were observed for positively valenced items, but not for negatively valenced items. These findings demonstrate that polarity effects extend to nonlinguistic stimuli and beyond two-alternative forced choice tasks. We discuss the results in terms of common-coding approaches to task-response mappings.


Effects of Offshore Wind Farms on the Early Life Stages of Dicentrarchus labrax.
Anthropogenically generated underwater noise in the marine environment is ubiquitous, comprising both intense impulse and continuous noise. The installation of offshore wind farms across the North Sea has triggered a range of ecological questions regarding the impact of anthropogenically produced underwater noise on marine wildlife. Our interest is on the impact on the "passive drifters," i.e., the early life stages of fish that form the basis of fish populations and are an important prey for pelagic predators. This study deals with the impact of pile driving and operational noise generated at offshore wind farms on Dicentrarchus labrax (sea bass) larvae.


Self-powered ultraflexible photonic skin for continuous bio-signal detection via air-operation-stable polymer light-emitting diodes.
Ultraflexible optical devices have been used extensively in next-generation wearable electronics owing to their excellent conformability to human skins. Long-term health monitoring also requires the integration of ultraflexible optical devices with an energy-harvesting power source; to make devices self-powered. However, system-level integration of ultraflexible optical sensors with power sources is challenging because of insufficient air operational stability of ultraflexible polymer light-emitting diodes. Here we develop an ultraflexible self-powered organic optical system for photoplethysmogram monitoring by combining air-operation-stable polymer light-emitting diodes, organic solar cells, and organic photodetectors. Adopting an inverted structure and a doped polyethylenimine ethoxylated layer, ultraflexible polymer light-emitting diodes retain 70% of the initial luminance even after 11.3 h of operation under air. Also, integrated optical sensors exhibit a high linearity with the light intensity exponent of 0.98 by polymer light-emitting diode. Such self-powered, ultraflexible photoplethysmogram sensors perform monitoring of blood pulse signals as 77 beats per minute.


Molecular and mechanical characterization of aciniform silk: uniformity of iterated sequence modules in a novel member of the spider silk fibroin gene family.
Araneoid spiders use specialized abdominal glands to produce up to seven different protein-based silks/glues that have diverse physical properties. The fibroin sequences that encode aciniform fibers (wrapping silk) and the mechanical properties of these fibers have not been characterized previously. To gain a better understanding of the molecular radiation of spider silk fibroin genes, cDNA libraries derived from aciniform glands of the banded garden spider, Argiope trifasciata, were constructed, and unique silk transcripts were sequenced. There was evidence for a single silk fibroin gene that was expressed in the aciniform glands, and the inferred amino acid composition of the novel fibroin closely matched the amino acid contents of these glands. The inferred protein, aciniform spidroin 1 (AcSp1), is composed of highly homogenized repeats that are 200 amino acids in length. The long stretches of poly-alanine and glycine-alanine subrepeats, which are thought to account for the crystalline regions of minor ampullate and major ampullate fibers, are very poorly represented in AcSp1. The AcSp1 repeat unit is iterated minimally 14 times and does not display substantial sequence similarity to any previously described genes or proteins. Database searches, however, showed that the nonrepetitive carboxy-terminus contains stretches of matches to known spider fibroin sequences, suggesting that the AcSp1 gene is a highly divergent member of the spider silk gene family. In phylogenetic analyses of carboxy-terminal sequences from araneid spiders, the aciniform sequence did not group strongly with clusters of fibroins from the flagelliform, minor ampullate, or major ampullate silk glands. Comparisons of stress/strain curves for major ampullate, minor ampullate, and aciniform silks from Argiope trifasciata showed significant differences in ultimate strength, extensibility, and toughness. Remarkably, the toughness of aciniform silk was 50% greater than the highest values typically recorded for major ampullate silk. These differences in performance, in combination with the radical divergence at the sequence level among fibroin paralogs, suggest a possible linkage between silk fibroin sequences and performance that should be explored in future structural/functional studies of aciniform silk.


Effect of Sesamin Supplementation on Cardiovascular Risk Factors in Women with Rheumatoid Arthritis.
Rheumatoid arthritis (RA) is an inflammatory disease with increased mortality from cardiovascular disease (CVD). Oxidative stress has a critical role in the pathogenesis of RA and CVD. Sesamin, the main lignin constituent of sesame, has several antioxidant and anti-inflammatory effects. This study aimed to investigate the effects of sesamin supplementation on anthropometric indices, lipid profile, blood pressure, and oxidative stress markers in women with RA. In this randomized, double-blind, placebo-controlled clinical trial, 44 patients with RA were randomly divided into 2 groups (intervention and control). Patients consumed 200 mg/day sesamin supplement and placebo in the intervention and control groups, respectively, for 6 weeks (spring 2014). At baseline and at the end of the study, anthropometric indices and blood pressure were assessed. Serum concentrations of lipid profile, malondialdehyde (MDA), and total antioxidant capacity (TAC) were also determined. At the end of study, sesamin supplementation significantly decreased serum levels of MDA (p = 0.018) and increased TAC and high-density lipoprotein cholesterol (HDL-C) levels in patients with RA (p = 0.020 and p = 0.007, respectively). In the sesamin group, the mean of weight, body mass index, waist-to-hip ratio, body fat, systolic blood pressure, and the concentration of other lipid profiles (triglycerides, total cholesterol, and low-density lipoprotein cholesterol [LDL-C]) were also significantly decreased at the end of study compared to baseline values (p < 0.05). However, the difference between the 2 groups was not statistically significant in this regard (p > 0.05). Sesamin exhibited a protective effect on cardiovascular risk factors in patients with RA. However, further investigation is suggested.


A qualitative study of lay beliefs about influenza immunisation in older people.
Although influenza immunisation is now recommended for all people aged 65 years and over in the UK, many people in that age group still remain unimmunised. To investigate lay beliefs about influenza and influenza vaccine in older people to identify appropriate ways of promoting vaccine uptake. Qualitative study using narrative interviews. Urban and rural communities in South Wales. Participants were 54 people aged 65 years and over who were interviewed in their own home. Of these, 11 were regularly immunised, 18 had consistently refused immunisation (refusers), 15 had defaulted (defaulters), five had never been offered immunisation, and five had recently been immunised for the first time. There was an overwhelming consensus among immunised and unimmunised individuals that they were not at risk from influenza. Even if they did catch influenza, they would not suffer from any serious consequences. Refusers and defaulters were more likely to believe that the influenza vaccine had serious side-effects, while the regularly immunised group were more likely to perceive the vaccine as effective. Multiple prompts from family, friends, or primary care staff were important triggers for receiving immunisation. Many older people did not feel vulnerable to influenza, regardless of their age, and this influenced their views on the need for immunisation. Both refusers and defaulters overstated adverse effects from influenza vaccine so this is a potential target for an intervention. Individual prompts, particularly from GPs, seemed to be the most significant motivators to attend for immunisation.


The EGFR pathway regulates BCRP expression in NSCLC cells: role of erlotinib.
While multidrug resistance (MDR) in cancer is well established, little is known about the cellular pathways regulating the expression and trafficking of the MDR efflux transporter like BCRP (ABCG2). Here we evaluated the role of signalling downstream of EGFR on BCRP expression and sub-cellular localization using lung cancer cells harboring BCRP but expressing various EGFR and Ras activating mutations; A549 (K-Ras-G12S), H292 wild-type EGFR and Ras, and H1650 (EGFR-DelE747-A750). Immunocytochemistry and immunofluorescence studies demonstrated that BCRP was predominantly intracellular but its expression was found also on the plasma membrane in A549 and H1650 cells with activated Ras and EGFR. Remarkably, EGFR inhibition by erlotinib at IC₅₀ concentrations induced a differential timedependent alteration in BCRP gene and protein expression. In H1650 cells, erlotinib enhanced both the total and plasma membrane degradation of BCRP by ubiquitination within 6-24 hours, whereas BCRP expression regained the original basal levels after 48 hours. In erlotinib treated H292 cells, BCRP levels decreased at 24 hours until 72 hours, whereas in A549 cells erlotinib initially reduced BCRP expression but then induced its accumulation on the plasma membrane at 72 hours. We further found that the PI3K/Akt inhibitor LY294002 down-regulated BCRP expression, hence showing that the Akt pathway is involved in the regulation of BCRP expression but not in its localization in these lung cancer cell lines. Finally, the selective BCRP transport inhibitor Ko143 did not increase erlotinib sensitivity, but did decrease the transport activity of BCRP in A549 and H1650 cells as it induced the accumulation of its transport substrate topotecan. In conclusion, our results suggest that the EGFR and Akt pathways are involved in regulation of BCRP expression, trafficking and drug transport activity. These findings warrant future studies on the pharmacologic modulation of these pathways to enhance the efficacy of anticancer combinations of erlotinib with drugs that are BCRP transport substrates.


Visual phenotype in Williams-Beuren syndrome challenges magnocellular theories explaining human neurodevelopmental visual cortical disorders.
Williams-Beuren syndrome (WBS), a neurodevelopmental genetic disorder whose manifestations include visuospatial impairment, provides a unique model to link genetically determined loss of neural cell populations at different levels of the nervous system with neural circuits and visual behavior. Given that several of the genes deleted in WBS are also involved in eye development and the differentiation of retinal layers, we examined the retinal phenotype in WBS patients and its functional relation to global motion perception. We discovered a low-level visual phenotype characterized by decreased retinal thickness, abnormal optic disk concavity, and impaired visual responses in WBS patients compared with age-matched controls by using electrophysiology, confocal and coherence in vivo imaging with cellular resolution, and psychophysics. These mechanisms of impairment are related to the magnocellular pathway, which is involved in the detection of temporal changes in the visual scene. Low-level magnocellular performance did not predict high-level deficits in the integration of motion and 3D information at higher levels, thereby demonstrating independent mechanisms of dysfunction in WBS that will require remediation strategies different from those used in other visuospatial disorders. These findings challenge neurodevelopmental theories that explain cortical deficits based on low-level magnocellular impairment, such as regarding dyslexia.


Is severe head injury associated with functional (psychogenic) seizures?
The aim of the current study was to compare the frequency of significant head injuries in three groups of people with seizures [idiopathic generalized epilepsies (IGE) vs. temporal lobe epilepsy (TLE) vs. functional seizures (FS)]. This was a retrospective study. All patients with a diagnosis of IGE, TLE, or FS were recruited at the outpatient epilepsy clinic at Shiraz University of Medical Sciences, Shiraz, Iran, from 2008 until 2020. One thousand and four hundred ninety-two patients were studied (559 patients with IGE, 646 people with TLE, and 287 persons with FS). Overall, 77 (5.2%) individuals of the studied people reported experiencing severe head injuries before the onset of their seizures [9 patients (1.6%) with IGE, 56 people (8.7%) with TLE, and 12 persons (4.2%) with FS; p = 0.0001]. Compared to people with IGE, the odds ratio of having a premorbid history of severe head injury in the FS group was 2.67 [95% Confidence Interval (CI): 1.11-6.40; p = 0.0280]. Compared to people with TLE, the odds ratio of having a premorbid history of severe head injury in the FS group was 0.46 (95% CI: 0.24-0.87; p = 0.0170). Severe head injury is significantly associated with FS. However, since head injury is also a significant risk factor for focal epilepsies, it may be necessary to ascertain the diagnosis of post-traumatic seizures by obtaing a detailed clinical history and also by performing video-EEG monitoring in order to adopt an appropriate treatment strategy in these patients.


Genetic variation in CADM2 as a link between psychological traits and obesity.
CADM2 has been associated with a range of behavioural and metabolic traits, including physical activity, risk-taking, educational attainment, alcohol and cannabis use and obesity. Here, we set out to determine whether CADM2 contributes to mechanisms shared between mental and physical health disorders. We assessed genetic variants in the CADM2 locus for association with phenotypes in the UK Biobank, IMPROVE, PROCARDIS and SCARFSHEEP studies, before performing meta-analyses. A wide range of metabolic phenotypes were meta-analysed. Psychological phenotypes analysed in UK Biobank only were major depressive disorder, generalised anxiety disorder, bipolar disorder, neuroticism, mood instability and risk-taking behaviour. In UK Biobank, four, 88 and 172 genetic variants were significantly (p < 1 × 10-5) associated with neuroticism, mood instability and risk-taking respectively. In meta-analyses of 4 cohorts, we identified 362, 63 and 11 genetic variants significantly (p < 1 × 10-5) associated with BMI, SBP and CRP respectively. Genetic effects on BMI, CRP and risk-taking were all positively correlated, and were consistently inversely correlated with genetic effects on SBP, mood instability and neuroticism. Conditional analyses suggested an overlap in the signals for physical and psychological traits. Many significant variants had genotype-specific effects on CADM2 expression levels in adult brain and adipose tissues. CADM2 variants influence a wide range of both psychological and metabolic traits, suggesting common biological mechanisms across phenotypes via regulation of CADM2 expression levels in adipose tissue. Functional studies of CADM2 are required to fully understand mechanisms connecting mental and physical health conditions.


Exploring perceived barriers, drivers, impacts and the need for evaluation of public involvement in health and social care research: a modified Delphi study.
To explore areas of consensus and conflict in relation to perceived public involvement (PI) barriers and drivers, perceived impacts of PI and ways of evaluating PI approaches in health and social care research. Internationally and within the UK the recognition of potential benefits of PI in health and social care research is gathering momentum and PI is increasingly identified by organisations as a prerequisite for funding. However, there is relatively little examination of the impacts of PI and how those impacts might be measured. Mixed method, three-phase, modified Delphi technique, conducted as part of a larger MRC multiphase project. Clinical and non-clinical academics, members of the public, research managers, commissioners and funders. This study found high levels of consensus about the most important barriers and drivers to PI. There was acknowledgement that tokenism was common in relation to PI; and strong support for the view that demonstrating the impacts and value of PI was made more difficult by tokenistic practice. PI was seen as having intrinsic value; nonetheless, there was clear support for the importance of evaluating its impact. Research team cohesion and appropriate resources were considered essential to effective PI implementation. Panellists agreed that PI can be challenging, but can be facilitated by clear guidance, together with models of good practice and measurable standards. This study is the first to present empirical evidence of the opinions voiced by key stakeholders on areas of consensus and conflict in relation to perceived PI barriers and drivers, perceived impacts of PI and the need to evaluate PI. As such it further contributes to debate around best practice in PI, the potential for tokenism and how best to evaluate the impacts of PI. These findings have been used in the development of the Public Involvement Impact Assessment Framework (PiiAF), an online resource which offers guidance to researchers and members of the public involved in the PI process.


#EEGManyLabs: Investigating the replicability of influential EEG experiments.
There is growing awareness across the neuroscience community that the replicability of findings about the relationship between brain activity and cognitive phenomena can be improved by conducting studies with high statistical power that adhere to well-defined and standardised analysis pipelines. Inspired by recent efforts from the psychological sciences, and with the desire to examine some of the foundational findings using electroencephalography (EEG), we have launched #EEGManyLabs, a large-scale international collaborative replication effort. Since its discovery in the early 20th century, EEG has had a profound influence on our understanding of human cognition, but there is limited evidence on the replicability of some of the most highly cited discoveries. After a systematic search and selection process, we have identified 27 of the most influential and continually cited studies in the field. We plan to directly test the replicability of key findings from 20 of these studies in teams of at least three independent laboratories. The design and protocol of each replication effort will be submitted as a Registered Report and peer-reviewed prior to data collection. Prediction markets, open to all EEG researchers, will be used as a forecasting tool to examine which findings the community expects to replicate. This project will update our confidence in some of the most influential EEG findings and generate a large open access database that can be used to inform future research practices. Finally, through this international effort, we hope to create a cultural shift towards inclusive, high-powered multi-laboratory collaborations.


Ischemic Modified Albumin Predicts Critical Coronary Artery Disease in Unstable Angina Pectoris and Non-ST-Elevation Myocardial Infarction.
In this study, whether ischemia modified albumin (IMA) has a role in showing severity or criticality of coronary arteries in patients with unstable angina pectoris (USAP)/non-ST-elevation myocardial infarction (NSTEMI) was assessed. A total of 65 patients (40 male (M) and 25 female (F) patients; mean age 59.7 ± 12.1 years) with the initial diagnosis of USAP/NSTEMI were included in this study. The levels of IMA, troponin T, creatine kinase MB (CK-MB), C-reactive protein (CRP), brain natriuretic peptide (BNP), creatinine, lipid panel, and whole blood count were measured from venous blood obtained from each patient within 3 h after the onset of symptoms. A 50% or greater coronary lumen stenosis of any coronary vessel or lateral branch was considered as critical stenosis. The severity of coronary artery disease (CAD) was assessed using the Gensini scoring system. IMA was significantly higher in patients with critical coronary artery stenosis (median, 206 vs. 23; P < 0.001). There was a weak correlation between the Gensini score and IMA; whereas there was a moderate correlation between the Gensini score and BNP levels (r = 0.44, P = 0.02). The level of IMA can predict the criticality of CAD; however, it cannot predict the severity of CAD according to Gensini score in patients with USAP/NSTEMI.


Situational determinants of use and treatment outcomes in marijuana dependent adults.
Research and theory strongly support the importance of situational determinants of substance use as targets for intervention, but few studies have systematically examined situational use characteristics in marijuana dependent adults. The present study describes situational use of marijuana in a population of 87 marijuana dependent adults and reports relationships with outcomes of treatment. Use in negative affective situations was independently associated with psychological distress, maladaptive coping strategies, lower self-efficacy, and poorer outcomes post-treatment. The findings were consistent with research on using drugs to cope with negative affect providing evidence of convergence between two different methods of assessing high risk situations for substance use. The results support continued emphasis on coping with negative affect as a target in treatments for marijuana dependence.


Identity and perceived peer relationship quality in emerging adulthood: the mediating role of attachment-related emotions.
Identity formation and the perceived quality of one's peer relationships are theorized to be intimately linked in emerging adulthood. The present study examined the associations between identity styles (i.e., information-oriented, normative, and diffuse-avoidant styles) and the quality of relationships with peers (as indexed by friendship quality and loneliness) in a sample of 343 college students from Belgium. High scores for the information-oriented style were positively related to friendship quality, whereas high scores for the diffuse-avoidant identity style were positively related to loneliness. These direct associations were mediated, at least in part, by attachment-related emotions (i.e., avoidance and anxiety). These associations, both direct and indirect, provide the first evidence linking identity styles and the quality of peer relationships. Suggestions for future research are provided, both at the methodological and the conceptual level.


Identifying patients who will not reachieve remission after breakthrough seizures.
We aim to identify people with epilepsy who are unlikely to reachieve a 12-month remission within 2 years after experiencing a breakthrough seizure following an initial 12-month remission. We apply a novel longitudinal discriminant approach to data from the Standard and New Antiepileptic Drugs study to dynamically predict the risk of a patient not achieving a second remission after a breakthrough seizure by combining both baseline covariates (collected at the time of breakthrough seizure) and follow-up data. The model classifies 83% of patients. Of these, 73% of patients (95% confidence interval [CI] = 58%-88%) who did not achieve a second remission were correctly identified (sensitivity), and 84% of patients (95% CI = 69%-96%) who achieved a second remission were correctly identified (specificity). The area under the curve from our model was 87% (95% CI = 80%-94%). Patients who did not achieve a second remission were correctly identified on average after 10 months of observation postbreakthrough. Occurrence of seizures after breakthrough and the number of seizures experienced were the most informative longitudinal variables. These longitudinal profiles were influenced by the following baseline covariates: age at breakthrough seizure, presence of neurological insult, and number of antiepileptic drugs required to achieve first remission. Using longitudinal data gathered during patient follow-up allows more accurate predictions than using baseline covariates in a standard Cox model. The model developed in this paper is a useful first step in developing a tool for identifying patients who develop drug resistance after an initial remission.


Cost-Effective PCR-Based Identification of Tunga penetrans (Siphonaptera) Larvae Extracted from Soil Samples Containing PCR Inhibitor-Rich Material.
Tungiasis is a neglected tropical disease caused by skin-penetrating female Tunga penetrans fleas. Although tungiasis causes severe health problems, its ecology is poorly understood and morphological descriptions of the larvae are unavailable. To identify T. penetrans immature stages and sites where they develop, diagnostic PCRs are required. However, flea larvae feed on soil organic matter rich in PCR inhibitors. Here, three DNA preparation methods, including a soil DNA kit that removes inhibitors, a simple ammonium acetate precipitation approach (AmAcet) and a crude lysate of larvae (CL), were combined with amplification by the highly processive FIREPol® Taq or the inhibitor-resistant Phusion® polymerase. Independent of the polymerase used, the frequency of successful amplification, Cq values and PCR efficacies for the low-cost CL and AmAcet methods were superior to the commercial kit for amplification of a 278 bp partial internal transcribed spacer-2 (ITS-2) and a 730 bp pan-Siphonaptera cytochrome oxidase II PCR. For the CL method combined with Phusion® polymerase, the costs were approximately 20-fold lower than for the methods based on the soil DNA kit, which is a considerable advantage in resource-poor settings. The ITS-2 PCR did not amplify Ctenocephalides felis genomic or Tunga trimammilata ITS-2 plasmid DNA, meaning it can be used to specifically identify T. penetrans.


pH gradients across phospholipid membranes caused by fast flip-flop of un-ionized fatty acids.
A central, unresolved question in cell physiology is how fatty acids move across cell membranes and whether protein(s) are required to facilitate transbilayer movement. We have developed a method for monitoring movement of fatty acids across protein-free model membranes (phospholipid bilayers). Pyranin, a water-soluble, pH-sensitive fluorescent molecule, was trapped inside well-sealed phosphatidylcholine vesicles (with or without cholesterol) in Hepes buffer (pH 7.4). Upon addition of a long-chain fatty acid (e.g., oleic acid) to the external buffer (also Hepes, pH 7.4), a decrease in fluorescence of pyranin was observed immediately (within 10 sec). This acidification of the internal volume was the result of the "flip" of un-ionized fatty acids to the inner leaflet, followed by a release of protons from approximately 50% of these fatty acid molecules (apparent pKa in the bilayer = 7.6). The proton gradient thus generated dissipated slowly because of slow cyclic proton transfer by fatty acids. Addition of bovine serum albumin to vesicles with fatty acids instantly removed the pH gradient, indicating complete removal of fatty acids, which requires rapid "flop" of fatty acids from the inner to the outer monolayer layer. Using a four-state kinetic diagram of fatty acids in membranes, we conclude that un-ionized fatty acid flip-flops rapidly (t1/2 < or = 2 sec) whereas ionized fatty acid flip-flops slowly (t1/2 of minutes). Since fatty acids move across phosphatidylcholine bilayers spontaneously and rapidly, complex mechanisms (e.g., transport proteins) may not be required for translocation of fatty acids in biological membranes. The proton movement accompanying fatty acid flip-flop is an important consideration for fatty acid metabolism in normal physiology and in disease states such as cardiac ischemia.


Prophylactic interventions after delivery of placenta for reducing bleeding during the postnatal period.
There are several Cochrane systematic reviews looking at postpartum haemorrhage (PPH) prophylaxis in the third stage of labour and another Cochrane review investigating the timing of prophylactic uterotonics in the third stage of labour (i.e. before or after delivery of the placenta). There are, however, no Cochrane reviews looking at the use of interventions given purely after delivery of the placenta. Ergometrine or methylergometrine are used for the prevention of PPH in the postpartum period (the period after delivery of the infant) after delivery of the placenta in some countries. There are, furthermore, no Cochrane reviews that have so far considered herbal therapies or homeopathic remedies for the prevention of PPH after delivery of the placenta. To assess the effectiveness of available prophylactic interventions for PPH including prophylactic use of ergotamine, ergometrine, methylergometrine, herbal therapies, and homeopathic remedies, administered after delivery of the placenta, compared with no uterotonic agents as well as with different routes of administration for prevention of PPH after delivery of the placenta. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 April 2013), The Food and Drug Administration (FDA) (USA), Medicines and Healthcare Products Regulatory Agency (MHRA) (UK), European Medicines Agency (EMA) (EU), Pharmaceuticals and Medical Devices Agency (PMDA) (Japan), Therapeutic Goods Administration (TGA) (Australia), ClinicalTrials.gov, Current Controlled Trials, WHO International Clinical Trials Registry Platform (ICTRP), University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; Japan), Japan Pharmaceutical Information Center Clinical Trials Information (Japic-CTI; Japan), Japan Medical Association Clinical Trial Registration (JMACCT CTR; Japan) (all on 30 April 2013) and reference lists of retrieved studies All randomised or quasi-randomised controlled trials comparing prophylactic ergotamine, ergometrine, methylergometrine, herbal therapies, and homeopathic remedies (using any route and timing of administration) during the postpartum period after delivery of the placenta with no uterotonic agents or trials comparing different routes or timing of administration of ergotamine, ergometrine, methylergometrine, herbal therapies, and homeopathic remedies, during the postpartum period after delivery of the placenta. Two review authors independently assessed trial eligibility and the methodological quality of trials, extracted data using the agreed form. Data were checked for accuracy. Five randomised studies involving 1466 women met the inclusion criteria. All studies were classified as having an unclear risk of bias. Two studies (involving 1097 women) compared oral methylergometrine with a placebo, and one (involving 171 women) compared oral methylergometrine with Kyuki-chouketsu-in, a Japanese traditional herbal medicine. The remaining two studies (involving 198 women) did not report the outcomes of interest for this review. None of the included studies reported primary outcomes prespecified in the review protocol (blood loss of 1000 mL or more over the period of observation, maternal death or severe morbidity). Overall, there was no clear evidence of differences between groups in the following PPH outcomes: blood loss of 500 mL or more (risk ratio (RR) 1.45; 95% confidence interval (CI) 0.39 to 5.47, two studies), amount of lochia during the first 72 hours of the puerperium (mean difference (MD) -25.00 g; 95% CI -69.79 to 19.79, one study), or amount of lochia by four weeks postpartum (MD -7.00 g; 95% CI -23.99 to 9.99).The Japanese study with a relatively small sample size comparing oral methylergometrine with a Japanese traditional herbal medicine found that oral methylergometrine significantly increased the blood haemoglobin concentration at day one postpartum (MD 0.50 g/dL; 95% CI 0.11 to 0.89) compared to herbal medicine. Adverse events were not well-reported in the included studies. We did not find any studies comparing homeopathic remedies with either a placebo or no treatment. There was insufficient evidence to support the use of prophylactic oral methylergometrine given after delivery of the placenta for the prevention of PPH. Additionally, the effectiveness of prophylactic use of herbal medicine or homeopathic remedies for PPH is still unclear as we could not find any clear evidence. Trials to assess the effectiveness of herbal medicines and homeopathic remedies in preventing PPH are warranted.


Isolated Rat Epididymal Basal Cells Share Common Properties with Adult Stem Cells.
There is little information on the function of epididymal basal cells. These cells secrete prostaglandins, can metabolize radical oxygen species, and have apical projections that are components of the blood-epididymis barrier. The objective of this study was to develop a reproducible protocol to isolate rat epididymal basal cells and to characterize their function by gene expression profiling. Integrin-alpha6 was used to isolate a highly purified population of basal cells. Microarray analysis indicated that expression levels of 552 genes were enriched in basal cells relative to other cell types. Among these genes, 45 were expressed at levels of 5-fold or greater. These highly expressed genes coded for proteins implicated in cell adhesion, cytoskeletal function, ion transport, cellular signaling, and epidermal function, and included proteases and antiproteases, signal transduction, and transcription factors. Several highly expressed genes have been reported in adult stem cells, suggesting that basal cells may represent an epididymal stem cell population. A basal cell culture was established that showed that these basal cells can differentiate in vitro from keratin (KRT) 5-positive cells to cells that express KRT8 and connexin 26, a marker of columnar cells. These data provide novel information on epididymal basal cell gene expression and suggest that these cells can act as adult stem cells.


Disruption of inducible nitric oxide synthase improves beta-adrenergic inotropic responsiveness but not the survival of mice with cytokine-induced cardiomyopathy.
Transgenic (TG) mice with cardiac-specific overexpression of tumor necrosis factor-alpha develop congestive heart failure. We have previously reported that short-term inhibition of inducible nitric oxide synthase (iNOS) ameliorates beta-adrenergic hyporesponsiveness in TG mice. To examine whether long-term inhibition of iNOS may rescue TG mice from developing congestive heart failure, we disrupted iNOS gene by crossing TG mice with iNOS knockout mice. Myocardial levels of iNOS protein were significantly increased in TG mice compared with age- and sex-matched wild-type (WT) mice. No iNOS protein was detected in TG mice with the disruption of iNOS. Myocardial levels of endothelial NOS were not different among these mice. To examine the effects of iNOS disruption on myocardial contractility, left ventricular pressure was measured. In TG mice, +dP/dt(max) was significantly suppressed, and its beta-adrenergic responsiveness was blunted. As in the case with short-term inhibition of iNOS, the disruption of iNOS gene improved beta-adrenergic inotropic responsiveness in TG mice but not in WT mice. However, the iNOS disruption did not alter myocardial inflammation, ventricular hypertrophy, or the survival of these mice. These results indicate that although myocardial expression of iNOS plays a key role in the attenuation of beta-adrenergic inotropic responsiveness, NO-independent mechanisms might be more important in the development of congestive heart failure.


Preventing violence-related injuries in England and Wales: a panel study examining the impact of on-trade and off-trade alcohol prices.
To examine the influence of real on-trade and off-trade alcohol prices and socioeconomic and environmental factors on rates of violence-related emergency department (ED) attendances in England and Wales over an 8-year period. Anonymised injury data which included attendance date, age and gender of patients aged over 18 years who reported injury in violence were collected from a structured sample of 100 EDs across England and Wales between 1 January 2005 and 31 December 2012. Alcohol prices and socioeconomic measures were obtained from the UK Office for National Statistics. Panel techniques were used to derive a statistical model. Real on-trade (β=-0.661, p<0.01) and off-trade (β=-0.277, p<0.05) alcohol prices were negatively related with rates of violence-related ED attendance among the adult population of England and Wales, after accounting for the effects of regional poverty, income inequality, youth spending power and seasonal effects. It is estimated that over 6000 fewer violence-related ED attendances per year in England and Wales would result from a 1% increase in both on-trade and off-trade alcohol prices above inflation. Of the variables studied, changes in regional poverty and income inequality had the greatest effect on violence-related ED attendances in England and Wales. Small increases in the price of alcohol, above inflation, in both markets, would substantially reduce the number of patients attending EDs for treatment of violence-related injuries in England and Wales. Reforming the current alcohol taxation system may be more effective at reducing violence-related injury than minimum unit pricing.


The potential risk of toxoplasmosis for traffic accidents: A systematic review and meta-analysis.
Toxoplasmosis is a prevalent infectious disease. Although most people infected by Toxoplasma gondii are asymptomatic, evidence has suggested that this disease might affect some aspects of a host's behavior and associate with schizophrenia, suicide attempt, changes in various aspects of personality, and poor neurocognitive performance. These associations may play roles in increasing the risk of a number of incidents, such as traffic accidents, among infected people. In this regard, this study aimed to provide summary estimates for the available data on the potential risk of toxoplasmosis for traffic accidents. To this end, using a number of search terms, i.e. toxoplasmosis, Toxoplasma gondii, traffic accident, road accident, car accident, crash, and prevalence, literature searches (up to October 1, 2017) were carried out via 6 databases. The meta-analysis was conducted using the StatsDirect statistical software and a P-value less than 0.05 was regarded as significant in all statistical analyses. Out of 1841 identified studies, 9 studies were finally considered eligible for carrying out this systematic review. Reviewing results of these studies indicated that 5 out of 9 studies reported a significant relationship between Toxoplasma gondii and traffic accidents. Additionally, data related to gender showed significant differences between infected and control men and women. Considering age, reviewing the results of these studies revealed a significant difference between the infected people and the Toxoplasma-negative subjects under 45 years of age. However, no significant difference was found between the two groups aged 45 or older. Given these results, it can be concluded that Toxoplasma gondii significantly increases the risk of having traffic accidents.


Randomized trial to evaluate indinavir/ritonavir versus saquinavir/ritonavir in human immunodeficiency virus type 1-infected patients: the MaxCmin1 Trial.
This trial assessed the rate of virological failure at 48 weeks in adult human immunodeficiency virus (HIV) type 1-infected patients assigned indinavir/ritonavir (Idv/Rtv; 800/100 mg 2 times daily) or saquinavir/ritonavir (Sqv/Rtv; 1000/100 mg 2 times daily) in an open-label, randomized (1:1), multicenter, phase 4 design. Three hundred six patients began the assigned treatment. At 48 weeks, virological failure was seen in 43 (27%) of 158 and 37 (25%) of 148 patients in the Idv/Rtv and Sqv/Rtv arms, respectively. The time to virological failure did not differ between study arms (P=.76). When switching from randomized treatment was counted as failure, this was seen in 78 of 158 patients in the Idv/Rtv arm, versus 51 of 148 patients in the Sqv/Rtv arm (P=.009). A switch from the randomized treatment occurred in 64 (41%) of 158 patients in the Idv/Rtv arm, versus 40 (27%) of 148 patients in the Sqv/Rtv arm (P=.013). Sixty-four percent of the switches occurred because of adverse events. A greater number of treatment-limiting adverse events were observed in the Idv/Rtv arm, relative to the Sqv/Rtv arm. In conclusion, Rtv-boosed Sqv and Idv were found to have comparable antiretroviral effects in the doses studied.


Preparation of raspberry-like γ-Fe2O3/crackled nitrogen-doped carbon capsules and their application as supports to improve catalytic activity.
In this manuscript, we have introduced a novel method to improve the catalytic activity of metal nanoparticles via optimizing the support structure. To this end, raspberry-like γ-Fe2O3/crackled nitrogen-doped carbon (CNC) capsules were prepared by a two-step method. Compared with traditional magnetic capsules, in γ-Fe2O3/CNC capsules, the γ-Fe2O3 nanoparticles were embedded in a CNC shell; therefore, they neither occupied the anchoring sites for metal nanoparticles nor came into contact with them, which was beneficial for increasing the metal nanoparticle loading. Numerous tiny cracks appeared on the porous CNC shell, which effectively improved the mass diffusion and transport in catalytic reactions. Additionally, the coordination interaction could be generated between the precursor metal ions and doped-nitrogen atoms in the capsule shell. With the help of these structural merits, γ-Fe2O3/CNC capsules were ideal supports for Pd nanoparticles, because they were beneficial for improving the Pd loading, reducing the nanoparticle size, increasing their dispersity and maximizing the catalytic performance of Pd nanoparticles anchored on the inner shell surface. As expected, γ-Fe2O3/CNC@Pd catalysts exhibited a dramatically enhanced catalytic activity towards hydrophilic 4-nitrophenol and hydrophobic nitrobenzene. The reaction rate constant k was compared with recent work and the corresponding reference samples. Moreover, they could be easily recycled by using a magnet and reused without an obvious loss of catalytic activity.


Microdroplet photobioreactor for the photoautotrophic culture of microalgal cells.
Microalgae, unicellular photoautotrophic microorganisms, have attracted great attention for the production of biofuel and high-value products, but the commercial use of microalgae has been limited by low photosynthetic productivity. To overcome this limitation, it is required to develop an efficient platform for the rapid evaluation of photoautotrophic growth performance and productivity of microalgal strains. Here we describe a droplet-based photobioreactor for high-throughput analysis of the photoautotrophic growth of microalgal cells. By integrating micropillar arrays and adjusting the height of the microchamber, we could accurately monitor the growth kinetics of microalgae in an immobilized microdroplet and improve the transfer rate of CO2 into the microdroplet photobioreactor with an increased contact area between the microdroplet and PDMS surface. The improvement of CO2 transfer into the microdroplet was also confirmed by improved microalgal cell growth and a decrease in pH measured using colorimetric and fluorescence-based assays. The photoautotrophic growth kinetics of Chlorella vulgaris were measured under different CO2 concentrations (ambient, 1%, 2.5%, 5% and 7.5%) and light intensity (35, 55, 100, 150, and 200 μmol photons per m(2) per s) conditions, which are key factors for photoautotrophic growth. Chlorella vulgaris in a microdroplet showed better cell growth performance compared to a flask culture due to the reduced shading effects and improved mass transfer. Finally, we could evaluate the photoautotrophic growth performance of four microalgal strains (Chlorella vulgaris, Chlorella protothecoides, Chlorella sorokiniana and Neochloris oleoabundans) for 120 hours. These results demonstrate that our microdroplet system can be used as an efficient photobioreactor for the rapid evaluation of the photoautotrophic growth of microalgal strains under various conditions.


Influence of impactor operating flow rate on particle size distribution of four jet nebulizers.
When a nebulizer is evaluated by the Andersen Cascade Impactor (ACI), the flow rate is generally maintained at 28.3 L/min, as recommended by the manufacturer. However, the nebulizer flow rate that a patient inhales is only around 18 L/min. Because the drive flow of a nebulizer is approximately 6-8 L/min, the nebulized drug is mixed with outside air when delivered. Evaluating impactor performance at the 28.3 L/min flow rate is less than ideal because an additional 10 L/min of outside air is mixed with the drug, thereby affecting the drug size distribution and dose before inhalation and deposition in the human lung. In this study we operated the ACI at an 18.0 L/min flow rate to test whether the effect of the changing ambient humidity was being exaggerated by the 28.3 L/min flow rate. The study was carried out at three different relative humidity levels and two different impactor flow rates with four commercially available nebulizers. The mass median aerodynamic diameter (MMAD) and the geometric standard deviation (GSD) of the droplets were found to increase when the impactor was operated at a flow rate of 18 L/min compared to that of 28.3 L/min. The higher MMAD and GSD could cause the patient to inhale less of the drug than expected if the nebulizer was evaluated by the ACI at the operating flow rate of 28.3 L/min.


Microglial activation and inflammation caused by traffic-related particulate matter.
Neurotoxicity caused by particulate matter (PM) has been highlighted as being a potential risk factor for neurodegenerative diseases. However, the effects of brain inflammation in response to traffic-related PM remain unclear. The objective of this study was to investigate the effects of traffic-related PM on microglial responses. We determined the cytotoxicity, oxidative stress, lipid peroxidation, inflammation, activation, autophagy, and apoptosis due to exposure to carbon black (CB) and diesel exhaust particles (DEPs) in Bv2 microglial cells. Additionally, cells were pretreated with corticosteroid to determine alterations in microglial activation and inflammation. For in vivo confirmation, Sprague Dawley (SD) rats were whole-body exposed to traffic-related PM1 (PM with an aerodynamic diameter of <1 μm) for 3 and 6 months. We observed that a decrease in cell viability and increases in dichlorodihydrofluorescein (DCFH), lactate dehydrogenase (LDH), and thiobarbituric acid-reactive substances (TBARSs) occurred due to CB and DEP. Production of interleukin (IL)-6 and soluble tumor necrosis factor (TNF)-α was significantly stimulated by CB and DEP, whereas production of cellular TNF-α was significantly stimulated by CB. Iba1 and prostaglandin E2 (PGE2) significantly increased due to CB and DEP. Consistently, we observed significant increases in Iba1 in the hippocampus of rats after 3 and 6 months of exposure to traffic-related PM1. We found that the light chain 3II (LC3II)/LC3I ratio and caspase-3 activity increased due to CB and DEP exposure. Subsequently, LDH, TBARS, LC3II/I, and caspase-3 activities did not clearly respond to corticosteroid pretreatment followed by DEP exposure in BV2 cells. Results of the present study suggested that traffic-related PM induced cytotoxicity, lipid peroxidation, microglial activation, and inflammation as well as autophagy and caspase-3 regulation in microglia. We demonstrated that microglial activation and inflammation may play important roles in the response of the brain to traffic-related PM.


Correlation of the immunostimulatory activities of honeys with their contents of identified bioactives.
Honeys with unique compositions and properties are worth studying for their health-promoting effects. In order to correlate bioactive content with immunostimulatory activity we compared the abilities of seventy eight New Zealand and non-New Zealand honeys to stimulate blood monocytes to release tumour necrosis factor (TNF)-α, and examined the compositions of selected honeys that had widely varying activities. All the honeys, except for a Malaysian "Amber honey" stimulated the release of TNF-α from monocytes. However, the honeys differed greatly in their immunostimulatory activity, even within the same honey type. They differed in their contents of immunostimulatory components, including apalbumins, arabinogalactan proteins, and apisimin, whose levels did not correlate exactly with immunostimulatory activities. We suggest that the immunostimulatory properties of honey may be influenced by other factors, including unidentified immunostimulatory bioactives and immunosuppressive components; the bioavailability of some bioactives may depend on unidentified factors.


Proteasome activity and expression of mammalian target of rapamycin signaling factors in skeletal muscle of dairy cows supplemented with conjugated linoleic acids during early lactation.
The mammalian target of rapamycin (mTOR) is a major regulator of protein synthesis via its main downstream effectors, ribosomal protein S6 kinase (S6K1) and eukaryotic initiation factor 4E binding protein (4EBP1). The ubiquitin-proteasome system (UPS) is the main proteolytic pathway in muscle, and the muscle-specific ligases tripartite motif containing 63 (TRIM63; also called muscle-specific ring-finger protein 1, MuRF-1) and F-box only protein 32 (FBXO32; also called atrogin-1) are important components of the UPS. We investigated 20S proteasome activity and mRNA expression of key components of mTOR signaling and UPS in skeletal muscle of dairy cows during late gestation and early lactation and tested the effects of dietary supplementation (from d 1 in milk) with conjugated linoleic acids (sCLA; 100 g/d; n = 11) compared with control fat-supplemented cows (CTR; n = 10). Blood and muscle tissue (semitendinosus) samples were collected on d -21, 1, 21, and 70 relative to parturition. Dry matter intake increased with time of lactation in both groups. It was lower in sCLA than in CTR on d 21, which resulted in a reduced calculated metabolizable protein balance. Most serum and muscle concentrations of AA followed time-related changes but were unaffected by CLA supplementation. In both groups, serum and muscle 3-methylhistidine (3-MH) concentrations and the ratio of 3-MH:creatinine increased from d -21 to d 1, followed by a decline on d 21. The mRNA abundance of MTOR on d 21 and 70 was greater in sCLA than in CTR. The abundance of 4EBP1 mRNA did not differ between groups but was upregulated in both on d 1. The mRNA abundance of S6K1 on d 70 was greater in CTR than in sCLA, but remained unchanged over time in both groups. The mRNA abundance of FBXO32 (encoding atrogin-1) on d 21 was greater in sCLA than in CTR. The mRNA abundance of TRIM63 (also known as MuRF1) showed a similar pattern as FBXO32 in both groups: an increase from d -21 to d 1, followed by a decline. The mRNA for the α (BCKDHA) and β (BCKDHB) polypeptide of branched-chain α-keto acid dehydrogenase was elevated in sCLA and CTR cows on d 21, respectively, suggesting a role of CLA in determining the metabolic fate of branched-chain AA. For the mTOR protein, no group differences were observed. The abundance of S6K1 protein was greater across all time points in sCLA versus CTR. The antepartum 20S proteasome activity in muscle was elevated in both groups compared with postpartum, probably reflecting the start of protein mobilization before parturition. Plasma insulin concentrations decreased in both groups postpartum but to a greater extent in CTR than in sCLA, resulting in greater insulin concentrations in sCLA than in CTR. Thus, the greater abundance of MTOR mRNA and S6K1 protein in sCLA compared with CTR might be mediated by the greater plasma insulin postpartum. The upregulation of MTOR mRNA in sCLA cows on d 21, despite greater FBXO32 mRNA abundance, may reflect a simultaneous activation of both anabolic and catabolic signaling pathways, likely resulting in greater protein turnover.


Influence of anatomic origin on intracranial distribution of micro-emboli in the baboon.
The purpose of this study was to investigate whether the anatomic origin of micro-emboli influences their intracranial distribution. In twenty-two baboons, we examined the distribution of 99-Technetium labelled albumin aggregates (5 to 40 microns in size) after injection into the circulation at the left atrium (LA), carotid trifurcation (CA), and anterior and posterior common carotid artery (CCI). In a further subgroup, the emboli were introduced at the carotid trifurcation with the contralateral carotid artery ligated (CA + L). The results of this study demonstrated that aggregates introduced at the carotid artery lodged preferentially in the ophthalmic (p = 0.032) and middle cerebral artery territories (p = 0.016). If the contralateral common carotid artery was ligated, however, more aggregates were found in the ipsi- and contralateral anterior cerebral artery territories (p = 0.01, p = 0.003). Aggregates introduced into the cardiac circulation were equally distributed throughout the brain. This experimental model determined patterns of flow that might be analogous to the human situation where unilateral or bilateral carotid stenosis or stenosis with contralateral occlusion has occurred or embolus from cardiac source has occurred. The results do not imply that the 40 micron microaggregates do cause TIA. These experimental findings support clinical observations that cardiac lesions may cause transient ischemic attacks (TIA) anywhere in the brain. In contrast, those of carotid artery origin cause predominantly middle cerebral or ophthalmic artery territory TIAs unless the contralateral carotid artery is severely stenosed or occluded.


Planar concentrators near the étendue limit.
Recently proposed aplanatic imaging designs are integrally combined with nonimaging flux boosters to produce an ultracompact planar glass-filled concentrator that performs near the étendue limit. Such optical devices are attractive for high-efficiency multijunction photovoltaics at high flux, with realistic power generation of 1 W from a 1 mm2 cell. When deployed in reverse, our designs provide collimation even for high-numerical-aperture light sources.


A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia.
Several CSF and blood biomarkers for genetic frontotemporal dementia have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain and phosphorylated neurofilament heavy chain), synapse dysfunction [neuronal pentraxin 2 (NPTX2)], astrogliosis (glial fibrillary acidic protein) and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage frontotemporal dementia, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic frontotemporal dementia using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. Two-hundred and seventy-five presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection ('converters'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on previous diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF neurofilament light chain, blood phosphorylated neurofilament heavy chain, blood glial fibrillary acidic protein and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The areas under the curve to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic frontotemporal dementia revealed that NPTX2 and neurofilament light chain are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model's ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions.


Photocatalytic Color Switching of Transition Metal Hexacyanometalate Nanoparticles for High-Performance Light-Printable Rewritable Paper.
Developing efficient photoreversible color switching systems for constructing rewritable paper is of significant practical interest owing to the potential environmental benefits including forest conservation, pollution reduction, and resource sustainability. Here we report that the color change associated with the redox chemistry of nanoparticles of Prussian blue and its analogues could be integrated with the photocatalytic activity of TiO2 nanoparticles to construct a class of new photoreversible color switching systems, which can be conveniently utilized for fabricating ink-free, light printable rewritable paper with various working colors. The current system also addresses the phase separation issue of the previous organic dye-based color switching system so that it can be conveniently applied to the surface of conventional paper to produce an ink-free light printable rewritable paper that has the same feel and appearance as the conventional paper. With its additional advantages such as excellent scalability and outstanding rewriting performance (reversibility >80 times, legible time >5 days, and resolution >5 μm), this novel system can serve as an eco-friendly alternative to regular paper in meeting the increasing global needs for environment protection and resource sustainability.


Dexamethasone but not the equivalent doses of hydrocortisone induces neurotoxicity in neonatal rat brain.
The use of dexamethasone (Dex) in premature infants to treat or prevent chronic lung disease adversely affects neurodevelopment. Recent clinical studies suggest that hydrocortisone (HC) is a safer alternative to Dex. We compared the effects of Dex and HC on neurotoxicity in newborn rats. Rat pups of a neurodevelopmental stage equivalent to premature human neonates were administered Dex or HC either as a single dose on postnatal day (PD) 6, repeated doses on PD 4 to 6 or tapering doses at PD 3 to 6 by i.p. injection. Brain weight, caspase-3 activity, and apoptotic cells were measured at PD 7; learning capability, memory, and motor function were measured at juvenile age. Dex decreased both body and brain weight gain, while HC did not. Tapering and repeated doses of Dex increased caspase-3 activity, cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells but HC, except at high doses, did not. Dex impaired learning and memory capability at juvenile age, while the rats exposed to HC showed normal cognitive behavior. HC is probably safer to use than Dex in the immediate postnatal period in neonatal rats. Cautious extrapolation of these findings to human premature infants is required.


Identification and expression of a soybean nodule-enhanced PEP-carboxylase kinase gene (NE-PpcK) that shows striking up-/down-regulation in vivo.
Various isoforms of plant phosphoenolpyruvate carboxylase (PEPC (Ppc)) are controlled post-translationally by an intricate interaction between allosteric regulation and reversible protein phosphorylation. In leaves and root nodules of legumes, these changes in PEPC phosphorylation state are governed primarily by PEPC-kinase (PpcK), a novel, 'minimal but functional' Ser/Thr kinase. To date, this plant-specific kinase has been investigated in molecular terms exclusively in non-leguminous plants, such as Crassulacean-acid-metabolism (CAM) species and Arabidopsis. As an important extension of our earlier biochemical studies on this dedicated kinase and PEPC phosphorylation in soybean (Glycine max) nodules, we now report the molecular cloning of the first legume PpcK from a soybean nodule cDNA library, which encodes a functional, 31.0 kDa PpcK polypeptide. Besides displaying organ, developmental, and spatial expression properties that are strikingly up-regulated in mature nodules, the expression pattern of this transcript is distinct from that of a second soybean PpcK isogene (GmPpcK). The steady-state abundance of this former, nodule-enhanced transcript (NE-PpcK) is markedly influenced by photosynthate supply from the shoots. This latter up-/down-regulation of NE-PpcK transcript level occurs in vivo in concert with the corresponding changes in the nodule PpcK activity, the phosphorylation-state of PEPC, and the abundance of a previously identified, nodule-enhanced transcript (GmPEPC7) that encodes the target enzyme (NE-Ppc). Furthermore, genomic Southern analysis and inspection of the public database indicate that there are at least three distinct PpcK and Ppc isogenes in soybean. Collectively, these and recent findings with Arabidopsis implicate the existence of multiple PpcK-Ppc'expression-partners' in plants, exemplified by NE-PpcK and NE-Ppc in the soybean nodule.


Prevalence of non-alcoholic fatty liver disease on computed tomography in patients with inflammatory bowel disease visiting an emergency department.
Non-alcoholic fatty liver disease (NAFLD) is common in patients with inflammatory bowel disease (IBD). The purpose of this study was to further examine the prevalence of NAFLD in IBD patients. We retrospectively reviewed the medical records of IBD patients who visited the emergency department because of abdominal pain between January 2009 and December 2014. These were compared with a group of 70 controls without IBD, matched for age and body mass index (BMI). Computed tomography data were analyzed for the presence or absence of hepatic steatosis. Patient with recent steroid or excessive alcohol use were excluded. Univariate and multivariate analyses were performed. NAFLD prevalence was 44% (31/70) in the IBD group vs. 16% (11/70) in controls (P<0.001). There was no significant difference between the 2 groups in age, sex distribution, BMI, presence of diabetes, or levels of serum transaminases, serum albumin or platelets. In multivariate analysis, the presence of IBD was independently associated with NAFLD (odds ratio 4.53, 95% confidence interval 2.00-10.26; P=0.002). The presence of IBD is strongly and independently associated with NAFLD. Systemic inflammation and alteration of the intestinal microbiome have been proposed as mechanisms, but further studies are needed to better elucidate the pathophysiology.


Efficacy of a specific polyclonal equine F(ab')2 against avian influenza (H5N1) in ferrets: synergy with oseltamivir.
Current therapies against avian influenza (H5N1) provide limited clinical benefit. FBF-001 is a highly purified equine polyclonal immunoglobulin fragment against H5N1. Using a ferret model of severe acute H5N1 infection, we assessed FBF-001 when administered on the same day or 1 day after viral challenge, in comparison with oseltamivir therapy. Untreated animals died 2-3 days after challenge. FBF-001 prevented most severe illness and reduced nasal viral load, with best efficacy when administered on the day of viral challenge. Oseltamivir and FBF-001 had synergistic impact on survival. FBF-001 prevented severe consequences of lethal H5N1 challenge in ferrets by controlling viral replication, an effect synergistic to oseltamivir. FBF-001 has recently been granted EMA orphan drug status.


Diacylglycerol kinase delta promotes lipogenesis.
We have studied the relationship between diacylglycerol kinase delta (DGKδ) and lipogenesis. There is a marked increase in the expression of DGKδ during the differentiation of 3T3-L1 cells to adipocytes, as well as in the synthesis of neutral and polar lipids. When 3T3-L1 undifferentiated fibroblasts are transfected to express DGKδ, there is increased triglyceride synthesis without differentiation to adipocytes. Hence, expression of DGKδ promotes lipogenesis. Lipid synthesis is decreased in DGKδ knockout mouse embryo fibroblasts, especially for lipids with shorter acyl chains and limited unsaturation. This reduction occurs for both neutral and polar lipids. These findings suggest reduced de novo lipid synthesis. This is confirmed by measuring the incorporation of glycerol into polar and neutral lipids, which is higher in the wild type cells than in the DGKδ knockouts. In comparison, there was no change in lipid synthesis in DGKε knockout mouse embryo fibroblasts. We also demonstrate that the DGKδ knockout cells had a lower expression of acetyl-CoA carboxylase and fatty acid synthase as well as a lower degree of activation by phosphorylation of ATP citrate lyase. These three enzymes are involved in the synthesis of long chain fatty acids. Our results demonstrate that DGKδ markedly increases lipid synthesis, at least in part as a result of promoting the de novo synthesis of fatty acids.


CARMA2sh and ULK2 control pathogen-associated molecular patterns recognition in human keratinocytes: psoriasis-linked CARMA2sh mutants escape ULK2 censorship.
The molecular complexes formed by specific members of the family of CARMA proteins, the CARD domain-containing adapter molecule BCL10 and MALT1 (CBM complex) represent a central hub in regulating activation of the pleiotropic transcription factor NF-κB. Recently, missense mutations in CARMA2sh have been shown to cause psoriasis in a dominant manner and with high penetrancy. Here, we demonstrate that in human keratinocytes CARMA2sh plays an essential role in the signal transduction pathway that connects pathogen-associated molecular patterns recognition to NF-κB activation. We also find that the serine/threonine kinase ULK2 binds to and phosphorylates CARMA2sh, thereby inhibiting its capacity to activate NF-κB by promoting lysosomal degradation of BCL10, which is essential for CARMA2sh-mediated NF-κB signaling. Remarkably, CARMA2sh mutants associated with psoriasis escape ULK2 inhibition. Finally, we show that a peptide blocking CARD-mediated BCL10 interactions reduces the capacity of psoriasis-linked CARMA2sh mutants to activate NF-κB. Our work elucidates a fundamental signaling mechanism operating in human keratinocytes and opens to novel potential tools for the therapeutical treatment of human skin disorders.


Emergency Department utilization among Deaf American Sign Language users.
Deaf American Sign Language (ASL) users comprise a linguistic minority population with poor health care access due to communication barriers and low health literacy. Potentially, these health care barriers could increase Emergency Department (ED) use. To compare ED use between deaf and non-deaf patients. A retrospective cohort from medical records. The sample was derived from 400 randomly selected charts (200 deaf ASL users and 200 hearing English speakers) from an outpatient primary care health center with a high volume of deaf patients. Abstracted data included patient demographics, insurance, health behavior, and ED use in the past 36 months. Deaf patients were more likely to be never smokers and be insured through Medicaid. In an adjusted analysis, deaf individuals were significantly more likely to use the ED (odds ratio [OR], 1.97; 95% confidence interval [CI], 1.11-3.51) over the prior 36 months. Deaf American Sign Language users appear to be at greater odds for elevated ED utilization when compared to the general hearing population. Efforts to further understand the drivers for increased ED utilization among deaf ASL users are much needed.


The Ideal Timing of Bedside Surgical Ligation of Patent Ductus Arteriosus in Premature Babies Less Than 30 Gestational Weeks.
The aim of our study is to determine the relationship between exposure to hemodynamically significant patent ductus arteriosus and morbidities in premature babies, the optimal number of pharmacologic treatment cycles, and ideal ductus ligation timing. The study was a retrospective single-center study conducted in a 3-year period between July 2017 and June 2020. Premature babies, born ≤30 weeks of gestation and transferred to our unit for bedside ductus ligation, were included in the study. The subjects were divided into 2 groups; Group A consisted of the patients who received ≥3 pharmacologic treatment cycles, and group B consisted of the patients who received ≤2 cycles. The groups were compared according to preoperative and postoperative features. The main outcome of the study was the presence of severe bronchopulmonary dysplasia. The secondary outcomes were specified as the length of stay in the neonatal intensive care unit and the duration of invasive mechanical ventilation (MV). The study group consisted of 24 patients. There were 10 patients in group A and 14 patients in group B. The mean gestational week and the mean birthweight were found to be 26,7 ± 2.2 weeks and 928 ± 190 g, respectively. The incidence of severe bronchopulmonary dysplasia was significantly higher in group A (70% vs. 14.3%; P = .019). Post-ligation invasive MV, duration, and length of stay in the intensive care unit were found to be significantly longer in group A. None of the patients had hemodynamic disturbances or complications during and after the operation. Bedside surgical ductus ligation is a safe procedure. Prolonging pharmacologic treatment in order to avoid surgery increases the risk of severe bronchopulmonary dysplasia and prolongs hospital stay.


Excitons and biexcitons in InGaN quantum dot like localization centers.
Indium segregation in a narrow InGaN single quantum well creates quantum dot (QD) like exciton localization centers. Cross-section transmission electron microscopy reveals varying shapes and lateral sizes in the range ∼1-5 nm of the QD-like features, while scanning near field optical microscopy demonstrates a highly inhomogeneous spatial distribution of optically active individual localization centers. Microphotoluminescence spectroscopy confirms the spectrally inhomogeneous distribution of localization centers, in which the exciton and the biexciton related emissions from single centers of varying geometry could be identified by means of excitation power dependencies. Interestingly, the biexciton binding energy (E(b)xx) was found to vary from center to center, between 3 to -22 meV, in correlation with the exciton emission energy. Negative binding energies are only justified by a three-dimensional quantum confinement, which confirms QD-like properties of the localization centers. The observed energy correlation is proposed to be understood as variations of the lateral extension of the confinement potential, which would yield smaller values of E(b)xx for reduced lateral extension and higher exciton emission energy. The proposed relation between lateral extension and E(b)xx is further supported by the exciton and the biexciton recombination lifetimes of a single QD, which suggest a lateral extension of merely ∼3 nm for a QD with strongly negative E(b)xx = -15.5 meV.


The EGFR-ADAM17 Axis in Chronic Obstructive Pulmonary Disease and Cystic Fibrosis Lung Pathology.
Chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) share molecular mechanisms that cause the pathological symptoms they have in common. Here, we review evidence suggesting that hyperactivity of the EGFR/ADAM17 axis plays a role in the development of chronic lung disease in both CF and COPD. The ubiquitous transmembrane protease A disintegrin and metalloprotease 17 (ADAM17) forms a functional unit with the EGF receptor (EGFR), in a feedback loop interaction labeled the ADAM17/EGFR axis. In airway epithelial cells, ADAM17 sheds multiple soluble signaling proteins by proteolysis, including EGFR ligands such as amphiregulin (AREG), and proinflammatory mediators such as the interleukin 6 coreceptor (IL-6R). This activity can be enhanced by injury, toxins, and receptor-mediated external triggers. In addition to intracellular kinases, the extracellular glutathione-dependent redox potential controls ADAM17 shedding. Thus, the epithelial ADAM17/EGFR axis serves as a receptor of incoming luminal stress signals, relaying these to neighboring and underlying cells, which plays an important role in the resolution of lung injury and inflammation. We review evidence that congenital CFTR deficiency in CF and reduced CFTR activity in chronic COPD may cause enhanced ADAM17/EGFR signaling through a defect in glutathione secretion. In future studies, these complex interactions and the options for pharmaceutical interventions will be further investigated.


Cooking fuels and risk of all-cause and cardiopulmonary mortality in urban China: a prospective cohort study.
Cooking practice has transitioned from use of solid fuels to use of clean fuels, with addition of better ventilation facilities. However, the change in mortality risk associated with such a transition remains unclear. The China Kadoorie Biobank (CKB) Study enrolled participants (aged 30-79 years) from ten areas across China; we chose to study participants from five urban areas where transition from use of solid fuels to clean fuels for cooking was prevalent. Participants who reported regular cooking (weekly or more frequently) at baseline were categorised as persistent clean fuel users, previous solid fuel users, or persistent solid fuel users, according to self-reported fuel use histories. All-cause and cardiopulmonary mortality were identified through linkage to China's Disease Surveillance Point system and local mortality records. Between June 24, 2004, and July 15, 2008, 226 186 participants living in five urban areas of China were enrolled in the CKB Study. Among 171 677 participants who reported cooking regularly (weekly or more frequently), 75 785 (44%) were persistent clean fuel users, 80 511 (47%) were previous solid fuel users, and 15 381 (9%) were persistent solid fuel users. During a mean of 9·8 (SD 1·7) years of follow-up, 10 831 deaths were documented, including 3819 cardiovascular deaths and 761 respiratory deaths. Compared with persistent clean fuel users, persistent solid fuel users had significantly higher risks of all-cause mortality (hazard ratio [HR] 1·19, 95% CI 1·10-1·28), cardiovascular mortality (1·24, 1·10-1·39), and respiratory mortality (1·43, 1·10-1·85). The excess risk of all-cause and cardiopulmonary mortality fell by more than 60% in 5 years after cessation of solid fuel use and continued to decrease afterwards. Use of ventilation was associated with lower all-cause mortality risk, even among persistent clean fuel users (HR 0·78, 0·69-0·89). Solid fuel use for cooking is associated with a higher risk of mortality, and cessation of solid fuel use cuts excess mortality risks swiftly and substantially within 5 years. Ventilation use also lowers the risk of mortality, even among people who persistently use clean fuels. It is of prime importance for both policy makers and the public to accelerate the transition from solid fuels to clean fuels and promote efficient ventilation to minimise further adverse health effects. National Natural Science Foundation of China, Wellcome Trust, and Kadoorie Charitable Foundation.


Sound-wave coherence in atmospheric turbulence with intrinsic and global intermittency.
The coherence function of sound waves propagating through an intermittently turbulent atmosphere is calculated theoretically. Intermittency mechanisms due to both the turbulent energy cascade (intrinsic intermittency) and spatially uneven production (global intermittency) are modeled using ensembles of quasiwavelets (QWs), which are analogous to turbulent eddies. The intrinsic intermittency is associated with decreasing spatial density (packing fraction) of the QWs with decreasing size. Global intermittency is introduced by allowing the local strength of the turbulence, as manifested by the amplitudes of the QWs, to vary in space according to superimposed Markov processes. The resulting turbulence spectrum is then used to evaluate the coherence function of a plane sound wave undergoing line-of-sight propagation. Predictions are made by a general simulation method and by an analytical derivation valid in the limit of Gaussian fluctuations in signal phase. It is shown that the average coherence function increases as a result of both intrinsic and global intermittency. When global intermittency is very strong, signal phase fluctuations become highly non-Gaussian and the average coherence is dominated by episodes with weak turbulence.