Who are the missing parents? Grandparentage analysis identifies multiple sources of gene flow into a wild population.
In order to increase the size of declining salmonid populations, supplementation programmes intentionally release fish raised in hatcheries into the wild. Because hatchery-born fish often have lower fitness than wild-born fish, estimating rates of gene flow from hatcheries into wild populations is essential for predicting the fitness cost to wild populations. Steelhead trout (Oncorhynchus mykiss) have both freshwater resident and anadromous (ocean-going) life history forms, known as rainbow trout and steelhead, respectively. Juvenile hatchery steelhead that 'residualize' (become residents rather than go to sea as intended) provide a previously unmeasured route for gene flow from hatchery into wild populations. We apply a combination of parentage and grandparentage methods to a three-generation pedigree of steelhead from the Hood River, Oregon, to identify the missing parents of anadromous fish. For fish with only one anadromous parent, 83% were identified as having a resident father while 17% were identified as having a resident mother. Additionally, we documented that resident hatchery males produced more offspring with wild anadromous females than with hatchery anadromous females. One explanation is the high fitness cost associated with matings between two hatchery fish. After accounting for all of the possible matings involving steelhead, we find that only 1% of steelhead genes come from residualized hatchery fish, while 20% of steelhead genes come from wild residents. A further 23% of anadromous steelhead genes come from matings between two resident parents. If these matings mirror the proportion of matings between residualized hatchery fish and anadromous partners, then closer to 40% of all steelhead genes come from wild trout each generation. These results suggest that wild resident fish contribute substantially to endangered steelhead 'populations' and highlight the need for conservation and management efforts to fully account for interconnected Oncorhynchus mykiss life histories.


Classifying the evolutionary and ecological features of neoplasms.
Neoplasms change over time through a process of cell-level evolution, driven by genetic and epigenetic alterations. However, the ecology of the microenvironment of a neoplastic cell determines which changes provide adaptive benefits. There is widespread recognition of the importance of these evolutionary and ecological processes in cancer, but to date, no system has been proposed for drawing clinically relevant distinctions between how different tumours are evolving. On the basis of a consensus conference of experts in the fields of cancer evolution and cancer ecology, we propose a framework for classifying tumours that is based on four relevant components. These are the diversity of neoplastic cells (intratumoural heterogeneity) and changes over time in that diversity, which make up an evolutionary index (Evo-index), as well as the hazards to neoplastic cell survival and the resources available to neoplastic cells, which make up an ecological index (Eco-index). We review evidence demonstrating the importance of each of these factors and describe multiple methods that can be used to measure them. Development of this classification system holds promise for enabling clinicians to personalize optimal interventions based on the evolvability of the patient's tumour. The Evo- and Eco-indices provide a common lexicon for communicating about how neoplasms change in response to interventions, with potential implications for clinical trials, personalized medicine and basic cancer research.


Maternal PRKAA1 and EDNRA genotypes are associated with birth weight, and PRKAA1 with uterine artery diameter and metabolic homeostasis at high altitude.
Low birth weight and intrauterine growth restriction (IUGR) increase the risk of mortality and morbidity during the perinatal period as well as in adulthood. Environmental and genetic factors contribute to IUGR, but the influence of maternal genetic variation on birth weight is largely unknown. We implemented a gene-by-environment study wherein we utilized the growth restrictive effects of high altitude. Multigenerational high-altitude residents (Andeans) are protected from altitude-associated IUGR compared with recent migrants (Europeans). Using a combined cohort of low- and high-altitude European and Andean women, we tested 63 single nucleotide polymorphisms (SNPs) from 16 natural selection-nominated candidate gene regions for associations with infant birth weight. We identified significant SNP associations with birth weight near coding regions for two genes involved in oxygen sensing and vascular control, PRKAA1 and EDNRA, respectively. Next, we identified a significant association for the PRKAA1 SNP with an intermediate phenotype, uterine artery diameter, which has been shown to be related to Andean protection from altitude-associated reductions in fetal growth. To explore potential functional relationships for the effect of maternal SNP genotype on birth weight, we evaluated the relationship between maternal PRKAA1 SNP genotype and gene expression patterns in general and, in particular, of key pathways involved in metabolic homeostasis that have been proposed to play a role in the pathophysiology of IUGR. Our observations suggest that maternal genetic variation within genes that regulate oxygen sensing, metabolic homeostasis, and vascular control influence fetal growth and birth weight outcomes and hence Andean adaptation to high altitude.


Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
Patients with cirrhosis hospitalized for an acute decompensation (AD) and organ failure are at risk for imminent death and considered to have acute-on-chronic liver failure (ACLF). However, there are no established diagnostic criteria for ACLF, so little is known about its development and progression. We aimed to identify diagnostic criteria of ACLF and describe the development of this syndrome in European patients with AD. We collected data from 1343 hospitalized patients with cirrhosis and AD from February to September 2011 at 29 liver units in 8 European countries. We used the organ failure and mortality data to define ACLF grades, assess mortality, and identify differences between ACLF and AD. We established diagnostic criteria for ACLF based on analyses of patients with organ failure (defined by the chronic liver failure-sequential organ failure assessment [CLIF-SOFA] score) and high 28-day mortality rate (>15%). Of the patients assessed, 303 had ACLF when the study began, 112 developed ACLF, and 928 did not have ACLF. The 28-day mortality rate among patients who had ACLF when the study began was 33.9%, among those who developed ACLF was 29.7%, and among those who did not have ACLF was 1.9%. Patients with ACLF were younger and more frequently alcoholic, had more associated bacterial infections, and had higher numbers of leukocytes and higher plasma levels of C-reactive protein than patients without ACLF (P < .001). Higher CLIF-SOFA scores and leukocyte counts were independent predictors of mortality in patients with ACLF. In patients without a prior history of AD, ACLF was unexpectedly characterized by higher numbers of organ failures, leukocyte count, and mortality compared with ACLF in patients with a prior history of AD. We analyzed data from patients with cirrhosis and AD to establish diagnostic criteria for ACLF and showed that it is distinct from AD, based not only on the presence of organ failure(s) and high mortality rate but also on age, precipitating events, and systemic inflammation. ACLF mortality is associated with loss of organ function and high leukocyte counts. ACLF is especially severe in patients with no prior history of AD.


Use of two MCF-7 cell variants to evaluate the growth regulatory potential of estrogen-induced products.
Two variants of the human estrogen-responsive breast cancer cell line MCF-7, were utilized to study the expression of an estrogen-induced gene, pS2, and an estrogen-induced Mr 52,000 protein. One variant cell line, I13, is growth inhibited after chronic exposure to estrogen. Both the pS2 gene product and the Mr 52,000 protein were produced at maximal levels at a time when I13 growth was inhibited by estrogen. The variant cell line, LY2, selected for its resistance to the growth-inhibitory effects of the antiestrogen, LY117018, grew normally in the presence of this drug, although both pS2 expression and Mr 52,000 protein production were inhibited. These results confirm that the pS2 gene and Mr 52,000 protein are estrogen-regulated elements, but the lack of correlation between their activities and variant cell growth suggests that they are not major autocrine growth-stimulatory agents.


Prenatal Exposure to BPA and Offspring Outcomes: The Diabesogenic Behavior of BPA.
Obesity and type 2 diabetes mellitus (T2DM) are the most common metabolic disorders, with prevalence rates that are reaching epidemic proportions. Both are complex conditions affecting virtually all ages and with serious health consequences. The underlying cause of the problem is still puzzling, but both genetic and environmental factors including unhealthy diet, sedentary lifestyle, or the exposure to some environmental endocrine disrupting chemicals (EDCs) are thought to have a causal influence. In addition, the impact of early environment has recently emerged as an important factor responsible for the increased propensity to develop adult-onset metabolic disease. Suboptimal maternal nutrition during critical windows in fetal development is the most commonly studied factor affecting early programming of obesity and T2DM. In recent years, increasing experimental evidence shows that exposure to EDCs could also account for this phenomenon. In the present review, we will overview the most relevant findings that confirm the critical role of bisphenol-A, one of the most widespread EDCs, in the development of metabolic disorders.


Applying professional values: the perspective of nurses of Isfahan hospitals.
Applying professional values is an important issue in nursing practice. It is also crucial to find out nurses' perspectives toward ethical and professional values in the clinical environment. For this purpose, we aimed to utilize a standard tool to survey perspectives on applying these values in nursing care in hospitals of Isfahan, Iran. This is a descriptive-analytical study in which 150 nurses working in hospitals of Isfahan, Iran in 2010 were recruited by quota convenience sampling, and their perspectives on professional values were assessed. Data were collected by the Nurses Professional Values Scale (NPVS) and analyzed using SPSS Software version 16 applying descriptive and interpretive statistics. In the present study, 84% of the participants were female and 88% had bachelor's degree in nursing. The average age was 34.2 (SD=7.3), and the average years of working in a hospital were 11 (SD=7.3). No significant association was present between demographic characteristics such as age, sex, educational level or work records and applying professional and ethical values. Results also demonstrated that respect for professional values is similar among nurses of different employment types. In this study, we addressed the most and the less important professional values specified by nurses with different types of employment and also different experiences. Iranian nurses believe in respecting the legal and ethical rights of patients as the most prominent value in the nursing profession. We suggest that these professional values be specified and assessed based on Iranian culture.


A single-repeat MYB transcription factor, GmMYB176, regulates CHS8 gene expression and affects isoflavonoid biosynthesis in soybean.
Here we demonstrate that GmMYB176 regulates CHS8 expression and affects isoflavonoid synthesis in soybean. We previously established that CHS8 expression determines the isoflavonoid level in soybean seeds by comparing the transcript profiles of cultivars with different isoflavonoid contents. In the present study, a functional genomic approach was used to identify the factor that regulates CHS8 expression and isoflavonoid synthesis. Candidate genes were cloned, and co-transfection assays were performed in Arabidopsis leaf protoplasts. The results showed that GmMYB176 can trans-activate the CHS8 promoter with maximum activity. Transient expression of GmMYB176 in soybean embryo protoplasts increased endogenous CHS8 transcript levels up to 169-fold after 48 h. GmMYB176 encodes an R1 MYB protein, and is expressed in soybean seed during maturation. Furthermore, GmMYB176 recognizes a 23 bp motif containing a TAGT(T/A)(A/T) sequence within the CHS8 promoter. A subcellular localization study confirmed nuclear localization of GmMYB176. A predicted pST binding site for 14-3-3 protein is required for subcellular localization of GmMYB176. RNAi silencing of GmMYB176 in hairy roots resulted in reduced levels of isoflavonoids, showing that GmMYB176 is necessary for isoflavonoid biosynthesis. However, over-expression of GmMYB176 was not sufficient to increase CHS8 transcript and isoflavonoid levels in hairy roots. We conclude that an R1 MYB transcription factor, GmMYB176, regulates CHS8 expression and isoflavonoid synthesis in soybean.


Empathy for pain and touch in the human somatosensory cortex.
Although feeling pain and touch has long been considered inherently private, recent neuroimaging and neurophysiological studies hint at the social implications of this experience. Here we used somatosensory-evoked potentials (SEPs) to investigate whether mere observation of painful and tactile stimuli delivered to a model would modulate neural activity in the somatic system of an onlooker. Viewing video clips showing pain and tactile stimuli delivered to others, respectively, increased and decreased the amplitude of the P45 SEP component that reflects the activity of the primary somatosensory cortex (S1). These modulations correlated with the intensity but not with the unpleasantness of the pain and touch ascribed to the model or the aversion induced in the onlooker by the video clips. Thus, modulation of S1 activity contingent upon observation of others' pain and touch may reflect the mapping of sensory qualities of observed painful and tactile stimuli. Results indicate that the S1 is not only involved in the actual perception of pain and touch but also plays an important role in extracting somatic features from social interactions.


Differences in the methyl ester distribution of homogalacturonans from near-isogenic wheat lines resistant and susceptible to the wheat stem rust fungus.
Plants possess an efficient nonself surveillance system triggering induced disease resistance mechanisms upon molecular recognition of microbial invaders. Successful pathogens have evolved strategies to evade or counteract these mechanisms, e.g., by the generation of suppressors. Pectic fragments produced during host cell wall degradation can act as endogenous suppressors of the hypersensitive response in wheat leaves. We have isolated and characterized homogalacturonans from cell walls of two wheat cultivars susceptible to the stem rust fungus, Puccinia graminis f. sp. tritici, namely cvs. Prelude and Marquis, and from near-isogenic lines of both cultivars containing the Sr5-gene for hypersensitive rust resistance. Two independent approaches were used to compare their methyl esterification: i) immunochemistry using the monoclonal antibodies JIM5, JIM7, PAM1, and LM7 and ii) chromatography of oligogalacturonides representing stretches of contiguous nonmethyl-esterified GalA residues. The results clearly indicate a significant difference in the homogalacturonans from susceptible and resistant wheat lines. The difference can best be explained by assuming a nonrandom and more blockwise distribution of the methyl esters in the homogalacturonans of susceptible wheat cultivars as compared with a presumably more random distribution in the near-isogenic resistant lines. Possible consequences of this difference for the enzymatic generation of endogenous suppressors are discussed.


Invasive Cancer Incidence, 2004-2013, and Deaths, 2006-2015, in Nonmetropolitan and Metropolitan Counties - United States.
Previous reports have shown that persons living in nonmetropolitan (rural or urban) areas in the United States have higher death rates from all cancers combined than persons living in metropolitan areas. Disparities might vary by cancer type and between occurrence and death from the disease. This report provides a comprehensive assessment of cancer incidence and deaths by cancer type in nonmetropolitan and metropolitan counties. 2004-2015. Cancer incidence data from CDC's National Program of Cancer Registries and the National Cancer Institute's Surveillance, Epidemiology, and End Results program were used to calculate average annual age-adjusted incidence rates for 2009-2013 and trends in annual age-adjusted incidence rates for 2004-2013. Cancer mortality data from the National Vital Statistics System were used to calculate average annual age-adjusted death rates for 2011-2015 and trends in annual age-adjusted death rates for 2006-2015. For 5-year average annual rates, counties were classified into four categories (nonmetropolitan rural, nonmetropolitan urban, metropolitan with population <1 million, and metropolitan with population ≥1 million). For the trend analysis, which used annual rates, these categories were combined into two categories (nonmetropolitan and metropolitan). Rates by county classification were examined by sex, age, race/ethnicity, U.S. census region, and cancer site. Trends in rates were examined by county classification and cancer site. During the most recent 5-year period for which data were available, nonmetropolitan rural areas had lower average annual age-adjusted cancer incidence rates for all anatomic cancer sites combined but higher death rates than metropolitan areas. During 2006-2015, the annual age-adjusted death rates for all cancer sites combined decreased at a slower pace in nonmetropolitan areas (-1.0% per year) than in metropolitan areas (-1.6% per year), increasing the differences in these rates. In contrast, annual age-adjusted incidence rates for all cancer sites combined decreased approximately 1% per year during 2004-2013 both in nonmetropolitan and metropolitan counties. This report provides the first comprehensive description of cancer incidence and mortality in nonmetropolitan and metropolitan counties in the United States. Nonmetropolitan rural counties had higher incidence of and deaths from several cancers related to tobacco use and cancers that can be prevented by screening. Differences between nonmetropolitan and metropolitan counties in cancer incidence might reflect differences in risk factors such as cigarette smoking, obesity, and physical inactivity, whereas differences in cancer death rates might reflect disparities in access to health care and timely diagnosis and treatment. Many cancer cases and deaths could be prevented, and public health programs can use evidence-based strategies from the U.S. Preventive Services Task Force and Advisory Committee for Immunization Practices (ACIP) to support cancer prevention and control. The U.S. Preventive Services Task Force recommends population-based screening for colorectal, female breast, and cervical cancers among adults at average risk for these cancers and for lung cancer among adults at high risk; screening adults for tobacco use and excessive alcohol use, offering counseling and interventions as needed; and using low-dose aspirin to prevent colorectal cancer among adults considered to be at high risk for cardiovascular disease based on specific criteria. ACIP recommends vaccination against cancer-related infectious diseases including human papillomavirus and hepatitis B virus. The Guide to Community Preventive Services describes program and policy interventions proven to increase cancer screening and vaccination rates and to prevent tobacco use, excessive alcohol use, obesity, and physical inactivity.


Subjective and objective assessment of sleep in adolescents with mild traumatic brain injury.
There is increased recognition that sleep problems may develop in children and adolescents after mild traumatic brain injury (mTBI). However, few studies have utilized both subjective and objective measures to comprehensively assess sleep problems in the pediatric population following the acute post-TBI period. The aims of this study were to compare sleep in adolescents with mTBI to healthy adolescents using subjective and objective measures, and to identify the clinical correlates associated with sleep problems. One hundred adolescents (50 adolescents with mTBI recruited from three to twelve months post-injury and 50 healthy adolescents) completed questionnaires assessing sleep quality, depression, and pain symptoms, and underwent 10 day actigraphic assessment of sleep patterns. Adolescents with mTBI reported poorer sleep quality and demonstrated significantly shorter actigraphic-measured sleep duration, poorer sleep efficiency, and more wake time after onset of sleep, compared with healthy adolescents (all, p<0.05). For both groups of adolescents, poorer self-reported sleep quality was predicted by greater depressive symptoms. Poorer actigraphic sleep efficiency was predicted by membership in the mTBI group after controlling for age, sex, depressive symptoms, and presence of pain. Our findings suggest that adolescents may experience subjective and objective sleep disturbances up to one year following mTBI. These findings require further replication in larger samples. Additionally, research is needed to identify possible mechanisms for poor sleep in youth with mTBI.


Lower-extremity amputation in diabetes. The independent effects of peripheral vascular disease, sensory neuropathy, and foot ulcers.
To identify risk factors for lower-extremity amputation (LEA) in individuals with diabetes and to estimate the incidence of LEA. This is a prospective study of 776 U.S. veterans in a general medicine clinic in Seattle, Washington. The outcome was first LEA during follow-up. Potential risk factors evaluated in proportional hazards models included, among others, peripheral vascular disease (PVD), sensory neuropathy, former LEA, foot deformities and ulcers, diabetes duration and treatment, and hyperglycemia. Associated with an increased risk for LEA were PVD defined as transcutaneous oxygen < or = 50 mmHg (relative risk [RR] = 3.0, 95% CI 1.3-7.1), insensitivity to monofilament testing (RR = 2.9, odds ratio = 1.1-7.8), lower-extremity ulcers (RR = 2.5, CI 1.1-5.4), former LEA, and treatment with insulin when controlling for duration of diabetes and other factors in the model. PVD defined as absent or diminished lower-extremity pulses or an ankle arm index < or = 0.8 was also associated with a significantly higher risk of LEA in separate models. Foot ulcers were associated with an increased ipsilateral risk of amputation. The age-adjusted incidence among men only for LEA standardized to the 1991 U.S. male diabetic population was 11.3/1,000 patient-years. This prospective study shows that peripheral sensory neuropathy, PVD, foot ulcers (particularly if they appear on the same side as the eventual LEA), former amputation, and treatment with insulin are independent risk factors for LEA in patients with diabetes.


A photoswitchable neurotransmitter analogue bound to its receptor.
Incorporation of the azobenzene derivative gluazo, a synthetic photochromic ligand, into a kainate receptor allows for the optical control of neuronal activity. The crystal structure of gluazo bound to a dimeric GluK2 ligand-binding domain reveals one monomer in a closed conformation, occupied by gluazo, and the other in an open conformation, with a bound buffer molecule. The glutamate group of gluazo interacts like the natural glutamate ligand, while its trans-azobenzene moiety protrudes into a tunnel. This elongated cavity presumably cannot accommodate a cis-azobenzene, which explains the reversible activation of the receptor upon photoisomerization.


Evaluation of curricula content based on Thai pharmacy competency standards.
To evaluate the curricula content of Thai pharmacy schools based on the Thai pharmacy competency standards. Course syllabi were collected from 11 pharmacy schools. A questionnaire was developed based on the Thai pharmacy competency standards. Course coordinators completed the questionnaire assessing the curricula content. The curricula for both the bachelor of science in pharmacy degree (BS Pharm) and doctor of pharmacy (PharmD) degree programs included the minimum content required by the 8 competency domains. The dominant content area in BS Pharm degree programs was product-oriented material. The content ratio of patient to product to social and administrative pharmacy in the BS Pharm degree programs was 2:3:1, respectively. However, the content ratio suggested by the Thai Pharmacy Council was 3:2:1, respectively. For the PharmD programs, the largest content area was patient-oriented material, which was in agreement with the framework suggested by the Thai Pharmacy Council. The curricula of all Thai pharmacy schools met the competency standards; however, some patient-oriented material should be expanded and some product-oriented content deleted in order to meet the recommended content ratio.


The effect of the daily intake of inulin on fasting lipid, insulin and glucose concentrations in middle-aged men and women.
The present study was carried out to examine the effect of the daily intake of 10 g inulin on fasting blood lipid, glucose and insulin levels in healthy middle-aged men and women with moderately raised total plasma cholesterol (TC) and triacylglycerol (TAG) levels. This study was a double-blind randomized placebo-controlled parallel study in which fifty-four middle-aged subjects received either inulin or placebo for a period of 8 weeks. Fasting blood samples were collected before the supplementation period (baseline samples 1 and 2, separated by 1 week) and at weeks 4 and 8, with a follow-up at week 12. Compared with baseline values, insulin concentrations were significantly lower at 4 weeks (P < 0.01) in the inulin group. There was a trend for TAG values, compared with baseline, to be lower in the inulin group at 8 weeks (P < 0.08) returning to baseline concentrations at week 12. On comparison of the inulin and placebo groups, the fasting TAG responses over the 8-week test period were shown to be significantly different (P < 0.05, repeated measures ANOVA), which was largely due to lower plasma TAG levels in the inulin group at week 8. The percentage change in TAG levels in the inulin group during the 8-week study was shown to correlate with the initial TAG level of the subjects (rs -0.499, P = 0.004). We therefore conclude that the daily addition of 10 g inulin to the diet significantly reduced fasting insulin concentrations during the 8-week test period and resulted in lower plasma TAG levels, particularly in subjects in whom fasting TAG levels were greater than 1.5 mmol/l. These data support findings from animal studies that fructans influence the formation and/or degradation of TAG-rich lipoprotein particles, and the insulin data are also consistent with recent studies showing attenuation of insulin levels in fructan-treated rats.


Aberrant expression of Wnt/β-catenin signaling pathway genes in aggressive malignant gastric gastrointestinal stromal tumors.
Recent reports on gene expression profiling (GEP) show several genes associated with malignant progression of GIST. However, genes associated with malignant transformation have not been clarified. Here, we aimed to reveal distinct genes in aggressive malignant GIST, using comprehensive gene expression analysis. We investigated GEP obtained by microarrays for 43 gastric GISTs, which mostly harbored KIT and PDGFRA mutations and integrated clinicopathological risk information. RT-PCR and immunohistochemistry were performed for FZD7, a receptor of Wnt ligands. GEP divided 43 gastric GISTs into two clusters. A cluster included seven of eight high-risk GISTs (88%) in modified NIH classification and was defined as high-risk cluster; the other cluster was defined as low-risk cluster. The number of probes with over 3-fold changes between the two clusters was 1,177, in which probes corresponding to 16 oncogenes were included. Genes involved in the Wnt signaling pathway were the most abundant among the 16 oncogenes. Focusing on 73 Wnt signaling pathway genes of the 21,578 probes, 12 upregulated and 5 downregulated genes were found in the high-risk cluster. Major cascade genes promoting the Wnt/β-catenin signaling pathway, including WNT11, FZD family, and DVL2, were upregulated in the high-risk cluster. SNAI1, SNAI2, and BIRC5, which are activated by this pathway and increase cell proliferation, were also upregulated. These gene expression alterations were consistent in the positive direction of this pathway. GISTs in high-risk cluster strongly expressed FZD7. Wnt/β-catenin signaling pathway may play an important role in malignant transformation of indolent GIST.


Polymorphic variants in tenascin-C (TNC) are associated with atherosclerosis and coronary artery disease.
Tenascin-C (TNC) is an extracellular matrix protein implicated in biological processes important for atherosclerotic plaque development and progression, including smooth muscle cell migration and proliferation. Previously, we observed differential expression of TNC in atherosclerotic aortas compared with healthy aortas. The goal of this study was to investigate whether common genetic variation within TNC is associated with risk of atherosclerosis and coronary artery disease (CAD) in three independent datasets. We genotyped 35 single nucleotide polymorphisms (SNPs), including 21 haplotype tagging SNPs, in two of these datasets: human aorta tissue samples (n = 205) and the CATHGEN cardiovascular study (n = 1,325). Eleven of these 35 SNPs were then genotyped in a third dataset, the GENECARD family study of early-onset CAD (n = 879 families). Three SNPs representing a block of linkage disequilibrium, rs3789875, rs12347433, and rs4552883, were significantly associated with atherosclerosis in multiple datasets and demonstrated consistent, but suggestive, genetic effects in all analyses. In combined analysis rs3789875 and rs12347433 were statistically significant after Bonferroni correction for 35 comparisons, p = 2 × 10(-6) and 5 × 10(-6), respectively. The SNP rs12347433 is a synonymous coding SNP and may be biologically relevant to the mechanism by which tenascin-C influences the pathophysiology of CAD and atherosclerosis. This is the first report of genetic association between polymorphisms in TNC and atherosclerosis or CAD.


Increased tissue oxygen extraction and acidosis with progressive severity of sepsis.
Lactic acidosis and increased production of CO(2) are common in septic shock. Presumably, both acidosis and CO(2) enhance the release of oxygen from hemoglobin. The purpose of this study was to assess the relationship of oxygen utilization, CO(2) production, acidosis, and hemoglobin oxygen (Hgb-O(2)) dissociation with progressive severity of sepsis to shock. Femoral arterial and vein, hepatic vein, portal vein, and pulmonary artery catheters were placed in 16 anesthetized swine. Organ blood flow was determined by timed injections of colored microspheres. After baseline measurements, Pseudomonas aeruginosa was infused in eight animals. This bacterial slurry was continued inciting a progression of sepsis to shock. Eight animals served as instrumented controls. With sepsis and shock, there was a progressive decrease in pH and an increase in pCO(2) in plasma with all sampling sites (P < 0.01 septic shock versus baseline versus control). Blood flow to the liver and intestines increased with sepsis (P < 0.01) but then returned to near baseline control values during shock. VO(2) and/or percent O(2) extraction increased with sepsis and septic shock for the whole body and for the liver, intestine and leg (P < 0.01). There was a strong correlation between venous O(2) saturation, acidosis, and pCO(2) to percent O(2) extraction (r > 60; P < 0.0001). However, calculated P(50) values for Hgb-O(2) dissociation remained unchanged. This study demonstrates that increased oxygen extraction in severe sepsis is related to a fall in tissue oxygen availability and not related to any allosteric change in Hgb-O(2) dissociation. Therefore, acidosis and hypercapnia do not have a demonstrable effect on altering oxygen availability during sepsis.


The Skin Microbiome of the Neotropical Frog Craugastor fitzingeri: Inferring Potential Bacterial-Host-Pathogen Interactions From Metagenomic Data.
Skin symbiotic bacteria on amphibians can play a role in protecting their host against pathogens. Chytridiomycosis, the disease caused by Batrachochytrium dendrobatidis, Bd, has caused dramatic population declines and extinctions of amphibians worldwide. Anti-Bd bacteria from amphibian skin have been cultured, and skin bacterial communities have been described through 16S rRNA gene amplicon sequencing. Here, we present a shotgun metagenomic analysis of skin bacterial communities from a Neotropical frog, Craugastor fitzingeri. We sequenced the metagenome of six frogs from two different sites in Panamá: three frogs from Soberanía (Sob), a Bd-endemic site, and three frogs from Serranía del Sapo (Sapo), a Bd-naïve site. We described the taxonomic composition of skin microbiomes and found that Pseudomonas was a major component of these communities. We also identified that Sob communities were enriched in Actinobacteria while Sapo communities were enriched in Gammaproteobacteria. We described gene abundances within the main functional classes and found genes enriched either in Sapo or Sob. We then focused our study on five functional classes of genes: biosynthesis of secondary metabolites, metabolism of terpenoids and polyketides, membrane transport, cellular communication and antimicrobial drug resistance. These gene classes are potentially involved in bacterial communication, bacterial-host and bacterial-pathogen interactions among other functions. We found that C. fitzingeri metagenomes have a wide array of genes that code for secondary metabolites, including antibiotics and bacterial toxins, which may be involved in bacterial communication, but could also have a defensive role against pathogens. Several genes involved in bacterial communication and bacterial-host interactions, such as biofilm formation and bacterial secretion systems were found. We identified specific genes and pathways enriched at the different sites and determined that gene co-occurrence networks differed between sites. Our results suggest that skin microbiomes are composed of distinct bacterial taxa with a wide range of metabolic capabilities involved in bacterial defense and communication. Differences in taxonomic composition and pathway enrichments suggest that skin microbiomes from different sites have unique functional properties. This study strongly supports the need for shotgun metagenomic analyses to describe the functional capacities of skin microbiomes and to tease apart their role in host defense against pathogens.


Frequency-dependent amplification of stretch-evoked excitatory input in spinal motoneurons.
Voltage-dependent calcium and sodium channels mediating persistent inward currents (PICs) amplify the effects of synaptic inputs on the membrane potential and firing rate of motoneurons. CaPIC channels are thought to be relatively slow, whereas the NaPIC channels have fast kinetics. These different characteristics influence how synaptic inputs with different frequency content are amplified; the slow kinetics of Ca channels suggest that they can only contribute to amplification of low frequency inputs (<5 Hz). To characterize frequency-dependent amplification of excitatory postsynaptic potentials (EPSPs), we measured the averaged stretch-evoked EPSPs in cat medial gastrocnemius motoneurons in decerebrate cats at different subthreshold levels of membrane potential. EPSPs were produced by muscle spindle afferents activated by stretching the homonymous and synergist muscles at frequencies of 5-50 Hz. We adjusted the stretch amplitudes at different frequencies to produce approximately the same peak-to-peak EPSP amplitude and quantified the amount of amplification by expressing the EPSP integral at different levels of depolarization as a percentage of that measured with the membrane hyperpolarized. Amplification was observed at all stretch frequencies but generally decreased with increasing stretch frequency. However, in many cells the amount of amplification was greater at 10 Hz than at 5 Hz. Fast amplification was generally reduced or absent when the lidocaine derivative QX-314 was included in the electrode solution, supporting a strong contribution from Na channels. These results suggest that NaPICs can combine with CaPICs to enhance motoneuron responses to modulations of synaptic drive over a physiologically significant range of frequencies.


Factors associated with depression in patients with type 2 diabetes in the Gaza Strip: a cross sectional study.
About 9% of the world's population has diabetes. Most people with diabetes live in developing countries. Diabetes is the fourth leading cause of death in the occupied Palestinian territory. The likelihood of diabetes complications increases with depression. Worldwide, about half of patients with diabetes have severe depression that has been misidentified by health providers. The aim of this study was to examine factors associated with depression in patients with type 2 diabetes in the Gaza governorate. This cross-sectional study included patients attending three primary health centres in 2016. A convenient purposive approach to sampling was used to select three centres from the 15 centres in the Gaza governorate, covering the east (border), middle, and west areas. Since 2014, all patients with type 2 diabetes have been screened for depression using the Patient Health Questionnaire 9. Data on demographic, socioeconomic, and health status and on patients' beliefs were collected during interviews with structured questionnaires, and medical data were collected from patient records. χ2 tests and logistic regression were used to test associations between dependent and independent variables. 380 patients were included in the study. 255 participants were women with type 2 diabetes and older than 40 years. The median age of participants was 59 years (IQR 13). 285 (75%) participants were married, and 221 (58%) had not completed high school. 103 (27%) participants screened positive for depression. Factors positively associated with depression were age (people younger than 50 years were at greater risk than people aged 50 years and older [odds ratio 2·25, 95% CI 1·2-4·2]), being single (2·04, 1·68-3·55), not believing that they can manage the disease (2·9, 1·6-5·6), and living in border areas (3·6, 2·0-6·2). More attention should be given to young, single patients and to those living in border areas. Treatment options and care for patients with depression should be strengthened with counselling and medications. Palestinian National Institute of Public Health.


Autonomic and muscular responses and recovery to one-hour laboratory mental stress in healthy subjects.
Stress is a risk factor for musculoskeletal pain. We wanted to explore stress related physiology in healthy subjects in order to gain insight into mechanisms of pain development which may relate to the pathophysiology of musculoskeletal pain disorders. Continuous blood pressure, heart rate, finger skin blood flow, respiration, surface electromyography together with perception of pain, fatigue and tension were recorded on 35 healthy women and 9 healthy men before, during a 60 minute period with task-related low-grade mental stress, and in the following 30 minute rest period. Subjects responded physiologically to the stressful task with an increase in trapezius and frontalis muscle activity, increased blood pressure, respiration frequency and heart rate together with reduced finger skin blood flow. The blood pressure response and the finger skin blood flow response did not recover to baseline values during the 30-minute rest period, whereas respiration frequency, heart rate, and surface electromyography of the trapezius and frontalis muscles recovered to baseline within 10 minutes after the stressful task. Sixty-eight percent responded subjectively with pain development and 64% reported at least 30% increase in pain. Reduced recovery of the blood pressure was weakly correlated to fatigue development during stress, but was not correlated to pain or tension. Based on a lack of recovery of the blood pressure and the acral finger skin blood flow response to mental stress we conclude that these responses are more protracted than other physiological stress responses.


Reexamination of depolarization in lidar measurements.
Almost all of the depolarization papers in the lidar literature employ a physically inappropriate notation and they use a definition of the depolarization ratio that is not linear in the quantity of interest. This depolarization lidar legacy is misleading and confusing. In particular, subscripts meaning parallel and perpendicular do not apply to atmospheric parameters, such as the volume backscatter coefficient, because (for linear polarization) the two components of the backscattered light are polarized in the transmitted sense and completely unpolarized; the unpolarized component is not "perpendicular." An analysis of lidar depolarization measurements with a particle scattering matrix recently provided in the literature yields algorithms for retrieving the depolarization parameter from either linear or circular depolarization lidar measurements. The analysis, notation, and definitions recommended here harmonize lidar depolarization analysis with radiative transfer theory, particle scattering theory, and standard polarization measurement techniques.


Fertility, kinship and the evolution of mass ideologies.
Traditional human societies are organised around kinship, and use kinship networks to generate large scale community projects. This is made possible by a combination of linguistic kin recognition, a uniquely human trait, which is mediated by the reliability of kin as collaborators. When effective fertility falls, this results in two simultaneous effects on social networks: there are fewer kin that can be relied on, and the limiting effect of the local kin-clustering becomes stronger. To capture this phenomenon, we used a model of kinship lineages to build populations with a range of fertility levels combined with a behavioural synchrony model to measure the efficiency of collective action generated on kin networks within populations. Our findings suggest that, whenever effective cooperation depends on kinship, falling fertility creates a crisis when it results in too few kin to join the community project. We conclude that, when societies transition to small effective kin networks, due to falling fertility, increased relative distance to kin due to urbanisation or high mortality due to war or epidemics, they will be able to remain socially cohesive only if they replace disappearing kin networks with quasi-kin alternatives based on membership of guilds or clubs.


Smoking status and health-related quality of life: a longitudinal study in young adults.
The possibility that tobacco use affects health-related quality of life (HRQoL) has attracted interest. However, a lack of prospective evidence weakens the case for a causal relationship. The aim was to examine the longitudinal relationship between change in smoking status and change in HRQoL in young adults. We conducted a population-based cohort study with data collected in 2004-2006 (aged 26-36) and 2009-2011 (aged 31-41). Exposure was change in self-reported smoking status during follow-up. Outcomes were changes in physical and mental HRQoL measured by SF-12. For physical HRQoL (n = 2080), quitters had a 2.12 (95 % confidence interval (CI) 0.73, 3.51) point improvement than continuing smokers, whereas former smokers who resumed smoking had a 2.08 (95 % CI 0.21, 3.94) point reduction than those who maintained cessation. Resumed smokers were 39 % (95 % CI 10, 75 %) more likely to have a clinically significant (>5 point) reduction of physical HRQoL than former smokers who maintained cessation. In contrast, quitters were 43 % (95 % CI 3, 98 %) more likely to have a clinically significant (>5 point) improvement in physical HRQoL than continuing smokers. Change in smoking status was not significantly associated with change in mental HRQoL (n = 1788). Smoking by young adults was cross-sectionally associated with lower physical HRQoL and longitudinally associated with reductions in physical HRQoL. The expectation of short- to medium-term gains in physical HRQoL as well as long-term health benefits may help motivate young adult smokers to quit.


Swept-source based, single-shot, multi-detectable velocity range Doppler optical coherence tomography.
Phase-Resolved Doppler Optical Coherence Tomography (PR-DOCT) allows visualization and characterization of the location, direction, velocity, and profile of flow activity embedded in a static sample structure. The detectable Velocity Dynamic Range (VDR) of each particular PR-DOCT system is governed by a detectable Doppler phase shift, a flow angle, and an acquisition time interval used to determine the Doppler phase shift. In general, the lower boundary of the detectable Doppler phase shift is limited by the phase stability of the system, while the upper boundary is limited by the π phase ambiguity. For a given range of detectable Doppler phase shift, shortening the acquisition duration will increase not only the maximum detectable velocity but unfortunately also the minimum detectable velocity, which may lead to the invisibility of a slow flow. In this paper, we present an alternative acquisition scheme for PR-DOCT that extends the lower limit of the velocity dynamic range, while maintaining the maximum detectable velocity, hence increasing the overall VDR of PR-DOCT system. The essence of the approach is to implement a technique of multi-scale measurement to simultaneously acquire multiple VDRs in a single measurement. We demonstrate an example of implementation of the technique in a dual VDR DOCT, where two Doppler maps having different detectable VDRs were simultaneously detected, processed, and displayed in real time. One was a fixed VDR DOCT capable of measuring axial velocity of up to 10.9 mm/s without phase unwrapping. The other was a variable VDR DOCT capable of adjusting its detectable VDR to reveal slow flow information down to 11.3 μm/s. The technique is shown to effectively extend the overall detectable VDR of the PR-DOCT system. Examples of real time Doppler imaging of an African frog tadpole are demonstrated using the dual-VDR DOCT system.


FAM19A5 Expression During Embryogenesis and in the Adult Traumatic Brain of FAM19A5-LacZ Knock-in Mice.
FAM19A5 is a secretory protein that is predominantly expressed in the brain. Although the FAM19A5 gene has been found to be associated with neurological and/or psychiatric diseases, only limited information is available on its function in the brain. Using FAM19A5-LacZ knock-in mice, we determined the expression pattern of FAM19A5 in developing and adult brains and identified cell types that express FAM19A5 in naïve and traumatic brain injury (TBI)-induced brains. According to X-gal staining results, FAM19A5 is expressed in the ventricular zone and ganglionic eminence at a very early stage of brain development, suggesting its functions are related to the generation of neural stem cells and oligodendrocyte precursor cells (OPCs). In the later stages of developing embryos and in adult mice, FAM19A5 expression expanded broadly to particular regions of the brain, including layers 2/3 and 5 of the cortex, cornu amonis (CA) region of the hippocampus, and the corpus callosum. X-gal staining combined with immunostaining for a variety of cell-type markers revealed that FAM19A5 is expressed in many different cell types, including neurons, OPCs, astrocytes, and microglia; however, only some populations of these cell types produce FAM19A5. In a subpopulation of neuronal cells, TBI led to increased X-gal staining that extended to the nucleus, marked by slightly condensed content and increased heterochromatin formation along the nuclear border. Similarly, nuclear extension of X-gal staining occurred in a subpopulation of OPCs in the corpus callosum of the TBI-induced brain. Together, these results suggest that FAM19A5 plays a role in nervous system development from an early stage and increases its expression in response to pathological conditions in subsets of neurons and OPCs of the adult brain.


Role of synaptic dynamics and heterogeneity in neuronal learning of temporal code.
Temporal codes are believed to play important roles in neuronal representation of information. Neuronal ability to classify and learn temporal spiking patterns is thus essential for successful extraction and processing of information. Understanding neuronal learning of temporal code has been complicated, however, by the intrinsic stochasticity of synaptic transmission. Using a computational model of a learning neuron, the tempotron, we studied the effects of synaptic unreliability and short-term dynamics on the neuron's ability to learn spike timing rules. Our results suggest that such a model neuron can learn to classify spike timing patterns even with unreliable synapses, albeit with a significantly reduced success rate. We explored strategies to improve correct spike timing classification and found that firing clustered spike bursts significantly improves learning performance. Furthermore, rapid activity-dependent modulation of synaptic unreliability, implemented with realistic models of dynamic synapses, further improved classification of different burst properties and spike timing modalities. Neuronal models with only facilitating or only depressing inputs exhibited preference for specific types of spike timing rules, but a mixture of facilitating and depressing synapses permitted much improved learning of multiple rules. We tested applicability of these findings to real neurons by considering neuronal learning models with the naturally distributed input release probabilities found in excitatory hippocampal synapses. Our results suggest that spike bursts comprise several encoding modalities that can be learned effectively with stochastic dynamic synapses, and that distributed release probabilities significantly improve learning performance. Synaptic unreliability and dynamics may thus play important roles in the neuron's ability to learn spike timing rules during decoding.


High power, widely tunable, narrowband superfluorescent source at 2 μm based on a monolithic Tm-doped fiber amplifier.
We present a widely tunable narrowband superfluorescent source near 2 μm employing a monolithic Tm-doped fiber amplifier (TDFA), and the output power exceeds 250 W. A broadband superfluorescent source with a narrowband tunable band pass filter was used as the seed source. The spectra of the seed source can be tuned in a range of ~1930-2030 nm with full width at half maximum (FWHM) of ~1.7 nm. The Tm-doped fiber amplifier scales up the power of the seed source to a level of more than 250 W with a tuning range of ~35 nm (1966-2001 nm) and a FWHM of ~1.5-2.0 nm, and the slope efficiency is about 0.50. The output power is limited by the available pump power, and the tuning range is limited by the amplifier spontaneous emission at other wavelengths. Higher output power can be achieved if launching more pump power into the amplifier, and the tuning range can be further improved by optimizing the parameters of the TDFA. To the best of our knowledge, this is the first demonstration on a widely tunable narrowband superfluorescent source at 2 μm with average output power exceeding 250 W.


How the mid-Victorians worked, ate and died.
Analysis of the mid-Victorian period in the U.K. reveals that life expectancy at age 5 was as good or better than exists today, and the incidence of degenerative disease was 10% of ours. Their levels of physical activity and hence calorific intakes were approximately twice ours. They had relatively little access to alcohol and tobacco; and due to their correspondingly high intake of fruits, whole grains, oily fish and vegetables, they consumed levels of micro- and phytonutrients at approximately ten times the levels considered normal today. This paper relates the nutritional status of the mid-Victorians to their freedom from degenerative disease; and extrapolates recommendations for the cost-effective improvement of public health today.


Foodborne and Food-Handler Norovirus Outbreaks: A Systematic Review.
Norovirus (NoV) is the commonest cause of gastrointestinal disease in the United Kingdom and in many developed countries, causing diarrhea and vomiting in millions of cases worldwide annually. Transmission is most often mediated from person to person. NoV infection has, however, additionally been associated with the consumption of food, either through the consumption of food contaminated at source such as seafood, berries, and salad, or as a consequence of the foodstuff being contaminated in some way by a food handler during processing or serving. A systematic review of outbreaks attributed to NoV between January 2003 and July 2017 was conducted to assess the contribution of food handlers to the burden of NoV, and to identify foods commonly associated with NoV outbreaks. A total of 3021 articles were screened, of which 27 met the definition of confirmed foodborne outbreaks and 47 met the criteria for definite food-handler NoV outbreaks. Of all food types, shellfish were implicated in the greatest number of definite foodborne outbreaks. Food handlers contributed to definite food-handler outbreaks involving a diverse range of foodstuffs and in a wide variety of settings, including weddings and military establishments. More genotypes of NoV were found in people who were ill than in samples from food and food handlers. The potential for both food products and food handlers to contribute to the burden of NoV infection is demonstrated conclusively.


Hyperfine interactions in graphene and related carbon nanostructures.
Hyperfine interactions, magnetic interactions between the spins of electrons and nuclei, in graphene and related carbon nanostructures are studied. By using a combination of accurate first principles calculations on graphene fragments and statistical analysis, I show that both isotropic and dipolar hyperfine interactions in sp2 carbon nanostructures can be accurately described in terms of the local electron spin distribution and atomic structure. A complete set of parameters describing the hyperfine interactions of 13C and other nuclear spins at substitution impurities and edge terminations is determined. These results permit the design of graphene-based nanostructures allowing for longer electron spin coherence times which are required by spintronics and quantum information processing applications. Practical recipes for minimizing hyperfine interactions in carbon nanostructures are given.


Training laboratory technicians from the Ethiopian periphery in the MODS technique enables rapid and low-cost diagnosis of Mycobacterium tuberculosis infection.
Tuberculosis (TB) is a leading cause of morbidity and mortality and is frequently complicated by emergence of drug-resistant strains. Diagnosis of TB in developing countries is often based on the relatively insensitive acid-fast staining that does not enable susceptibility profiling. Microscopic observation drug susceptibility assay (MODS) is an inexpensive, simple method that enables rapid TB culture coupled with susceptibility testing. A 3-week MODS training of three Ethiopian laboratory technicians was conducted at Hadassah-Hebrew University Medical Center, Israel. Results of the trainee readings were blindly assessed by an experienced instructor. Two hundred fifty-five (255) trainee culture readings were evaluated throughout the course. The sensitivity and specificity were 75-100% and 31.5-100%, respectively. Multivariate analysis revealed that sensitivity and duration of incubation were positively correlated, although specificity was positively correlated with the length of training. MODS can be reliably performed by laboratory technicians inexperienced in culture techniques in developing countries, with high sensitivity and specificity reached after a brief learning period.


Unusual infrared absorption increases in photo-degraded organic films.
Degradation is among the most pressing problems facing organic materials, occurring through ingress of moisture and oxygen, and light exposure. We determine the nanoscale pathways underlying degradation by light-soaking organic films in an environmental chamber, and performing infrared spectroscopy, to identify atomic bonding changes. We utilize as a prototype the low band gap PTB7-PCBM blend. Films light-soaked in the presence of oxygen show unusual increased absorption at 1727 cm-1 attributable to increased C[double bond, length as m-dash]O modes, and a broad increase at 3240 cm-1 attributable to hydroxyl (O-H) groups bonded within the organic matrix. Films exposed to oxygen in the dark, or light-soaked in an inert atmosphere, do not exhibit significant absorption changes, suggesting simultaneous exposure of oxygen and light that creates singlet excited oxygen is the detrimental factor. Our ab initio electronic structure simulations interpret these by oxidation at the α-C site of the alkyl chains in PTB7, with an irreversible rupture of the alkyl chain and formation of new C[double bond, length as m-dash]O and C-O-H conformations at the α-C. Infrared spectroscopy coupled with ab initio simulation can provide a powerful tool for quantifying photo-structural atomic bonding changes. Understanding nanoscale light-induced structural changes will open avenues to designing more stable organic materials for organic electronics.


Distribution and Severity of Pasmo on Flax in North Dakota and Evaluation of Fungicides and Cultivars for Management.
Pasmo, caused by Septoria linicola, reduces flax (Linum usitatissimum) yield in the Canadian provinces of Manitoba and Saskatchewan, but little is known about its distribution and effect on yield in North Dakota. Field surveys for pasmo were conducted in 74 and 87 flax fields across 19 and 23 North Dakota counties in 2002 and 2003, respectively. The surveys indicated that pasmo was present in 17 and 18 counties in 2002 and 2003, respectively. County mean plant incidences ranged from 0 to 21% and 0 to 84.5% in 2002 and 2003, respectively. County mean pasmo severity ranged from 0 to 38.8% and 0 to 29.3% in 2002 and 2003, respectively. Significant (P ≤ 0.07) positive Pearson correlations were detected between total rainfall accumulated for June to August and pasmo severity in 2002 and 2003 and for rainfall and pasmo incidence in 2003. Field trials were conducted to determine the effect of fungicides and flax cultivars on pasmo severity and flax yield. Pasmo severity was significantly (P ≤ 0.05) reduced with azoxystrobin and sulfur fungicides compared with the untreated control. Flax yields were significantly (P ≤ 0.05) greater in azoxystrobin- and prothioconazole-treated plots than in the untreated control plots. Cv. Omega had significantly lower pasmo severity than the other three cultivars, but cv. Rahab 94 had the greatest yield of all the cultivars. Based on the results presented, pasmo is an important disease of flax in North Dakota, and its distribution is widespread throughout the flax-production region. Fungicides such as azoxystrobin and prothioconazole appear to be excellent potential tools for pasmo management.


Bright light therapy and/or imipramine for inpatients with recurrent non-seasonal depression.
The aim of a double-blind study was to assess the efficacy of bright light therapy and/or imipramine in the treatment of inpatients suffering with recurrent non-seasonal major depressive disorder. 34 in-patients with DSM-III-R diagnosis of major depressive disorder, recurrent type, were randomly allocated into 3 treatment groups. After 4-day washout period with baseline assessment they underwent 3 weeks of different types of treatment: a) Group A: bright light therapy (5000 lux from 6-8 a.m.) and imipramine 150 mg/day. b) Group B: bright light therapy (5000 lux from 6-8 a.m.) and imipramine-like placebo. c) Group C: dim red light (500 lux from 6-8 a.m.) and imipramine 150 mg/day. Outcome measures included weekly Hamilton Psychiatric Rating Scale for Depression, Clinical Global Impression Scale, Montgomery and Asberg Psychiatric Rating Scale for Depression and Beck Depression Inventory. Patients of all three groups improved significantly. The improvement of the patients of group B treated with bright light therapy plus placebo was superior to the other two groups, but not significantly. Bright light therapy can be effective in the treatment of non-seasonal major depressive disorder.


Two arterial effective reflecting sites may appear as one to the heart.
The relation between reflected waves and features of ascending aortic pressure waveforms and impedance patterns was investigated with a modified T-tube model of the systemic arterial circulation. Ascending aortic pressure and flow and descending aortic flow were measured in 10 dogs under basal conditions and under the effect of an agent (methoxamine) that caused vasoconstriction and an increase of mean aortic pressure. A broad range of aortic pressure amplitudes and features was obtained. These waveshapes were classified into four groups. Under basal conditions, cases for which a prominent diastolic fluctuation was present (n = 8) were grouped in A. Cases for which this fluctuation was absent (n = 2) were grouped in B. Groups C (n = 4) and D (n = 3) included cases that, under vasoconstricted conditions, did or did not display, respectively, a diastolic fluctuation in pressure. Arterial T-tube model parameters were estimated by simultaneously fitting the model to both ascending and descending aortic flow with aortic pressure as input. A good fit was obtained in any case considered. After parameter estimation, forward and reflected waves and impedance patterns at the entrance of head circulation (head and upper limbs) and body circulation (trunk and lower limbs) as well as their merger in the ascending aorta were determined. T-tube input impedance compared well with impedance data points obtained from the ratio of corresponding harmonics of ascending aortic pressure and flow. In some cases (group A), modulus and phase spectra displayed two distinct minima, in the range from 0 to 10 Hz. In some other circumstances, these minima were less distinct (groups B and C) and could even appear as one (group D). Whether one or two minima appeared in the ascending aortic impedance spectra at low frequency and whether a prominent diastolic fluctuation did or did not appear in aortic pressure, pressure and flow waveshapes proximal to the heart were explained by the presence of two effective reflecting sites in the systemic circulation. In group B, a diastolic fluctuation in pressure was absent despite the fact that head-end and body-end reflected waves were distinct. This happened because body-end reflected waves peaked corresponding to a minimum of the head-end reflected wave. In group D, a diastolic fluctuation in aortic pressure was absent because the body-end reflected wave moved into systole and superimposed on the head-end reflected wave. This superimposition was due to increased pulse wave velocity in the body transmission path as a result of decreased arterial distensibility.(ABSTRACT TRUNCATED AT 400 WORDS)


PIK3R1 (p85α) is somatically mutated at high frequency in primary endometrial cancer.
Phosphoinositide 3-kinase (PI3K) is an important therapeutic target. Mutations in PIK3CA, which encodes p110α, the catalytic subunit of PI3K, occur in endometrioid endometrial cancers (EEC) and nonendometrioid endometrial cancers (NEEC). The goal of this study was to determine whether PIK3R1, which encodes p85α, the inhibitory subunit of PI3K, is mutated in endometrial carcinoma. We carried out exonic sequencing of PIK3R1 from 42 EECs and 66 NEECs. The pattern of PIK3R1 mutations was compared with the patterns of PIK3CA, PTEN, and KRAS mutations. The biochemical effect of seven PIK3R1 mutations was examined by stable expression in U2OS cells, followed by coimmunoprecipitation analysis of p110α, and Western blotting of phospho-AKT(Ser473) (p-AKT(Ser473)). We found that PIK3R1 was somatically mutated in 43% of EECs and 12% of NEECs. The majority of mutations (93.3%) were localized to the p85α-nSH2 and -iSH2 domains. Several mutations were recurrent. PIK3R1 mutations were significantly (P = 0.0015) more frequent in PIK3CA-wild type EECs (70%) than in PIK3CA mutant EECs (18%). Introduction of wild-type p85α into U2OS cells reduced the level of p-AKT(Ser473) compared with the vector control. Five p85α mutants, p85αdelH450-E451, p85αdelK459, p85αdelY463-L466, p85αdelR574-T576, and the p85αN564D positive control, were shown to bind p110α and led to increased levels of p-AKT(Ser473). The p85αR348X and p85αK511VfsX2 mutants did not bind p110α and showed no appreciable change in p-AKT(Ser473) levels. In conclusion, our study has revealed a new mode of PI3K alteration in primary endometrial tumors and warrants future studies to determine whether PIK3R1 mutations correlate with clinical outcome to targeted therapies directed against the PI3K pathway in EEC and NEEC.


Administration route-dependent vaccine efficiency of murine dendritic cells pulsed with antigens.
Dendritic cells (DCs) loaded with tumour antigens have been successfully used to induce protective tumour immunity in murine models and human trials. However, it is still unclear which DC administration route elicits a superior therapeutic effect. Herein, we investigated the vaccine efficiency of DC2.4 cells, a murine dendritic cell line, pulsed with ovalbumin (OVA) in the murine E.G7-OVA tumour model after immunization via various routes. After a single vaccination using 1 x 10(6)OVA-pulsed DC2.4 cells, tumour was completely rejected in the intradermally (i.d.; three of four mice), subcutaneously (s.c.; three of four mice), and intraperitoneally (i.p.; one of four mice) immunized groups. Double vaccinations enhanced the anti-tumour effect in all groups except the intravenous (i.v.) group, which failed to achieve complete rejection. The anti-tumour efficacy of each immunization route was correlated with the OVA-specific cytotoxic T lymphocyte (CTL) activity evaluated on day 7 post-vaccination. Furthermore, the accumulation of DC2.4 cells in the regional lymph nodes was detected only in the i.d.-and s.c.-injected groups. These results demonstrate that the administration route of antigen-loaded DCs affects the migration of DCs to lymphoid tissues and the magnitude of antigen-specific CTL response. Furthermore, the immunization route affects vaccine efficiency.


Endogenous Gibbon Ape Leukemia Virus Identified in a Rodent (Melomys burtoni subsp.) from Wallacea (Indonesia).
Gibbon ape leukemia virus (GALV) and koala retrovirus (KoRV) most likely originated from a cross-species transmission of an ancestral retrovirus into koalas and gibbons via one or more intermediate as-yet-unknown hosts. A virus highly similar to GALV has been identified in an Australian native rodent (Melomys burtoni) after extensive screening of Australian wildlife. GALV-like viruses have also been discovered in several Southeast Asian species, although screening has not been extensive and viruses discovered to date are only distantly related to GALV. We therefore screened 26 Southeast Asian rodent species for KoRV- and GALV-like sequences, using hybridization capture and high-throughput sequencing, in the attempt to identify potential GALV and KoRV hosts. Only the individuals belonging to a newly discovered subspecies of Melomys burtoni from Indonesia were positive, yielding an endogenous provirus very closely related to a strain of GALV. The sequence of the critical receptor domain for GALV infection in the Indonesian M. burtoni subsp. was consistent with the susceptibility of the species to GALV infection. The second record of a GALV in M. burtoni provides further evidence that M. burtoni, and potentially other lineages within the widespread subfamily Murinae, may play a role in the spread of GALV-like viruses. The discovery of a GALV in the most western part of the Australo-Papuan distribution of M. burtoni, specifically in a transitional zone between Asia and Australia (Wallacea), may be relevant to the cross-species transmission to gibbons in Southeast Asia and broadens the known distribution of GALVs in wild rodents. Gibbon ape leukemia virus (GALV) and the koala retrovirus (KoRV) are very closely related, yet their hosts neither are closely related nor overlap geographically. Direct cross-species infection between koalas and gibbons is unlikely. Therefore, GALV and KoRV may have arisen via a cross-species transfer from an intermediate host whose range overlaps those of both gibbons and koalas. Using hybridization capture and high-throughput sequencing, we have screened a wide range of rodent candidate hosts from Southeast Asia for KoRV- and GALV-like sequences. Only a Melomys burtoni subspecies from Wallacea (Indonesia) was positive for GALV. We report the genome sequence of this newly identified GALV, the critical domain for infection of its potential cellular receptor, and its phylogenetic relationships with the other previously characterized GALVs. We hypothesize that Melomys burtoni, and potentially related lineages with an Australo-Papuan distribution, may have played a key role in cross-species transmission to other taxa.


Gene specificity of suppression of transgene-mediated insertional transcriptional activation by the chicken HS4 insulator.
Insertional mutagenesis has emerged as a major obstacle for gene therapy based on vectors that integrate randomly in the genome. Reducing the genotoxicity of genomic viral integration can, in first approximation, be equated with reducing the risk of oncogene activation, at least in the case of therapeutic payloads that have no known oncogenic potential, such as the globin genes. An attractive solution to the problem of oncogene activation is the inclusion of insulators/enhancer-blockers in the viral vectors. In this study we have used Recombinase-Mediated Cassette Exchange to characterize the effect of integration of globin therapeutic cassettes in the presence or absence of the chicken HS4 and three other putative insulators inserted near Stil, Tal1 and MAP17, three well-known cellular proto-oncogenes in the SCL/Tal1 locus. We show that insertion of a Locus Control Region-driven globin therapeutic globin transgene had a dramatic activating effect on Tal1 and Map17, the two closest genes, a minor effect on Stil, and no effect on Cyp4x1, a non-expressed gene. Of the four element tested, cHS4 was the only one that was able to suppress this transgene-mediated insertional transcriptional activation. cHS4 had a strong suppressive effect on the activation expression of Map17 but has little or no effect on expression of Tal1. The suppressive activity of cHS4 is therefore promoter specific. Importantly, the observed suppressive effect of cHS4 on Map17 activation did not depend on its intercalation between the LCR and the Map 17 promoter. Rather, presence of one or two copies of cHS4 anywhere within the transgene was sufficient to almost completely block the activation of Map17. Therefore, at this complex locus, suppression of transgene-mediated insertional transcriptional activation by cHS4 could not be adequately explained by models that predict that cHS4 can only suppress expression through an enhancer-blocking activity that requires intercalation between an enhancer and a promoter. This has important implications for our theoretical understanding of the possible effects of the insertion of cHS4 on gene therapy vectors. We also show that cHS4 decreased the level of expression of the globin transgene. Therefore, the benefits of partially preventing insertional gene activation are in part negated by the lower expression level of the transgene. A cost/benefit analysis of the utility of incorporation of insulators in gene therapy vectors will require further studies in which the effects of insulators on both the therapeutic gene and the flanking genes are determined at a large number of integration sites. Identification of insulators with minimal promoter specificity would also be of great value.


Nephrotic syndrome in adults.
Nephrotic syndrome is an important presentation of glomerular disease characterised by heavy proteinuria, hypoalbuminaemia and oedema. The differential diagnosis of the underlying condition is wide including primary renal disorders and secondary diseases such as malignancy, infection, diabetes and amyloid. Presentations to acute medicine may be with hypervolaemia, complications of the nephrotic state (such as venous thromboembolism), or complications of therapy (such as infection). Early recognition of nephrotic syndrome is possible through simple urinalysis for protein and testing serum albumin, although a high index of suspicion is sometimes required in patients with comorbidities including potentially distracting cardiac or hepatic diseases.


An integrated system for perception-driven autonomy with modular robots.
The theoretical ability of modular robots to reconfigure in response to complex tasks in a priori unknown environments has frequently been cited as an advantage and remains a major motivator for work in the field. We present a modular robot system capable of autonomously completing high-level tasks by reactively reconfiguring to meet the needs of a perceived, a priori unknown environment. The system integrates perception, high-level planning, and modular hardware and is validated in three hardware demonstrations. Given a high-level task specification, a modular robot autonomously explores an unknown environment, decides when and how to reconfigure, and manipulates objects to complete its task. The system architecture balances distributed mechanical elements with centralized perception, planning, and control. By providing an example of how a modular robot system can be designed to leverage reactive reconfigurability in unknown environments, we have begun to lay the groundwork for modular self-reconfigurable robots to address tasks in the real world.


Delta-thalassemia caused by disruption of the site for an erythroid-specific transcription factor, GATA-1, in the delta-globin gene promoter.
Delta-thalassemia is a complex group of inherited disorders of globin genes characterized by impaired synthesis of the delta-globin chain. The T-C substitution was detected at position -77 of the delta-globin gene isolated from three independent Japanese individuals who were homozygotes for delta-thalassemia. To elucidate the significance of the mutation in delta-globin gene expression, we investigated the genotype of three delta-thalassemia homozygotes and 58 normal individuals using dot blot hybridization of the polymerase chain reaction (PCR)-amplified DNA. The mutation was observed in six alleles of three homozygotes, while no mutation was detected in 116 alleles of normal individuals, thereby indicating the close association of this mutation with the thalassemia phenotype. Since the mutation (TTATCT-TCATCT) is located within the inverted binding motif of GATA-1 (T or A-G-A-T-A-G or A), an erythroid cell-specific transcription factor, we did gel retardation assays using nuclear extracts from the erythroid cells. We found that GATA-1 binds the oligonucleotide spanning positions -61 to -90, but does not bind to the oligonucleotide with the mutation at position -77. Competition gel retardation assays showed that GATA-1 binding can be competed out by the fragment with the GATA-1 motif, but not with the mutant oligonucleotide. Analysis of the transient expression of the CAT gene linked to the delta-globin gene promoter region demonstrated that the construct with the mutant promoter region was expressed about 20-fold less compared with the normal one. Thus, the mutation at position -77 impairs delta-globin gene expression by abolishing GATA-1 binding to the AGATAA sequence of the promoter region of the delta-globin gene. This provides a good example of involvement of tissue-specific transacting factors in the molecular pathogenesis of hereditary diseases.


Environmental and socioeconomic analysis of malaria transmission in the Brazilian Amazon, 2010-2015.
To analyze the environmental and socioeconomic risk factors of malaria transmission at municipality level, from 2010 to 2015, in the Brazilian Amazon. The municipalities were stratified into high, moderate, and low transmission based on the annual parasite incidence. A multinomial logistic regression that compared low with medium transmission and low with high transmission was performed. For each category, three models were analyzed: one only with socioeconomic risk factors (Gini index, illiteracy, number of mines and indigenous areas); a second with the environmental factors (forest coverage and length of the wet season); and a third with all covariates (full model). The full model showed the best performance. The most important risks factors for high transmission were Gini index, length of the wet season and illiteracy, OR 2.06 (95%CI 1.19-3.56), 1.73 (95%CI 1.19-2.51) and 1.10 (95%CI 1.03-1.17), respectively. The medium transmission showed a weaker influence of the risk factors, being illiteracy, forest coverage and indigenous areas statistically significant but with marginal influence. As a disease of poverty, the reduction in wealth inequalities and, therefore, health inequalities, could reduce the transmission considerably. Besides, environmental risk factors as length of the wet season should be considered in the planning, prevention and control. Municipality-level and fine-scale analysis should be done together to improve the knowledge of the local dynamics of transmission.


When self-assembly meets topology: an enhanced micelle stability.
The topology of hydrophobic moieties can affect the stability of self-assembled micelles. Curved corannulene and flat perylene were selected as model hydrophobic molecules with poly(ethylene glycol) as the hydrophilic segment. The curvature can enhance the intermolecular π-π interaction, and hence the driving force of micelle formation.


Spatial heterodyne interferometry with polarization gratings.
The implementation of a polarization-based spatial heterodyne interferometer (SHI) is described. While a conventional SHI uses a Michelson interferometer and diffraction gratings, our SHI exploits mechanically robust Wollaston prisms and polarization gratings. A theoretical model for the polarization SHI is provided and validated with data from our proof of concept experiments. This device is expected to provide a compact monolithic sensor for subangstrom resolution spectroscopy in remote sensing, biomedical imaging, and machine vision applications.


A pyrazole curcumin derivative restores membrane homeostasis disrupted after brain trauma.
We have assessed potential mechanisms associated with the deleterious effects of TBI on the integrity of plasma membranes in the hippocampus, together with consequences for behavioral function. In addition, we have investigated the efficacy of a dietary intervention based on a pyrazole curcumin derivative with demonstrated bioactivity and brain absorption, to re-establish membrane integrity. We report that moderate fluid percussion injury (FPI) increases levels of 4-Hydroxynonenal (HNE), an intermediary for the harmful effects of lipid peroxidation on neurons. A more direct action of FPI on membrane homeostasis was evidenced by a reduction in calcium-independent phospholipase A2 (iPLA₂) important for metabolism of membrane phospholipids such as DHA, and an increase in the fatty acid transport protein (FATP) involved in translocation of long-chain fatty acids across the membrane. A potential association between membrane disruption and neuronal function was suggested by reduced levels of the NR2B subunit of the transmembrane NMDA receptor, in association with changes in iPLA2 and syntaxin-3 (STX-3, involved in the action of membrane DHA on synaptic membrane expansion). In addition, changes in iPLA2, 4-HNE, and STX-3 were proportional to reduced performance in a spatial learning task. In turn, the dietary supplementation with the curcumin derivative counteracted all the effects of FPI, effectively restoring parameters of membrane homeostasis. Results show the potential of the curcumin derivative to promote membrane homeostasis following TBI, which may foster a new line of non-invasive therapeutic treatments for TBI patients by endogenous up-regulation of molecules important for neural repair and plasticity.


The N-terminal domain of a glycolipid-anchored prion protein is essential for its endocytosis via clathrin-coated pits.
The cellular prion protein (PrPC) is a glycolipid-anchored protein that is involved in the pathogenesis of fatal spongiform encephalopathies. We have shown previously that, in contrast to several other glycolipid-anchored proteins, chPrP, the chicken homologue of mammalian PrPC, is endocytosed via clathrin-coated pits in cultured neuroblastoma cells, as well as in embryonic neurons and glia (Shyng, S.-L., Heuser, J. E., and Harris, D. A. (1994) J. Cell Biol. 125, 1239-1250). In this study, we have determined that the N-terminal half of the chPrP polypeptide chain is essential for its endocytosis. Deletions within this region reduce the amount of chPrP internalized, as measured by surface iodination or biotinylation, and decrease its concentration in clathrin-coated pits, as determined by quantitative electron microscopic immunogold labeling. Mouse PrP, as well as two mouse PrP/chPrP chimeras, are internalized as efficiently as chPrP, suggesting that conserved features of secondary and tertiary structure are involved in interaction with the endocytic machinery. Our results indicate that the ectodomain of a protein can contain endocytic targeting information, and they strongly support a model in which the polypeptide chain of PrPC binds to the extracellular domain of a transmembrane protein that contains a coated pit localization signal in its cytoplasmic tail.


Fruit, vegetable and vitamin C intakes and plasma vitamin C: cross-sectional associations with insulin resistance and glycaemia in 9-10 year-old children.
To examine whether low circulating vitamin C concentrations and low fruit and vegetable intakes were associated with insulin resistance and other Type 2 diabetes risk markers in childhood. We conducted a cross-sectional, school-based study in 2025 UK children aged 9-10 years, predominantly of white European, South-Asian and black African origin. A 24-h dietary recall was used to assess fruit, vegetable and vitamin C intakes. Height, weight and fat mass were measured and a fasting blood sample collected to measure plasma vitamin C concentrations and Type 2 diabetes risk markers. In analyses adjusting for confounding variables (including socio-economic status), a one interquartile range higher plasma vitamin C concentration (30.9 μmol/l) was associated with a 9.6% (95% CI 6.5, 12.6%) lower homeostatic model assessment of insulin resistance value, 0.8% (95% CI 0.4, 1.2%) lower fasting glucose, 4.5% (95% CI 3.2, 5.9%) lower urate and 2.2% (95% CI 0.9, 3.4%) higher HDL cholesterol. HbA1c concentration was 0.6% (95% CI 0.2, 1.0%) higher. Dietary fruit, vegetable and total vitamin C intakes were not associated with any Type 2 diabetes risk markers. Lower plasma vitamin C concentrations in South-Asian and black African-Caribbean children could partly explain their higher insulin resistance. Lower plasma vitamin C concentrations are associated with insulin resistance and could partly explain ethnic differences in insulin resistance. Experimental studies are needed to establish whether increasing plasma vitamin C can help prevent Type 2 diabetes at an early stage.


DTX3L and ARTD9 inhibit IRF1 expression and mediate in cooperation with ARTD8 survival and proliferation of metastatic prostate cancer cells.
Prostate cancer (PCa) is one of the leading causes of cancer-related mortality and morbidity in the aging male population and represents the most frequently diagnosed malignancy in men around the world. The Deltex (DTX)-3-like E3 ubiquitin ligase (DTX3L), also known as B-lymphoma and BAL-associated protein (BBAP), was originally identified as a binding partner of the diphtheria-toxin-like macrodomain containing ADP-ribosyltransferase-9 (ARTD9), also known as BAL1 and PARP9. We have previously demonstrated that ARTD9 acts as a novel oncogenic survival factor in high-risk, chemo-resistant, diffuse large B cell lymphoma (DLBCL). The mono-ADP-ribosyltransferase ARTD8, also known as PARP14 functions as a STAT6-specific co-regulator of IL4-mediated proliferation and survival in B cells. Co-expression of DTX3L, ARTD8, ARTD9 and STAT1 was analyzed in the metastatic PCa (mPCa) cell lines PC3, DU145, LNCaP and in the normal prostate luminal epithelial cell lines HPE and RWPE1. Effects on cell proliferation, survival and cell migration were determined in PC3, DU145 and/or LNCaP cells depleted of DTX3L, ARTD8, ARTD9, STAT1 and/or IRF1 compared to their proficient control cells, respectively. In further experiments, real-time RT-PCR, Western blot, immunofluorescence and co-immunoprecipitations were conducted to evaluate the physical and functional interactions between DTX3L, ARTD8 and ARTD9. Here we could identify DTX3L, ARTD9 and ARTD8 as novel oncogenic survival factors in mPCa cells. Our studies revealed that DTX3L forms a complex with ARTD8 and mediates together with ARTD8 and ARTD9 proliferation, chemo-resistance and survival of mPCa cells. In addition, DTX3L, ARTD8 and ARTD9 form complexes with each other. Our study provides first evidence that the enzymatic activity of ARTD8 is required for survival of mPCa cells. DTX3L and ARTD9 act together as repressors of the tumor suppressor IRF1 in mPCa cells. Furthermore, the present study shows that DTX3L together with STAT1 and STAT3 is implicated in cell migration of mPCa cells. Our data strongly indicate that a crosstalk between STAT1, DTX3L and ARTD-like mono-ADP-ribosyltransferases mediates proliferation and survival of mPCa cells. The present study further suggests that the combined targeted inhibition of STAT1, ARTD8, ARTD9 and/or DTX3L could increase the efficacy of chemotherapy or radiation treatment in prostate and other high-risk tumor types with an increased STAT1 signaling.


The Gender Divide: The Impact of Surgeon Gender on Surgical Practice Patterns in Urology.
There is a perception in urology that female urologists encounter gender based role assignments and are often pigeonholed into caring for more female patients and female specific urological issues than their male colleagues. We assessed the influence of surgeon gender on patient gender demographics by exploring the surgical case logs of American urologists. Six-month case logs of certifying urologists from 2003 to 2012 were obtained from the ABU (American Board of Urology). We reviewed case logs based on CPT codes of common urological procedures, focusing on 6 index gender neutral and gender specific procedure groups, including treatment of nephrolithiasis, nephrectomy, resection of bladder tumors, treatment of stress urinary incontinence, elective sterilization and treatment of prostate cancer. Among a cohort of 6,166 urologists 1,011,800 cases were logged. Female surgeons operated on a significantly higher percent of female patients than their male peers (54.4% vs 32.5%, p <0.01). Female surgeons performed significantly more female specific procedures, such as slings, than their male counterparts (18 vs 10 per year, p <0.001). Male urologists performed significantly more male specific procedures than their female colleagues, including 3 times as many vasectomies (32 vs 12 per year, p <0.001) and more than twice as many prostatectomies (15 vs 6 per year, p <0.001). These trends were consistent across all subspecialties and geographic regions (p <0.01). Female surgeon gender has a significant influence on patient gender demographics among index urological procedures. As the number of women in urology grows, increasing attention to gender biases is necessary to understand how these disparities will shape the clinical landscape.


A multiplex set of species-specific primers for rapid identification of members of the genus Saccharomyces.
The Saccharomyces genus (previously Saccharomyces sensu stricto) formally comprises Saccharomyces arboricola, Saccharomyces bayanus, Saccharomyces cariocanus, Saccharomyces cerevisiae, Saccharomyces kudriavzevii, Saccharomyces mikatae, Saccharomyces paradoxus and Saccharomyces pastorianus. Species-specific primer pairs that produce a single band of known and different product size have been developed for each member of the clade with the exception of S. pastorianus, which is a polyphyletic allopolyploid hybrid only found in lager breweries, and for which signature sequences could not be reliably created. Saccharomyces cariocanus is now regarded as an American variant of S. paradoxus, and accordingly a single primer pair that recognizes both species was developed. A different orthologous and essential housekeeping gene was used to detect each species, potentially avoiding competition between PCR primers and overlap between amplicons. In multiplex format, two or more different species could be identified in a single reaction; double and triple hybrids could not always be correctly identified. Forty-two unidentified yeasts from sugar cane juice fermentations were correctly identified as S. cerevisiae. A colony PCR method was developed that is rapid, robust, inexpensive and capable of automation, requires no mycological expertise on the part of the user and is thus useful for large-scale preliminary screens.


A variational perspective on accelerated methods in optimization.
Accelerated gradient methods play a central role in optimization, achieving optimal rates in many settings. Although many generalizations and extensions of Nesterov's original acceleration method have been proposed, it is not yet clear what is the natural scope of the acceleration concept. In this paper, we study accelerated methods from a continuous-time perspective. We show that there is a Lagrangian functional that we call the Bregman Lagrangian, which generates a large class of accelerated methods in continuous time, including (but not limited to) accelerated gradient descent, its non-Euclidean extension, and accelerated higher-order gradient methods. We show that the continuous-time limit of all of these methods corresponds to traveling the same curve in spacetime at different speeds. From this perspective, Nesterov's technique and many of its generalizations can be viewed as a systematic way to go from the continuous-time curves generated by the Bregman Lagrangian to a family of discrete-time accelerated algorithms.


Surgical treatment results in scaphoid nonunion.
Fracture of the scaphoid is the most common fracture in the wrist. We retrospectively reviewed 42 cases of established nonunion of the scaphoid that had been treated by four methods: with two Kirschner wires (K wires) and pronator quadratus pedicled bone graft in 5 patients; AO cannulated screw and graft in 8 patients; Herbert screw and graft in 19 patients; and two K wires and graft in 10 patients. Follow-up ranged from 1 to 5 years (between January 1995 and January 2000). Radiographs and computed tomography (CT) scans were analyzed for confirmation of osseous union. The average period of clinical and radiologic union was 13.2 weeks (range, 10 to 33 weeks). There was a significant improvement in the grasping power, radiologic healing, clinical satisfaction, and pain relief in the patients who had operation.


Biophysical investigation of type A PutAs reveals a conserved core oligomeric structure.
Many enzymes form homooligomers, yet the functional significance of self-association is seldom obvious. Herein, we examine the connection between oligomerization and catalytic function for proline utilization A (PutA) enzymes. PutAs are bifunctional enzymes that catalyze both reactions of proline catabolism. Type A PutAs are the smallest members of the family, possessing a minimal domain architecture consisting of N-terminal proline dehydrogenase and C-terminal l-glutamate-γ-semialdehyde dehydrogenase modules. Type A PutAs form domain-swapped dimers, and in one case (Bradyrhizobium japonicum PutA), two of the dimers assemble into a ring-shaped tetramer. Whereas the dimer has a clear role in substrate channeling, the functional significance of the tetramer is unknown. To address this question, we performed structural studies of four-type A PutAs from two clades of the PutA tree. The crystal structure of Bdellovibrio bacteriovorus PutA covalently inactivated by N-propargylglycine revealed a fold and substrate-channeling tunnel similar to other PutAs. Small-angle X-ray scattering (SAXS) and analytical ultracentrifugation indicated that Bdellovibrio PutA is dimeric in solution, in contrast to the prediction from crystal packing of a stable tetrameric assembly. SAXS studies of two other type A PutAs from separate clades also suggested that the dimer predominates in solution. To assess whether the tetramer of B. japonicum PutA is necessary for catalytic function, a hot spot disruption mutant that cleanly produces dimeric protein was generated. The dimeric variant exhibited kinetic parameters similar to the wild-type enzyme. These results implicate the domain-swapped dimer as the core structural and functional unit of type A PutAs. Proline dehydrogenase (EC 22.214.171.124); l-glutamate-γ-semialdehyde dehydrogenase (EC 18.104.22.168). The atomic coordinates and structure factor amplitudes have been deposited in the Protein Data Bank under accession number 5UR2. The SAXS data have been deposited in the SASBDB under the following accession codes: SASDCP3 (BbPutA), SASDCQ3 (DvPutA 1.5 mg·mL-1 ), SASDCX3 (DvPutA 3.0 mg·mL-1 ), SASDCY3 (DvPutA 4.5 mg·mL-1 ), SASDCR3 (LpPutA 3.0 mg·mL-1 ), SASDCV3 (LpPutA 5.0 mg·mL-1 ), SASDCW3 (LpPutA 8.0 mg·mL-1 ), SASDCS3 (BjPutA 2.3 mg·mL-1 ), SASDCT3 (BjPutA 4.7 mg·mL-1 ), SASDCU3 (BjPutA 7.0 mg·mL-1 ), SASDCZ3 (R51E 2.3 mg·mL-1 ), SASDC24 (R51E 4.7 mg·mL-1 ), SASDC34 (R51E 7.0 mg·mL-1 ).


Rovibrational energy levels of the F(-)(H2O) and F(-)(D2O) complexes.
The variational nuclear-motion codes ElVibRot and GENIUSH have been used to compute rotational-vibrational states of the F(-)(H2O) anion and its deuterated isotopologue, F(-)(D2O), employing a full-dimensional, semiglobal potential energy surface (PES) called SLBCL, developed as part of this study for the ground electronic state of the complex. The PES is determined from all-electron, explicitly correlated coupled-cluster singles, doubles, and connected triples [CCSD(T)-F12a] computations with an atom-centered, fixed-exponent Gaussian basis set of cc-pCVTZ-F12 quality. The SLBCL PES accurately reproduces the two equivalent minima of the complex, the corresponding transition barrier of C2v point-group symmetry, as well as the proton transfer and the dissociation asymptotes towards the products HF + OH(-) and F(-) + H2O, respectively. The code ElVibRot has been updated so that it can use curvilinear internal coordinates corresponding to a reaction path. The variationally computed vibrational energy levels are compared to relevant experimental and previously determined first-principles results. The vibrational states reveal the presence of pronounced anharmonic effects and considerable intermode couplings resulting in strong resonances, involving in particular the HOH bend and the ionic OH stretch motions. Tunneling results in particularly significant splittings for F(-)(H2O); as expected, the splittings are orders of magnitude smaller for the F(-)(D2O) molecule. The rovibrational energy levels reveal that, despite the large-amplitude vibrational motions, the rotations of F(-)(H2O) basically follow rigid-rotor characteristics.


The effect of a self-care program based on the teach back method on the postpartum quality of life.
The postpartum period is a critical stage of life with major changes in the quality of life. Therefore, special consideration is needed to this issue. To determine the effect of a self-care program based on the Teach Back method on the postpartum quality of life. This experimental study was conducted on eighty postpartum women who had given birth in health centers across Darreh Shahr County, Ilam Province, Iran in 2016. The control group received only routine postpartum care according to the national guidelines. The trial group received the routine care in addition to two sessions of physical and psychological postpartum self-care based on the Teach Back method. The two groups were assessed in terms of their quality of life before and after the intervention using the Postpartum Quality of Life Questionnaire. The data were analyzed using SPSS version 21. Descriptive statistic tests, Chi squared, independent-samples t-test, paired-samples t-test, Wilcoxon and Mann Whitney's test was used. Before the intervention, the postpartum quality of life score was 106.23±11.866 in the trial group and 107.30±13.197 in the control group; after the intervention, the score was 124.73±10.706 and 115.03±12.687 in the two groups respectively, suggesting a significant inter-group difference after the intervention (p<0.001). Significant differences were also observed between the two groups in terms of the mother's feelings toward herself, toward her child and toward her spouse and others, and physical health before and after the intervention (p<0.001). Using the Teach Back model for a self-care program appears to dramatically improve the postpartum quality of life and is therefore recommended as a useful method for postpartum care. The trial was registered at the Iranian Registry of Clinical Trials (http://www.irct.ir) with the Irct ID: IRCT2015012820854N1. The authors received no financial support for the research, authorship, and/or publication of this article.