Comparison of multivariate predictive power of major risk factors for coronary heart diseases in different countries: results from eight nations of the Seven Countries Study, 25-year follow-up.
It was hypothesized that among eight national groups of men aged 40-59 years enrolled in the Seven Countries Study, the multivariate coefficients of major risk factors predicting coronary heart disease mortality over 25 years would be relatively similar. Sixteen cohorts were located in eight nations and pooled, comprising one cohort in the USA, two in Finland, one in the Netherlands, three in Italy, two in Croatia (former Yugoslavia), three in Serbia (Yugoslavia), two in Greece and two in Japan, for a total of over 12000 subjects at entry. Coronary heart disease (CHD) mortality was defined as fatal myocardial infarction or sudden coronary death, and proportional hazard models were solved, for each country, with age, serum cholesterol level, systolic blood pressure and cigarette consumption as covariates. The relationships between risk factors and CHD mortality were statistically significant for all risk factors and for all countries, except for age in Croatia and Japan, cholesterol in Croatia and Japan, systolic blood pressure in Serbia and Greece, and cigarette-smoking in the Netherlands, Croatia, Serbia and Greece. When comparing all pairs of coefficients (28 comparisons for each factor) significant differences were found on four occasions for age, on six occasions for cholesterol, on no occasion for blood pressure and on four occasions for cigarette-smoking. Other tests suggested a substantial homogeneity among multivariate coefficients. Estimates for pooled coefficients were: age, in years, 0.0570 (95% confidence limits 0.0465 and 0.0673); relative risk for 5 years 1.33 (95% confidence limits 1.26 and 1.40); serum cholesterol level in mg/dl, 0.0057 (95% confidence limits 0.0045 and 0.0069); relative risk for 40 mg/dl 1.31 (95% confidence limits 1.20 and 1.31); systolic blood pressure in mmHg, 0.0160, (95% confidence limits 0.0134 and 0.0185), relative risk for 20 mmHg 1.38 (95% confidence limits 1.31 and 1.45); cigarettes per day, 0.0220 (95% confidence limits 0.0170 and 0.0272); relative risk for 10 cigarettes per day 1.25 (95% confidence limits 1.18 and 1.31). Great similarities were found in the multivariate coefficients of major coronary risk factors to CHD risk derived from population samples varying in CHD frequency.


Gradient-based reliability maps for ACM-based segmentation of hippocampus.
Automatic segmentation of deep brain structures, such as the hippocampus (HC), in MR images has attracted considerable scientific attention due to the widespread use of MRI and to the principal role of some structures in various mental disorders. In this literature, there exists a substantial amount of work relying on deformable models incorporating prior knowledge about structures' anatomy and shape information. However, shape priors capture global shape characteristics and thus fail to model boundaries of varying properties; HC boundaries present rich, poor, and missing gradient regions. On top of that, shape prior knowledge is blended with image information in the evolution process, through global weighting of the two terms, again neglecting the spatially varying boundary properties, causing segmentation faults. An innovative method is hereby presented that aims to achieve highly accurate HC segmentation in MR images, based on the modeling of boundary properties at each anatomical location and the inclusion of appropriate image information for each of those, within an active contour model framework. Hence, blending of image information and prior knowledge is based on a local weighting map, which mixes gradient information, regional and whole brain statistical information with a multi-atlas-based spatial distribution map of the structure's labels. Experimental results on three different datasets demonstrate the efficacy and accuracy of the proposed method.


The impact of next-generation sequencing technologies on HLA research.
In the past decade, the development of next-generation sequencing (NGS) has paved the way for whole-genome analysis in individuals. Research on the human leukocyte antigen (HLA), an extensively studied molecule involved in immunity, has benefitted from NGS technologies. The HLA region, a 3.6-Mb segment of the human genome at 6p21, has been associated with more than 100 different diseases, primarily autoimmune diseases. Recently, the HLA region has received much attention because severe adverse effects of various drugs are associated with particular HLA alleles. Owing to the complex nature of the HLA genes, classical direct sequencing methods cannot comprehensively elucidate the genomic makeup of HLA genes. Thus far, several high-throughput HLA-typing methods using NGS have been developed. In HLA research, NGS facilitates complete HLA sequencing and is expected to improve our understanding of the mechanisms through which HLA genes are modulated, including transcription, regulation of gene expression and epigenetics. Most importantly, NGS may also permit the analysis of HLA-omics. In this review, we summarize the impact of NGS on HLA research, with a focus on the potential for clinical applications.


The Endometriotic Tumor Microenvironment in Ovarian Cancer.
Women with endometriosis are at increased risk of developing ovarian cancer, specifically ovarian endometrioid, low-grade serous, and clear-cell adenocarcinoma. An important clinical caveat to the association of endometriosis with ovarian cancer is the improved prognosis for women with endometriosis at time of ovarian cancer staging. Whether endometriosis-associated ovarian cancers develop from the molecular transformation of endometriosis or develop because of the endometriotic tumor microenvironment remain unknown. Additionally, how the presence of endometriosis improves prognosis is also undefined, but likely relies on the endometriotic microenvironment. The unique tumor microenvironment of endometriosis is composed of epithelial, stromal, and immune cells, which adapt to survive in hypoxic conditions with high levels of iron, estrogen, and inflammatory cytokines and chemokines. Understanding the unique molecular features of the endometriotic tumor microenvironment may lead to impactful precision therapies and/or modalities for prevention. A challenge to this important study is the rarity of well-characterized clinical samples and the limited model systems. In this review, we will describe the unique molecular features of endometriosis-associated ovarian cancers, the endometriotic tumor microenvironment, and available model systems for endometriosis-associated ovarian cancers. Continued research on these unique ovarian cancers may lead to improved prevention and treatment options.


Initial experience of laparoscopic management of apparent early endometrial cancer.
The traditional treatment for endometrial cancer is a staging laparotomy. In patients with apparent early stage disease, laparoscopic assisted vaginal hysterectomy has been employed as an alternative. We present a retrospective uncontrolled case series of 16 cases with apparent stage I endometrial cancer from November 1994 to April 2001 managed by laparoscopic assisted surgical staging (LASS) at the Gynaecological Oncology Department, KK Women's and Children's Hospital, Singapore. We have analysed outcome measures in terms of intra-operative complications, surgical morbidity and length of hospital stay, and have evaluated treatment success in terms of conversion to laparotomy, recurrent disease and mortality. Our findings indicate that LASS is a viable option in selected patients with apparent early endometrial cancer. Our initial experience with this modality of treatment thus proves that it has great potential in both treatment success and reduction of surgical morbidity. A larger case controlled trial would be ideal in order to substantiate these benefits.


MinION sequencing to genotype US strains of infectious laryngotracheitis virus.
Over the last decade the US broiler industry has fought long-lasting outbreaks of infectious laryngotracheitis (ILTV). Previously, nine genotypes (I-IX) of ILTVs have been recognized using the polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) method with three viral alleles (gB, gM and UL47/gG). In this study, the genotyping system was simplified to six genotypes by amplicon sequencing and examining discriminating single nucleotide polymorphisms (SNPs) within these open reading frames. Using phylogenomic analysis of 27 full genomes of ILTV, a single allele (ORF A/ORF B) was identified containing SNPs that could differentiate ILTVs into genotypes congruent with the phylogenetic partitioning. The allelic variations allowed for the cataloging of the 27 strains into 5 genotypes: vaccinal TCO, vaccinal CEO, virulent CEO-like, virulent US and virulent US backyard flocks from 1980 to 1990, correlating with the PCR-RFLP genotypes I/ II/ III (TCO), IV (CEO), V (virulent CEO-like), VI (virulent US) and VII/VIII/IX (virulent US backyard flock isolates). With the unique capabilities of third generation sequencing, we investigated the application of Oxford Nanopore MinION technology for rapid sequencing of the amplicons generated in the single-allele assay. This technology was an improvement over Sanger-based sequencing of the single allele amplicons due to a booster amplification step in the MinION sequencing protocol. Overall, there was a 90% correlation between the genotyping results of the single-allele assay and the multi-allele assay. Surveillance of emerging ILTV strains could greatly benefit from real-time amplicon sequencing using the single-allele assay and MinION sequencing. RESEARCH HIGHLIGHTS A multi-allelic assay identified nine ILTV genotypes circulating in the US Single-allele genotyping is congruent with whole genome phylogenetic partitioning US ILTV strains can be grouped into five genotypes using the single-allele assay The single-allele assay can be done using MinION sequencing of barcoded amplicons.


Tissue-specific stable isotope measurements of postprandial lipid metabolism in familial combined hyperlipidaemia.
The metabolic defects underlying familial combined hyperlipidaemia (FCHL) are not clearly understood. We used stable isotope techniques combined with tissue-specific measurements in adipose tissue and forearm muscle to investigate fatty acid handling by these tissues in the fasting and postprandial states. Patients were insulin resistant as shown by higher glucose and insulin concentrations and lower muscle glucose extraction than controls. Plasma triacylglycerol (TAG) concentrations were higher in patients. Adipose tissue TAG extraction was not lower in patients than controls, although TAG clearance was lower, probably representing saturation. Following a test meal, patients showed a greater increase in chylomicron-TAG concentrations. There were no differences between FCHL patients and controls in postprandial suppression of non-esterified fatty acid (NEFA) concentrations or postprandial NEFA release, but patients had greater trapping of exogenous fatty acids in adipose tissue. 3-Hydroxybutyrate concentrations were lower in patients indicative of decreased hepatic fatty acid oxidation. In this group of patients with FCHL, the major defect appeared to be overproduction of TAG by the liver due to decreased fatty acid oxidation, with fatty acids directed to TAG synthesis. We found no evidence of decreased lipoprotein lipase action or impaired fatty acid re-esterification in adipose tissue.


The urgent need for advance directives in India.
Many individuals at the end of life are unable to convey their wishes regarding medical treatments. Advance directives (ADs) or living wills (LWs) allow them to crystallise their wishes in a written form so that these can be carried out if the relevant situation arises. In many countries, ADs are legally valid and enforceable; they reduce the use of life-sustaining treatments, which often merely prolong life without improving or even maintaining the quality of life. Such treatment puts a financial burden on the patient's family, often leading to penury. Resources are limited, the more so in countries like ours, and should be spent only when/where they can make a difference. The general public is not well versed in the advantages and disadvantages of life-sustaining treatments and needs to be educated on how to distinguish between them. A well-designed legislation for legalising ADs would help society at large. In addition to legalising ADs, some countries are contemplating making them compulsory. We could learn from them and empower our citizens by giving them the right to self-determination at the end of life.


Diffusion propagator estimation from sparse measurements in a tractography framework.
Estimation of the diffusion propagator from a sparse set of diffusion MRI (dMRI) measurements is a field of active research. Sparse reconstruction methods propose to reduce scan time and are particularly suitable for scanning un-coperative patients. Recent work on reconstructing the diffusion signal from very few measurements using compressed sensing based techniques has focussed on propagator (or signal) estimation at each voxel independently. However, the goal of many neuroscience studies is to use tractography to study the pathology in white matter fiber tracts. Thus, in this work, we propose a joint framework for robust estimation of the diffusion propagator from sparse measurements while simultaneously tracing the white matter tracts. We propose to use a novel multi-tensor model of diffusion which incorporates the biexponential radial decay of the signal. Our preliminary results on in-vivo data show that the proposed method produces consistent and reliable fiber tracts from very few gradient directions while simultaneously estimating the bi-exponential decay of the diffusion propagator.


Are torpid bats immune to anthropogenic noise?
Anthropogenic noise has a negative impact on a variety of animals. However, many bat species roost in places with high levels of anthropogenic noise. Here, we tested the hypothesis that torpid bats are insensitive to anthropogenic noise. In a laboratory experiment, we recorded skin temperature (Tsk) of bats roosting individually that were subjected to playbacks of different types of noise. We found that torpid bats with Tsk ~10°C lower than their active Tsk responded to all types of noise by elevating Tsk. Bats responded most strongly to colony and vegetation noise, and most weakly to traffic noise. The time of day when torpid bats were exposed to noise had a pronounced effect on responses. Torpid bats showed increasing responses from morning towards evening, i.e. towards the onset of the active phase. Skin temperature at the onset of noise exposure (Tsk,start, 17-29°C) was not related to the response. Moreover, we found evidence that torpid bats rapidly habituated to repeated and prolonged noise exposure.


Hospital nurse practice environment, burnout, job outcomes and quality of care: test of a structural equation model.
The aim of the study was to investigate relationships between nurse practice environment, burnout, job outcomes and nurse-assessed quality of care. A growing line of work confirms that, in countries with distinctly different healthcare systems, nurses report similar shortcomings in their work environments and the quality of care in hospitals. Neither the specific work environment factors most involved in dissatisfaction, burnout and other negative job outcomes, and patient outcomes, nor the mechanisms tying nurse job outcomes to quality of care are well understood. A Nurse Practice Environment and Outcome causal structure involving pathways between practice environment dimensions and outcome variables with components of burnout in a mediating position was developed. Survey data from 401 staff nurses across 31 units in two hospitals (including the Revised Nursing Work Index, the Maslach Burnout Inventory, and job outcome and nurse-assessed quality of care variables) were used to test this model using structural equation modelling techniques. The data were collected from December 2006 to January 2007. Goodness of fit statistics confirmed an improved model with burnout dimensions in mediating positions between nurse practice environment dimensions and both job outcomes and nurse-assessed quality of care, explaining 20% and 46% of variation in these two indicators, respectively. These findings suggest that hospital organizational properties, including nurse-physician relations, are related to quality of care assessments, and to the outcomes of job satisfaction and turnover intentions, with burnout dimensions appearing to play mediating roles. Additionally, a direct relationship between assessments of care quality and management at the unit level was observed.


Effects of ⁵⁶Fe-particle cranial radiation on hippocampus-dependent cognition depend on the salience of the environmental stimuli.
Ionizing radiation reduces the numbers of neurons expressing activity-regulated cytoskeleton-associated protein (Arc) in the hippocampal dentate gyrus (DG). It is currently unclear if that change relates to cognitive function. We assessed the effects of 1 Gy of head-only ⁵⁶Fe-particle irradiation on hippocampus-dependent and hippocampus-independent fear conditioning and determined how those changes related to Arc expression within the DG. Irradiated mice that did not receive tone-shock pairings on day 1 showed less freezing in the same context on a second day and a lower fraction of Arc-expressing neurons in the free (lower) blade of the DG than sham-irradiated mice. Those data suggested reduced hippocampus-dependent spatial habituation learning. Changes in Arc expression in the free blade correlated positively with freezing in mice that did not receive tone-shock pairings. However, irradiated mice that did receive tone-shock pairings showed enhanced contextual freezing but a reduced percentage of Arc-expressing neurons in the enclosed (upper) blade. Changes in Arc expression correlated negatively with freezing in mice that received tone-shock pairings. In animals receiving cued fear conditioning, radiation did not affect cognitive performance or the fractions of Arc-expressing neurons. While the relationship between Arc expression and cognitive performance is complex, our data suggest that radiation effects on hippocampus-dependent cognition might depend on the prominence (salience) of environmental stimuli and blade-specific Arc expression.


Association of Body Mass Index and Age With Subsequent Breast Cancer Risk in Premenopausal Women.
The association between increasing body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) and risk of breast cancer is unique in cancer epidemiology in that a crossover effect exists, with risk reduction before and risk increase after menopause. The inverse association with premenopausal breast cancer risk is poorly characterized but might be important in the understanding of breast cancer causation. To investigate the association of BMI with premenopausal breast cancer risk, in particular by age at BMI, attained age, risk factors for breast cancer, and tumor characteristics. This multicenter analysis used pooled individual-level data from 758 592 premenopausal women from 19 prospective cohorts to estimate hazard ratios (HRs) of premenopausal breast cancer in association with BMI from ages 18 through 54 years using Cox proportional hazards regression analysis. Median follow-up was 9.3 years (interquartile range, 4.9-13.5 years) per participant, with 13 082 incident cases of breast cancer. Participants were recruited from January 1, 1963, through December 31, 2013, and data were analyzed from September 1, 2013, through December 31, 2017. Body mass index at ages 18 to 24, 25 to 34, 35 to 44, and 45 to 54 years. Invasive or in situ premenopausal breast cancer. Among the 758 592 premenopausal women (median age, 40.6 years; interquartile range, 35.2-45.5 years) included in the analysis, inverse linear associations of BMI with breast cancer risk were found that were stronger for BMI at ages 18 to 24 years (HR per 5 kg/m2 [5.0-U] difference, 0.77; 95% CI, 0.73-0.80) than for BMI at ages 45 to 54 years (HR per 5.0-U difference, 0.88; 95% CI, 0.86-0.91). The inverse associations were observed even among nonoverweight women. There was a 4.2-fold risk gradient between the highest and lowest BMI categories (BMI≥35.0 vs <17.0) at ages 18 to 24 years (HR, 0.24; 95% CI, 0.14-0.40). Hazard ratios did not appreciably vary by attained age or between strata of other breast cancer risk factors. Associations were stronger for estrogen receptor-positive and/or progesterone receptor-positive than for hormone receptor-negative breast cancer for BMI at every age group (eg, for BMI at age 18 to 24 years: HR per 5.0-U difference for estrogen receptor-positive and progesterone receptor-positive tumors, 0.76 [95% CI, 0.70-0.81] vs hormone receptor-negative tumors, 0.85 [95% CI: 0.76-0.95]); BMI at ages 25 to 54 years was not consistently associated with triple-negative or hormone receptor-negative breast cancer overall. The results of this study suggest that increased adiposity is associated with a reduced risk of premenopausal breast cancer at a greater magnitude than previously shown and across the entire distribution of BMI. The strongest associations of risk were observed for BMI in early adulthood. Understanding the biological mechanisms underlying these associations could have important preventive potential.


Laparoscopic aortobifemoral bypass in a USA academic center.
Although aortoiliac occlusive disease (AIOD) is preferentially treated endovascularly, some patients are still better served with an aortobifemoral bypass (ABF). For those patients, surgical treatment options include both standard open operations as well as laparoscopic ABF (LapABF). Several European centers perform LapABF with favorable results instead of open surgery, but this has not been widely embraced in the United States. We reviewed our ten-year experience with LapABF, evolving from a completely laparoscopic to a standardized laparoscopic-assisted approach. A retrospective review of all laparoscopic aortic operations performed at a single US academic institution from 2005 to 2015 was completed. Demographics, co-morbidities, intraoperative parameters and clinical outcomes were recorded. Patients were excluded from consideration for laparoscopic surgery if they had previous aortic surgery, aneurysmal disease or gastrointestinal pathology (e.g. diverticulitis or an enteric stoma). Thirty men and sixteen women were treated, (n=46) with a mean age of 55.7 (range 38-75 years). All operations were performed by a single surgeon. LapABF was successfully completed in 95.6%. A completely laparoscopic approach was undertaken in eight patients and a laparoscopic-assisted approach was used in the remaining 38 patients. Mean follow-up was 46 months (range 1 to 131). The indication for operation was claudication (n=35, 76%), rest pain (n=8, 17%) or tissue loss (n=3, 7%). Twenty-one limbs had a history of a prior failed aortoiliac endovascular intervention (23%). Median length of stay was 6 days (range 2-30). Within 30 days there were two myocardial infarctions (4.3%), one transient ischemic attack (2.2%) and one death (2.2%). Re-intervention was performed in 12 patients over the course of the study period (26.1%). Primary, primary-assisted and secondary patency was 79.4%, 93.9% and 94.9% at 60 months, respectively. Overall mortality was 17% with a mean duration of follow-up of 60 months (range 1-116). Multivariable analysis revealed coronary artery disease (CAD; P=0.03) conferred a sixteen-fold risk for death during long-term follow-up. In this large US series of LapABF, we observed acceptable long-term patency, short length of stay and minimal morbidity. We suggest that this standardized approach for laparoscopic-assisted ABF is a viable option for patients with AIOD not suitable for endovascular therapy. The use of laparoscopic-assisted ABF affords practitioners the benefits of a completely laparoscopic approach while reducing the duration and complexity of the operation. Given the rate of re-interventions in the early era practitioners should be aware of the learning curve with this approach.


Selective characterization of microsecond motions in proteins by NMR relaxation.
The three-dimensional structures of macromolecules fluctuate over a wide range of time-scales. Separating the individual dynamic processes according to frequency is of importance in relating protein motions to biological function and stability. We present here a general NMR method for the specific characterization of microsecond motions at backbone positions in proteins even in the presence of other dynamics such as large-amplitude nanosecond motions and millisecond chemical exchange processes. The method is based on measurement of relaxation rates of four bilinear coherences and relies on the ability of strong continuous radio frequency fields to quench millisecond chemical exchange. The utility of the methodology is demonstrated and validated through two specific examples focusing on the thermo-stable proteins, ubiquitin and protein L, where it is found that small-amplitude microsecond dynamics are more pervasive than previously thought. Specifically, these motions are localized to alpha helices, loop regions, and regions along the rim of beta sheets in both of the proteins examined. A third example focuses on a 28 kDa ternary complex of the chaperone Chz1 and the histones H2A.Z/H2B, where it is established that pervasive microsecond motions are localized to a region of the chaperone that is important for stabilizing the complex. It is further shown that these motions can be well separated from extensive millisecond dynamics that are also present and that derive from exchange of Chz1 between bound and free states. The methodology is straightforward to implement, and data recorded at only a single static magnetic field are required.


Modulation of embryonic glutathione reductase and phenytoin teratogenicity by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU).
The teratogenicity of phenytoin may be mediated through a reactive electrophilic and/or free radical intermediate which, if not detoxified, may interact with fetal cellular macromolecules and initiate teratologic effects. Glutathione (GSH) maintains cellular physiological processes and detoxifies xenobiotic reactive intermediates. The role of GSH in protection against phenytoin embryopathy was studied by altering GSH homeostasis using 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), an inhibitor of glutathione reductase. BCNU was administered to pregnant CD-1 mice on gestational day 12, in doses ranging from 10 to 50 mg/kg i.p., with or without phenytoin, 55 or 65 mg/kg i.p., given 4 and 24 hr after BCNU. BCNU alone in doses of 10, 25 or 50 mg/kg resulted in a dose-related increase in the incidence of resorptions, cleft palates and postpartum death (P less than .05), and in lowered fetal weight (P less than .05). Fetuses exposed to 50 mg/kg of BCNU had an array of gross abnormalities, and this dose was not used in subsequent studies. BCNU, 25 mg/kg, inhibited GSH reductase activity by 23% in the placenta (P less than .05) and by 30% in the embryo (P less than .05) at 4 hr after treatment. Embryonic, but not placental GSH reductase activity remained significantly inhibited at 24 hr after BCNU. A BCNU dose-related increase in the incidence of resorptions (P less than .0001) and postpartum death (P less than .05) was seen in groups treated with both BCNU and 65 mg/kg of phenytoin, compared to controls treated with either chemical alone.(ABSTRACT TRUNCATED AT 250 WORDS)


Acute activation, desensitization and smoldering activation of human acetylcholine receptors.
The behavioral effects of nicotine and other nicotinic agonists are mediated by AChRs in the brain. The relative contribution of acute activation versus chronic desensitization of AChRs is unknown. Sustained "smoldering activation" occurs over a range of agonist concentrations at which activated and desensitized AChRs are present in equilibrium. We used a fluorescent dye sensitive to changes in membrane potential to examine the effects of acute activation and chronic desensitization by nicotinic AChR agonists on cell lines expressing human α4β2, α3β4 and α7 AChRs. We examined the effects of acute and prolonged application of nicotine and the partial agonists varenicline, cytisine and sazetidine-A on these AChRs. The range of concentrations over which nicotine causes smoldering activation of α4β2 AChRs was centered at 0.13 µM, a level found in smokers. However, nicotine produced smoldering activation of α3β4 and α7 AChRs at concentrations well above levels found in smokers. The α4β2 expressing cell line contains a mixture of two stoichiometries, namely (α4β2)2β2 and (α4β2)2α4. The (α4β2)2β2 stoichiometry is more sensitive to activation by nicotine. Sazetidine-A activates and desensitizes only this stoichiometry. Varenicline, cytisine and sazetidine-A were partial agonists on this mixture of α4β2 AChRs, but full agonists on α3β4 and α7 AChRs. It has been reported that cytisine and varenicline are most efficacious on the (α4β2)2α4 stoichiometry. In this study, we distinguish the dual effects of activation and desensitization of AChRs by these nicotinic agonists and define the range of concentrations over which smoldering activation can be sustained.


Urbanization drives cross-taxon declines in abundance and diversity at multiple spatial scales.
The increasing urbanization process is hypothesized to drastically alter (semi-)natural environments with a concomitant major decline in species abundance and diversity. Yet, studies on this effect of urbanization, and the spatial scale at which it acts, are at present inconclusive due to the large heterogeneity in taxonomic groups and spatial scales at which this relationship has been investigated among studies. Comprehensive studies analysing this relationship across multiple animal groups and at multiple spatial scales are rare, hampering the assessment of how biodiversity generally responds to urbanization. We studied aquatic (cladocerans), limno-terrestrial (bdelloid rotifers) and terrestrial (butterflies, ground beetles, ground- and web spiders, macro-moths, orthopterans and snails) invertebrate groups using a hierarchical spatial design, wherein three local-scale (200 m × 200 m) urbanization levels were repeatedly sampled across three landscape-scale (3 km × 3 km) urbanization levels. We tested for local and landscape urbanization effects on abundance and species richness of each group, whereby total richness was partitioned into the average richness of local communities and the richness due to variation among local communities. Abundances of the terrestrial active dispersers declined in response to local urbanization, with reductions up to 85% for butterflies, while passive dispersers did not show any clear trend. Species richness also declined with increasing levels of urbanization, but responses were highly heterogeneous among the different groups with respect to the richness component and the spatial scale at which urbanization impacts richness. Depending on the group, species richness declined due to biotic homogenization and/or local species loss. This resulted in an overall decrease in total richness across groups in urban areas. These results provide strong support to the general negative impact of urbanization on abundance and species richness within habitat patches and highlight the importance of considering multiple spatial scales and taxa to assess the impacts of urbanization on biodiversity.


Characterization of subdomain IIA binding site of human serum albumin in its native, unfolded, and refolded states using small molecular probes.
Subdomain IIA binding site of human serum albumin (HSA) was characterized by examining the change in HSA fluorescence in the native, unfolded, and refolded states. The study was carried out in the absence and presence of small molecular probes using steady-state and time-resolved fluorescence measurements. 2-Pyridone, 3-pyridone, and 4-pyridone bear similar molecular structures to those found in many drugs and are used here as probes. They are found to specifically bind in subdomain IIA and cause a reduction in the fluorescence intensity and lifetime of the Trp-214 residue in native HSA which is located in the same subdomain. The efficiency of energy transfer from Trp-214 fluorescence to the probes was found to depend on the degree of the spectral overlap between the donor's fluorescence and the acceptor's absorption. After probe binding in subdomain IIA, the distance between the donor and acceptor was calculated using Forster theory. The calculated quenching rate constants and binding constants were also shown to depend on the degree of spectral overlap. The results point to a static quenching mechanism operating in the complexes. Denaturation of HSA in the presence of guanidine hydrochloride (GdnHCl) starts at [GdnHCl] > 1.0 M and is complete at [GdnHCl] > or = 6.0 M. Upon unfolding, two fluorescence peaks were observed. One peak was assigned to the fluorescence of Trp-214 in a polar environment, and the other peak was assigned to tyrosine fluorescence. A reduction of the fluorescence intensity of the two peaks upon binding of the probes to the denatured HSA indicates that Tyr-263 in subdomain IIA is one of the tyrosine residues responsible for the second fluorescence peak. The results were confirmed by measuring the fluorescence spectra and lifetimes of denatured HSA at different excitation wavelengths, and of L-tryptophan and L-tyrosine free in buffer. The measured lifetimes of denatured HSA are typical of tryptophan in a polar environment and are slightly reduced upon probe binding. Dilution of the denatured HSA by buffer results in a partial refolding of subdomain IIA. This partial refolding is attributed to some swelling of the binding site caused by water. The swelling prevents a full recovery from the denatured state.


A DNA methylation fingerprint of 1628 human samples.
Most of the studies characterizing DNA methylation patterns have been restricted to particular genomic loci in a limited number of human samples and pathological conditions. Herein, we present a compromise between an extremely comprehensive study of a human sample population with an intermediate level of resolution of CpGs at the genomic level. We obtained a DNA methylation fingerprint of 1628 human samples in which we interrogated 1505 CpG sites. The DNA methylation patterns revealed show this epigenetic mark to be critical in tissue-type definition and stemness, particularly around transcription start sites that are not within a CpG island. For disease, the generated DNA methylation fingerprints show that, during tumorigenesis, human cancer cells underwent a progressive gain of promoter CpG-island hypermethylation and a loss of CpG methylation in non-CpG-island promoters. Although transformed cells are those in which DNA methylation disruption is more obvious, we observed that other common human diseases, such as neurological and autoimmune disorders, had their own distinct DNA methylation profiles. Most importantly, we provide proof of principle that the DNA methylation fingerprints obtained might be useful for translational purposes by showing that we are able to identify the tumor type origin of cancers of unknown primary origin (CUPs). Thus, the DNA methylation patterns identified across the largest spectrum of samples, tissues, and diseases reported to date constitute a baseline for developing higher-resolution DNA methylation maps and provide important clues concerning the contribution of CpG methylation to tissue identity and its changes in the most prevalent human diseases.


Dipping low-velocity layer in the mid-lower mantle: evidence for geochemical heterogeneity
Data from western United States short-period seismic networks reveal a conversion from an S to a P wave within a low seismic velocity layer (greater than or equal to the 4 percent velocity difference compared to the surrounding mantle) in the mid-lower mantle (1400 to 1600 kilometers deep) east of the Mariana and Izu-Bonin subduction zones. The low-velocity layer (about 8 kilometers thick) dips 30 degrees to 40 degrees southward and is at least 500 kilometers by 300 kilometers. Its steep dip, large velocity contrast, and sharpness imply a chemical rather than a thermal origin. Ancient oceanic crust subducted into the lower mantle is a plausible candidate for the low-velocity layer because of its broad thin extent.


Pathogenesis, diagnosis, and management of Kikuchi-Fujimoto disease.
Kikuchi-Fujimoto disease (KFD) is a rare lymphohistiocytic disorder with an unknown etiopathogenesis. This disease is misdiagnosed as malignant lymphoma in up to one-third of cases and is associated with the development of systemic lupus erythematosus (SLE). The medical literature between the years 1972 and 2014 was searched for KFD, and the data were collected and analyzed regarding the epidemiology, clinical presentations, diagnosis, management, and suggested diagnostic and treatment algorithms. Although KFD has been reported in other ethnic groups and geographical areas, it is more frequently diagnosed in young women of Asian descent. Patients with the disease typically present with rapidly evolving tender cervical lymphadenopathy, night sweats, fevers, and headache. Diagnosis is based on histopathological examination. Excisional lymph node biopsy is essential for a correct diagnosis. Apoptotic coagulation necrosis with karyorrhectic debris and the proliferation of histiocytes, plasmacytoid dendritic cells, and CD8(+) T cells in the absence of neutrophils are characteristic cytomorphology features. Interface dermatitis at the onset of KFD may be a marker for the subsequent evolution of SLE. The natural course of the disease is typically benign. Short courses of steroids, nonsteroidal anti-inflammatory drugs, or hydroxychloroquine can be administered to patients with more severe symptoms. Although KFD was described more than 40 years ago, the etiology of this disease remains unsolved. Infectious or autoimmune processes were proposed but have not been definitively confirmed. Clinical presentation with systemic B symptoms and adenopathy may lead to an erroneous diagnosis of malignant lymphoma. The introduction of modern methods into hematopathology, including immunohistochemistry, flow cytometry, and molecular clonality studies, has decreased the probability of misdiagnosis. Until reliable prognostic markers are available, patients with KFD should have continued long-term follow-up care due to their increased risk of SLE.


What plausibly affects plausibility? Concept coherence and distributional word coherence as factors influencing plausibility judgments.
Our goal was to investigate the basis of human plausibility judgements. Previous research had suggested that plausibility is affected by two factors: concept coherence (the inferences made between parts of a discourse) and word coherence (the distributional properties of the words used). In two experiments, participants were asked to rate the plausibility of sentence pairs describing events. In the first, we manipulated concept coherence by using different inference types to link the sentences in a pair (e.g., causal or temporal). In the second, we manipulated word coherence by using latent semantic analysis, so two sentence pairs describing the same event had different distributional properties. The results showed that inference type affects plausibility; sentence pairs linked by causal inferences were rated highest, followed by attributal, temporal, and unrelated inferences. The distributional manipulations had no reliable effect on plausibility ratings. We conclude that the processes involved in rating plausibility are based on evaluating concept coherence, not word coherence.


Transcription regulation of the rRNA gene by a multifunctional nucleolar protein, B23/nucleophosmin, through its histone chaperone activity.
It is well established that the transcription rate of the rRNA gene is closely associated with profound alterations in the cell growth rate. Regulation of rRNA gene transcription is likely to be dependent on the dynamic conversion of the chromatin structure. Previously, we identified B23/nucleophosmin, a multifunctional nucleolar phosphoprotein, as a component of template activating factor III that remodels the chromatin-like structure of the adenovirus genome complexed with viral basic proteins. It has also been shown that B23 has histone chaperone activity. Here, we examined the effect of B23 on rRNA gene transcription. B23 was found to be associated with the rRNA gene chromatin. Small-interfering-RNA-mediated down-regulation of the B23 expression level resulted in reduction of the transcription rate of the rRNA gene. We constructed a B23 mutant termed B23DeltaC, which lacks the domain essential for the histone chaperone activity and inhibited the histone binding activity of B23 in a dominant-negative manner. Expression of B23DeltaC decreased rRNA gene transcription and the rate of cell proliferation. These results suggest that B23 is involved in the transcription regulation of the rRNA gene as a nucleolar histone chaperone.


Dissociation and posttraumatic stress 1 year after the World Trade Center disaster: follow-up of a longitudinal survey.
We conducted a 1-year follow-up of an original mail survey of early reactions to the World Trade Center disaster. Of the 75 subjects originally surveyed, 58 (77%) responded. The survey included measures of dissociation (Dissociative Experiences Scale, Cambridge Depersonalization Scale, Clinician-Administered Dissociative States Scale), post-traumatic stress (Impact of Event Scale-Revised), social support (Interpersonal Support Evaluation List-short form), and a life quality measure (Quality of Life Enjoyment and Satisfaction Questionnaire-short form). We hypothesized that dissociative versus posttraumatic symptoms at follow-up could be dissected on the basis of early reactions. Responders and nonresponders did not differ in baseline characteristics. Exposure was not associated with dissociation or posttraumatic stress at follow-up. Of distress, dissociation, and posttraumatic stress at baseline, baseline dissociation was the strongest predictor of outcome dissociation while baseline posttraumatic stress was the strongest predictor of outcome posttraumatic stress. Of 4 peritraumatic distress factors generated in the original survey, "loss of control" and "guilt/shame" were significantly related to dissociation and posttraumatic stress at outcome, while "helplessness/anger" was only associated with posttraumatic stress at outcome. Lesser improvement in posttraumatic stress over the first year was significantly related to less social support and greater comorbid dissociation. Interim social support was associated with better life quality and fewer symptoms at outcome. There was evidence for partly independent pathways toward dissociation versus posttraumatic stress 1 year after the disaster. Feelings of guilt and shame, and persistent dissociation, were poor prognostic factors, while social support had a powerful ameliorating influence.


Inhibition of E2F-mediated transcription by p202.
Many of the antimicrobial, immunomodulatory and cell growth inhibitory activities of the interferons are mediated by interferon-inducible proteins. Earlier we characterized an interferon-inducible murine protein, p202, whose expression in transfected cells inhibits cell proliferation and which can form a complex with retinoblastoma protein (pRb). Here we report that in transfected cells expression of p202 inhibits E2F-stimulated transcription of a reporter gene and of endogenous genes. Inhibition of the transcriptional activity of E2F by p202 does not depend on fully functional pRb and is correlated with inhibition of the sequence-specific DNA binding of E2F. p202 interacts with the transcription factor E2F (E2F-1/DP-1) in vitro and in vivo. Inhibition of E2F activity by p202 may contribute to growth inhibition by the interferons.


Safety and feasibility of long-term intravenous sodium nitrite infusion in healthy volunteers.
Infusion of sodium nitrite could provide sustained therapeutic concentrations of nitric oxide (NO) for the treatment of a variety of vascular disorders. The study was developed to determine the safety and feasibility of prolonged sodium nitrite infusion. Healthy volunteers, aged 21 to 60 years old, were candidates for the study performed at the National Institutes of Health (NIH; protocol 05-N-0075) between July 2007 and August 2008. All subjects provided written consent to participate. Twelve subjects (5 males, 7 females; mean age, 38.8±9.2 years (range, 21-56 years)) were intravenously infused with increasing doses of sodium nitrite for 48 hours (starting dose at 4.2 µg/kg/hr; maximal dose of 533.8 µg/kg/hr). Clinical, physiologic and laboratory data before, during and after infusion were analyzed. The maximal tolerated dose for intravenous infusion of sodium nitrite was 267 µg/kg/hr. Dose limiting toxicity occurred at 446 µg/kg/hr. Toxicity included a transient asymptomatic decrease of mean arterial blood pressure (more than 15 mmHg) and/or an asymptomatic increase of methemoglobin level above 5%. Nitrite, nitrate, S-nitrosothiols concentrations in plasma and whole blood increased in all subjects and returned to preinfusion baseline values within 12 hours after cessation of the infusion. The mean half-life of nitrite estimated at maximal tolerated dose was 45.3 minutes for plasma and 51.4 minutes for whole blood. Sodium nitrite can be safely infused intravenously at defined concentrations for prolonged intervals. These results should be valuable for developing studies to investigate new NO treatment paradigms for a variety of clinical disorders, including cerebral vasospasm after subarachnoid hemorrhage, and ischemia of the heart, liver, kidney and brain, as well as organ transplants, blood-brain barrier modulation and pulmonary hypertension. http://www.clinicaltrials.gov; NCT00103025.


Retinal transfer of nicotinate by H+ -monocarboxylate transporter at the inner blood-retinal barrier.
Nicotinic acid is a constituent of the coenzymes NAD and NADP. It also serves as an agonist for the G-protein-coupled receptor GPR109A. Nicotinic acid is widely used at high doses as a lipid-lowering drug, which is associated with an ocular side effect known as niacin maculopathy. Here we investigated the mechanism by which nicotinate is transferred into retina across the inner blood-retinal barrier (BRB). In vivo the blood-to-retina transport of [(3)H]-nicotinate was studied using the carotid artery injection technique. The characteristics of nicotinate transport at the inner BRB were examined in a conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB2), an in vitro model of inner BRB. The expression of transporters in TR-iBRB2 cells was determined by reverse transcription-polymerase chain reaction. In vivo [(3)H]-nicotinate uptake by the retina was 5.4-fold greater than that of [(14)C]-sucrose, a BRB impermeable vascular space marker. Excess amounts of unlabeled nicotinate and salicylate significantly decreased the in vivo retinal uptake of [(3)H]-nicotinate. [(3)H]-Nicotinate was taken up by TR-iBRB2 cells via an H(+)-dependent saturable process with a Michaelis constant of ~7 mM. Na(+) had minimal effect on the uptake. The H(+)-dependent uptake was significantly inhibited by endogenous monocarboxylates such as lactate and pyruvate, and monocarboxylic drugs such as valproate, salicylate, and ibuprofen. These characteristics are consistent with those of H(+)-coupled monocarboxylate transporters (MCTs). MCT1, MCT2, and MCT4 mRNAs were expressed in TR-iBRB2 cells. The Na(+)-dependent monocarboxylate transporters SMCT1 and SMCT2 were not expressed in these cells. In conclusion, transfer of nicotinate from blood to retina across the inner BRB occurs primarily via H(+)-coupled monocarboxylate transporters.


Allogeneic transplantation for lymphoma.
Historically, high levels of treatment-related mortality restricted the use of standard myeloablative allogeneic stem-cell transplantation to a minority of young and fit patients with lymphoma. Over the last decade, increasing numbers of patients with lymphoma have undergone allogeneic stem-cell transplantation using reduced-intensity protocols that are associated with lower toxicity and reduced transplantation-related mortality. Graft-versus-lymphoma effects contribute to the therapeutic effect in patients with indolent or Hodgkin's lymphoma. However, definitive evidence for efficacy of this strategy is lacking because most patients undergoing transplantation do so after failure of several lines of treatment, leaving no obvious comparator arm for randomized controlled studies. Nevertheless, encouraging results have been reported for selected patients for most lymphoma subtypes, with pretransplantation disease status emerging as the most important predictor of outcome. The major long-term toxicity is chronic graft-versus-host disease that contributes to ill health in a significant minority of survivors. In the future, risk-adapted trials that evaluate reduced-intensity allogeneic transplantation in patients with predicted poor outcomes with immunochemotherapy or autologous transplantation will be important in determining the role of this treatment.


Hemodynamic response to visual stimulation in newborn infants using functional near-infrared spectroscopy.
Brain activity is associated with physiological changes, which alter the optical properties of tissue. These changes can be detected by near-infrared spectroscopy (NIRS). Aim of the study was to determine changes in cerebral oxygenation in response to stimulation in the visual cortex in newborn infants during spontaneous sleep in the first days of life. We used an in-house developed multichannel NIRS imaging instrument, the MCP-II, to measure changes in concentration of oxyhemoglobin (O(2)Hb) and deoxyhemoglobin (HHb) in specific brain areas. In 10 out of 15 subjects, a significant increase in O(2)Hb and/or a significant decrease in HHb were found in one or more channels over the occipital cortex. During stimulation, O(2)Hb increased by a mean of 0.98 mumol/l, HHb decreased by a mean 0.17 mumol/l, and total-Hb increased by a mean of 0.81 mumol/l. The hemodynamic response to visual stimulation in the occipital cortex in newborn infants is similar to adults. The increase in O(2)Hb and the simultaneous decrease in HHb during stimulation suggest an increase in cerebral blood flow (CBF) that overcompensates for the increased oxygen consumption (CMRO(2)) in the activated cortical area.


Flexible Bayesian Dynamic Modeling of Correlation and Covariance Matrices.
Modeling correlation (and covariance) matrices can be challenging due to the positive-definiteness constraint and potential high-dimensionality. Our approach is to decompose the covariance matrix into the correlation and variance matrices and propose a novel Bayesian framework based on modeling the correlations as products of unit vectors. By specifying a wide range of distributions on a sphere (e.g. the squared-Dirichlet distribution), the proposed approach induces flexible prior distributions for covariance matrices (that go beyond the commonly used inverse-Wishart prior). For modeling real-life spatio-temporal processes with complex dependence structures, we extend our method to dynamic cases and introduce unit-vector Gaussian process priors in order to capture the evolution of correlation among components of a multivariate time series. To handle the intractability of the resulting posterior, we introduce the adaptive Δ-Spherical Hamiltonian Monte Carlo. We demonstrate the validity and flexibility of our proposed framework in a simulation study of periodic processes and an analysis of rat's local field potential activity in a complex sequence memory task.


Healthcare Programmes for Truck Drivers in Sub-Saharan Africa: A Systematic Review and Meta-Analysis.
Truck drivers have unique health needs, and by virtue of their continuous travel, experience difficulty in accessing healthcare. Currently, planning for effective care is hindered by lack of knowledge about their health needs and about the impact of on-going programmes on this population's health outcomes. We reviewed healthcare programmes implemented for sub-Saharan African truck drivers, assessed the evaluation methods, and examined impact on health outcomes. We searched scientific and institutional databases, and online search engines to include all publications describing a healthcare programme in sub-Saharan Africa where the main clients were truck drivers. We consulted experts and organisations working with mobile populations to identify unpublished reports. Forest plots of impact and outcome indicators with unadjusted risk ratios and 95% confidence intervals were created to map the impact of these programmes. We performed a subgroup analysis by type of indicator using a random-effects model to assess between-study heterogeneity. We conducted a sensitivity analysis to examine both the summary effect estimate chosen (risk difference vs. risk ratio) and model to summarise results (fixed vs. random effects). Thirty-seven publications describing 22 healthcare programmes across 30 countries were included from 5,599 unique records. All programmes had an HIV-prevention focus with only three expanding their services to cover conditions other primary healthcare services. Twelve programmes were evaluated and most evaluations assessed changes in input, output, and outcome indicators. Absence of comparison groups, preventing attribution of the effect observed to the programme and lack of biologically confirmed outcomes were the main limitations. Four programmes estimated a quantitative change in HIV prevalence or reported STI incidence, with mixed results, and one provided anecdotal evidence of changes in AIDS-related mortality and social norms. Most programmes showed positive changes in risk behaviours, knowledge, and attitudes. Our conclusions were robust in sensitivity analyses. Diverse healthcare programmes tailored to the needs of truck drivers implemented in 30 sub-Saharan African countries have shown potential benefits. However, information gaps about availability of services and their effects impede further planning and implementation of effective healthcare programmes for truck drivers.


Socio-cultural features and help-seeking preferences for leprosy and turbeculosis: a cultural epidemiological study in a tribal district of Maharashtra, India.
India is a major contributor to the global burden of leprosy and tuberculosis (TB), which adversely affects the poorest tribal communities. Despite prioritisation by disease control programmes, programme performance for leprosy and TB in tribal communities continues to be a challenge. In addition to access to services and infrastructural limitations, socio-cultural concepts of illness causation and related help seeking (HS) rooted in distinct features of tribal culture need to be addressed to improve programme outcomes. A cultural epidemiological survey of leprosy and TB patients was carried out using a locally adapted, semi-structured explanatory model interviews. A total of 100 leprosy and 50 TB patients registered for treatment at government health facilities were selected randomly from tribal dominant blocks of the Thane district, Maharashtra state. The perceived causes (PCs) of leprosy and TB in patients were compared based on prominence categories. The relationship between PCs as predictors, and disease conditions and HS preferences as outcome variables were assessed using multivariate logistic regression. In the multivariate logistic regression model with disease conditions as outcome variables, TB patients were significantly more likely to report PCs in the categories of ingestion; health, illness and injury; and traditional, cultural and supernatural. Tuberculosis patients more frequently first sought help from private facilities as compared to leprosy patients who preferred government health facilities. In a combined analysis of leprosy and TB patients employing multivariate logistic regression, it was found that patients who reported PCs in the environmental and contact-related categories were more likely to visit traditional rather than non-traditional practitioners. In another multivariate combined model, it was found that patients who reported PCs in the traditional, cultural and supernatural category were significantly more likely to visit private rather than public health facilities. Cultural concepts about illness causation and associated HS behaviours should be considered as priorities for action, which in turn would provide the necessary impetus to ensure that tribal patients seek help in a timely and appropriate manner, and could facilitate improvement in programme performance in general.


The relation of functional visual acuity measurement methodology to tear functions and ocular surface status.
To investigate the relation of functional visual acuity (FVA) measurements with dry eye test parameters and to compare the testing methods with and without blink suppression and anesthetic instillation. A prospective comparative case series. Thirty right eyes of 30 dry eye patients and 25 right eyes of 25 normal subjects seen at Keio University School of Medicine, Department of Ophthalmology were studied. FVA testing was performed using a FVA measurement system with two different approaches, one in which measurements were made under natural blinking conditions without topical anesthesia (FVA-N) and the other in which the measurements were made under the blink suppression condition with topical anesthetic eye drops (FVA-BS). Tear function examinations, such as the Schirmer test, tear film break-up time, and fluorescein and Rose Bengal vital staining as ocular surface evaluation, were performed. The mean logMAR FVA-N scores and logMAR Landolt visual acuity scores were significantly lower in the dry eye subjects than in the healthy controls (p < 0.05), while there were no statistical differences between the logMAR FVA-BS scores of the dry eye subjects and those of the healthy controls. There was a significant correlation between the logMAR Landolt visual acuities and the logMAR FVA-N and logMAR FVA-BS scores. The FVA-N scores correlated significantly with tear quantities, tear stability and, especially, the ocular surface vital staining scores. FVA measurements performed under natural blinking significantly reflected the tear functions and ocular surface status of the eye and would appear to be a reliable method of FVA testing. FVA measurement is also an accurate predictor of dry eye status.


Effect of Speech Rate on Neural Tracking of Speech.
Speech comprehension requires effort in demanding listening situations. Selective attention may be required for focusing on a specific talker in a multi-talker environment, may enhance effort by requiring additional cognitive resources, and is known to enhance the neural representation of the attended talker in the listener's neural response. The aim of the study was to investigate the relation of listening effort, as quantified by subjective effort ratings and pupil dilation, and neural speech tracking during sentence recognition. Task demands were varied using sentences with varying levels of linguistic complexity and using two different speech rates in a picture-matching paradigm with 20 normal-hearing listeners. The participants' task was to match the acoustically presented sentence with a picture presented before the acoustic stimulus. Afterwards they rated their perceived effort on a categorical effort scale. During each trial, pupil dilation (as an indicator of listening effort) and electroencephalogram (as an indicator of neural speech tracking) were recorded. Neither measure was significantly affected by linguistic complexity. However, speech rate showed a strong influence on subjectively rated effort, pupil dilation, and neural tracking. The neural tracking analysis revealed a shorter latency for faster sentences, which may reflect a neural adaptation to the rate of the input. No relation was found between neural tracking and listening effort, even though both measures were clearly influenced by speech rate. This is probably due to factors that influence both measures differently. Consequently, the amount of listening effort is not clearly represented in the neural tracking.


Careful accounting of extrinsic noise in protein expression reveals correlations among its sources.
In order to grow and replicate, living cells must express a diverse array of proteins, but the process by which proteins are made includes a great deal of inherent randomness. Understanding this randomness-whether it arises from the discrete stochastic nature of chemical reactivity ("intrinsic" noise), or from cell-to-cell variability in the concentrations of molecules involved in gene expression, or from the timings of important cell-cycle events like DNA replication and cell division ("extrinsic" noise)-remains a challenge. In this article we analyze a model of gene expression that accounts for several extrinsic sources of noise, including those associated with chromosomal replication, cell division, and variability in the numbers of RNA polymerase, ribonuclease E, and ribosomes. We then attempt to fit our model to a large proteomics and transcriptomics data set and find that only through the introduction of a few key correlations among the extrinsic noise sources can we accurately recapitulate the experimental data. These include significant correlations between the rate of mRNA degradation (mediated by ribonuclease E) and the rates of both transcription (RNA polymerase) and translation (ribosomes) and, strikingly, an anticorrelation between the transcription and the translation rates themselves.


Free flap donor site refinement using tissue expansion.
Posttransfer tissue expansion has been used to negate concern for the aesthetic donor site deformity following 15 free tissue transfers involving donor sites of the scalp, trunk, and extremities. There appears to be no contraindication to placing these implants immediately, as was done in 87% of cases, although it is recommended that expansion be delayed until adequate wound healing has occurred at any skin graft interface. This technique has had major positive benefits for refining the radial forearm flap and hair-bearing temporoparietal fasciocutaneous flap defects, which may have heretofore been avoided secondary to aesthetic concerns. Tissue expansion techniques should be considered as an important adjunct for any microsurgical reconstructive effort.


The APOE4 allele is associated with a decreased risk of retinopathy in type 2 diabetics.
Common polymorphisms within the apolipoprotein E (APOE) gene are suggested to be associated with the development of type 2 diabetes mellitus (T2DM), but the potential association with T2DM complications (nephropathy, neuropathy and retinopathy) remains unclear. We perform the case-control study to analyse the association between the APOE polymorphism and risk of T2DM and to analysed the potential relationship between the APOE and T2DM complications. APOE variants (rs429358 and rs7412) were genotyped by TaqMan assay in T2DM patients (N = 1274; N = 829 with complications including retinopathy, neuropathy and nephropathy status) and with PCR-RFLP in healthy nondiabetic controls (N = 2055). The comparison of subjects with genotypes associated with low plasma cholesterol (APOE2/E2 and APOE2/E3 carriers vs. others) did not show an association with T2DM (OR [95% CI] = 0.88 [0.71-1.08). The differences remained insignificant after adjusting for diabetes duration, sex and BMI. Carriers of at least one APOE4 allele (rs429358) are protected against T2DM related retinopathy (OR [95% CI] = 0.65 [0.42-0.99]. Protection against retinopathy is driven mostly by females (OR [95% CI] = 0.50 [0.25-0.99]); and remains significant (P = 0.044) after adjustment for diabetes duration and BMI. Common APOE polymorphism was not associated with T2DM in the Czech population. Yet, APOE4 allele revealed an association with retinopathy. In particular, female T2DM patients with at least one APOE4 allele exhibit lower prevalence of retinopathy in our study subjects.


[Coupling of brain oscillatory systems with cognitive (experience and valence) and physiological (cardiovascular reactivity) components of emotion].
We investigated the coupling of EEG oscillators with cognitive (experience and valence) and physiological (cardiovascular reactivity) components of emotion. Emotions of anger and joy were evoked in healthy males (n = 49) using a guided imagery method, multichannel EEG and cardiovascular reactivity (Finometer) were simultaneously recorded. Correlational analysis revealed that specially distributed EEG oscillators seem to be selectively involved into cognitive (experience and valence) and physiological (cardiovascular reactivity) components of emotional responding. We showed that low theta (4-6 Hz) activity from medial and lateral frontal cortex of the right hemisphere predominantly correlated with the anger experience, high alpha (10-12 and 12-14 Hz) and gamma (30-45 Hz) activity from central-parieto-occipital regions of the left hemisphere--with cardiovascular reactivity to anger and joy, gamma-activity (30-45 Hz) from the left hemisphere in parietal areas--with cardiovascular reactivity to joy. The findings suggest that specially distributed neuronal networks oscillating at different frequencies may be regarded as a putative neurobiological mechanism coordination dynamical balance between cognitive and physiological components of emotion as well as psycho-neuro-somatic relationships within the mind-brain-body system.


Stress Tolerance-Related Genetic Traits of Fish Pathogen Flavobacterium psychrophilum in a Mature Biofilm.
Flavobacterium psychrophilum is the causative agent of bacterial cold-water disease and rainbow trout fry syndrome, and hence this bacterium is placed among the most important salmonid pathogens in the freshwater aquaculture industry. Since bacteria in biofilms differ substantially from free-living counterparts, this study sought to find the main differences in gene expression between sessile and planktonic states of F. psychrophilum LM-02-Fp and NCMB1947T, with focus on stress-related changes in gene expression occurring during biofilm formation. To this end, biofilm and planktonic samples were analyzed by RNA sequencing to detect differentially expressed candidate genes (DECGs) between the two growth states, and decreasing the effects of interstrain variation by considering only genes with log2-fold changes ≤ -2 and ≥ 2 at Padj-values ≤ 0.001 as DECGs. Overall, 349 genes accounting for ~15% of total number of genes expressed in transcriptomes of F. psychrophilum LM-02-Fp and NCMB1947T (n = 2327) were DECGs between biofilm and planktonic states. Approximately 83 and 81% of all up- and down-regulated candidate genes in mature biofilms, respectively, were assigned to at least one gene ontology term; these were primarily associated with the molecular function term "catalytic activity." We detected a potential stress response in mature biofilms, characterized by a generalized down-regulation of DECGs with roles in the protein synthesis machinery (n = 63, primarily ribosomal proteins) and energy conservation (seven ATP synthase subunit genes), as well as an up-regulation of DECGs involved in DNA repair (ruvC, recO, phrB1, smf, and dnaQ) and oxidative stress response (cytochrome C peroxidase, probable peroxiredoxin, and a probable thioredoxin). These results support the idea of a strategic trade-off between growth-related processes and cell homeostasis to preserve biofilm structure and metabolic functioning. In addition, LDH-based cytotoxicity assays and an intraperitoneal challenge model for rainbow trout fry agreed with the transcriptomic evidence that the ability of F. psychrophilum to form biofilms could contribute to the virulence. Finally, the reported changes in gene expression, as induced by the plankton-to-biofilm transition, represent the first transcriptomic guideline to obtain insights into the F. psychrophilum biofilm lifestyle that could help understand the prevalence of this bacterium in aquaculture settings.


β-Catenin is essential for Müllerian duct regression during male sexual differentiation.
During male sexual differentiation, the transforming growth factor-β (TGF-β) signaling molecule anti-Müllerian hormone (AMH; also known as Müllerian inhibiting substance, MIS) is secreted by the fetal testes and induces regression of the Müllerian ducts, the primordia of the female reproductive tract organs. Currently, the molecular identity of downstream events regulated by the AMH signaling pathway remains unclear. We found that male-specific Wnt4 expression in mouse Müllerian duct mesenchyme depends upon AMH signaling, implicating the WNT pathway as a downstream mediator of Müllerian duct regression. Inactivation of β-catenin, a mediator of the canonical WNT pathway, did not affect AMH signaling activation in the Müllerian duct mesenchyme, but did block Müllerian duct regression. These data suggest that β-catenin mediates AMH signaling for Müllerian duct regression during male sexual differentiation.


Calcium extrusion from mammalian photoreceptor terminals.
Ribbon synapses of vertebrate photoreceptors constantly release glutamate in darkness. Transmitter release is maintained by a steady influx of calcium through voltage-dependent calcium channels, implying the presence of a mechanism that is able to extrude calcium at an equal rate. The two predominant mechanisms of intracellular calcium extrusion are the plasma membrane calcium ATPase (PMCA) and the Na+/Ca2+-exchanger. Immunohistochemical staining of retina sections revealed strong immunoreactivity for the PMCA in rod and cone terminals, whereas staining for the Na+/Ca2+-exchanger was very weak. The PMCA was localized to the plasma membrane along the sides of the photoreceptor terminals and was excluded from the base of the terminals where the active zones are located. The amplitude of a calcium-activated chloride current was used to monitor the intracellular calcium concentration. An upper limit for the time required to remove intracellular free calcium is obtained from two time constants measured for the calcium-activated chloride current tail currents: one of 50 msec and a second of 190 msec. Calcium extrusion was inhibited in the absence of intracellular ATP or in the presence of the PMCA inhibitor orthovanadate, but was unaffected by replacement of external Na+ with Li+. The data indicate that the PMCA, rather than the Na+/Ca2+-exchanger, is the predominant mechanism for calcium extrusion from photoreceptor synaptic terminals.


The Pathways Study: a prospective study of breast cancer survivorship within Kaiser Permanente Northern California.
With 2.3 million breast cancer survivors in the US today, identification of modifiable factors associated with breast cancer recurrence and survival is increasingly important. Only recently new studies have been designed to examine the impact of lifestyle factors on prognosis, including Pathways, a prospective study of women with breast cancer in Kaiser Permanente Northern California (KPNC). Pathways aims to examine the effect on recurrence and survival of (1) lifestyle factors such as diet, physical activity, quality of life, and use of alternative therapies and (2) molecular factors such as genetic polymorphisms involved in metabolism of chemotherapeutic agents. Eligibility includes any woman diagnosed with invasive breast cancer within KPNC, no previous diagnosis of other invasive cancer, age 21 years or older, and ability to speak English, Spanish, Cantonese, or Mandarin. Newly diagnosed patients are identified daily from electronic pathology records and are enrolled within two months of diagnosis. An extensive baseline interview is conducted, blood and saliva samples are collected, and body measurements are taken. Women are followed for lifestyle updates, treatment, and outcomes by self-report and query of KPNC databases. Recruitment began in 9 January, 2006, and as of 16 January, 2008, 1,539 women have been enrolled along with collection of 1,323 blood samples (86%) and 1,398 saliva samples (91%). The Pathways Study will become a rich resource to examine behavioral and molecular factors and breast cancer prognosis.


Mucosal surface morphology of the toad urinary bladder. Scanning electron microscope study of the natriferic and hydro-osmotic response to vasopressin.
The mucosal cell surface of the toad urinary bladder was examined by scanning electron microscopy, and changes in the structure of the surface of the granular cell were correlated with specific physiological responses to vasopressin. Survey views of the mucosal surface demonstrated that there was no consistent repeating anatomical relationship between the granular cell and the mitochondria-rich cell that would support the concept of cooperativeness in the response to vasopressin. During base-line states of Na+-transport and water flux, the microvilli on the mucosal surface of the granular cell are arranged in a ridge-like network with occasional individual projections. When water flux is increased by exposing the tissue to vasopressin, in the presence of an osmotic gradient across the tissue the microvilli on the granular cell lose the ridge structure and appear, predominantly, as individual projection. Variability-of this appearance points out the necessity of examining large areas and many samples before the significance of any morphological change can be assessed. Blocking the simultaneously occurring natriferic response of the toad urinary bladder with 10(-2)M ouabain does not prevent these changes in the microvilli. When the hydro-osmotic response is blocked by eliminating the osmotic gradient, the granular cell shows no consistent change in mucosal surface morphology even when fixed at the height of the natriferic response. The mitochondria-rich and mucous cells did not show any change in morphology throughout these studies. We conclude that the changes in the mucosal surface morphology of the toad bladder seen after exposure to vasopressin are a result of the increased water flux that occurs when an osmotic gradient exists across the tissue, and are not related to the natriferic response or any specific alteration in the membrane properties.


Reproduction, genetics and the law.
Both reproductive medicine and genetics are seeing rapid, and in some instances revolutionary, medical and scientific advances. Courts have been called upon to resolve a variety of novel disputes arising from these areas, and more can be anticipated as these technologies continue to develop and their use becomes more widespread. This article discusses some of the most relevant areas of the law and litigation that currently bear on reproduction and genetics or that may be anticipated to do so in the future. Specific developments and judicial decisions addressing them include: legal theories of wrongful birth and wrongful life and their application to children born with genetic impairments; a physician's duty to warn family members about a relative's genetic disease; disputes over reproductive materials and non-reproductive cells and tissues; unauthorized genetic testing in the workplace; and genetic discrimination. It is hoped that this discussion will be of value to medical and legal professionals and policy makers who work with these concepts in the increasingly inter-related fields of law and medicine.


Diversity of Mycotoxin-Producing Black Aspergilli in Canadian Vineyards.
Several Aspergillus species produce ochratoxin A (OTA) and/or fumonisins on wine and table grapes. The relevant species and their mycotoxins have been investigated in a number of wine-producing regions around the world; however, similar data have not been reported for Canadian vineyards. A multiyear survey of black Aspergilli in Niagara, ON, vineyards was conducted to determine the diversity of species present and to assess the risk of OTA and fumonisin contamination of wine grapes from this region. From 2012 to 2014, 253 black Aspergilli were isolated from soil samples and the fruits of 10 varieties of grapes. The isolates were identified by DNA sequencing: Aspergillus welwitschiae (43%), Aspergillus uvarum (32%), Aspergillus brasiliensis (11%), Aspergillus tubingensis (9%), and Aspergillus niger (4%). Aspergillus carbonarius, the primary OTA producer on grapes in other parts of the world, was isolated only once, and this is the first report for it in Canada. All 10 A. niger strains produced fumonisins, but, in contrast, only 26% of the 109 A. welwitschiae isolates were producers, and no strains of either species produced OTA. Grape samples were analyzed for OTA and fumonisins from sites where strains with mycotoxigenic potential were isolated. Fumonisin B2 (FB2) was detected in 7 of 22 (32%) of these grape samples in the 1-15 ppb range, but no OTA was detected. Additionally, the recently reported nonaminated fumonisins were detected in 3 of 22 grape samples. These results suggest that fumonisin-producing Aspergilli can occur in Ontario vineyards but, at present, the risk of contamination of grapes appears low. The risk of OTA contamination in Niagara wine is also low because of the low prevalence of A. carbonarius.


A Bax-mediated mechanism for obatoclax-induced apoptosis of cholangiocarcinoma cells.
Apoptosis induction by BH3 mimetics is a therapeutic strategy for human cancer. These mimetics exert single-agent activity in cells "primed" for cell death. Primed cells are dependent upon antiapoptotic Bcl-2 proteins for survival and are characterized by the ability of the BH3 mimetic to induce cytochrome c release from their isolated mitochondria. Our aim was to examine the single-agent activity of obatoclax, a BH3 mimetic in cholangiocarcinoma cell lines. In clonogenic assays, inhibition of colony formation was observed by obatoclax treatment. Despite single-agent activity by obatoclax, the mitochondria from these cells did not release cytochrome c after incubation with this BH3 mimetic. However, immunofluorescence and cell fractionation studies identified Bax activation and translocation to mitochondria after treatment with obatoclax. shRNA targeted knockdown of Bax doubled the IC50 for obatoclax but did not abrogate its cytotoxicity, whereas knockdown of Bak did not alter the IC50. In a cell-free system, obatoclax induced an activating conformational change of Bax, which was attenuated by a site-directed mutagenesis of a previously identified protein activation site. Finally, the drug also elicited a significant in vivo response in a rodent model of this disease. In conclusion, single-agent obatoclax treatment results in Bax activation, which contributes, in part, to cell death in cholangiocarcinoma cells. These data indicate that BH3 mimetics may also function as direct activators of Bax and induce cytotoxicity in cells not otherwise primed for cell death.


Linoleic and alpha-linolenic acids differently modify the effects of elaidic acid on polyunsaturated fatty acid metabolism and some immune indices in rats.
To explore whether the metabolic responses to trans, compared with cis, fatty acids depend on the source of dietary polyunsaturated fatty acids (PUFA), male Sprague-Dawley rats, 5 weeks old, were fed on diets containing 30 g oleic (cis) or elaidic (trans) acids/kg in combination with either 70 g perilla oil (alpha-linolenic acid) or safflowerseed oil (linoleic acid)/kg for 3 weeks in separate experiments. The dietary fats were adjusted to have the same level of total PUFA. The dietary manipulation did not influence the growth indices, but spleen weight was greater when the dietary PUFA source was perilla oil. The incorporation of trans fatty acid into liver phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol and phosphatidylserine and adipose tissue lipids, particularly phospholipids, was significantly higher when rats were fed on safflowerseed oil compared with perilla oil. However, only limited differences were observed in the effects of cis and trans fatty acids on the proportions of PUFA in liver phospholipids. Splenic production of prostaglandin E2 was reduced by trans fatty acid when safflowerseed oil was the PUFA source, but no trans effect was observed on leukotriene C4 production. Dietary PUFA significantly influenced the concentration of plasma immunoglobulins (Ig) but the effect of geometry was only seen in IgG which was increased by trans acid. Dietary trans fatty acid increased the CD4+:CD8+ T-lymphocyte ratio in the spleen, reflecting a decreasing trend of the proportion of CD8+, when combined with perilla oil. These observations indicate that the type of PUFA simultaneously ingested specifically influences the effect that trans acid exerts on PUFA metabolism, eicosanoid production and some immune indices.


Submicromolar levels of calcium control the balance of beating between the two flagella in demembranated models of Chlamydomonas.
When detergent-extracted, demembranated cell models of Chlamydomonas were resuspended in reactivation solutions containing less than 10(-8) M Ca++, many models initially swam in helical paths similar to those of intact cells; others swam in circles against the surface of the slide or coverslip. With increasing time after reactivation, fewer models swam in helices and more swam in circles. This transition from helical to circular swimming was the result of a progressive inactivation of one of the axonemes; in the extreme case, one axoneme was completely inactive whereas the other beat with a normal waveform. At these low Ca++ concentrations, the inactivated axoneme was the trans-axoneme (the one farthest from the eyespot) in 70-100% of the models. At 10(-7) or 10(-6) M Ca++, cell models also proceeded from helical to circular swimming as a result of inactivation of one of the axonemes; however, under these conditions the cis-axoneme was usually the one that was inactivated. At 10(-8) M Ca++, most cells continued helical swimming, indicating that both axonemes were remaining relatively active. The progressive, Ca++-dependent inactivation of the trans- or cis-axoneme was reversed by switching the cell models to higher or lower Ca++ concentrations, respectively. A similar reversible, selective inactivation of the trans-flagellum occurred in intact cells swimming in medium containing 0.5 mM EGTA and no added Ca++. The results show that there are functional differences between the two axonemes of Chlamydomonas. The differential responses of the axonemes to submicromolar concentrations of Ca++ may form the basis for phototactic turning.


Effect of bioresorbable fibres (Polyfibre) and a bioresorbable foam (Polyfoam) on new bone formation. A short term experimental study on the rabbit skull.
The aim of the study was to evaluate two bioresorbable polylactic acid (PLA) filler materials in a guided bone regeneration (GBR) model system. The first was Polyfibre, a fibrous PLA filler material. Polyfoam, the second material tested, consisted of a spongy PLA filler material. In each group there were eight rabbits. In test rabbits a flap was raised uncovering the calvaria. A hemispherical PLA dome was filled with Polyfibre or Polyfoam material and periphereal blood and anchored onto the calvaria. Eight rabbits with the same domes, filled with blood alone, served as controls. The rabbits were sacrificed at 1 or 2 months. Histomorphometric measurements of regenerated total tissue volume, bone height and bone volume were carried out in undecalcified sections under a light microscope. At 1 month the totally filled volume attained 87% (range 82-91) in the fibre group, including 25% (23-27) fibres, 87% (85-95) in the foam group, including 15% (15-16) foam, and 55% (16-100) in the controls. The volume of mineralized bone was 12% (7-15) in the fibre group, 15% (12-18) in the foam group and 6% (1-11) in control domes. Bone height attained 48% (27-79) in the fibre group, 37% (31-58) in the foam group and 45% (14-67) in the control group. At 2 months, tissue volume attained 86% (85-87) including 26% (22-29) fibres, bone volume attained 13% (7-21) and bone height attained 56% (42-78) in the Polyfibre group. In the Polyfoam group, they were 83% (55-99) including 18% (15-19) foam, 13% (7-24) and 49% (29-74). In control domes, tissue volume was 82% (35-100), bone volume 20% (9-27) and bone height 86% (60-100). The Polyfibre and Polyfoam material was excellently integrated. No adverse reactions were found in the surrounding tissues. Direct bone apposition was observed onto the material. In conclusion, Polyfibre and Polyfoam material had a positive effect on initial bone and tissue formation but was a hindrance to increasing tissue volume, bone volume or bone height at 2 months compared to control specimens. The Polyfibre and Polyfoam material provoked no adverse reactions in the surrounding tissues and allowed for extensive angiogenesis.


Local infiltration of rabies immunoglobulins without systemic intramuscular administration: An alternative cost effective approach for passive immunization against rabies.
Presently the dose of rabies immunoglobulin (RIG) which is an integral part of rabies post exposure prophylaxis (PEP) is calculated based on body weight though the recommendation is to infiltrate the wound(s). This practice demands large quantities of RIG which may be unaffordable to many patients. In this background, we conducted this study to know if the quantity and cost of RIG can be reduced by restricting passive immunization to local infiltration alone and avoiding systemic intramuscular administration based on the available scientific evidence. Two hundred and sixty nine category III patients bitten by suspect or confirmed rabid dogs/animals were infiltrated with equine rabies immunoglobulin (ERIGs) in and around the wound. The quantity of ERIG used was proportionate to the size and number of wounds irrespective of their body weight. They were followed with a regular course of rabies vaccination by intra-dermal route. As against 363 vials of RIGs required for all these cases as per current recommendation based on body weight, they required only 42 vials of 5ml RIG. Minimum dose of RIGs given was 0.25 ml and maximum dose given was 8 ml. On an average 1.26 ml of RIGs was required per patient that costs Rs. 150 ($3). All the patients were followed for 9 months and they were healthy and normal at the end of observation period. With local infiltration, that required small quantities of RIG, the RIGs could be made available to all patients in times of short supply in the market. A total of 30 (11%) serum samples of patients were tested for rabies virus neutralizing antibodies by the rapid fluorescent focus inhibition test (RFFIT) and all showed antibody titers >0.5 IU/mL by day 14. In no case the dose was higher than that required based on body weight and no immunosuppression resulted. To conclude, this pilot study shows that local infiltration of RIG need to be considered in times of non-availability in the market or unaffordability by poor patients. This preliminary study needs to be done on larger scale in other centers with long term follow up to substantiate the results of our study.


Explanatory factors for health inequalities across different ethnic and gender groups: data from a national survey in England.
The objective of this study was to examine the relative contribution of factors explaining ethnic health inequalities (EHI) in poor self-reported health (pSRH) and limiting long-standing illness (LLI) between Health Survey for England (HSE) participants. Using HSE 2003-2006 data, the odds of reporting pSRH or of LLI in 8573 Bangladeshi, Black African, Black Caribbean, Chinese, Indian, Irish and Pakistani participants was compared with 28,470 White British participants. The effects of demographics, socioeconomic position (SEP), psychosocial variables, community characteristics and health behaviours were assessed using separate regression models. Compared with White British men, age-adjusted odds (OR, 95% CI) of pSRH were higher among Bangladeshi (2.05, 1.34 to 3.14), Pakistani (1.77, 1.34 to 2.33) and Black Caribbean (1.60, 1.18 to 2.18) men, but these became non-significant following adjustment for SEP and health behaviours. Unlike Black Caribbean men, Black African men exhibited a lower risk of age-adjusted pSRH (0.66, 0.43 to 1.00 (p=0.048)) and LLI (0.45, 0.28 to 0.72), which were significant in every model. Likewise, Chinese men had a lower risk of age-adjusted pSRH (0.51, 0.26 to 1.00 (p=0.048)) and LLI (0.22, 0.10 to 0.48). Except in Black Caribbean women, adjustment for SEP rendered raised age-adjusted associations for pSRH among Pakistani (2.51, 1.99 to 3.17), Bangladeshi (1.85, 1.08 to 3.16), Black Caribbean (1.78, 1.44 to 2.21) and Indian women (1.37, 1.13 to 1.66) insignificant. Adjustment for health behaviours had the largest effect for South Asian women. By contrast, Irish women reported better age-adjusted SRH (0.70, 1.51 to 0.96). SEP and health behaviours were major contributors explaining EHI. Policies to improve health equity need to monitor these pathways and be informed by them.


Co-occurring conditions associated with FMR1 gene variations: findings from a national parent survey.
Parents enrolling in a national survey of families of children with fragile X (FX) reported whether each of their children had been diagnosed or treated for developmental delay or eight conditions frequently associated with FX: attention problems, hyperactivity, aggressiveness, self-injury, autism, seizures, anxiety, or depression. This article reports results for 976 full mutation males, 259 full mutation females, 57 premutation males, and 199 premutation females. Co-occurring conditions were frequently reported for all FMR1 gene variations. The number of co-occurring conditions experienced was strongly associated with parent reports of their child's ability to learn, adaptability, and quality of life. Most individuals with the full mutation experienced multiple co-occurring conditions, with a modal number of 4 for males and 2 for females. Most (>80%) full mutation males and females had been diagnosed or treated for attention problems. Premutation males, when compared with a matched group of non-FX males, were more likely to have been diagnosed or treated for developmental delay, attention problems, aggression, seizures, autism, and anxiety. Premutation females were more likely to have been diagnosed or treated for attention problems, anxiety, depression, and developmental delay. Clusters of conditions were identified, seeming to occur in an additive fashion. Self-injury, autism, and seizures rarely occurred in isolation, but were more likely in individuals who also had problems with attention, anxiety, and hyperactivity. The findings provide a reference point for future studies on the prevalence and nature of co-occurring conditions in FX; suggest the possibility that certain conditions cluster together; provide evidence that male and female carriers experience elevated rates of co-occurring conditions compared with matched groups of non-carrier children; and emphasize the importance of including an assessment of co-occurring conditions in any clinical evaluation of individuals with abnormal variation in the FMR1 gene.


Hot or cold: is communicating anger or threats more effective in negotiation?
Is communicating anger or threats more effective in eliciting concessions in negotiation? Recent research has emphasized the effectiveness of anger communication, an emotional strategy. In this article, we argue that anger communication conveys an implied threat, and we document that issuing threats is a more effective negotiation strategy than communicating anger. In 3 computer-mediated negotiation experiments, participants received either angry or threatening messages from a simulated counterpart. Experiment 1 showed that perceptions of threat mediated the effect of anger (vs. a control) on concessions. Experiment 2 showed that (a) threat communication elicited greater concessions than anger communication and (b) poise (being confident and in control of one's own feelings and decisions) ascribed to the counterpart mediated the positive effect of threat compared to anger on concessions. Experiment 3 replicated this positive effect of threat over anger when recipients had an attractive alternative to a negotiated agreement. These findings qualify previous research on anger communication in negotiation. Implications for the understanding of emotion and negotiation are discussed.


Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment.
Cell-intrinsic checkpoints limit the proliferative capacity of primary cells in response to telomere dysfunction. It is not known, however, whether telomere dysfunction contributes to cell-extrinsic alterations that impair stem cell function and organ homeostasis. Here we show that telomere dysfunction provokes defects of the hematopoietic environment that impair B lymphopoiesis but increase myeloid proliferation in aging telomerase knockout (Terc(-/-)) mice. Moreover, the dysfunctional environment limited the engraftment of transplanted wild-type hematopoietic stem cells (HSCs). Dysfunction of the hematopoietic environment was age dependent and correlated with progressive telomere shortening in bone marrow stromal cells. Telomere dysfunction impaired mesenchymal progenitor cell function, reduced the capacity of bone marrow stromal cells to maintain functional HSCs, and increased the expression of various cytokines, including granulocyte colony-stimulating factor (G-CSF), in the plasma of aging mice. Administration of G-CSF to wild-type mice mimicked some of the defects seen in aging Terc(-/-) mice, including impairment of B lymphopoiesis and HSC engraftment. Conversely, inhibition of G-CSF improved HSC engraftment in aged Terc(-/-) mice. Taken together, these results show that telomere dysfunction induces alterations of the environment that can have implications for organismal aging and cell transplantation therapies.


First record of the leafhopper genus Varicopsella Hamilton, 1980 (Hemiptera: Cicadellidae: Macropsinae) in China, with descriptions of a new subgenus and new species, a checklist, and a key to species.
A new monobasic leafhopper subgenus, Varicopsella (Multispinulosa) Li, Dai, and Li, subgen. nov., of the subfamily Macropsinae (Hemiptera: Auchenorrhyncha: Membracoidea: Cicadellidae) is proposed to accommodate Varicopsella (Multispinulosa) hamiltoni Li, Dai, and Li, sp. nov.from Guangxi province of China. The new subgenus and new species are described and illustrated. They can be distinguished mainly by characteristics of the fore wings with two anteapical cells; weak dorsoventrally flattened body; aedeagal shaft with paired apical processes on ventral margin; and the shape of the dorsal connective. An updated checklist and an illustrated key for identification of the species of Varicopsella along with geographical distributions of the species are given.


ISLES 2016 and 2017-Benchmarking Ischemic Stroke Lesion Outcome Prediction Based on Multispectral MRI.
Performance of models highly depend not only on the used algorithm but also the data set it was applied to. This makes the comparison of newly developed tools to previously published approaches difficult. Either researchers need to implement others' algorithms first, to establish an adequate benchmark on their data, or a direct comparison of new and old techniques is infeasible. The Ischemic Stroke Lesion Segmentation (ISLES) challenge, which has ran now consecutively for 3 years, aims to address this problem of comparability. ISLES 2016 and 2017 focused on lesion outcome prediction after ischemic stroke: By providing a uniformly pre-processed data set, researchers from all over the world could apply their algorithm directly. A total of nine teams participated in ISLES 2015, and 15 teams participated in ISLES 2016. Their performance was evaluated in a fair and transparent way to identify the state-of-the-art among all submissions. Top ranked teams almost always employed deep learning tools, which were predominately convolutional neural networks (CNNs). Despite the great efforts, lesion outcome prediction persists challenging. The annotated data set remains publicly available and new approaches can be compared directly via the online evaluation system, serving as a continuing benchmark (www.isles-challenge.org).


High-resolution global maps of 21st-century forest cover change.
Quantification of global forest change has been lacking despite the recognized importance of forest ecosystem services. In this study, Earth observation satellite data were used to map global forest loss (2.3 million square kilometers) and gain (0.8 million square kilometers) from 2000 to 2012 at a spatial resolution of 30 meters. The tropics were the only climate domain to exhibit a trend, with forest loss increasing by 2101 square kilometers per year. Brazil's well-documented reduction in deforestation was offset by increasing forest loss in Indonesia, Malaysia, Paraguay, Bolivia, Zambia, Angola, and elsewhere. Intensive forestry practiced within subtropical forests resulted in the highest rates of forest change globally. Boreal forest loss due largely to fire and forestry was second to that in the tropics in absolute and proportional terms. These results depict a globally consistent and locally relevant record of forest change.