Multicenter laboratory evaluation of the bioMérieux Vitek antimicrobial susceptibility testing system with 11 antimicrobial agents versus members of the family Enterobacteriaceae and Pseudomonas aeruginosa.
A four-center study in which a total of 1,082 recent clinical isolates of members of the family Enterobacteriaceae and Pseudomonas aeruginosa were examined versus 11 antimicrobial agents with the bioMérieux Vitek susceptibility test system (Hazelwood, Mo.) and the GNS-F6 card was conducted. In addition, a challenge set consisting of the same 200 organisms was examined in each of the four participating laboratories. Results obtained with the Vitek system were compared to MICs determined by a standardized broth microdilution method. For purposes of comparison, susceptibility categories (susceptible, intermediate, or resistant) were assigned on the basis of the results of both methods. The result of the broth microdilution test was considered definitive. The total category error rate with the Vitek system and the recent clinical isolates (11,902 organism-antimicrobial comparisons) was 4.5%, i.e., 1.7% very major errors, 0.9% major errors, and 1.9% minor errors. The total category error rate calculated from tests performed with the challenge set (i.e., 8,800 organism-antimicrobial comparisons) was 5.9%, i.e., 2.2% very major errors, 1.1% major errors, and 2.6% minor errors. Very major error rates higher than the totals were noted with Enterobacter cloacae versus ampicillin-sulbactam, aztreonam, ticarcillin, and ticarcillin-clavulanate and with P. aeruginosa versus mezlocillin, ticarcillin, and ticarcillin-clavulanate. Major error rates higher than the averages were observed with Proteus mirabilis versus imipenem and with Klebsiella pneumoniae versus ofloxacin. Excellent overall interlaboratory reproducibility was observed with the Vitek system. The importance of inoculum size as a primary determinant in the accuracy of susceptibility test results with the Vitek system was clearly demonstrated in this study. Specifically, when an inoculum density fourfold higher than that recommended by the manufacturer was used, high rates of false resistance results were obtained with cell wall-active antimicrobial agents versus both the Enterobacteriaceae and P. aeruginosa.


Abnormalities of the corpus callosum in nonpsychotic children with chromosome 22q11 deletion syndrome.
Chromosome 22q11 deletion syndrome (22q11DS) is associated with elevated rates of schizophrenia and other psychoses in adulthood. Childhood morphologic brain abnormalities are frequently reported, but the significance of these and their relationship to the development of schizophrenia are unclear. We sought to delineate midline neuroanatomical abnormalities in nonpsychotic children with 22q11DS and their age- and sex-matched controls and compare these to those reported in individuals with schizophrenia. On qualitative analysis, we found a high incidence of midline developmental abnormalities (cavum septum pellucidum, or CSP). On quantitative analysis, the total corpus callosum (CC) area was significantly increased in the patient group and among the subregions, the patients had a significantly larger isthmus. These findings of an increased area of the corpus callosum, specifically the isthmus, have not been reported before in individuals with 22q11DS. We also found a relative lack of the age-related increase in the size of the corpus callosum in the children with 22q11DS. There were no differences in cerebellar vermis measurements between the patient and control groups. Our findings are indicative of frequent midline brain anomalies, including dysgenesis of the corpus callosum, in nonpsychotic children with 22q11DS. Although the increased size of the corpus callosum in our 22q11DS patients is in direct contrast to the decrease seen in schizophrenia, the high frequency of structural midline abnormalities in these nonpsychotic children with 22q11DS is similar to that seen in schizophrenia. Further longitudinal studies on these children will help determine which of these structural abnormalities is/are pertinent to the development of psychosis.


Global, regional, and national under-5 mortality, adult mortality, age-specific mortality, and life expectancy, 1970-2016: a systematic analysis for the Global Burden of Disease Study 2016.
Detailed assessments of mortality patterns, particularly age-specific mortality, represent a crucial input that enables health systems to target interventions to specific populations. Understanding how all-cause mortality has changed with respect to development status can identify exemplars for best practice. To accomplish this, the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) estimated age-specific and sex-specific all-cause mortality between 1970 and 2016 for 195 countries and territories and at the subnational level for the five countries with a population greater than 200 million in 2016. We have evaluated how well civil registration systems captured deaths using a set of demographic methods called death distribution methods for adults and from consideration of survey and census data for children younger than 5 years. We generated an overall assessment of completeness of registration of deaths by dividing registered deaths in each location-year by our estimate of all-age deaths generated from our overall estimation process. For 163 locations, including subnational units in countries with a population greater than 200 million with complete vital registration (VR) systems, our estimates were largely driven by the observed data, with corrections for small fluctuations in numbers and estimation for recent years where there were lags in data reporting (lags were variable by location, generally between 1 year and 6 years). For other locations, we took advantage of different data sources available to measure under-5 mortality rates (U5MR) using complete birth histories, summary birth histories, and incomplete VR with adjustments; we measured adult mortality rate (the probability of death in individuals aged 15-60 years) using adjusted incomplete VR, sibling histories, and household death recall. We used the U5MR and adult mortality rate, together with crude death rate due to HIV in the GBD model life table system, to estimate age-specific and sex-specific death rates for each location-year. Using various international databases, we identified fatal discontinuities, which we defined as increases in the death rate of more than one death per million, resulting from conflict and terrorism, natural disasters, major transport or technological accidents, and a subset of epidemic infectious diseases; these were added to estimates in the relevant years. In 47 countries with an identified peak adult prevalence for HIV/AIDS of more than 0·5% and where VR systems were less than 65% complete, we informed our estimates of age-sex-specific mortality using the Estimation and Projection Package (EPP)-Spectrum model fitted to national HIV/AIDS prevalence surveys and antenatal clinic serosurveillance systems. We estimated stillbirths, early neonatal, late neonatal, and childhood mortality using both survey and VR data in spatiotemporal Gaussian process regression models. We estimated abridged life tables for all location-years using age-specific death rates. We grouped locations into development quintiles based on the Socio-demographic Index (SDI) and analysed mortality trends by quintile. Using spline regression, we estimated the expected mortality rate for each age-sex group as a function of SDI. We identified countries with higher life expectancy than expected by comparing observed life expectancy to anticipated life expectancy on the basis of development status alone. Completeness in the registration of deaths increased from 28% in 1970 to a peak of 45% in 2013; completeness was lower after 2013 because of lags in reporting. Total deaths in children younger than 5 years decreased from 1970 to 2016, and slower decreases occurred at ages 5-24 years. By contrast, numbers of adult deaths increased in each 5-year age bracket above the age of 25 years. The distribution of annualised rates of change in age-specific mortality rate differed over the period 2000 to 2016 compared with earlier decades: increasing annualised rates of change were less frequent, although rising annualised rates of change still occurred in some locations, particularly for adolescent and younger adult age groups. Rates of stillbirths and under-5 mortality both decreased globally from 1970. Evidence for global convergence of death rates was mixed; although the absolute difference between age-standardised death rates narrowed between countries at the lowest and highest levels of SDI, the ratio of these death rates-a measure of relative inequality-increased slightly. There was a strong shift between 1970 and 2016 toward higher life expectancy, most noticeably at higher levels of SDI. Among countries with populations greater than 1 million in 2016, life expectancy at birth was highest for women in Japan, at 86·9 years (95% UI 86·7-87·2), and for men in Singapore, at 81·3 years (78·8-83·7) in 2016. Male life expectancy was generally lower than female life expectancy between 1970 and 2016, and the gap between male and female life expectancy increased with progression to higher levels of SDI. Some countries with exceptional health performance in 1990 in terms of the difference in observed to expected life expectancy at birth had slower progress on the same measure in 2016. Globally, mortality rates have decreased across all age groups over the past five decades, with the largest improvements occurring among children younger than 5 years. However, at the national level, considerable heterogeneity remains in terms of both level and rate of changes in age-specific mortality; increases in mortality for certain age groups occurred in some locations. We found evidence that the absolute gap between countries in age-specific death rates has declined, although the relative gap for some age-sex groups increased. Countries that now lead in terms of having higher observed life expectancy than that expected on the basis of development alone, or locations that have either increased this advantage or rapidly decreased the deficit from expected levels, could provide insight into the means to accelerate progress in nations where progress has stalled. Bill & Melinda Gates Foundation, and the National Institute on Aging and the National Institute of Mental Health of the National Institutes of Health.


Temperature- and pressure-induced proton transfer in the 1:1 adduct formed between squaric acid and 4,4'-bipyridine.
We have applied a combination of spectroscopic and diffraction methods to study the adduct formed between squaric acid and bypridine, which has been postulated to exhibit proton transfer associated with a single-crystal to single-crystal phase transition at ca. 450 K. A combination of X-ray single-crystal and very-high flux powder neutron diffraction data confirmed that a proton does transfer from the acid to the base in the high-temperature form. Powder X-ray diffraction measurements demonstrated that the transition was reversible but that a significant kinetic energy barrier must be overcome to revert to the original structure. Computational modeling is consistent with these results. Modeling also revealed that, while the proton transfer event would be strongly discouraged in the gas phase, it occurs in the solid state due to the increase in charge state of the molecular ions and their arrangement inside the lattice. The color change is attributed to a narrowing of the squaric acid to bipyridine charge-transfer energy gap. Finally, evidence for the possible existence of two further phases at high pressure is also presented.


Exercise Physiology From 1980 to 2020: Application of the Natural Sciences.
The field of exercise physiology has enjoyed tremendous growth in the past 40 years. With its foundations in the natural sciences, it is an interdisciplinary field that is highly relevant to human performance and health. The focus of this review is on highlighting new approaches, knowledge, and opportunities that have emerged in exercise physiology over the last four decades. Key among these is the adoption of advanced technologies by exercise physiologists to address fundamental research questions, and the expansion of research topics to range from molecular to organismal, and population scales in order to clarify the underlying mechanisms and impact of physiological responses to exercise in health and disease. Collectively, these advances have ensured the position of the field as a partner in generating new knowledge across many scientific and health disciplines.


Will Exercise Advice Be Sufficient for Treatment of Young Adults With Prehypertension and Hypertension? A Systematic Review and Meta-Analysis.
Previous studies report benefits of exercise for blood pressure control in middle age and older adults, but longer-term effectiveness in younger adults is not well established. We performed a systematic review and meta-analysis of published randomized control trials with meta-regression of potential effect modifiers. An information specialist completed a comprehensive search of available data sources, including studies published up to June 2015. Authors applied strict inclusion and exclusion criteria to screen 9524 titles. Eligible studies recruited younger adults with a cardiovascular risk factor (with at least 25% of cohort aged 18-40 years); the intervention had a defined physical activity strategy and reported blood pressure as primary or secondary outcome. Meta-analysis included 14 studies randomizing 3614 participants, mean age 42.2±6.3 (SD) years. At 3 to 6 months, exercise was associated with a reduction in systolic blood pressure of -4.40 mm Hg (95% confidence interval, -5.78 to -3.01) and in diastolic blood pressure of -4.17 mm Hg (95% confidence interval, -5.42 to -2.93). Intervention effect was not significantly influenced by baseline blood pressure, body weight, or subsequent weight loss. Observed intervention effect was lost after 12 months of follow-up with no reported benefit over control, mean difference in systolic blood pressure -1.02 mm Hg (95% confidence interval, -2.34 to 0.29), and in diastolic blood pressure -0.91 mm Hg (95% confidence interval, -1.85 to 0.02). Current exercise guidance provided to reduce blood pressure in younger adults is unlikely to benefit long-term cardiovascular risk. There is need for continued research to improve age-specific strategies and recommendations for hypertension prevention and management in young adults.


Neural processing of reward and punishment in young people at increased familial risk of depression.
Abnormalities in the neural representation of rewarding and aversive stimuli have been well-described in patients with acute depression, and we previously found abnormal neural responses to rewarding and aversive sight and taste stimuli in recovered depressed patients. The aim of the present study was to determine whether similar abnormalities might be present in young people at increased familial risk of depression but with no personal history of mood disorder. We therefore used functional magnetic resonance imaging to examine the neural responses to pleasant and aversive sights and tastes in 25 young people (16-21 years of age) with a biological parent with depression and 25 age- and gender-matched control subjects. We found that, relative to the control subjects, participants with a parental history of depression showed diminished responses in the orbitofrontal cortex to rewarding stimuli, whereas activations to aversive stimuli were increased in the lateral orbitofrontal cortex and insula. In anterior cingulate cortex the at-risk group showed blunted neural responses to both rewarding and aversive stimuli. Our findings suggest that young people at increased familial risk of depression have altered neural representation of reward and punishment, particularly in cortical regions linked to the use of positive and negative feedback to guide adaptive behavior.


Genetic structure of Tunisian ethnic groups revealed by paternal lineages.
Tunisia has experienced a variety of human migrations that have modeled the myriad cultural groups inhabiting the area. Both Arabic and Berber-speaking populations live in Tunisia. Berbers are commonly considered as in situ descendants of peoples who settled roughly in Palaeolithic times, and posterior demographic events such as the arrival of the Neolithic, the Arab migrations, and the expulsion of the "Moors" from Spain, had a strong cultural influence. Nonetheless, the genetic structure and the population relationships of the ethnic groups living in Tunisia have been poorly assessed. In order to gain insight into the paternal genetic landscape and population structure, more than 40 Y-chromosome single nucleotide polymorphisms and 17 short tandem repeats were analyzed in five Tunisian ethnic groups (three Berber-speaking isolates, one Andalusian, and one Cosmopolitan Arab). The most common lineage was the North African haplogroup E-M81 (71%), being fixed in two Berber samples (Chenini-Douiret and Jradou), suggesting isolation and genetic drift. Differential levels of paternal gene flow from the Near East were detected in the Tunisian samples (J-M267 lineage over 30%); however, no major sub-Saharan African or European influence was found. This result contrasts with the high amount of sub-Saharan and Eurasian maternal lineages previously described in Tunisia. Overall, our results reveal a certain genetic inter-population diversity, especially among Berber groups, and sexual asymmetry, paternal lineages being mostly of autochthonous origin. In addition, Andalusians, who are supposed to be migrants from southern Spain, do not exhibit any substantial contribution of European lineages, suggesting a North African origin for this ethnic group.


Cognitive change predicts symptom reduction with cognitive therapy for posttraumatic stress disorder.
There is a growing body of evidence for the effectiveness of trauma-focused cognitive behavior therapy (TF-CBT) for posttraumatic stress disorder (PTSD), but few studies to date have investigated the mechanisms by which TF-CBT leads to therapeutic change. Models of PTSD suggest that a core treatment mechanism is the change in dysfunctional appraisals of the trauma and its aftermath. If this is the case, then changes in appraisals should predict a change in symptoms. The present study investigated whether cognitive change precedes symptom change in Cognitive Therapy for PTSD, a version of TF-CBT. The study analyzed weekly cognitive and symptom measures from 268 PTSD patients who received a course of Cognitive Therapy for PTSD, using bivariate latent growth modeling. Results showed that (a) dysfunctional trauma-related appraisals and PTSD symptoms both decreased significantly over the course of treatment, (b) changes in appraisals and symptoms were correlated, and (c) weekly change in appraisals significantly predicted subsequent reduction in symptom scores (both corrected for the general decrease over the course of therapy). Changes in PTSD symptom severity did not predict subsequent changes in appraisals. The study provided preliminary evidence for the temporal precedence of a reduction in negative trauma-related appraisals in symptom reduction during trauma-focused CBT for PTSD. This supports the role of change in appraisals as an active therapeutic mechanism.


Validity of self-reported height and weight in 4808 EPIC-Oxford participants.
To assess the validity of self-reported height and weight by comparison with measured height and weight in a sample of middle-aged men and women, and to determine the extent of misclassification of body mass index (BMI) arising from differences between self-reported and measured values. Analysis of self-reported and measured height and weight data from participants in the Oxford cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Oxford). Four thousand eight hundred and eight British men and women aged 35-76 years. Spearman rank correlations between self-reported and measured height, weight and BMI were high (r > 0.9, P < 0.0001). Height was overestimated by a mean of 1.23 (95% confidence interval (CI) 1.11-1.34) cm in men and 0.60 (0.51-0.70) cm in women; the extent of overestimation was greater in older men and women, shorter men and heavier women. Weight was underestimated by a mean of 1.85 (1.72-1.99) kg in men and 1.40 (1.31-1.49) kg in women; the extent of underestimation was greater in heavier men and women, but did not vary with age or height. Using standard categories of BMI, 22.4% of men and 18.0% of women were classified incorrectly based on self-reported height and weight. After correcting the self-reported values using predictive equations derived from a 10% sample of subjects, misclassification decreased to 15.2% in men and 13.8% in women. Self-reported height and weight data are valid for identifying relationships in epidemiological studies. In analyses where anthropometric factors are the primary variables of interest, measurements in a representative sample of the study population can be used to improve the accuracy of estimates of height, weight and BMI.


Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders.
Duplications at 15q11.2-q13.3 overlapping the Prader-Willi/Angelman syndrome (PWS/AS) region have been associated with developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. Duplications of maternal origin are associated with disease, whereas the pathogenicity of paternal ones is unclear. To clarify the role of maternal and paternal duplications, we conducted the largest and most detailed study to date of parental origin of 15q11.2-q13.3 interstitial duplications in DD, ASD and SZ cohorts. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA), but do not appear to increase risk for SZ. The importance of the epigenetic status of 15q11.2-q13.3 duplications was further underlined by analysis of a number of families, in which the duplication was paternally derived in the mother, who was unaffected, whereas her offspring, who inherited a maternally derived duplication, suffered from psychotic illness. Interestingly, the most consistent clinical characteristics of SZ patients with 15q11.2-q13.3 duplications were learning or developmental problems, found in 76% of carriers. Despite their lower pathogenicity, paternal duplications are less frequent in the general population with a general population prevalence of 0.0033% compared to 0.0069% for maternal duplications. This may be due to lower fecundity of male carriers and differential survival of embryos, something echoed in the findings that both types of duplications are de novo in just over 50% of cases. Isodicentric chromosome 15 (idic15) or interstitial triplications were not observed in SZ patients or in controls. Overall, this study refines the distinct roles of maternal and paternal interstitial duplications at 15q11.2-q13.3, underlining the critical importance of maternally expressed imprinted genes in the contribution of Copy Number Variants (CNVs) at this interval to the incidence of psychotic illness. This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling.


Dendritic Core-Multishell Nanocarriers in Murine Models of Healthy and Atopic Skin.
Dendritic hPG-amid-C18-mPEG core-multishell nanocarriers (CMS) represent a novel class of unimolecular micelles that hold great potential as drug transporters, e.g., to facilitate topical therapy in skin diseases. Atopic dermatitis is among the most common inflammatory skin disorders with complex barrier alterations which may affect the efficacy of topical treatment.Here, we tested the penetration behavior and identified target structures of unloaded CMS after topical administration in healthy mice and in mice with oxazolone-induced atopic dermatitis. We further examined whole body distribution and possible systemic side effects after simulating high dosage dermal penetration by subcutaneous injection.Following topical administration, CMS accumulated in the stratum corneum without penetration into deeper viable epidermal layers. The same was observed in atopic dermatitis mice, indicating that barrier alterations in atopic dermatitis had no influence on the penetration of CMS. Following subcutaneous injection, CMS were deposited in the regional lymph nodes as well as in liver, spleen, lung, and kidney. However, in vitro toxicity tests, clinical data, and morphometry-assisted histopathological analyses yielded no evidence of any toxic or otherwise adverse local or systemic effects of CMS, nor did they affect the severity or course of atopic dermatitis.Taken together, CMS accumulate in the stratum corneum in both healthy and inflammatory skin and appear to be highly biocompatible in the mouse even under conditions of atopic dermatitis and thus could potentially serve to create a depot for anti-inflammatory drugs in the skin.


"A conscious control over life and my emotions:" mindfulness practice and healthy young people. A qualitative study.
Although quantitative benefits of mindfulness training have been demonstrated in youth, little is known about the processes involved. The aim of this study was to gain a detailed understanding of how young people engage with the ideas and practices known as mindfulness using qualitative enquiry. Following completion of a six-week mindfulness training program with a nonclinical group of 11 young people (age 16-24), a focus group (N = 7) and open-ended interviews (n = 5) were held and audio-recorded. Qualitative data, collected at eight time points over three months from the commencement of training, were coded with the aid of computer software. Grounded theory methodology informed the data collection process and generation of themes and an explanatory model that captured participants' experiences. Participants described their daily lives as beset by frequent experiences of distress sometimes worsened by their unhelpful or destructive reactions. With mindfulness practice, they initially reported greater calm, balance, and control. Subsequently they commented on a clearer understanding of themselves and others. Mindfulness was then described as a "mindset" associated with greater confidence and competence and a lessened risk of future distress. Participants demonstrated a sophisticated understanding of and engagement with mindfulness principles and practice. Their reported experience aligned well with qualitative research findings in adults and theoretical literature on mindfulness. An encouraging finding was that, with ongoing mindfulness practice and within a relatively short time, participants were able to move beyond improved emotion regulation and gain greater confidence in their ability to manage life challenges.


An attributional analysis of stigma associated with sexually transmitted diseases and its relationship with communication efficacy.
People typically attribute more responsibility to those individuals who are infected with sexually transmitted diseases (STD) than other diseases. This study tested how different routes (i.e., sexually transmitted or foodborne) of transmission have an impact on individuals' general perception on stigma/shame and the attributions of responsibility, when controlling for symptoms/conditions of the hypothetical virus infection. Two hundreds and ninety eight college students were recruited for the study. As predicted, people who were attributed with control over contracting the virus (i.e., sexually transmitted route) were likely to be assigned a greater level of personal responsibility and were more likely to receive blame from others than people who were attributed relatively less control over contracting the virus (i.e., foodborne). The relationship between the attribution of responsibility and communication efficacy was also assessed. The results supported our prediction that there was a significant association between the attribution of responsibility and communication efficacy, in that the perceived controllability of the situation, perceived responsibility for the situation, and blame were all significantly correlated with communication efficacy in a negative direction. Practical applications by evaluating the effectiveness of the actual Merck's Gardasil advertisement were discussed that the Gardasil advertisement appears to reduce the perceived shame and stigma associated with the sexually transmitted nature of the virus by not revealing the true nature of the virus upfront.


A unigene catalogue of 5700 expressed genes in cassava.
Two economically important characters, starch content and cassava bacterial blight resistance, were targeted to generate a large collection of cassava ESTs. Two libraries were constructed from cassava root tissues of varieties with high and low starch contents. Other libraries were constructed from plant tissues challenged by the pathogen Xanthomonas axonopodis pv.manihotis. We report here the single pass sequencing of 11,954 cDNA clones from the 5' ends, including 111 from the 3' ends. Cluster analysis permitted the identification of a unigene set of 5,700 sequences. Sequence analyses permitted the assignment of a putative functional category for 37% of sequences whereas approximately 16% sequences did not show any significant similarity with other proteins present in the database and therefore can be considered as cassava specific genes. A group of genes belonging to a large multigene family was identified. We characterize a set of genes detected only in infected libraries putatively involved in the defense response to pathogen infection. By comparing two libraries obtained from cultivars contrasting in their starch content a group of genes associated to starch biosynthesis and differentially expressed was identified. This is the first large cassava EST resource developed today and publicly available thus making a significant contribution to genomic knowledge of cassava.


An agent independent axis for executed and modeled choice in medial prefrontal cortex.
Adaptive success in social animals depends on an ability to infer the likely actions of others. Little is known about the neural computations that underlie this capacity. Here, we show that the brain models the values and choices of others even when these values are currently irrelevant. These modeled choices use the same computations that underlie our own choices, but are resolved in a distinct neighboring medial prefrontal brain region. Crucially, however, when subjects choose on behalf of a partner instead of themselves, these regions exchange their functional roles. Hence, regions that represented values of the subject's executed choices now represent the values of choices executed on behalf of the partner, and those that previously modeled the partner now model the subject. These data tie together neural computations underlying self-referential and social inference, and in so doing establish a new functional axis characterizing the medial wall of prefrontal cortex.


Targeting neuronal nitric oxide synthase with gene transfer to modulate cardiac autonomic function.
Microdomains of neuronal nitric oxide synthase (nNOS) are spatially localised within both autonomic neurons innervating the heart and post-junctional myocytes. This review examines the use of gene transfer to investigate the role of nNOS in cardiac autonomic control. Furthermore, it explores techniques that may be used to improve upon gene delivery to the cardiac autonomic nervous system, potentially allowing more specific delivery of genes to the target neurons/myocytes. This may involve modification of the tropism of the adenoviral vector, or the use of alternative viral and non-viral gene delivery mechanisms to minimise potential immune responses in the host. Here we show that adenoviral vectors provide an efficient method of gene delivery to cardiac-neural tissue. Functionally, adenovirus-nNOS can increase cardiac vagal responsiveness by facilitating cholinergic neurotransmission and decrease beta-adrenergic excitability. Whether gene transfer remains the preferred strategy for targeting cardiac autonomic impairment will depend on site-specific promoters eliciting sustained gene expression that results in restoration of physiological function.


Domain organization of long signal peptides of single-pass integral membrane proteins reveals multiple functional capacity.
Targeting signals direct proteins to their extra- or intracellular destination such as the plasma membrane or cellular organelles. Here we investigated the structure and function of exceptionally long signal peptides encompassing at least 40 amino acid residues. We discovered a two-domain organization ("NtraC model") in many long signals from vertebrate precursor proteins. Accordingly, long signal peptides may contain an N-terminal domain (N-domain) and a C-terminal domain (C-domain) with different signal or targeting capabilities, separable by a presumably turn-rich transition area (tra). Individual domain functions were probed by cellular targeting experiments with fusion proteins containing parts of the long signal peptide of human membrane protein shrew-1 and secreted alkaline phosphatase as a reporter protein. As predicted, the N-domain of the fusion protein alone was shown to act as a mitochondrial targeting signal, whereas the C-domain alone functions as an export signal. Selective disruption of the transition area in the signal peptide impairs the export efficiency of the reporter protein. Altogether, the results of cellular targeting studies provide a proof-of-principle for our NtraC model and highlight the particular functional importance of the predicted transition area, which critically affects the rate of protein export. In conclusion, the NtraC approach enables the systematic detection and prediction of cryptic targeting signals present in one coherent sequence, and provides a structurally motivated basis for decoding the functional complexity of long protein targeting signals.


Haplotype-based analysis of common variation in the acetyl-coA carboxylase alpha gene and breast cancer risk: a case-control study nested within the European Prospective Investigation into Cancer and Nutrition.
A key fatty acid synthesis enzyme, acetyl-CoA carboxylase alpha (ACC-alpha), has been shown to be highly expressed in human breast cancer and other tumor types and also to specifically interact with the protein coded by one of two major breast cancer susceptibility genes BRCA1. We used a comprehensive haplotype analysis to examine the contribution of the ACC-alpha common genetic variation (allele frequency >5%) to breast cancer in a case-control study (1,588 cases/2,600 controls) nested within the European Prospective Investigation into Cancer and Nutrition. We identified 21 haplotype-tagging polymorphisms efficiently capturing common variation within 325 kb of ACC-alpha and surrounding sequences using genotype data from the HapMap project and our resequencing data. We found an effect on overall risk of breast cancer in homozygous carriers of one common haplotype [odds ratio (OR), 1.74; 95% confidence interval (95% CI), 1.03-2.94]. When the data were subdivided by menopausal status, we found statistical evidence of heterogeneity for two other common haplotypes (P value for heterogeneity = 0.016 and 0.045). In premenopausal women, the carriers of these haplotypes, compared with noncarriers, had an altered risk of breast cancer (OR, 0.70; 95% CI, 0.53-0.92 and OR, 1.35; 95% CI, 1.04-1.76). These findings were not significant after adjustment for multiple testing and therefore should be considered as preliminary and evaluated in larger independent studies. However, they suggest a possible role of the ACC-alpha common sequence variants in susceptibility to breast cancer and encourage studies of other genes involved in fatty acid synthesis.


Improved renal ischemia tolerance in females influences kidney transplantation outcomes.
Experimentally, females show an improved ability to recover from ischemia-reperfusion injury (IRI) compared with males; however, this sex-dependent response is less established in humans. Here, we developed a series of murine renal ischemia and transplant models to investigate sex-specific effects on recovery after IRI. We found that IRI tolerance is profoundly increased in female mice compared with that observed in male mice and discovered an intermediate phenotype after neutering of either sex. Transplantation of adult kidneys from either sex into a recipient of the opposite sex followed by ischemia at a remote time resulted in ischemia recovery that reflected the sex of the recipient, not the donor, revealing that the host sex determines recovery. Likewise, renal IRI was exacerbated in female estrogen receptor α-KO mice, while female mice receiving supplemental estrogen before ischemia were protected. We examined data from the United Network for Organ Sharing (UNOS) to determine whether there is an association between sex and delayed graft function (DGF) in patients who received deceased donor renal transplants. A multivariable logistic regression analysis determined that there was a greater association with DGF in male recipients than in female recipients. Together, our results demonstrate that sex affects renal IRI tolerance in mice and humans and indicate that estrogen administration has potential as a therapeutic intervention to clinically improve ischemia tolerance.


Humans at tropical latitudes produce more females.
Skews in the human sex ratio at birth have captivated scientists for over a century. The accepted average human natal sex ratio is slightly male biased, at 106 males per 100 females or 51.5 per cent males. Studies conducted on a localized scale show that sex ratios deviate from this average in response to a staggering number of social, economical and physiological variables. However, these patterns often prove inconsistent when expanded to other human populations, perhaps because the nature of the influences themselves exhibit substantial cultural variation. Here, data collected from 202 countries over a decade show that latitude is a primary factor influencing the ratio of males and females produced at birth; countries at tropical latitudes produced significantly fewer boys (51.1% males) annually than those at temperate and subarctic latitudes (51.3%). This pattern remained strong despite enormous continental variation in lifestyle and socio-economic status, suggesting that latitudinal variables may act as overarching cues on which sex ratio variation in humans is based.


FGF10 controls the patterning of the tracheal cartilage rings via Shh.
During embryonic development, appropriate dorsoventral patterning of the trachea leads to the formation of periodic cartilage rings from the ventral mesenchyme and continuous smooth muscle from the dorsal mesenchyme. In this work, we have investigated the role of two crucial morphogens, fibroblast growth factor 10 and sonic hedgehog, in the formation of periodically alternating cartilaginous and non-cartilaginous domains in the ventral mesenchyme. Using a combination of gain- and loss-of-function approaches for FGF10 and SHH, we demonstrate that precise spatio-temporal patterns and appropriate levels of expression of these two signaling molecules in the ventral area are crucial between embryonic day 11.5 and 13.5 for the proper patterning of the cartilage rings. We conclude that the expression level of FGF10 in the mesenchyme has to be within a critical range to allow for periodic expression of Shh in the ventral epithelium, and consequently for the correct patterning of the cartilage rings. We propose that disturbed balances of Fgf10 and Shh may explain a subset of human tracheomalacia without tracheo-esophageal fistula or tracheal atresia.


Imaging in population science: cardiovascular magnetic resonance in 100,000 participants of UK Biobank - rationale, challenges and approaches.
UK Biobank is a prospective cohort study with 500,000 participants aged 40 to 69. Recently an enhanced imaging study received funding. Cardiovascular magnetic resonance (CMR) will be part of a multi-organ, multi-modality imaging visit in 3-4 dedicated UK Biobank imaging centres that will acquire and store imaging data from 100,000 participants (subject to successful piloting). In each of UK Biobank's dedicated bespoke imaging centres, it is proposed that 15-20 participants will undergo a 2 to 3 hour visit per day, seven days a week over a period of 5-6 years. The imaging modalities will include brain MRI at 3 Tesla, CMR and abdominal MRI at 1.5 Tesla, carotid ultrasound and DEXA scans using carefully selected protocols. We reviewed the rationale, challenges and proposed approaches for concise phenotyping using CMR on such a large scale. Here, we discuss the benefits of this imaging study and review existing and planned population based cardiovascular imaging in prospective cohort studies. We will evaluate the CMR protocol, feasibility, process optimisation and costs. Procedures for incidental findings, quality control and data processing and analysis are also presented. As is the case for all other data in the UK Biobank resource, this database of images and related information will be made available through UK Biobank's Access Procedures to researchers (irrespective of their country of origin and whether they are academic or commercial) for health-related research that is in the public interest.


Exploration of factors driving incorporation of unnatural dNTPS into DNA by Klenow fragment (DNA polymerase I) and DNA polymerase alpha.
In order to further understand how DNA polymerases discriminate against incorrect dNTPs, we synthesized two sets of dNTP analogues and tested them as substrates for DNA polymerase alpha (pol alpha) and Klenow fragment (exo-) of DNA polymerase I (Escherichia coli). One set of analogues was designed to test the importance of the electronic nature of the base. The bases consisted of a benzimidazole ring with one or two exocyclic substituent(s) that are either electron-donating (methyl and methoxy) or electron-withdrawing (trifluoromethyl and dinitro). Both pol alpha and Klenow fragment exhibit a remarkable inability to discriminate against these analogues as compared to their ability to discriminate against incorrect natural dNTPs. Neither polymerase shows any distinct electronic or steric preferences for analogue incorporation. The other set of analogues, designed to examine the importance of hydrophobicity in dNTP incorporation, consists of a set of four regioisomers of trifluoromethyl benzimidazole. Whereas pol alpha and Klenow fragment exhibited minimal discrimination against the 5- and 6-regioisomers, they discriminated much more effectively against the 4- and 7-regioisomers. Since all four of these analogues will have similar hydrophobicity and stacking ability, these data indicate that hydrophobicity and stacking ability alone cannot account for the inability of pol alpha and Klenow fragment to discriminate against unnatural bases. After incorporation, however, both sets of analogues were not efficiently elongated. These results suggest that factors other than hydrophobicity, sterics and electronics govern the incorporation of dNTPs into DNA by pol alpha and Klenow fragment.


Hypotonic activation of the myo-inositol transporter SLC5A3 in HEK293 cells probed by cell volumetry, confocal and super-resolution microscopy.
Swelling-activated pathways for myo-inositol, one of the most abundant organic osmolytes in mammalian cells, have not yet been identified. The present study explores the SLC5A3 protein as a possible transporter of myo-inositol in hyponically swollen HEK293 cells. To address this issue, we examined the relationship between the hypotonicity-induced changes in plasma membrane permeability to myo-inositol P ino [m/s] and expression/localization of SLC5A3. P ino values were determined by cell volumetry over a wide tonicity range (100-275 mOsm) in myo-inositol-substituted solutions. While being negligible under mild hypotonicity (200-275 mOsm), P ino grew rapidly at osmolalities below 200 mOsm to reach a maximum of ∼ 3 nm/s at 100-125 mOsm, as indicated by fast cell swelling due to myo-inositol influx. The increase in P ino resulted most likely from the hypotonicity-mediated incorporation of cytosolic SLC5A3 into the plasma membrane, as revealed by confocal fluorescence microscopy of cells expressing EGFP-tagged SLC5A3 and super-resolution imaging of immunostained SLC5A3 by direct stochastic optical reconstruction microscopy (dSTORM). dSTORM in hypotonic cells revealed a surface density of membrane-associated SLC5A3 proteins of 200-2000 localizations/μm2. Assuming SLC5A3 to be the major path for myo-inositol, a turnover rate of 80-800 myo-inositol molecules per second for a single transporter protein was estimated from combined volumetric and dSTORM data. Hypotonic stress also caused a significant upregulation of SLC5A3 gene expression as detected by semiquantitative RT-PCR and Western blot analysis. In summary, our data provide first evidence for swelling-mediated activation of SLC5A3 thus suggesting a functional role of this transporter in hypotonic volume regulation of mammalian cells.


Use of cell-based assays in myasthenia gravis and other antibody-mediated diseases.
The increasing demand on diagnostic assays that are sensitive and specific for pathogenic antibodies, and the interest in identifying new antigens, prompted the development of cell-based assays for the detection of autoantibodies in myasthenia gravis and other autoimmune disorders. Cell-based assays were initially used to show that clustering the AChR improved the positivity in myasthenia gravis, and similar assays have now been applied to detection of antibodies to neuromuscular junction candidate proteins such as LRP4 and agrin. In addition cell-based assays have been used in the routine detection of antibodies to proteins expressed on the surface of neurons (NMDAR, LGI1, CASPR2, AMPAR, GABA-A/B, GlyR, and DPPX) and glia (AQP4, MOG). Here, we summarize the findings in myasthenia and discuss the advantages, disadvantages and controversial issues of using cell-based assays in the detection of these antibodies, and their relevance to the testing of preclinical models of disease.


The role of calcium and nicotinic acid adenine dinucleotide phosphate (NAADP) in human osteoclast formation and resorption.
Osteoclasts are specialised bone resorbing cells which form by fusion of circulating mononuclear phagocyte precursors. Bone resorption results in the release of large amounts of calcium into the extracellular fluid (ECF), but it is not certain whether changes in extracellular calcium concentration [Ca(2+)]e influence osteoclast formation and resorption. In this study, we sought to determine the effect of [Ca(2+)]e and NAADP, a potent calcium mobilising messenger that induces calcium uptake, on human osteoclast formation and resorption. CD14+ human monocytes were cultured with M-CSF and RANKL in the presence of different concentrations of calcium and NAADP and the effect on osteoclast formation and resorption evaluated. We found that the number of TRAP+ multinucleated cells and the extent of lacunar resorption were reduced when there was an increase in extracellular calcium and NAADP. This was associated with a decrease in RANK mRNA expression by CD14+ cells. At high concentrations (20 mM) of [Ca(2+)]e mature osteoclast resorption activity remained unaltered relative to control cultures. Our findings indicate that osteoclast formation is inhibited by a rise in [Ca(2+)]e and that RANK expression by mononuclear phagocyte osteoclast precursors is also [Ca(2+)]e dependent. Changes in NAADP also influence osteoclast formation, suggesting a role for this molecule in calcium handling. Osteoclasts remained capable of lacunar resorption, even at high ECF [Ca(2+)]e, in keeping with their role in physiological and pathological bone resorption.


Indications for early aspirin use in acute ischemic stroke : A combined analysis of 40 000 randomized patients from the chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups.
Long-term daily aspirin is of benefit in the years after ischemic stroke, and 2 large randomized trials (the Chinese Acute Stroke Trial [CAST] and the International Stroke Trial [IST]), with 20 000 patients in each, have shown that starting daily aspirin promptly in patients with suspected acute ischemic stroke also reduces the immediate risk of further stroke or death in hospital and the overall risk of death or dependency. However, some uncertainty remains about the effects of early aspirin in particular categories of patient with acute stroke. To assess the balance of benefits and risks of aspirin in particular categories of patient with acute stroke (eg, the elderly, those without a CT scan, or those with atrial fibrillation), a prospectively planned meta-analysis is presented of the data from 40 000 individual patients from both trials on events that occurred in the hospital during the scheduled treatment period (4 weeks in CAST, 2 weeks in IST), with 10 characteristics used to define 28 subgroups. This represents 99% of the worldwide evidence from randomized trials. There was a highly significant reduction of 7 per 1000 (SD 1) in recurrent ischemic stroke (320 [1.6%] aspirin versus 457 [2. 3%] control, 2P<0.000001) and a less clearly significant reduction of 4 (SD 2) per 1000 in death without further stroke (5.0% versus 5. 4%, 2P=0.05). Against these benefits, there was an increase of 2 (SD 1) per 1000 in hemorrhagic stroke or hemorrhagic transformation of the original infarct (1.0% versus 0.8%, 2P=0.07) and no apparent effect on further stroke of unknown cause (0.9% versus 0.9%). In total, therefore, there was a net decrease of 9 (SD 3) per 1000 in the overall risk of further stroke or death in hospital (8.2% versus 9.1%, 2P=0.001). For the reduction of one third in recurrent ischemic stroke, subgroup-specific analyses found no significant heterogeneity of the proportional benefit of aspirin (chi(2)(18)=20. 9, NS), even though the overall treatment effect (chi(2)(1)=24.8, 2P<0.000001) was sufficiently large for such subgroup analyses to be statistically informative. The absolute risk among control patients was similar in all 28 subgroups, so the absolute reduction of approximately 7 per 1000 in recurrent ischemic stroke does not differ substantially with respect to age, sex, level of consciousness, atrial fibrillation, CT findings, blood pressure, stroke subtype, or concomitant heparin use. There was no good evidence that the apparent decrease of approximately 4 per 1000 in death without further stroke was reversed in any subgroup or that in any subgroup the increase in hemorrhagic stroke was much larger than the overall average of approximately 2 per 1000. Finally, there was no significant heterogeneity between the reductions in the composite outcome of any further stroke or death (chi(2)(18)=16.5, NS). Among the 9000 patients (22%) randomized without a prior CT scan, aspirin appeared to be of net benefit with no unusual excess of hemorrhagic stroke; moreover, even among the 800 (2%) who had inadvertently been randomized after a hemorrhagic stroke, there was no evidence of net hazard (further stroke or death, 63 aspirin versus 67 control). Early aspirin is of benefit for a wide range of patients, and its prompt use should be routinely considered for all patients with suspected acute ischemic stroke, mainly to reduce the risk of early recurrence.


Large-scale roll out of electronic longitudinal mood-monitoring for research in affective disorders: Report from the UK bipolar disorder research network.
Electronic longitudinal mood monitoring has been shown to be acceptable to patients with affective disorders within clinical settings, but its use in large-scale research has not yet been established. Using both postal and email invitations, we invited 4080 past research participants with affective disorders who were recruited into the Bipolar Disorder Research Network (BDRN) over a 10 year period to participate in online weekly mood monitoring. In addition, since January 2015 we have invited all newly recruited BDRN research participants to participate in mood monitoring at the point they were recruited into BDRN. Online mood monitoring uptake among past participants was 20%, and among new participants to date was 46% with participants recruited over the last year most likely to register (61%). More than 90% mood monitoring participants engaged for at least one month, with mean engagement period greater than one year (58 weeks) and maximum engagement for longer than three years (165 weeks). There were no significant differences in the proportion of past and new BDRN participants providing data for at least 4 weeks (91%, 92% respectively), 3 months (78%, 82%), 6 months (65%, 54%) or one year (51%, 44%). Our experiences with recruiting participants for electronic prospective mood monitoring may not necessarily generalise fully to research situations that are very different from those we describe. Large-scale electronic longitudinal mood monitoring in affective disorders for research purposes is feasible with uptake highest among newly recruited participants.


Phosphorylation dynamics during early differentiation of human embryonic stem cells.
Pluripotent stem cells self-renew indefinitely and possess characteristic protein-protein networks that remodel during differentiation. How this occurs is poorly understood. Using quantitative mass spectrometry, we analyzed the (phospho)proteome of human embryonic stem cells (hESCs) during differentiation induced by bone morphogenetic protein (BMP) and removal of hESC growth factors. Of 5222 proteins identified, 1399 were phosphorylated on 3067 residues. Approximately 50% of these phosphosites were regulated within 1 hr of differentiation induction, revealing a complex interplay of phosphorylation networks spanning different signaling pathways and kinase activities. Among the phosphorylated proteins was the pluripotency-associated protein SOX2, which was SUMOylated as a result of phosphorylation. Using the data to predict kinase-substrate relationships, we reconstructed the hESC kinome; CDK1/2 emerged as central in controlling self-renewal and lineage specification. The findings provide new insights into how hESCs exit the pluripotent state and present the hESC (phospho)proteome resource as a complement to existing pluripotency network databases.


Clinical Outcomes With Abemaciclib After Prior CDK4/6 Inhibitor Progression in Breast Cancer: A Multicenter Experience.
Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are widely used as first-line therapy for hormone receptor-positive metastatic breast cancer (HR+ MBC). Although abemaciclib monotherapy is also FDA-approved for treatment of disease progression on endocrine therapy, there is limited insight into the clinical activity of abemaciclib after progression on prior CDK4/6i. We identified patients with HR+ MBC from 6 cancer centers in the United States who received abemaciclib after disease progression on prior CDK4/6i, and abstracted clinical features, outcomes, toxicity, and predictive biomarkers. In the multicenter cohort, abemaciclib was well tolerated after a prior course of CDK4/6i (palbociclib)-based therapy; a minority of patients discontinued abemaciclib because of toxicity without progression (9.2%). After progression on palbociclib, most patients (71.3%) received nonsequential therapy with abemaciclib (with ≥1 intervening non-CDK4/6i regimens), with most receiving abemaciclib with an antiestrogen agent (fulvestrant, 47.1%; aromatase inhibitor, 27.6%), and the remainder receiving abemaciclib monotherapy (19.5%). Median progression-free survival for abemaciclib in this population was 5.3 months and median overall survival was 17.2 months, notably similar to results obtained in the MONARCH-1 study of abemaciclib monotherapy in heavily pretreated HR+/HER2-negative CDK4/6i-naïve patients. A total of 36.8% of patients received abemaciclib for ≥6 months. There was no relationship between the duration of clinical benefit while on palbociclib and the subsequent duration of treatment with abemaciclib. RB1, ERBB2, and CCNE1 alterations were noted among patients with rapid progression on abemaciclib. A subset of patients with HR+ MBC continue to derive clinical benefit from abemaciclib after progression on prior palbociclib. These results highlight the need for future studies to confirm molecular predictors of cross-resistance to CDK4/6i therapy and to better characterize the utility of abemaciclib after disease progression on prior CDK4/6i.


Role of endoplasmic reticulum stress-induced apoptosis in rat thyroid toxicity caused by excess fluoride and/or iodide.
Excess fluoride and iodide coexist in drinking water in many regions, but few studies have investigated the single or interactive effects on thyroid in vivo. In our study, Wistar rats were exposed to excess fluoride and/or iodide through drinking water for 2 or 8 months. The structure and function of the thyroid, cells apoptosis and the expression of inositol-requiring enzyme 1 (IRE1) pathway-related factors were analyzed. Results demonstrated that excess fluoride and/or iodide could change thyroid follicular morphology and alter thyroid hormone levels in rats. After 8 months treatment, both single and co-exposure of the two microelements could raise the thyroid cells apoptosis. However, the expressions of IRE1-related factors were only increased in fluoride-alone and the combined groups. In conclusion, thyroid structure and thyroid function were both affected by excess fluoride and/or iodide. IRE1-induced apoptosis were involved in this cytotoxic process caused by fluoride or the combination of two microelements.


Are there specialized circuits for social cognition and are they unique to humans?
Discussions of the neural underpinnings of social cognition frequently emphasize the distinctiveness of human social cognition. Here, however, we review the discovery of similar correlations between neural networks and social networks in humans and other primates. We suggest that component parts of these neural networks in dorsal frontal cortex, anterior cingulate cortex (ACC), and superior temporal sulcus (STS) are linked to basic social cognitive processes common to several primate species including monitoring the actions of others, assigning importance to others, and orienting behavior toward or away from others. Changes in activity in other brain regions occur in tandem with changes in social status and may be related to the different types of behaviors associated with variation in social status.


Is Homo heidelbergensis a distinct species? New insight on the Mauer mandible.
The discovery of new fossils in Africa, Asia, and Europe, and the recognition of a greater diversity in the middle Pleistocene fossil record, has led to a reconsideration of the species Homo heidelbergensis. This nomen, formulated by Schoetensack in 1908 to describe the Mauer jaw (Germany), was almost forgotten during most of the past century. Numerous fossils have been attributed to it but no consensus has arisen concerning their classification. The holotype anatomical traits are still poorly understood, and numerous fossils with no mandibular remains have been placed in the taxon. Some researchers propose H. heidelbergensis as an Afro-European taxon that is ancestral to both modern humans and Neandertals whereas others think it is a strictly European species that is part of the Neandertal lineage. We focus on the validity of H. heidelbergensis, using the traditional basis of species recognition: anatomical description. We provide a comparative morphological analysis using 47 anatomical traits of 36 Pleistocene fossils from Africa, Asia, and Europe and 35 extant human mandibles. We re-examine the mandibular features of Mauer and discuss the specimen's inclusion in H. heidelbergensis, as well as alternative evolutionary theories. To lend objectivity to specimen grouping, we use multiple correspondence analysis associated with hierarchical classification that creates clusters corresponding to phenetic similarities between jaws. Our phenetic and comparative morphological analyses support the validity of H. heidelbergensis as a taxon. A set of morphological features can be statistically identified for the definition of the species. Some traits can be used to delimit H. heidelbergensis in an evolutionary framework (e.g., foramina mentale posteriorly positioned, horizontal retromolar surface). Those traits are also present on African (e.g., Tighenif) and European (e.g., Sima de los Huesos) specimens that show a close relationship with the Mauer mandible. Therefore, the definition of H. heidelbergensis is more precise and mainly supports the theory of an Afro-European taxon, which is the last common ancestor of H. neanderthalensis and H. sapiens. However, the results of this study fail to entirely discount the hypothesis that considers H. heidelbergensis as a chronospecies leading to the Neandertals.


Mapping human genetic diversity in Asia.
Asia harbors substantial cultural and linguistic diversity, but the geographic structure of genetic variation across the continent remains enigmatic. Here we report a large-scale survey of autosomal variation from a broad geographic sample of Asian human populations. Our results show that genetic ancestry is strongly correlated with linguistic affiliations as well as geography. Most populations show relatedness within ethnic/linguistic groups, despite prevalent gene flow among populations. More than 90% of East Asian (EA) haplotypes could be found in either Southeast Asian (SEA) or Central-South Asian (CSA) populations and show clinal structure with haplotype diversity decreasing from south to north. Furthermore, 50% of EA haplotypes were found in SEA only and 5% were found in CSA only, indicating that SEA was a major geographic source of EA populations.


Salad and satiety: energy density and portion size of a first-course salad affect energy intake at lunch.
We tested the effect on meal intake of varying the energy density and portion size of a compulsory first-course salad. The study used a randomized crossover design. Forty-two women from the State College, PA, university community ate lunch in the laboratory once per week for 7 weeks. Lunch comprised one of six first-course salads, or no salad in the control condition, followed by a main course of pasta. Subjects were required to consume the entire salad, but ate as much pasta as they wanted. The salads varied in energy density (0.33, 0.67, or 1.33 kcal/g) and portion size (150 or 300 g). The energy density of the salad was reduced by changing the amount and type of dressing and cheese. Energy intake and ratings of hunger, satiety, and food characteristics were measured. Outcomes were analyzed using a linear mixed model with repeated measures. Compared with having no first course, consuming the low-energy-dense salads reduced meal energy intake (by 7% for the small portion and 12% for the large), and consuming the high-energy-dense salads increased intake (by 8% for the small portion and 17% for the large). When two salads with the same number of calories were compared, meal intake was decreased when the large portion of the lower-energy-dense salad was consumed. Eating a low-energy-dense first course enhances satiety and reduces meal energy intake. Consuming a large portion of a low-energy-dense food at the start of a meal may be an effective strategy for weight management.


Notum is required for neural and head induction via Wnt deacylation, oxidation, and inactivation.
Secreted Wnt morphogens are essential for embryogenesis and homeostasis and require a lipid/palmitoleoylate modification for receptor binding and activity. Notum is a secreted Wnt antagonist that belongs to the α/β hydrolase superfamily, but its mechanism of action and roles in vertebrate embryogenesis are not fully understood. Here, we report that Notum hydrolyzes the Wnt palmitoleoylate adduct extracellularly, resulting in inactivated Wnt proteins that form oxidized oligomers incapable of receptor binding. Thus, Notum is a Wnt deacylase, and palmitoleoylation is obligatory for the Wnt structure that maintains its active monomeric conformation. Notum is expressed in naive ectoderm and neural plate in Xenopus and is required for neural and head induction. These findings suggest that Notum is a prerequisite for the "default" neural fate and that distinct mechanisms of Wnt inactivation by the Tiki protease in the Organizer and the Notum deacylase in presumptive neuroectoderm orchestrate vertebrate brain development.


The clip-segment of the von Willebrand domain 1 of the BMP modulator protein Crossveinless 2 is preformed.
Bone Morphogenetic Proteins (BMPs) are secreted protein hormones that act as morphogens and exert essential roles during embryonic development of tissues and organs. Signaling by BMPs occurs via hetero-oligomerization of two types of serine/threonine kinase transmembrane receptors. Due to the small number of available receptors for a large number of BMP ligands ligand-receptor promiscuity presents an evident problem requiring additional regulatory mechanisms for ligand-specific signaling. Such additional regulation is achieved through a plethora of extracellular antagonists, among them members of the Chordin superfamily, that modulate BMP signaling activity by binding. The key-element in Chordin-related antagonists for interacting with BMPs is the von Willebrand type C (VWC) module, which is a small domain of about 50 to 60 residues occurring in many different proteins. Although a structure of the VWC domain of the Chordin-member Crossveinless 2 (CV2) bound to BMP-2 has been determined by X-ray crystallography, the molecular mechanism by which the VWC domain binds BMPs has remained unclear. Here we present the NMR structure of the Danio rerio CV2 VWC1 domain in its unbound state showing that the key features for high affinity binding to BMP-2 is a pre-oriented peptide loop.


Attention is required for maintenance of feature binding in visual working memory.
Working memory and attention are intimately connected. However, understanding the relationship between the two is challenging. Currently, there is an important controversy about whether objects in working memory are maintained automatically or require resources that are also deployed for visual or auditory attention. Here we investigated the effects of loading attention resources on precision of visual working memory, specifically on correct maintenance of feature-bound objects, using a dual-task paradigm. Participants were presented with a memory array and were asked to remember either direction of motion of random dot kinematograms of different colour, or orientation of coloured bars. During the maintenance period, they performed a secondary visual or auditory task, with varying levels of load. Following a retention period, they adjusted a coloured probe to match either the motion direction or orientation of stimuli with the same colour in the memory array. This allowed us to examine the effects of an attention-demanding task performed during maintenance on precision of recall on the concurrent working memory task. Systematic increase in attention load during maintenance resulted in a significant decrease in overall working memory performance. Changes in overall performance were specifically accompanied by an increase in feature misbinding errors: erroneous reporting of nontarget motion or orientation. Thus in trials where attention resources were taxed, participants were more likely to respond with nontarget values rather than simply making random responses. Our findings suggest that resources used during attention-demanding visual or auditory tasks also contribute to maintaining feature-bound representations in visual working memory-but not necessarily other aspects of working memory.


Endurance exercise training blunts the deleterious effect of high-fat feeding on whole body efficiency.
We recently showed that a week-long, high-fat diet reduced whole body exercise efficiency in sedentary men by >10% (Edwards LM, Murray AJ, Holloway CJ, Carter EE, Kemp GJ, Codreanu I, Brooker H, Tyler DJ, Robbins PA, Clarke K. FASEB J 25: 1088-1096, 2011). To test if a similar dietary regime would blunt whole body efficiency in endurance-trained men and, as a consequence, hinder aerobic exercise performance, 16 endurance-trained men were given a short-term, high-fat (70% kcal from fat) and a moderate carbohydrate (50% kcal from carbohydrate) diet, in random order. Efficiency was assessed during a standardized exercise task on a cycle ergometer, with aerobic performance assessed during a 1-h time trial and mitochondrial function later measured using (31)P-magnetic resonance spectroscopy. The subjects then underwent a 2-wk wash-out period, before the study was repeated with the diets crossed over. Muscle biopsies, for mitochondrial protein analysis, were taken at the start of the study and on the 5th day of each diet. Plasma fatty acids were 60% higher on the high-fat diet compared with moderate carbohydrate diet (P < 0.05). However, there was no change in whole body efficiency and no change in mitochondrial function. Endurance exercise performance was significantly reduced (P < 0.01), most probably due to glycogen depletion. Neither diet led to changes in citrate synthase, ATP synthase, or mitochondrial uncoupling protein 3. We conclude that prior exercise training blunts the deleterious effect of short-term, high-fat feeding on whole body efficiency.


The contribution of cytotoxic chemotherapy to 5-year survival in adult malignancies.
The debate on the funding and availability of cytotoxic drugs raises questions about the contribution of curative or adjuvant cytotoxic chemotherapy to survival in adult cancer patients. We undertook a literature search for randomised clinical trials reporting a 5-year survival benefit attributable solely to cytotoxic chemotherapy in adult malignancies. The total number of newly diagnosed cancer patients for 22 major adult malignancies was determined from cancer registry data in Australia and from the Surveillance Epidemiology and End Results data in the USA for 1998. For each malignancy, the absolute number to benefit was the product of (a) the total number of persons with that malignancy; (b) the proportion or subgroup(s) of that malignancy showing a benefit; and (c) the percentage increase in 5-year survival due solely to cytotoxic chemotherapy. The overall contribution was the sum total of the absolute numbers showing a 5-year survival benefit expressed as a percentage of the total number for the 22 malignancies. The overall contribution of curative and adjuvant cytotoxic chemotherapy to 5-year survival in adults was estimated to be 2.3% in Australia and 2.1% in the USA. As the 5-year relative survival rate for cancer in Australia is now over 60%, it is clear that cytotoxic chemotherapy only makes a minor contribution to cancer survival. To justify the continued funding and availability of drugs used in cytotoxic chemotherapy, a rigorous evaluation of the cost-effectiveness and impact on quality of life is urgently required.


Identification of neural targets for the treatment of psychiatric disorders: the role of functional neuroimaging.
Neurosurgical treatment of psychiatric disorders has been influenced by evolving neurobiological models of symptom generation. The advent of functional neuroimaging and advances in the neurosciences have revolutionized understanding of the functional neuroanatomy of psychiatric disorders. This article reviews neuroimaging studies of depression from the last 3 decades and describes an emerging neurocircuitry model of mood disorders, focusing on critical circuits of cognition and emotion, particularly those networks involved in the regulation of evaluative, expressive and experiential aspects of emotion. The relevance of this model for neurotherapeutics is discussed, as well as the role of functional neuroimaging of psychiatric disorders.


Long-term effects of treatment and response in patients with chronic hepatitis C on quality of life. An international, multicenter, randomized, controlled study.
Hepatitis C decreases health related quality of life (HRQL) which is further diminished by antiviral therapy. HRQL improves after successful treatment. This trial explores the course of and factors associated with HRQL in patients given individualized or standard treatment based on early treatment response (Ditto-study). The Short Form (SF)-36 Health Survey was administered at baseline (n = 192) and 24 weeks after the end of therapy (n = 128). At baseline HRQL was influenced by age, participating center, severity of liver disease and income. Exploring the course of HRQL (scores at follow up minus baseline), only the dimension general health increased. In this dimension patients with a relapse or sustained response differed from non-responders. Men and women differed in the dimension bodily pain. Treatment schedule did not influence the course of HRQL. Main determinants of HRQL were severity of liver disease, age, gender, participating center and response to treatment. Our results do not exclude a more profound negative impact of individualized treatment compared to standard, possibly caused by higher doses and extended treatment duration in the individualized group. Antiviral therapy might have a more intense and more prolonged negative impact on females.


Towards a genome-scale kinetic model of cellular metabolism.
Advances in bioinformatic techniques and analyses have led to the availability of genome-scale metabolic reconstructions. The size and complexity of such networks often means that their potential behaviour can only be analysed with constraint-based methods. Whilst requiring minimal experimental data, such methods are unable to give insight into cellular substrate concentrations. Instead, the long-term goal of systems biology is to use kinetic modelling to characterize fully the mechanics of each enzymatic reaction, and to combine such knowledge to predict system behaviour. We describe a method for building a parameterized genome-scale kinetic model of a metabolic network. Simplified linlog kinetics are used and the parameters are extracted from a kinetic model repository. We demonstrate our methodology by applying it to yeast metabolism. The resultant model has 956 metabolic reactions involving 820 metabolites, and, whilst approximative, has considerably broader remit than any existing models of its type. Control analysis is used to identify key steps within the system. Our modelling framework may be considered a stepping-stone toward the long-term goal of a fully-parameterized model of yeast metabolism. The model is available in SBML format from the BioModels database (BioModels ID: MODEL1001200000) and at http://www.mcisb.org/resources/genomescale/.


Thymosin beta4 induces epicardium-derived neovascularization in the adult heart.
The inability of the human heart to effectively repair itself after acute ischaemic injury has driven the search for efficacious means of promoting cardiac regenerative growth. Central to this has been the emergence of cell-based strategies to stimulate and augment both myocardial regeneration and neovascularization. Autologous cell transplantation of a variety of adult progenitor cells has been taken forward in clinical trials and, in parallel, investigators have begun to focus on the activation of resident cardiac cell populations as a means to stimulate endogenous repair. The latter approach depends on characterizing native progenitors with self-renewal, clonality, multipotency and arguably an analogous embryological counterpart. Recently, we have focused on adult EPDCs (epicardium-derived progenitor cells), which, when induced by the actin monomer-binding protein Tbeta4 (thymosin beta4), are able to revert to their embryonic phenotype and give rise to endothelial cells and vascular smooth muscle cells ex vivo. Studies are ongoing to determine whether activated adult EPDCs can contribute to bona fide neovascularization in the injured adult mammalian heart proper, as a therapeutic means to support surviving cardiac muscle cells and sustain regenerating myocardium.


WHO Expert Committee on Biological Standardization.
This report presents the recommendations of a WHO Expert Committee commissioned to coordinate activities leading to the adoption of international recommendations for the production and control of vaccines and other biologicals and the establishment of international biological reference materials. The report starts with a discussion of general issues brought to the attention of the Committee and provides information on the status and development of reference materials for various antibodies, antigens, blood products and related substances, cytokines, growth factors, and endocrinological substances. The second part of the report, of particular relevance to manufacturers and national regulatory authorities, contains guidelines on the production and quality control of candidate tetravalent dengue virus vaccines and recommendations for the preparation, characterization and establishment of international and other biological reference standards. Also included are a list of recommendations, guidelines and other documents for biological substances used in medicine, and of international standards and reference reagent for biological substances.


Role of fatty acids in the pathogenesis of insulin resistance and NIDDM.
Evidence is reviewed that free fatty acids (FFAs) are one important link between obesity and insulin resistance and NIDDM. First, plasma FFA levels are elevated in most obese subjects. Second, physiological elevations in plasma FFA concentrations inhibit insulin stimulated peripheral glucose uptake in a dose-dependent manner in normal controls and in patients with NIDDM. Two possible mechanisms are identified: 1) a fat-related inhibition of glucose transport or phosphorylation, which appears after 3-4 h of fat infusion, and 2) a decrease in muscle glycogen synthase activity, which appears after 4-6 h of fat infusion. Third, FFAs stimulate insulin secretion in nondiabetic individuals. Some of this insulin is transmitted in the peripheral circulation and is able to compensate for FFA-mediated peripheral insulin resistance. FFA-mediated portal hyperinsulinemia counteracts the stimulation of FFAs on hepatic glucose production (HGP) and thus prevents hepatic glucose overproduction. We speculate that, in obese individuals who are genetically predisposed to develop NIDDM, FFAs will eventually fail to promote insulin secretion. The stimulatory effect of FFAs on HGP would then become unchecked, resulting in hyperglycemia. Hence, continuously elevated levels of plasma FFAs may play a key role in the pathogenesis of NIDDM in predisposed individuals by impairing peripheral glucose utilization and by promoting hepatic glucose overproduction.


Topography of cortical and subcortical connections of the human pedunculopontine and subthalamic nuclei.
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is the most common surgical therapy for Parkinson' s disease (PD). DBS of the pedunculopontine nucleus (PPN) is emerging as a promising surgical therapy for PD as well. In order to better characterize these nuclei in humans, we determined the anatomical connections of the PPN and STN and the topography of these connections using probabilistic diffusion tractography. Diffusion tractography was carried out in eight healthy adult subjects using diffusion data acquired at 1.5 T MRI (60 directions, b=1000 s/mm(2), 2 x 2 x 2 mm(3) voxels). The major connections that we identified from single seed voxels within STN or PPN were present in at least half the subjects and the topography of these connections within a 36-voxel region surrounding the initial seed voxel was then examined. Both the PPN and STN showed connections with the cortex, basal ganglia, cerebellum, and down the spinal cord, largely matching connections demonstrated in primates. The topography of motor and associative brain areas in the human STN was strikingly similar to that shown in animals. PPN Topography has not been extensively demonstrated in animals, but we showed significant topography of cortical and subcortical connections in the human PPN. In addition to demonstrating the usefulness of PDT in determining the connections and topography of small grey matter structures in vivo, these results allow for inference of optimal DBS target locations and add to our understanding of the role of these nuclei in PD.


Complex gastric surgery in Germany-is centralization beneficial? Observational study using national hospital discharge data.
This observational study explored the association between hospital volume and short-term outcome following gastric resections for non-bariatric indication, aiming to contribute to the discussion on centralization of complex visceral surgery in Germany. Based on complete national hospital discharge data from 2010 to 2015, the association between hospital volume and in-hospital mortality was evaluated according to volume quintiles and volume deciles. Case-mix differences regarding surgical indication, age, sex, and comorbidities were considered for risk adjustment. In addition, rates of major complications and failure to rescue were analyzed across hospital volume categories. Inpatient episodes (72,528) with gastric resection were analyzed. Risk-adjusted mortality in patients treated in very low volume hospitals (median volume of 5 surgeries per year) was higher (12.0% [95% CI 11.4 to 12.5]) compared to those treated in very high volume hospitals (50 surgeries per year; 10.6% [10.0 to 11.1]). Failure to rescue patients with complications was 28.1% [27.0 to 29.3] in very low volume hospitals and 22.7% [21.6 to 23.8] in very high volume hospitals. Differences were similar within the subgroup of patients operated for gastric cancer. Treatment in very high volume hospitals is associated with a lower in-hospital mortality compared to treatment in very low volume hospitals. This effect seems to be determined by the ability to rescue patients who experience complications. As the observed benefit is only related to very high volumes, the results do not clearly indicate that centralization may improve short-term results substantially, unless a very high degree of centralization would be achieved. Possibly, further research focusing on other outcome measures, such as clinical processes or long-term results, might lead to divergent conclusions.


A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease.
Genome-wide association studies have identified 11 common variants convincingly associated with coronary artery disease (CAD)¹⁻⁷, a modest number considering the apparent heritability of CAD⁸. All of these variants have been discovered in European populations. We report a meta-analysis of four large genome-wide association studies of CAD, with ∼575,000 genotyped SNPs in a discovery dataset comprising 15,420 individuals with CAD (cases) (8,424 Europeans and 6,996 South Asians) and 15,062 controls. There was little evidence for ancestry-specific associations, supporting the use of combined analyses. Replication in an independent sample of 21,408 cases and 19,185 controls identified five loci newly associated with CAD (P < 5 × 10⁻⁸ in the combined discovery and replication analysis): LIPA on 10q23, PDGFD on 11q22, ADAMTS7-MORF4L1 on 15q25, a gene rich locus on 7q22 and KIAA1462 on 10p11. The CAD-associated SNP in the PDGFD locus showed tissue-specific cis expression quantitative trait locus effects. These findings implicate new pathways for CAD susceptibility.


Effectiveness of acupuncture and bee venom acupuncture in idiopathic Parkinson's disease.
This study aimed to explore the effectiveness of both acupuncture and bee venom acupuncture as adjuvant therapies for idiopathic Parkinson's disease. We recruited 43 adults with idiopathic Parkinson's disease who had been on a stable dose of antiparkinsonian medication for at least 1 month. They were randomly assigned to 1 of 3 groups: acupuncture, bee venom acupuncture, or control. All participants were assessed using the Unified Parkinson's Disease Rating Scale, the Parkinson's Disease Quality of Life Questionnaire, the Beck Depression Inventory, the Berg Balance Scale, and the time and number of steps required to walk 30 m. Treatment groups underwent stimulation of 10 acupuncture points using acupuncture or bee venom acupuncture twice a week for 8 weeks. The initial assessment was repeated at the completion of treatment. The control group did not receive any treatment. Participants in the bee venom acupuncture group showed significant improvement on the Unified Parkinson's Disease Rating Scale (total score, as well as parts II and III individually), the Berg Balance Scale, and the 30 m walking time. When compared to the control group, the bee venom acupuncture group experienced significantly greater improvement on the Unified Parkinson's Disease Rating Scale. In the acupuncture group, the Unified Parkinson's Disease Rating Scale (part III and total scores) and the Beck Depression Inventory showed significant improvement. The control group showed no significant changes in any outcome after 8 weeks. In this pilot study, both acupuncture and bee venom acupuncture showed promising results as adjuvant therapies for Parkinson's disease.


Understanding dyspnea as a complex individual experience.
Dyspnea is the highly threatening experience of breathlessness experienced by patients with diverse pathologies, including respiratory, cardiovascular, and neuromuscular diseases, cancer and panic disorder. This debilitating symptom is especially prominent in the elderly and the obese, two growing populations in the Western world. It has further been found that women suffer more strongly from dyspnea than men. Despite optimization of disease-specific treatments, dyspnea is often inadequately treated. The immense burden faced by patients, families and the healthcare system makes improving management of chronic dyspnea a priority. Dyspnea is a multidimensional sensation that encompasses an array of unpleasant respiratory sensations that vary according to underlying cause and patient characteristics. Biopsychological factors beyond disease pathology exacerbate the perception of dyspnea, increase symptom severity and reduce quality of life. Psychological state (especially comorbid anxiety and depression), hormone status, gender, body weight (obesity) and general fitness level are particularly important. Neuroimaging has started to uncover the neural mechanisms involved in the processing of sensory and affective components of dyspnea. Awareness of biopsychological factors beyond pathology is essential for diagnosis and treatment of dyspnea. Increasing understanding the interactions between biopsychological factors and dyspnea perception will enhance the development of symptomatic treatments that specifically address each patient's most pressing needs at a specific stage in life. Future neuroimaging research can provide objective markers to fully understand the role of biopsychological factors in the perception of dyspnea in the hope of uncovering target areas for pharmacologic and non-pharmacologic therapy.


Ultrathin, high-efficiency, broad-band, omni-acceptance, organic solar cells enhanced by plasmonic cavity with subwavelength hole array.
Three of central challenges in solar cells are high light coupling into solar cell, high light trapping and absorption in a sub-absorption-length-thick active layer, and replacement of the indium-tin-oxide (ITO) transparent electrode used in thin-film devices. Here, we report a proposal and the first experimental study and demonstration of a new ultra-thin high-efficiency organic solar cell (SC), termed "plasmonic cavity with subwavelength hole-array (PlaCSH) solar cell", that offers a solution to all three issues with unprecedented performances. The ultrathin PlaCSH-SC is a thin plasmonic cavity that consists of a 30 nm thick front metal-mesh electrode with subwavelength hole-array (MESH) which replaces ITO, a thin (100 nm thick) back metal electrode, and in-between a polymer photovoltaic active layer (P3HT/PCBM) of 85 nm thick (1/3 average absorption-length). Experimentally, the PlaCSH-SCs have achieved (1) light coupling-efficiency/absorptance as high as 96% (average 90%), broad-band, and Omni acceptance (light coupling nearly independent of both light incident angle and polarization); (2) an external quantum efficiency of 69% for only 27% single-pass active layer absorptance; leading to (3) a 4.4% power conversion efficiency (PCE) at standard-solar-irradiation, which is 52% higher than the reference ITO-SC (identical structure and fabrication to PlaCSH-SC except MESH replaced by ITO), and also is among the highest PCE for the material system that was achievable previously only by using thick active materials and/or optimized polymer compositions and treatments. In harvesting scattered light, the Omni acceptance can increase PCE by additional 81% over ITO-SC, leading to a total 175% increase (i.e. 8% PCE). Furthermore, we found that (a) after formation of PlaCSH the light reflection and absorption by MESH are reduced by 2 to 6 fold from the values when it is alone; and (b) the sheet resistance of a 30 nm thick MESH is 2.2 ohm/sq or less-4.5 fold or more lower than the best reported value for a 100 nm thick ITO film, giving a lowest reflectance-sheet-resistance product. Finally, fabrication of PlaCSH has used nanoimprint on 4" wafer and is scalable to roll-to-roll manufacturing. The designs, fabrications, and findings are applicable to thin solar cells in other materials.


Impact of microscopic motility on the swimming behavior of parasites: straighter trypanosomes are more directional.
Microorganisms, particularly parasites, have developed sophisticated swimming mechanisms to cope with a varied range of environments. African Trypanosomes, causative agents of fatal illness in humans and animals, use an insect vector (the Tsetse fly) to infect mammals, involving many developmental changes in which cell motility is of prime importance. Our studies reveal that differences in cell body shape are correlated with a diverse range of cell behaviors contributing to the directional motion of the cell. Straighter cells swim more directionally while cells that exhibit little net displacement appear to be more bent. Initiation of cell division, beginning with the emergence of a second flagellum at the base, correlates to directional persistence. Cell trajectory and rapid body fluctuation correlation analysis uncovers two characteristic relaxation times: a short relaxation time due to strong body distortions in the range of 20 to 80 ms and a longer time associated with the persistence in average swimming direction in the order of 15 seconds. Different motility modes, possibly resulting from varying body stiffness, could be of consequence for host invasion during distinct infective stages.


Neuroprotective and disease-modifying effects of the ketogenic diet.
The ketogenic diet has been in clinical use for over 80 years, primarily for the symptomatic treatment of epilepsy. A recent clinical study has raised the possibility that exposure to the ketogenic diet may confer long-lasting therapeutic benefits for patients with epilepsy. Moreover, there is evidence from uncontrolled clinical trials and studies in animal models that the ketogenic diet can provide symptomatic and disease-modifying activity in a broad range of neurodegenerative disorders including Alzheimer's disease and Parkinson's disease, and may also be protective in traumatic brain injury and stroke. These observations are supported by studies in animal models and isolated cells that show that ketone bodies, especially beta-hydroxybutyrate, confer neuroprotection against diverse types of cellular injury. This review summarizes the experimental, epidemiological and clinical evidence indicating that the ketogenic diet could have beneficial effects in a broad range of brain disorders characterized by the death of neurons. Although the mechanisms are not yet well defined, it is plausible that neuroprotection results from enhanced neuronal energy reserves, which improve the ability of neurons to resist metabolic challenges, and possibly through other actions including antioxidant and anti-inflammatory effects. As the underlying mechanisms become better understood, it will be possible to develop alternative strategies that produce similar or even improved therapeutic effects without the need for exposure to an unpalatable and unhealthy, high-fat diet.


A novel mouse synaptonemal complex protein is essential for loading of central element proteins, recombination, and fertility.
The synaptonemal complex (SC) is a proteinaceous, meiosis-specific structure that is highly conserved in evolution. During meiosis, the SC mediates synapsis of homologous chromosomes. It is essential for proper recombination and segregation of homologous chromosomes, and therefore for genome haploidization. Mutations in human SC genes can cause infertility. In order to gain a better understanding of the process of SC assembly in a model system that would be relevant for humans, we are investigating meiosis in mice. Here, we report on a newly identified component of the murine SC, which we named SYCE3. SYCE3 is strongly conserved among mammals and localizes to the central element (CE) of the SC. By generating a Syce3 knockout mouse, we found that SYCE3 is required for fertility in both sexes. Loss of SYCE3 blocks synapsis initiation and results in meiotic arrest. In the absence of SYCE3, initiation of meiotic recombination appears to be normal, but its progression is severely impaired resulting in complete absence of MLH1 foci, which are presumed markers of crossovers in wild-type meiocytes. In the process of SC assembly, SYCE3 is required downstream of transverse filament protein SYCP1, but upstream of the other previously described CE-specific proteins. We conclude that SYCE3 enables chromosome loading of the other CE-specific proteins, which in turn would promote synapsis between homologous chromosomes.


Global cost of correcting vision impairment from uncorrected refractive error.
To estimate the global cost of establishing and operating the educational and refractive care facilities required to provide care to all individuals who currently have vision impairment resulting from uncorrected refractive error (URE). The global cost of correcting URE was estimated using data on the population, the prevalence of URE and the number of existing refractive care practitioners in individual countries, the cost of establishing and operating educational programmes for practitioners and the cost of establishing and operating refractive care facilities. The assumptions made ensured that costs were not underestimated and an upper limit to the costs was derived using the most expensive extreme for each assumption. There were an estimated 158 million cases of distance vision impairment and 544 million cases of near vision impairment caused by URE worldwide in 2007. Approximately 47 000 additional full-time functional clinical refractionists and 18 000 ophthalmic dispensers would be required to provide refractive care services for these individuals. The global cost of educating the additional personnel and of establishing, maintaining and operating the refractive care facilities needed was estimated to be around 20 000 million United States dollars (US$) and the upper-limit cost was US$ 28 000 million. The estimated loss in global gross domestic product due to distance vision impairment caused by URE was US$ 202 000 million annually. The cost of establishing and operating the educational and refractive care facilities required to deal with vision impairment resulting from URE was a small proportion of the global loss in productivity associated with that vision impairment.


Lung cancer deaths from indoor radon and the cost effectiveness and potential of policies to reduce them.
To determine the number of deaths from lung cancer related to radon in the home and to explore the cost effectiveness of alternative policies to control indoor radon and their potential to reduce lung cancer mortality. Cost effectiveness analysis. United Kingdom. Epidemiological data on risks from indoor radon and from smoking, vital statistics on deaths from lung cancer, survey information on effectiveness and costs of radon prevention and remediation. Estimated number of deaths from lung cancer related to indoor radon, lifetime risks of death from lung cancer before and after various potential interventions to control radon, the cost per quality adjusted life year (QALY) gained from different policies for control of radon, and the potential of those policies to reduce lung cancer mortality. The mean radon concentration in UK homes is 21 becquerels per cubic metre (Bq/m(3)). Each year around 1100 deaths from lung cancer (3.3% of all deaths from lung cancer) are related to radon in the home. Over 85% of these arise from radon concentrations below 100 Bq/m(3) and most are caused jointly by radon and active smoking. Current policy requiring basic measures to prevent radon in new homes in selected areas is highly cost effective, and such measures would remain cost effective if extended to the entire UK, with a cost per QALY gained of pound11,400 ( euro12 200; $16,913). Current policy identifying and remediating existing homes with high radon levels is, however, neither cost effective (cost per QALY gained pound36,800) nor effective in reducing lung cancer mortality. Policies requiring basic preventive measures against radon in all new homes throughout the UK would be cost effective and could complement existing policies to reduce smoking. Policies involving remedial work on existing homes with high radon levels cannot prevent most radon related deaths, as these are caused by moderate exposure in many homes. These conclusions are likely to apply to most developed countries, many with higher mean radon concentrations than the UK.