Gastrointestinal tissue polyamine contents of patients with Barrett's esophagus treated with alpha-difluoromethylornithine.
alpha-Difluoromethylornithine (DFMO), an investigational chemopreventive agent, suppresses polyamine contents and decreases epithelial carcinogenesis in experimental models. The ability of this drug to decrease polyamine contents in human esophageal tissues has not yet been determined. Eight patients with Barrett's esophagus were treated with DFMO at a dose of 1.5 g/m2/day for 12 weeks. Four sites (Barrett's lesion, adjacent normal squamous esophagus, gastric tissue, and small bowel) were biopsied in each patient before, during, and after DFMO treatment in order to assess the effects of this drug on tissue polyamine levels. Ornithine decarboxylase activities and polyamine contents varied in each site analyzed. The rank orders were Barrett's > small bowel congruent to normal esophagus > gastric tissue for ODC activities, and small bowel > or = Barrett's congruent to normal esophagus > gastric tissue for putrescine contents. Spermidine, but not spermine, contents in the Barrett's lesions and normal squamous esophageal tissue were suppressed by systemic DFMO treatment and recovered to untreated control values when DFMO therapy was discontinued. Systemic DFMO treatment did not affect the levels of either of these two amines in gastric tissue and small bowel. Since DFMO can suppress polyamine contents in several gastrointestinal tissues, including Barrett's mucosa, we conclude that it is an effective agent with which to test the hypothesis that depletion of spermidine contents may prevent the development of adenocarcinoma of the esophagus in this specific patient group.


TRIM26 negatively regulates interferon-β production and antiviral response through polyubiquitination and degradation of nuclear IRF3.
Virus infection leads to the activation of transcription factor IRF3 and subsequent production of type I inteferons, which induce the transcription of various antiviral genes called interferon stimulated genes (ISGs) to eliminate viral infection. IRF3 activation requires phosphorylation, dimerization and nuclear translocation. However, the mechanisms for the termination of IRF3 activation in nucleus are elusive. Here we report the identification of TRIM26 to negatively regulate IFN-β production and antiviral response by targeting nuclear IRF3. TRIM26 bound to IRF3 and promoted its K48-linked polyubiquitination and degradation in nucleus. TRIM26 degraded WT IRF3 and the constitutive active mutant IRF3 5D, but not the phosphorylation deficient mutant IRF3 5A. Furthermore, IRF3 mutant in the Nuclear Localization Signal (NLS), which could not move into nucleus, was not degraded by TRIM26. Importantly, virus infection promoted TRIM26 nuclear translocation, which was required for IRF3 degradation. As a consequence, TRIM26 attenuated IFN-β promoter activation and IFN-β production downstream of TLR3/4, RLR and DNA sensing pathways. TRIM26 transgenic mice showed much less IRF3 activation and IFN-β production, while increased virus replication. Our findings delineate a novel mechanism for the termination of IRF3 activation in nucleus through TRIM26-mediated IRF3 ubiquitination and degradation.


Recipe1M+: A Dataset for Learning Cross-Modal Embeddings for Cooking Recipes and Food Images.
In this paper, we introduce Recipe1M+, a new large-scale, structured corpus of over one million cooking recipes and 13 million food images. As the largest publicly available collection of recipe data, Recipe1M+ affords the ability to train high-capacity models on aligned, multi-modal data. Using these data, we train a neural network to learn a joint embedding of recipes and images that yields impressive results on an image-recipe retrieval task. Moreover, we demonstrate that regularization via the addition of a high-level classification objective both improves retrieval performance to rival that of humans and enables semantic vector arithmetic. We postulate that these embeddings will provide a basis for further exploration of the Recipe1M+ dataset and food and cooking in general. Code, data and models are publicly available.


Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival.
Breakdown or absence of vascular oxygen delivery is a hallmark of many common human diseases, including cancer, myocardial infarction, and stroke. The chief mediator of hypoxic response in mammalian tissues is the transcription factor hypoxia-inducible factor 1 (HIF-1), and its oxygen-sensitive component HIF-1alpha. A key question surrounding HIF-1alpha and the hypoxic response is the role of this transcription factor in cells removed from a functional vascular bed; in this regard there is evidence indicating that it can act as either a survival factor or induce growth arrest and apoptosis. To study more closely how HIF-1alpha functions in hypoxia in vivo, we used tissue-specific targeting to delete HIF-1alpha in an avascular tissue: the cartilaginous growth plate of developing bone. We show here the first evidence that the developmental growth plate in mammals is hypoxic, and that this hypoxia occurs in its interior rather than at its periphery. As a result of this developmental hypoxia, cells that lack HIF-1alpha in the interior of the growth plate die. This is coupled to decreased expression of the CDK inhibitor p57, and increased levels of BrdU incorporation in HIF-1alpha null growth plates, indicating defects in HIF-1alpha-regulated growth arrest occurs in these animals. Furthermore, we find that VEGF expression in the growth plate is regulated through both HIF-1alpha-dependent and -independent mechanisms. In particular, we provide evidence that VEGF expression is up-regulated in a HIF-1alpha-independent manner in chondrocytes surrounding areas of cell death, and this in turn induces ectopic angiogenesis. Altogether, our findings have important implications for the role of hypoxic response and HIF-1alpha in development, and in cell survival in tissues challenged by interruption of vascular flow; they also illustrate the complexities of HIF-1alpha response in vivo, and they provide new insights into mechanisms of growth plate development.


Effect of divalproex on brain morphometry, chemistry, and function in youth at high-risk for bipolar disorder: a pilot study.
Divalproex has been found efficacious in treating adolescents with and at high risk for bipolar disorder (BD), but little is known about the effects of mood stabilizers on the brain itself. We sought to examine the effects of divalproex on the structure, chemistry, and function of specific brain regions in children at high-risk for BD. A total of 24 children with mood dysregulation but not full BD, all offspring of a parent with BD, were treated with divalproex monotherapy for 12 weeks. A subset of 11 subjects and 6 healthy controls were scanned with magnetic resonance imaging (MRI, magnetic resonance spectroscopy [MRS], and functional MRI [fMRI]) at baseline and after 12 weeks. There were no significant changes in amygdalar or cortical volume found over 12 weeks. Furthermore, no changes in neurometabolite ratios were found. However, we found the degree of decrease in prefrontal brain activation to correlate with degree of decrease in depressive symptom severity. Bipolar offspring at high risk for BD did not show gross morphometric, neurometabolite, or functional changes after 12 weeks of treatment with divalproex. Potential reasons include small sample size, short exposure to medications, or lack of significant neurobiological impact of divalproex in this particular population.


Environmental tobacco smoke exposure in the home and worksite and health effects in adults: results from the 1991 National Health Interview Survey.
To determine the effect of environmental tobacco smoke (ETS) exposure in the home and worksite on the health of adults in the United States. Cross-sectional survey. Nationally representative population. 43,732 adults who completed the Health Promotion and Disease Prevention supplement in the 1991 National Health Interview Survey. Rate of restricted activity, bed confinement, and work absence in the two weeks preceding the survey and self-reported health status among adults with and without exposure to ETS. We found that only 20.2% of never-smokers and 23.1% of former smokers reported exposure to ETS at home or work, whereas 87.2% of current smokers reported exposure to ETS. Among never-smokers, after adjusting for covariates, people who were exposed to ETS were more likely to report one or more days of restricted activity (relative risk (RR) = 1.27, 95% confidence interval (CI) = 1.10 to 1.46), one or more days of bed confinement (RR = 1.43, 95% CI = 1.19 to 1.73), and one or more days of work absence (RR = 1.33, 95% CI = 1.05 to 1.73) in the two weeks before the survey than were people without such exposure. We detected smaller trends for one or more days of restricted activity among current and former smokers (RR = 1.16, 95% CI = 0.97 to 1.40; and RR = 1.11, 95% CI = 0.82 to 1.51), one or more days of bed confinement among current smokers (RR = 1.34, 95% CI = 0.95 to 1.88), and one or more days of work absence among former smokers (RR = 1.13, 95% CI = 0.84 to 1.50) in the two weeks before the survey than among people without such exposure, although the CIs were wide and chance cannot be excluded as an explanation for these findings. Never-smokers (RR = 1.47, 95% CI = 1.34 to 1.62), former smokers (RR = 1.22, 95% CI = 1.07 to 1.39) and current smokers (RR = 1.31, 95% CI = 1.10 to 1.56) exposed to ETS were all more likely to report a less than very good health status than were people without such exposure. This study demonstrates that never-smoking adults exposed to ETS report more acute health effects than unexposed, never-smoking adults, and suggests similar findings in current and former smoking adults.


Obesity and low vision as a result of excessive Internet use and television viewing.
The technological age has resulted in children spending prolonged hours in front of television (TV) and computer screens (on the Internet). The aim of this prospective cross-sectional study is to determine the effect of this phenomenon on both childhood obesity and low vision in the State of Qatar. A total of 3000 school students aged 6 to 18 years were approached from September 2009 to March 2010 and 2467 (82.2%) students agreed to participate. Face-to-face interviews based on a designed questionnaire were conducted. The highest proportion of obese children were aged between 15-18 years (9.4%; p < 0.001); spent ≥ 3 hours on the Internet (5.6%; p < 0.001), and spent between 5-7 hours or less sleeping (4.1%; p < 0.001). Forty-six (1.9%) children spent ≥ 3 hours/day on the Internet, and were either overweight/obese and had low vision. The study findings confirmed a positive association between obesity and low vision as a result of excessive time spent on the TV view and Internet use.


Ecophysiological adaptations of anaerobic bacteria to low pH: analysis of anaerobic digestion in acidic bog sediments.
The dynamics of anaerobic digestion were examined in the low-pH sediments of Crystal Bog in Wisconsin. The sediments (pH 4.9) contained 71% organic matter and the following concentrations of dissolved gases (micromoles per liter): CO2, 1,140; CH4, 490; and H2, 0.01. The rate of methane production was 6.2 mumol/liter of sediment per h, which is slower than eutrophic, neutral sediments. Microbial metabolic processes displayed the following pH optima: hydrolysis reactions, between 4.2 and 5.6; aceticlastic methanogenesis, 5.2; and hydrogen-consuming reactions, 5.6. The turnover rate constants for key intermediary metabolites were (h-1): glucose, 1.10; lactate, 0.277; acetate, 0.118; and ethanol, 0.089. The populations of anaerobes were low, with hydrolytic groups (10(6)/ml) several orders of magnitude higher than methanogens (10(2)/ml). The addition of carbon electron donors to the sediment resulted in the accumulation of hydrogen, whereas the addition of hydrogen resulted in the accumulation of fatty acids and the inhibition of hydrogen-producing acetogenic reactions. Strains of Lactobacillus, Clostridium, and Sarcina ventriculi were isolated from the bog, and their physiological attributes were characterized in relation to hydrolytic process functions in the sediments. The present studies provide evidence that the pH present in the bog sediments alter anaerobic digestion processes so that total biocatalytic activity is lower but the general carbon and electron flow pathways are similar to those of neutral anoxic sediments.


Germline methylation patterns determine the distribution of recombination events in the dog genome.
The positive-regulatory domain containing nine gene, PRDM9, which strongly associates with the location of recombination events in several vertebrates, is inferred to be inactive in the dog genome. Here, we address several questions regarding the control of recombination and its influence on genome evolution in dogs. First, we address whether the association between CpG islands (CGIs) and recombination hotspots is generated by lack of methylation, GC-biased gene conversion (gBGC), or both. Using a genome-wide dog single nucleotide polymorphism data set and comparisons of the dog genome with related species, we show that recombination-associated CGIs have low CpG mutation rates, and that CpG mutation rate is negatively correlated with recombination rate genome wide, indicating that nonmethylation attracts the recombination machinery. We next use a neighbor-dependent model of nucleotide substitution to disentangle the effects of CpG mutability and gBGC and analyze the effects that loss of PRDM9 has on these rates. We infer that methylation patterns have been stable during canid genome evolution, but that dog CGIs have experienced a drastic increase in substitution rate due to gBGC, consistent with increased levels of recombination in these regions. We also show that gBGC is likely to have generated many new CGIs in the dog genome, but these mostly occur away from genes, whereas the number of CGIs in gene promoter regions has not increased greatly in recent evolutionary history. Recombination has a major impact on the distribution of CGIs that are detected in the dog genome due to the interaction between methylation and gBGC. The results indicate that germline methylation patterns are the main determinant of recombination rates in the absence of PRDM9.


Renal dysfunction and the risk of postoperative atrial fibrillation after cardiac surgery: role beyond the CHA2DS2-VASc score.
To investigate whether renal dysfunction is a useful predictor of postoperative atrial fibrillation (POAF) after cardiac surgery. We also aimed to determine whether the addition of renal dysfunction into the scoring system could improve diagnostic accuracy of the CHA2DS2-VASc score to predict POAF. The study prospectively enrolled 350 consecutive patients who underwent cardiac surgery. Echocardiography was performed before cardiac surgery. Renal dysfunction was defined as estimated glomerular filtration rate < 60 mL min(-1) 1.73 m(-2). All patients were monitored with continuous electrocardiographic telemetry for the occurrence of POAF until the day of hospital dismissal. Postoperative atrial fibrillation occurred in 103 of 350 patients (29%). Patients with POAF was associated with longer intensive care unit stay compared with those without POAF (3.7 ± 2.2 vs. 3.1 ± 1.4 days, P = 0.002). Both the CHA2DS2-VASc score and renal dysfunction were independent predictors of POAF in multivariate analysis. Renal dysfunction can further stratify patients with a CHA2DS2-VASc score of 0 or 1 into two groups with different POAF rates (3.1% vs. 68.8%, P < 0.001). A new scoring system (R-CHA2DS2-VASc score) derived by assigning an additional point representing renal dysfunction to the CHA2DS2-VASc score could improve its predictive accuracy. The area under the receiver operating characteristic curve increased from 0.68 to 0.71 (P < 0.001). Furthermore, the rate of left ventricular diastolic dysfunction also increased with increasing renal dysfunction. Renal dysfunction, associated with left ventricular diastolic dysfunction, was a significant risk factor for POAF after cardiac surgery and may improve the diagnostic accuracy of the CHA2DS2-VASc score.


Effects of acute tryptophan depletion on mood and facial emotion perception related brain activation and performance in healthy women with and without a family history of depression.
The present study examined the effects of acute tryptophan (Trp) depletion (ATD), a well-recognized method to lower central serotonin (5-HT) metabolism, on brain activation during a facial emotion perception task. Brain activation was measured using fMRI, and healthy female volunteers with a positive family history of unipolar depression (FH+) were compared to healthy female volunteers without such a history (FH-). Participants viewed two morphed faces and were instructed to choose between the faces based either on the intensity of the emotional expression (direct task) or the gender of the face (incidental task). In the FH+ group, depletion led to the expected lowering of mood, which partly determined the effect of depletion on performance and brain activation. A stronger mood lowering effect was associated with less accurate performance on faces expressing a negative emotion in the incidental task and a stronger right amygdala response to fearful faces in comparison to happy faces. These results were explained in terms of a mood-induced bias leading to a stronger impact of the expressed negative emotion which subsequently leads to more interference in the incidental task and a stronger amygdala response. It was concluded that the effects of ATD on mood, performance, and brain activation in a facial emotion perception task depend on family history of depression. Performance and brain activation partly depend on the effect of ATD on mood.


Duration of untreated bipolar disorder: missed opportunities on the long road to optimal treatment.
Duration of untreated illness represents a potentially modifiable component of any diagnosis-treatment pathway. In bipolar disorder (BD), this concept has rarely been systematically defined or not been applied to large clinically representative samples. In a well-characterized sample of 501 patients with BD, we estimated the duration of untreated bipolar disorder (DUB: the interval between the first major mood episode and first treatment with a mood stabilizer). Associations between DUB and clinical onset and the temporal sequence of key clinical milestones were examined. The mean DUB was 9.6 years (SD 9.7; median 6). The median DUB for those with a hypomanic onset (14.5 years) exceeded that for depressive (13 years) and manic onset (8 years). Early onset BD cases have the longest DUB (P < 0.0001). An extended DUB was associated with more mood episodes (P < 0.0001), more suicidal behaviour (P = 0.0003) and a trend towards greater lifetime mood instability (e.g. rapid cycling, possible antidepressant-induced mania). Duration of untreated bipolar disorder (DUB) will only be significantly reduced by more aggressive case finding strategies. Reliable diagnosis (especially for BD-II) and/or instigation of recommended treatments is currently delayed by insufficient awareness of the early, polymorphous presentations of BD, lack of systematic screening and/or failure to follow established guidelines.


Functional analysis of transcriptional activity of cytosine and adenine (CA) repeats polymorphism in the estrogen receptor beta gene.
Cytosine and adenine (CA) repeats polymorphism (D14S1026) iterating "cytosine and adenine" nucleotide motifs is one of the genomic microsatellites in intron 5 of the estrogen receptor beta (ER beta) gene (14q22-24). Relations between CA repeats polymorphism and several diseases have been shown. Although the relation between number of CA repeats and gene transcription has been actively studied using several genes, results have remained contradictory until this time. In this study, we examined the functional effects of CA repeats polymorphism on transcriptional activity based on our knowledge of the ER beta gene. After preparing four types of reporter gene constructs containing 15, 18, 24 or 27 CA repeats, luciferase reporter gene assays were performed. Relative luciferase activities of these constructs were not significantly different from that of the no inserted vector and variation of CA repeats did not affect these activities. Our results indicate that CA repeats polymorphism might not only affect transcriptional activity but also other processes of gene expressions. Further studies are needed to clarify the specific functions of CA repeats polymorphism in the ER beta gene.


Molecular analysis of ancient caries.
An 84 base pair sequence of the Streptococcus mutans virulence factor, known as dextranase, has been obtained from 10 individuals from the Bronze Age to the Modern Era in Europe and from before and after the colonization in America. Modern samples show four polymorphic sites that have not been found in the ancient samples studied so far. The nucleotide and haplotype diversity of this region have increased over time, which could be reflecting the footprint of a population expansion. While this segment has apparently evolved according to neutral evolution, we have been able to detect one site that is under positive selection pressure both in present and past populations. This study is a first step to study the evolution of this microorganism, analysed using direct evidence obtained from ancient remains.


Mediators of the effect of neighborhood poverty on physical functioning among breast cancer survivors: a longitudinal study.
Female breast cancer survivors, a large and growing population, experience impaired physical functioning after treatment. Survivors living in impoverished neighborhoods may suffer even greater impairment, but the mechanisms linking neighborhood poverty and individual outcomes are poorly understood. This study sought to identify mediators of the effect of neighborhood poverty on physical functioning using longitudinal data from a Missouri cancer registry-based sample of 909 female breast cancer survivors. Survivors were recruited 1 year after diagnosis (Y1) and completed two telephone interviews, at Y1 and 1 year later (Y2). The association between census-tract-level poverty and physical functioning (RAND SF-36) was tested using a multilevel a priori path model with 19 hypothesized mediators, demographic and socioeconomic confounders, and covariates. Hypothesized mediators included clinical and treatment variables, psychosocial factors (depression, stress, social support), perceived neighborhood characteristics, behavioral risk factors (physical activity, smoking, body mass index, alcohol use), and comorbidity. In unadjusted analysis, women living in neighborhoods with higher poverty were more likely to report lower physical functioning at Y2 (β = -.19, p < .001). The final mediated model fit the data well (χ(2)(8) = 12.25, p = 0.14; CFI = .996; RMSEA = .024). The effect of neighborhood poverty on physical functioning was fully mediated by physical activity and body mass index. Breast cancer survivors living in neighborhoods with greater poverty reported lower physical functioning, but this effect was fully explained by physical activity and body mass index. Community-based lifestyle interventions sensitive to the unique challenges faced by cancer survivors and the challenges of living in a high-poverty neighborhood are needed to ameliorate neighborhood socioeconomic disparities in physical functioning.


Cellular and Molecular Responses to Mechanical Expansion of Tissue.
The increased use of tissue expander in the past decades and its potential market values in near future give enough reasons to sum up the consequences of tissue expansion. Furthermore, the patients have the right to know underlying mechanisms of adaptation of inserted biomimetic, its bioinspired materials and probable complications. The mechanical strains during tissue expansion are related to several biological phenomena. Tissue remodeling during the expansion is highly regulated and depends on the signal transduction. Any alteration may lead to tumor formation, necrosis and/or apoptosis. In this review, stretch induced cell proliferation, apoptosis, the roles of growth factors, stretch induced ion channels, and roles of second messengers are organized. It is expected that readers from any background can understand and make a decision about tissue expansion.


A DNA-structured mathematical model of cell-cycle progression in cyclic hypoxia.
New experimental data have shown how the periodic exposure of cells to low oxygen levels (i.e., cyclic hypoxia) impacts their progress through the cell-cycle. Cyclic hypoxia has been detected in tumours and linked to poor prognosis and treatment failure. While fluctuating oxygen environments can be reproduced in vitro, the range of oxygen cycles that can be tested is limited. By contrast, mathematical models can be used to predict the response to a wide range of cyclic dynamics. Accordingly, in this paper we develop a mechanistic model of the cell-cycle that can be combined with in vitro experiments to better understand the link between cyclic hypoxia and cell-cycle dysregulation. A distinguishing feature of our model is the inclusion of impaired DNA synthesis and cell-cycle arrest due to periodic exposure to severely low oxygen levels. Our model decomposes the cell population into five compartments and a time-dependent delay accounts for the variability in the duration of the S phase which increases in severe hypoxia due to reduced rates of DNA synthesis. We calibrate our model against experimental data and show that it recapitulates the observed cell-cycle dynamics. We use the calibrated model to investigate the response of cells to oxygen cycles not yet tested experimentally. When the re-oxygenation phase is sufficiently long, our model predicts that cyclic hypoxia simply slows cell proliferation since cells spend more time in the S phase. On the contrary, cycles with short periods of re-oxygenation are predicted to lead to inhibition of proliferation, with cells arresting from the cell-cycle in the G2 phase. While model predictions on short time scales (about a day) are fairly accurate (i.e, confidence intervals are small), the predictions become more uncertain over longer periods. Hence, we use our model to inform experimental design that can lead to improved model parameter estimates and validate model predictions.


Cranberry proanthocyanidins inhibit MMP production and activity.
Matrix metalloproteinases (MMPs) produced by resident and inflammatory cells in response to periodontopathogens play a major role in periodontal tissue destruction. Our aim was to investigate the effects of A-type cranberry proanthocyanidins (AC-PACs) on: (i) the production of various MMPs by human monocyte-derived macrophages stimulated with Aggregatibacter actinomycetemcomitans lipopolysaccharide (LPS), and (ii) the catalytic activity of recombinant MMP-1 and MMP-9. The effects of AC-PACs on the expression of 5 protein kinases and the activity of nuclear factor-kappa B (NF-kappaB) p65 in macrophages stimulated with LPS were also monitored. Our results indicated that AC-PACs inhibited the production of MMPs in a concentration-dependent manner. Furthermore, the catalytic activity of MMP-1 and MMP-9 was also inhibited. The inhibition of MMP production was associated with reduced phosphorylation of key intracellular kinases and the inhibition of NF-kappaB p65 activity. AC-PACs thus show potential for the development of novel host-modulating strategies to inhibit MMP-mediated tissue destruction during periodontitis.


Metals removal from stormwater by commercial and non-commercial granular activated carbons.
Removing dissolved metals from urban storMwater may be required to protect aquatic species in particular watersheds. This research examined the adsorption of zinc and copper on 12 granular activated carbons, of which six were obtained commercially and six were produced by thermal activation of agricultural byproducts in the laboratory. Batch studies were used to obtain single solute distribution coefficients at pH 7. Copper distribution coefficients were higher than those for zinc on each of the 12 adsorbents. Granular activated carbon (GAC) produced from nutshells was less effective than that produced from rice materials (straw and hulls). The rice-derived GACs had the highest zinc distribution coefficients, and the commercial GACs typically exhibited higher copper distribution coefficients. Distribution coefficients for zinc and copper typically were higher for the materials tested in this study than in previous research, possibly because of the lower dissolved metal concentrations used, which were chosen to represent highway stormwater. Adsorption isotherms were obtained for zinc and copper adsorption on one commercial GAC and on activated rice hulls in buffered laboratory water and in highway stormwater. The constituents in stormwater caused a reduction in sorption of zinc and copper of up to 80%. The results suggest that 1 kg of activated rice hulls could treat up to 7 m3 of stormwater for zinc or 46 m3 of copper before exhaustion at the 90th percentile dissolved concentrations in California highway stormwater. The higher stormwater concentration and lower GAC affinity of zinc means that this constituent typically will limit adsorption system design for removal of multiple metals from stormwater.


Larger whole brain grey matter associated with long-term Sahaja Yoga Meditation: A detailed area by area comparison.
Our previous study showed that long-term practitioners of Sahaja Yoga Meditation (SYM) had around 7% larger grey matter volume (GMV) in the whole brain compared with healthy controls; however, when testing individual regions, only 5 small brain areas were statistically different between groups. Under the hypothesis that those results were statistically conservative, with the same dataset, we investigated in more detail the regional differences in GMV associated with the practice of SYM, with a different statistical approach. Twenty-three experienced practitioners of SYM and 23 healthy non-meditators matched on age, sex and education level, were scanned using structural magnetic resonance imaging (MRI). Their GMV were extracted and compared using Voxel-Based Morphometry (VBM). Using a novel ad-hoc general linear model, statistical comparisons were made to observe if the GMV differences between meditators and controls were statistically significant. In the 16 lobe area subdivisions, GMV was statistically significantly different in 4 out of 16 areas: in right hemispheric temporal and frontal lobes, left frontal lobe and brainstem. In the 116 AAL area subdivisions, GMV difference was statistically significant in 11 areas. The GMV differences were statistically more significant in right hemispheric brain areas. The study shows that long-term practice of SYM is associated with larger GMV overall, and with significant differences mainly in temporal and frontal areas of the right hemisphere and the brainstem. These neuroplastic changes may reflect emotional and attentional control mechanisms developed with SYM. On the other hand, our statistical ad-hoc method shows that there were more brain areas with statistical significance compared to the traditional methodology which we think is susceptible to conservative Type II errors.


Out-of-plane nanomechanical tuning of double-coupled one-dimensional photonic crystal cavities.
We demonstrate tuning of double-coupled one-dimensional photonic crystal cavities by their out-of-plane nanomechanical deformations. The coupled cavities are pulled by the vertical electrostatic force generated by the potential difference between the device layer and the handle layer in a silicon-on-insulator chip, and the induced deformations are analyzed by the finite element method. Applied with a voltage of 12 V, the cavities obtain a redshift of 0.0405 nm (twice the linewidth) for their second-order odd resonance mode and a blueshift of 0.0635 nm (three times the linewidth) for their second-order even resonance mode, which are mainly attributed to out-of-plane relative displacement. Out-of-plane tuning of coupled cavities does not need actuators and corresponding circuits; thus the device is succinct and compact. This working principle can be potentially applied in chip-level optoelectronic devices, such as sensors, switches, routers, and tunable filters.


Perivascular signals alter global gene expression profile of glioblastoma and response to temozolomide in a gelatin hydrogel.
Glioblastoma (GBM) is the most common primary malignant brain tumor, with patients exhibiting poor survival (median survival time: 15 months). Difficulties in treating GBM include not only the inability to resect the diffusively-invading tumor cells, but also therapeutic resistance. The perivascular niche (PVN) within the GBM tumor microenvironment contributes significantly to tumor cell invasion, cancer stem cell maintenance, and has been shown to protect tumor cells from radiation and chemotherapy. In this study, we examine how the inclusion of non-tumor cells in culture with tumor cells within a hydrogel impacts the overall gene expression profile of an in vitro artificial perivascular niche (PVN) comprised of endothelial and stromal cells directly cultured with GBM tumor cells within a methacrylamide-functionalized gelatin hydrogel. Using RNA-seq, we demonstrate that genes related to angiogenesis and extracellular matrix remodeling are upregulated in the PVN model compared to hydrogels containing only tumor or perivascular niche cells, while downregulated genes are related to cell cycle and DNA damage repair. Signaling pathways and genes commonly implicated in GBM malignancy, such as MGMT, EGFR, PI3K-Akt signaling, and Ras/MAPK signaling are also upregulated in the PVN model. We describe the kinetics of gene expression within the PVN hydrogels over a course of 14 days, observing the patterns associated with tumor cell-mediated endothelial network co-option and regression. We finally examine the effect of temozolomide, a frontline chemotherapy used clinically against GBM, on the PVN culture. Notably, the PVN model is less responsive to TMZ compared to hydrogels containing only tumor cells. Overall, these results demonstrate that inclusion of cellular and matrix-associated elements of the PVN within an in vitro model of GBM allows for the development of gene expression patterns and therapeutic response relevant to GBM.


Antimycobacterial activity of 2-methyl-adenosine.
The aims of this study were to assess the in vitro activity of 2-methyl-adenosine against Mycobacterium tuberculosis and evaluate, and to intracellular efficacy, and to evaluate its effectiveness against M. tuberculosis in a persistent state model and examine its potential mechanism of action. In vitro activity was determined by means of a colorimetric microdilution broth assay. Intracellular activity was assessed with a Mono Mac 6 human monocytic cell line. A hypoxic shift-down model was used to evaluate the effect of 2-methyl-adenosine on M. tuberculosis in a persistent state. Mechanism-of-action studies were conducted by examining the effect of 2-methyl-adenosine on the uptake of appropriate radiolabelled precursors into respective mycobacterial macromolecular components. Studies confirmed the in vitro activity of 2-methyl-adenosine against M. tuberculosis and demonstrated intracellular efficacy against M. tuberculosis within macrophages. 2-Methyl-adenosine was able to significantly affect the viability of M. tuberculosis in a hypoxic shift-down model previously described to simulate the persistent state that results during tuberculosis. Mechanism-of-action studies revealed that the immediate inhibitory effects of 2-methyl-adenosine were associated with protein and DNA synthesis and not RNA synthesis. Results indicate that 2-methyl-adenosine, or similar derivatives, might be effective against M. tuberculosis infections during latency. This information should be helpful in understanding purine metabolism of M. tuberculosis and also the metabolic activity of this important human pathogen in the persistent state.


Synthesis, characterization, and ligand behaviour of a new ditelluroether (C10H7)Te(CH2)4Te(C10H7) and the concurrently formed ionic [(C10H7)Te(CH2)4]Br.
The reaction of 1-naphthyl bromide with n-butyl lithium, elemental tellurium, and 1,4-dibromobutane in THF affords both (C10H7)Te(CH2)4Te(C10H7) (1) and [(C10H7)Te(CH2)4]Br (2) in good yields. 1 is preferentially formed at low temperatures and is a rare example of a structurally characterized ditelluroether in which the tellurium atoms are bridged by a hydrocarbon chain. In the solid state, 1 shows secondary bonding TeTe interactions, which connect the molecules into layers which are further linked to 3-dimensional frameworks by TeH hydrogen bonds. [(C10H7)Te(CH2)4]Br (2) is formed concurrently during the synthesis of 1 and is the main product, when the reaction is carried out at room temperature. The revPBE/def2-TZVPP calculations of the reaction profiles indicate that the formation of 2 is somewhat more favourable than that of 1. Furthermore, at room temperature the activation energy for the formation of 2 is lower than that of 1. At low temperatures the activation energy of the reaction leading to 1 is lower than that to 2, which is consistent with the synthetic observations. When 1 was treated with CuBr, [Cu2(μ-Br)2{μ-(C10H7)Te(CH2)4Te(C10H7)}2] (3) was formed. It crystallizes as two polymorphs (3a) and (3b) in which both the packing and the conformation of the ditelluroether ligands are different. The reaction of 1 with HgCl2 produces [(C10H7)Te(CH2)4]2[HgCl4]·CH2Cl2 (4·CH2Cl2) and that of 1 with CuCl2 affords [(C10H7)Te(CH2)4]Cl (5). 2 and 5 are isomorphous.


Polymorphisms in the CYP19A1 (aromatase) gene and endometrial cancer risk in Chinese women.
Aromatase, encoded by the CYP19A1 gene, is a key enzyme in estradiol biosynthesis, which catalyzes the conversion of androstenedione and testosterone to estrone and estradiol, respectively. Given the critical role of estrogen in the development of endometrial cancer risk, we evaluated genetic polymorphisms of the CYP19A1 gene, including rs1065779, rs700519, rs28566535, rs752760, and rs1870050, in association with endometrial cancer in a population-based case-control study conducted in Shanghai, China. Genotypes of 1,040 incident endometrial cancer cases and 1,031 frequency-matched controls were included in the study. We applied a logistic regression model to derive adjusted odds ratios (OR) and their 95% confidence intervals (95% CI). Six common haplotypes with a frequency >or=5% were estimated; the highest frequency haplotype was GCACA (27.8% in cases and 26.2% in controls). We observed an inverse association between CYP19A1 haplotype TCATC and endometrial cancer in our population (OR, 0.76; 95% CI, 0.62-0.92). An inverse association was found between endometrial cancer and single nucleotide polymorphism rs1870050 in the promoter region with ORs of 0.81 (95% CI, 0.68-0.97) and 0.58 (95% CI, 0.42-0.80) for the AC and CC genotypes, respectively. We observed a multiplicative interaction between single nucleotide polymorphism rs700519 and body mass index among postmenopausal women (P = 0.01), with stronger associations between rs700519 genotypes and endometrial cancer risk among heavier (body mass index, >or=25) postmenopausal women. In summary, our data show that polymorphisms in the CYP19A1 gene may contribute to endometrial carcinogenesis.


Intrinsic sequence specificity of the Cas1 integrase directs new spacer acquisition.
The adaptive prokaryotic immune system CRISPR-Cas provides RNA-mediated protection from invading genetic elements. The fundamental basis of the system is the ability to capture small pieces of foreign DNA for incorporation into the genome at the CRISPR locus, a process known as Adaptation, which is dependent on the Cas1 and Cas2 proteins. We demonstrate that Cas1 catalyses an efficient trans-esterification reaction on branched DNA substrates, which represents the reverse- or disintegration reaction. Cas1 from both Escherichia coli and Sulfolobus solfataricus display sequence specific activity, with a clear preference for the nucleotides flanking the integration site at the leader-repeat 1 boundary of the CRISPR locus. Cas2 is not required for this activity and does not influence the specificity. This suggests that the inherent sequence specificity of Cas1 is a major determinant of the adaptation process.


Antioxidant capacity of calendula officinalis flowers extract and prevention of radiation induced oropharyngeal mucositis in patients with head and neck cancers: a randomized controlled clinical study.
This study was designed to determine the effect of Calendula officinalis flowers extract mouthwash as oral gel on radiation-induced oropharyngeal mucositis (OM) in patients with head-and-neck cancer. Forty patients with neck and head cancers under radiotherapy or concurrent chemoradiotherapy protocols were randomly assigned to receive either 2% calendula extract mouthwash or placebo (20 patients in each group). Patients were treated with telecobalt radiotherapy at conventional fractionation (200 cGy/fraction, five fractions weekly, 30-35 fractions within 4-7 weeks). The oropharyngeal mucositis was evaluated by two clinical investigators (a radiation oncologist and a dentist), using the oral mucositis assessment scale (OMAS). Trying to find out the possible mechanism of action of the treatment, total antioxidant, polyphenol and flavonoid contents, and quercetin concentration of the mouth wash were measured. Calendula mouthwash significantly decreased the intensity of OM compared to placebo at week 2 (score: 5.5 vs. 6.8, p = 0.019), week 3 (score: 8.25 vs. 10.95, p < 0.0001) and week 6 (score: 11.4 vs. 13.35, p = 0.031). Total antioxidant, polyphenol and flavonoid contents and quercetin concentration of the 2% extract were 2353.4 ± 56.5 μM, 313.40 ± 6.52 mg/g, 76.66 ± 23.24 mg/g, and 19.41 ± 4.34 mg/l, respectively. Calendula extract gel could be effective on decreasing the intensity of radiotherapy- induced OM during the treatment and antioxidant capacity may be partly responsible for the effect.


Clinical and angioarchitectural characteristics of spinal vascular malformations of the cervical spine.
Vascular malformations of the cervical spine are exceedingly rare. To date there have been no large case series describing the clinical presentation and angioarchitectural characteristics of cervical spine vascular malformations. The authors report their institutional case series on cervical spine vascular malformations diagnosed and treated at their institution. The authors retrospectively reviewed all patients with spinal vascular malformations from their institution from January 2001 to December 2018. Patients with vascular malformations of the cervical spine were included. Lesions were characterized by their angioarchitectural characteristics by an interventional neuroradiologist and endovascular neurosurgeon. Data were collected on clinical presentation, imaging findings, treatment outcomes, and long-term follow-up. Descriptive statistics are reported. Of a total of 213 patients with spinal vascular malformations, 27 (12.7%) had vascular malformations in the cervical spine. The mean patient age was 46.1 ± 21.9 years and 16 (59.3%) were male. The most common presentations were lower-extremity weakness (13 patients, 48.1%), tetraparesis (8 patients, 29.6%), and lower-extremity sensory dysfunction (7 patients, 25.9%). Nine patients (33.3%) presented with hemorrhage. Fifteen patients (55.6%) had modified Rankin Scale scores of 0-2 at the time of diagnosis. Regarding angioarchitectural characteristics, 8 patients (29.6%) had intramedullary arteriovenous malformations (AVMs), 5 (18.5%) had epidural arteriovenous fistulas (AVFs), 4 (14.8%) had paraspinal fistulas, 4 (14.8%) had mixed epidural/intradural fistulas, 3 (11.1%) had perimedullary AVMs, 2 (7.4%) had dural fistulas, and 1 patient (3.7%) had a perimedullary AVF. This retrospective study of 27 patients with cervical spine vascular malformations is the largest series to date on these lesions. The authors found substantial angioarchitectural heterogeneity with the most common types being intramedullary AVMs followed by epidural AVFs, paraspinal fistulas, and mixed intradural/extradural fistulas. Angioarchitecture dictated the clinical presentation as intradural shunts were more likely to present with hemorrhage and acute onset myelopathy, while dural and extradural shunts presented as either incidental lesions or gradually progressive congestive myelopathy.


Evolution of hole shape and size during short and ultrashort pulse laser deep drilling.
A detailed study of the influence of the pulse duration, from the femtosecond to the nanosecond regime, on the evolution of the hole shape and depth during percussion drilling in silicon is presented. Real-time backlight imaging of the hole development is obtained for holes up to 2 mm deep with aspect ratios extending to 25:1. For low pulse energies, the hole-shape and drilling characteristics are similar for femtosecond, picoseconds and nanosecond regimes. At higher pulse energies, ns-pulses exhibit slower average drilling rates but eventually reach greater final depths. The shape of these holes is however dominated by branching and large internal cavities. For ps-pulses, a cylindrical shape is maintained with frequent small bulges on the side-walls. In contrast, fs-pulses cause only a limited number of imperfections on a tapered hole shape.


Astigmatism and White cells: theoretical considerations on the construction of an anastigmatic White cell.
The subject of this study is the theoretical background of astigmatism at spheres and its compensation. As a result of this study, it is shown that it is possible to construct White cells free of astigmatism for one light pass or more by separating the two rows of foci on the field mirror by a distance h. This row distance h depends on the number of passes of the light beam, the common radius of curvature R, the distance between entrance and exit focus, and the distance between the two central points on the objective mirrors. The theoretically derived mathematical equations describing this relationship are compared with results of computer simulations, and excellent agreement is observed.


Stress and telomere shortening among central Indian conservation refugees.
Research links psychosocial stress to premature telomere shortening and accelerated human aging; however, this association has only been demonstrated in so-called "WEIRD" societies (Western, educated, industrialized, rich, and democratic), where stress is typically lower and life expectancies longer. By contrast, we examine stress and telomere shortening in a non-Western setting among a highly stressed population with overall lower life expectancies: poor indigenous people--the Sahariya--who were displaced (between 1998 and 2002) from their ancestral homes in a central Indian wildlife sanctuary. In this setting, we examined adult populations in two representative villages, one relocated to accommodate the introduction of Asiatic lions into the sanctuary (n = 24 individuals), and the other newly isolated in the sanctuary buffer zone after their previous neighbors were moved (n = 22). Our research strategy combined physical stress measures via the salivary analytes cortisol and α-amylase with self-assessments of psychosomatic stress, ethnographic observations, and telomere length assessment [telomere-fluorescence in situ hybridization (TEL-FISH) coupled with 3D imaging of buccal cell nuclei], providing high-resolution data amenable to multilevel statistical analysis. Consistent with expectations, we found significant associations between each of our stress measures--the two salivary analytes and the psychosomatic symptom survey--and telomere length, after adjusting for relevant behavioral, health, and demographic traits. As the first study (to our knowledge) to link stress to telomere length in a non-WEIRD population, our research strengthens the case for stress-induced telomere shortening as a pancultural biomarker of compromised health and aging.


Anthropometric parameters of schoolchildren with different life-styles.
Height and weight data obtained from a 2-year longitudinal survey were analyzed for 2272 children aged 6 through 18 years who were attending public schools or Seventh-Day Adventist (SDA) schools in southern California. The SDAs do not use alcohol or tobacco, and many adhere to a lacto-ovovegetarian diet. For both sexes, in each school group, the mean height and weight were at or above national reference values. Age-adjusted regression analysis showed that SDA school-boys were 1.6 cm taller than public schoolboys. There were no significant differences in height for girls. After controlling for height, boys and girls in the SDA schools were found to be leaner than their public school peers, ie, 1.27 and 1.16 kg, respectively. These results suggest that a health-oriented life-style in childhood and adolescence, such as the one followed by SDAs, is compatible with adequate growth and associated with a lower weight for height.


Super-resolution microscopy compatible fluorescent probes reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics.
The glucagon-like peptide-1 receptor (GLP1R) is a class B G protein-coupled receptor (GPCR) involved in metabolism. Presently, its visualization is limited to genetic manipulation, antibody detection or the use of probes that stimulate receptor activation. Herein, we present LUXendin645, a far-red fluorescent GLP1R antagonistic peptide label. LUXendin645 produces intense and specific membrane labeling throughout live and fixed tissue. GLP1R signaling can additionally be evoked when the receptor is allosterically modulated in the presence of LUXendin645. Using LUXendin645 and LUXendin651, we describe islet, brain and hESC-derived β-like cell GLP1R expression patterns, reveal higher-order GLP1R organization including membrane nanodomains, and track single receptor subpopulations. We furthermore show that the LUXendin backbone can be optimized for intravital two-photon imaging by installing a red fluorophore. Thus, our super-resolution compatible labeling probes allow visualization of endogenous GLP1R, and provide insight into class B GPCR distribution and dynamics both in vitro and in vivo.


The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells.
Regulatory T cells (Tregs) have a central role in maintaining immune homoeostasis through various mechanisms. Although the Forkhead transcription factor Foxp3 defines the Treg cell lineage and functions, the molecular mechanisms of Foxp3 induction and maintenance remain elusive. Here we show that Foxp3 is one of the direct targets of Nr4a2. Nr4a2 binds to regulatory regions of Foxp3, where it mediates permissive histone modifications. Ectopic expression of Nr4a2 imparts Treg-like suppressive activity to naïve CD4(+) T cells by inducing Foxp3 and by repressing cytokine production, including interferon-γ and interleukin-2. Deletion of Nr4a2 in T cells attenuates induction of Tregs and causes aberrant induction of Th1, leading to the exacerbation of colitis. Nr4a2-deficeint Tregs are prone to lose Foxp3 expression and have attenuated suppressive ability both in vitro and in vivo. Thus, Nr4a2 has the ability to maintain T-cell homoeostasis by regulating induction, maintenance and suppressor functions of Tregs, and by repression of aberrant Th1 induction.


Integrative network-based Bayesian analysis of diverse genomics data.
In order to better understand cancer as a complex disease with multiple genetic and epigenetic factors, it is vital to model the fundamental biological relationships among these alterations as well as their relationships with important clinical outcomes. We develop an integrative network-based Bayesian analysis (iNET) approach that allows us to jointly analyze multi-platform high-dimensional genomic data in a computationally efficient manner. The iNET approach is formulated as an objective Bayesian model selection problem for Gaussian graphical models to model joint dependencies among platform-specific features using known biological mechanisms. Using both simulated datasets and a glioblastoma (GBM) study from The Cancer Genome Atlas (TCGA), we illustrate the iNET approach via integrating three data types, microRNA, gene expression (mRNA), and patient survival time. We show that the iNET approach has greater power in identifying cancer-related microRNAs than non-integrative approaches based on realistic simulated datasets. In the TCGA GBM study, we found many mRNA-microRNA pairs and microRNAs that are associated with patient survival time, with some of these associations identified in previous studies. The iNET discovers relationships consistent with the underlying biological mechanisms among these variables, as well as identifying important biomarkers that are potentially relevant to patient survival. In addition, we identified some microRNAs that can potentially affect patient survival which are missed by non-integrative approaches.


Polarization-induced noise in a fiber-optic Michelson interferometer with Faraday rotator mirror elements.
Faraday rotator mirror elements have been used in a number of applications as compensators for induced birefringence in retracing paths. In interferometric systems, such as the fiber-optic Michelson interferometer, this approach proved to be useful in providing maximum fringe visibility and insensitivity to the polarization state of light injected into the interferometer. However, it is found that, when the characteristics of the fiber coupler depend on the polarization state of the input beam, the efficiency of the Faraday mirror elements is limited. Theoretical analysis and experimental results in support of this statement are presented.


Association between parental depression and children's health care use.
The objective of this study was to determine the association between parental depression and pediatric health care use patterns. We selected all children who were 0 to 17 years of age, enrolled in Kaiser Permanente of Colorado during the study period July 1997 to December 2002, and linked to at least 1 parent/subscriber who was enrolled for at least 6 months during that period. Unexposed children were selected from a pool of children whose parents did not have a depression diagnosis. Outcome measures were derived from the child's payment files and electronic medical charts and included 5 categories of use: well-child-care visits, sick visits to primary care departments, specialty clinic visits, emergency department visits, and inpatient visits. We compared the rate of use per enrollment month for these 5 categories between exposed and unexposed children within each of the 5 age strata. Our study population had 24,391 exposed and 45,274 age-matched, unexposed children. For the outcome of well-child-care visits, teenagers showed decreased rates of visits among exposed children. The rate of specialty department visits was higher in exposed children in the 4 oldest age groups. The rates of both emergency department visits and sick visits to primary care departments were higher for exposed children across all 5 age categories. The rate of inpatient visits was higher among exposed children in 2 of the 5 age groups. Overall, having at least 1 depressed parent is associated with greater rate of emergency department and sick visits across all age groups, greater use of inpatient and specialty services in some age groups, and a lower rate of well-child-care visits among 13- to 17-year-olds. This pattern of increased use of expensive resources and decreased use of preventive services represents one of the hidden costs of adult depression.


Genetic variation reveals large-scale population expansion and migration during the expansion of Bantu-speaking peoples.
The majority of sub-Saharan Africans today speak a number of closely related languages collectively referred to as 'Bantu' languages. The current distribution of Bantu-speaking populations has been found to largely be a consequence of the movement of people rather than a diffusion of language alone. Linguistic and single marker genetic studies have generated various hypotheses regarding the timing and the routes of the Bantu expansion, but these hypotheses have not been thoroughly investigated. In this study, we re-analysed microsatellite markers typed for large number of African populations that-owing to their fast mutation rates-capture signatures of recent population history. We confirm the spread of west African people across most of sub-Saharan Africa and estimated the expansion of Bantu-speaking groups, using a Bayesian approach, to around 5600 years ago. We tested four different divergence models for Bantu-speaking populations with a distribution comprising three geographical regions in Africa. We found that the most likely model for the movement of the eastern branch of Bantu-speakers involves migration of Bantu-speaking groups to the east followed by migration to the south. This model, however, is only marginally more likely than other models, which might indicate direct movement from the west and/or significant gene flow with the western Branch of Bantu-speakers. Our study use multi-loci genetic data to explicitly investigate the timing and mode of the Bantu expansion and it demonstrates that west African groups rapidly expanded both in numbers and over a large geographical area, affirming the fact that the Bantu expansion was one of the most dramatic demographic events in human history.


Phasic modulation of visual representations during sustained attention.
Sustained attention has long been thought to benefit perception in a continuous fashion, but recent evidence suggests that it affects perception in a discrete, rhythmic way. Periodic fluctuations in behavioral performance over time, and modulations of behavioral performance by the phase of spontaneous oscillatory brain activity point to an attentional sampling rate in the theta or alpha frequency range. We investigated whether such discrete sampling by attention is reflected in periodic fluctuations in the decodability of visual stimulus orientation from magnetoencephalographic (MEG) brain signals. In this exploratory study, human subjects attended one of the two grating stimuli, while MEG was being recorded. We assessed the strength of the visual representation of the attended stimulus using a support vector machine (SVM) to decode the orientation of the grating (clockwise vs. counterclockwise) from the MEG signal. We tested whether decoder performance depended on the theta/alpha phase of local brain activity. While the phase of ongoing activity in the visual cortex did not modulate decoding performance, theta/alpha phase of activity in the frontal eye fields and parietal cortex, contralateral to the attended stimulus did modulate decoding performance. These findings suggest that phasic modulations of visual stimulus representations in the brain are caused by frequency-specific top-down activity in the frontoparietal attention network, though the behavioral relevance of these effects could not be established.


Human immunodeficiency virus (HIV) modulates the associations between insulin resistance and cognition in the current combination antiretroviral therapy (cART) era: a study of the Women's Interagency HIV Study (WIHS).
Cognitive impairment (CI) remains common despite access to combination antiretroviral therapy (cART); it has been linked to HIV-specific, HIV-related, and HIV-unrelated factors. Insulin resistance (IR) was associated with CI in the early cART era, when antiretroviral medications had greater mitochondrial and metabolic toxicity. We sought to examine these relationships in the current cART era of reduced antiretroviral toxicities. This study examined IR among non-diabetics in relation to a 1-h neuropsychological test battery among 994 women (659 HIV-infected and 335 HIV-uninfected controls) assessed between 2009 and 2011. The mean (standard deviation (SD)) age of the sample was 45.1 (9.3) years. The HIV-infected sample had a median interquartile range (IQR) cluster of differentiation 4 (CD4) T-lymphocyte count of 502 (310-727) cells/μL, and 54 % had undetectable plasma HIV RNA levels. Among all, the homeostasis model assessment (HOMA) of IR ranged from 0.25 to 37.14. In adjusted models, increasing HOMA was significantly associated with reduced performance on Letter-Number Sequencing (LNS) attention task (β = -0.10, p < 0.01) and on Hopkins Verbal Learning Test (HVLT) recognition (β = -0.10, p < 0.01) with weaker but statistically significant associations on phonemic fluency (β = -0.09, p = 0.01). An HIV*HOMA interaction effect was identified on the LNS attention task and Stroop trials 1 and 2, with worse performance in HIV-infected vs. HIV-uninfected women. In separate analyses, cohort members who had diabetes mellitus (DM) performed worse on the grooved pegboard test of psychomotor speed and manual dexterity. These findings confirm associations between both IR and DM on some neuropsychological tests and identify an interaction between HIV status and IR.


Complexes between two GAA Repeats within DNA introduced into Cos-1 cells.
We have recently shown that GAA repeats severely impede replication elongation during the first replication cycle of transfected DNA wherein the chromatin is still at the formation stage.1 Here we extend this study by showing that two GAA repeats located within the same plasmid in the direct orientation can form complexes upon transient transfection of mammalian Cos-1 cells. However, these complexes do not form in DNA that went through several replication rounds in mammalian cells. We suggest that formation of such complexes in mammalian genomes can contribute to genomic instability.


A method for characterizing illumination systems for hyperspectral imaging.
Near-infrared hyperspectral imaging is becoming a popular tool in various fields. In all imaging systems, proper illumination is crucial for attaining optimal image quality that is needed for the best performance of image analysis algorithms. In hyperspectral imaging, the acquired spectral signature has to be representative in all parts of the imaged object. Therefore, the whole object must be equally well illuminated-without shadows or specular reflections. As there are no restrictions imposed on the material and geometry of the object, the desired illumination of the object can only be achieved with completely diffuse illumination. In order to minimize shadows and specular reflections, the light illuminating the object must be spatially, angularly and spectrally uniform. The quality of illumination systems for hyperspectral imaging can therefore be assessed using spatial-intensity, spatial-spectral, angular-intensity and angular-spectral non-uniformity measures that are presented in this paper. Emphasis is given to the angular-intensity and angular-spectral non-uniformity measures, which are the most important contributions of this paper. The measures were defined on images of two reference targets-a flat, white diffuse reflectance target and a sphere grid target-acquired with an acousto-optic tunable filter (AOTF) based hyperspectral imaging system. The proposed measures were tested on a ring light and on a diffuse dome illumination system.


microRNA-122 regulates hypoxia-inducible factor-1 and vimentin in hepatocytes and correlates with fibrosis in diet-induced steatohepatitis.
miR-122 is the most abundant miRNA in the liver particularly in hepatocytes where it targets cholesterol metabolism. Steatosis, a key component of non-alcoholic fatty liver disease, is regulated by hypoxia-inducible factor-1α (HIF-1α). Here, we hypothesized that reduced miR-122 has a pathogenic role in steatohepatitis. miR-122 and its target genes were evaluated in mouse livers and/or isolated hepatocytes after methionine-choline-deficient (MCD) or methionine-choline-supplemented (MCS) diet. Liver and hepatocyte miR-122 expression was significantly decreased in steatohepatitis. A maximum reduction in miR-122 occurred at the fibrosis stage (8 weeks of MCD diet). MAP3K3, a miR-122 target gene, was induced at all stages of non-alcoholic steatohepatitis (NASH; 3-8 weeks) only at the mRNA level. Increased NF-κB activation was found in MCD diet-fed mice and MAP3K3 regulated the NF-κB DNA binding in naive hepatocytes. HIF-1α mRNA and DNA binding and expression of the HIF-1α target gene, profibrotic lysyl oxidase, was increased in advanced steatohepatitis (8 weeks). In addition, increase in vimentin and Sirius red staining (liver fibrosis) was found at 8 weeks of MCD diet. Using miR-122 overexpression and inhibition approaches, we confirmed that HIF-1α, vimentin and MAP3K3 are novel miR-122 targets in hepatocytes. We report transcriptional repression of miR-122 in NASH. Decreased liver miR-122 was associated with elevated circulating miR-122 in both exosome-rich and protein-rich serum fractions. Our novel data suggest that decreased liver miR-122 contributes to upregulation of modulators of tissue remodelling (HIF-1α, vimentin and MAP3K3) and might play a role in NASH-induced liver fibrosis.


MyD88 signaling inhibits protective immunity to the gastrointestinal helminth parasite Heligmosomoides polygyrus.
Helminth parasites remain one of the most common causes of infections worldwide, yet little is still known about the immune signaling pathways that control their expulsion. C57BL/6 mice are chronically susceptible to infection with the gastrointestinal helminth parasite Heligmosomoides polygyrus. In this article, we report that C57BL/6 mice lacking the adapter protein MyD88, which mediates signaling by TLRs and IL-1 family members, showed enhanced immunity to H. polygyrus infection. Alongside increased parasite expulsion, MyD88-deficient mice showed heightened IL-4 and IL-17A production from mesenteric lymph node CD4(+) cells. In addition, MyD88(-/-) mice developed substantial numbers of intestinal granulomas around the site of infection, which were not seen in MyD88-sufficient C57BL/6 mice, nor when signaling through the adapter protein TRIF (TIR domain-containing adapter-inducing IFN-β adapter protein) was also ablated. Mice deficient solely in TLR2, TLR4, TLR5, or TLR9 did not show enhanced parasite expulsion, suggesting that these TLRs signal redundantly to maintain H. polygyrus susceptibility in wild-type mice. To further investigate signaling pathways that are MyD88 dependent, we infected IL-1R1(-/-) mice with H. polygyrus. This genotype displayed heightened granuloma numbers compared with wild-type mice, but without increased parasite expulsion. Thus, the IL-1R-MyD88 pathway is implicated in inhibiting granuloma formation; however, protective immunity in MyD88-deficient mice appears to be granuloma independent. Like IL-1R1(-/-) and MyD88(-/-) mice, animals lacking signaling through the type 1 IFN receptor (i.e., IFNAR1(-/-)) also developed intestinal granulomas. Hence, IL-1R1, MyD88, and type 1 IFN receptor signaling may provide pathways to impede granuloma formation in vivo, but additional MyD88-mediated signals are associated with inhibition of protective immunity in susceptible C57BL/6 mice.


Incomplete Large Vessel Occlusions in Mechanical Thrombectomy: An Independent Predictor of Favorable Outcome in Ischemic Stroke.
Cerebral large vessel occlusion (LVO) in acute ischemic stroke (AIS) may be complete (CLVO) or incomplete (ILVO). The influence of ILVO on clinical outcome after mechanical thrombectomy (MT) remains unclear. We investigated primarily the clinical outcome in patients with AIS due to ILVO or CLVO. Five hundred three consecutive AIS patients with LVO treated with stent-retriever or direct aspiration-based MT between 2010 and 2016 were analyzed. The primary endpoint was favorable clinical outcome (modified Rankin Scale ≤2) at 90 days; secondary endpoints were periprocedural parameters. Forty-nine patients (11.3%) with a median National Institutes of Health Stroke Scale (NIHSS) of 11 presented with ILVO and the remainder presented with CLVO and median NIHSS of 15 (p < 0.001). The median groin puncture-to-reperfusion time was 30 vs. 67 min, respectively (p < 0.001). Successful reperfusion was reached in 47 out of 49 ILVO (95.9%) vs. 298 out of 381 CLVO (78.2%; p < 0.005) with less retrieval maneuvers (1.7 ± 2.2 vs. 3.0 ± 2.5; p < 0.001). The favorable outcome at 90 days was 81% in patients with ILVO vs. 29.1% in CLVO (p < 0.001); respective all-cause mortality rates were 6.4 vs. 28.5% (p < 0.001). Periprocedural complications (6.9%) occurred exclusively in CLVO patients (p < 0.05). ILVO was associated with favorable clinical outcome independent of age and NIHSS in multivariate logistic regression both in the anterior (OR 3.6; 95% CI 1.8-6.9; p < 0.001) and posterior circulation (OR 3.5; 95% CI 1.8-6.9; p < 0.001). AIS due to ILVO is frequent and is associated with a nearly threefold higher chance of favorable clinical outcome at 90 days, independent of age and initial NIHSS compared to CLVO.


Evidence that a ryanodine receptor triggers signal transduction in the osteoclast.
We have investigated the effect of the alkaloid ryanodine on the release of intracellularly stored Ca2+ in response to activation of the osteoclast Ca2+ receptor by the surrogate agonist, Ni2+, Ni2+ (6 mM) in the presence of ethylene-glycol bis-(aminoethyl ether) tetraacetic acid (EGTA) (1.2 mM) and valinomycin (5 microM) induced a transient elevation of cytosolic [Ca2+] in fura 2-loaded osteoclasts. This transient was superimposed upon a small steady elevation of cytosolic [Ca2+] induced by the initial application of valinomycin alone. Ryanodine (10 microM) completely abolished such responsiveness. However, cytosolic [Ca2+] transients were restored when osteoclasts were depolarized by the extracellular inclusion of 100 mM-[K+] in the same solution. Thus, we demonstrate a sensitivity of the osteoclast signal transduction system to ryanodine for the first time to our knowledge.


Combined and interactive effects of global climate change and toxicants on populations and communities.
Increased temperature and other environmental effects of global climate change (GCC) have documented impacts on many species (e.g., polar bears, amphibians, coral reefs) as well as on ecosystem processes and species interactions (e.g., the timing of predator-prey interactions). A challenge for ecotoxicologists is to predict how joint effects of climatic stress and toxicants measured at the individual level (e.g., reduced survival and reproduction) will be manifested at the population level (e.g., population growth rate, extinction risk) and community level (e.g., species richness, food-web structure). The authors discuss how population- and community-level responses to toxicants under GCC are likely to be influenced by various ecological mechanisms. Stress due to GCC may reduce the potential for resistance to and recovery from toxicant exposure. Long-term toxicant exposure can result in acquired tolerance to this stressor at the population or community level, but an associated cost of tolerance may be the reduced potential for tolerance to subsequent climatic stress (or vice versa). Moreover, GCC can induce large-scale shifts in community composition, which may affect the vulnerability of communities to other stressors. Ecological modeling based on species traits (representing life-history traits, population vulnerability, sensitivity to toxicants, and sensitivity to climate change) can be a promising approach for predicting combined impacts of GCC and toxicants on populations and communities.


Effect of whole-body vibration therapy on performance recovery.
To compare whole-body vibration (WBV) with traditional recovery protocols after a high-intensity training bout. In a randomized crossover study, 16 athletes performed 6 × 30-s Wingate sprints before completing either an active recovery (10 min of cycling and stretching) or WBV for 10 min in a series of exercises on a vibration platform. Muscle hemodynamics (assessed via near-infrared spectroscopy) were measured before and during exercise and into the 10-min recovery period. Blood lactate concentration, vertical jump, quadriceps strength, flexibility, rating of perceived exertion (RPE), muscle soreness, and performance during a single 30-s Wingate test were assessed at baseline and 30 and 60 min postexercise. A subset of participants (n = 6) completed a 3rd identical trial (1 wk later) using a passive 10-min recovery period (sitting). There were no clear effects between the recovery protocols for blood lactate concentration, quadriceps strength, jump height, flexibility, RPE, muscle soreness, or single Wingate performance across all measured recovery time points. However, the WBV recovery protocol substantially increased the tissue-oxygenation index compared with the active (11.2% ± 2.4% [mean ± 95% CI], effect size [ES] = 3.1, and -7.3% ± 4.1%, ES = -2.1 for the 10 min postexercise and postrecovery, respectively) and passive recovery conditions (4.1% ± 2.2%, ES = 1.3, 10 min postexercise only). Although WBV during recovery increased muscle oxygenation, it had little effect in improving subsequent performance compared with a normal active recovery.


Phenyl radical + propene: a prototypical reaction surface for aromatic-catalyzed 1,2-hydrogen-migration and subsequent resonance-stabilized radical formation.
The C9H11 potential energy surface (PES) was experimentally and theoretically explored because it is a relatively simple, prototypical alkylaromatic radical system. Although the C9H11 PES has already been extensively studied both experimentally (under single-collision and thermal conditions) and theoretically, new insights were made in this work by taking a new experimental approach: flash photolysis combined with time-resolved molecular beam mass spectrometry (MBMS) and visible laser absorbance. The C9H11 PES was experimentally accessed by photolytic generation of the phenyl radical and subsequent reaction with excess propene (C6H5 + C3H6). The overall kinetics of C6H5 + C3H6 was measured using laser absorbance with high time-resolution from 300 to 700 K and was found to be in agreement with earlier measurements over a lower temperature range. Five major product channels of C6H5 + C3H6 were observed with MBMS at 600 and 700 K, four of which were expected: hydrogen (H)-abstraction (measured by the stable benzene, C6H6, product), methyl radical (CH3)-loss (styrene detected), H-loss (phenylpropene isomers detected) and radical adduct stabilization. The fifth, unexpected product observed was the benzyl radical, which was rationalized by the inclusion of a previously unreported pathway on the C9H11 PES: aromatic-catalysed 1,2-H-migration and subsequent resonance stabilized radical (RSR, benzyl radical in this case) formation. The current theoretical understanding of the C9H11 PES was supported (including the aromatic-catalyzed pathway) by quantitative comparisons between modelled and experimental MBMS results. At 700 K, the branching to styrene + CH3 was 2-4 times greater than that of any other product channel, while benzyl radical + C2H4 from the aromatic-catalyzed pathway accounted for ∼10% of the branching. Single-collision conditions were also simulated on the updated PES to explain why previous crossed molecular beam experiments did not see evidence of the aromatic-catalyzed pathway. This experimentally validated knowledge of the C9H11 PES was added to the database of the open-source Reaction Mechanism Generator (RMG), which was then used to generalize the findings on the C9H11 PES to a slightly more complicated alkylaromatic system.


[Participation and creativity as tools of analysis of public policies].
In the context of current globalization, important modifications of the international relations and of the ideological, technical, and cultural components in the administration of the States are expressed by non-legitimate public action principles which account for social iniquity and the weakening of the role of the State. Regardless of its political origin or ideological orientation, the economic development plans and programs exhibit a prevailing uniformity. The challenge today implies mobilizing in local capacities with the objective of changing the quality of public action through the adoption of new development strategies able to integrate new social dimensions with other mechanisms of action. One of them, the intersectoral action, demands the structural revision of the administrative and cultural frontiers of the public and private social agents as a means of making a new tentative sociopolitical arrangement. The complexity of politics, projects and programs is taken as a methodological landmark based on the following theoretical presuppositions: integrality, social networks, and sociopraxis, constructing a participative process of knowledge to a political analysis in search of a change in the approach of the sociopolitical processes, starting from local social networks.


Tele-ophthalmology for diabetic retinopathy screening: 8 years of experience.
To describe the results of a diabetic retinopathy screening program implemented in a primary care area. A retrospective study was conducted using data automatically collected since the program began on 1 January 2007 until 31 December 2015. The number of screened diabetic patients has progressively increased, from 7,173 patients in 2007 to 42,339 diabetic patients in 2015. Furthermore, the ability of family doctors to correctly interpret retinographies has improved, with the proportion of retinal images classified as normal having increased from 55% in 2007 to 68% at the end of the study period. The proportion of non-evaluable retinographies decreased to 7% in 2015, having peaked at 15% during the program. This was partly due to a change in the screening program policy that allowed the use of tropicamide. The number of severe cases detected has declined, from 14% with severe non-proliferative and proliferativediabetic retinopathy in the initial phase of the program to 3% in 2015. Diabetic eye disease screening by tele-ophthalmology has shown to be a valuable method in a growing population of diabetics. It leads to a regular medical examination of patients, helps ease the workload of specialised care services and favours the early detection of treatable cases. However, the results of implementing a program of this type are not immediate, achieving only modest results in the early years of the project that have improved over subsequent years.


Molecular analysis of microflora associated with dentoalveolar abscesses.
The microflora associated with three dentoalveolar abscesses was determined by cultural and molecular methods. 16S rRNA genes were randomly amplified by means of conserved eubacterial primers and cloned. Restriction fragment length polymorphism analysis of the clones and amplified genes encoding 16S rRNA from the cultured bacteria was used to detect putative unculturable bacteria. Clones representative of five predominant groups of uncultured organisms were sequenced. Two were identified as Porphyromonas gingivalis and Prevotella oris, and one was found to be closely related to Peptostreptococcus micros. The remaining two clones did not correspond to known, previously sequenced organisms. One was related to Zoogloea ramigera, a species of aerobic waterborne organisms, while the other was distantly related to the genus Prevotella. This study has demonstrated the possibility of the characterization of microflora associated with human infection by molecular methods without the inherent biases of culture.


Girls in residential care: from child maltreatment to trauma-related symptoms in emerging adulthood.
The current study examined the association between child maltreatment and trauma-related symptoms in emerging adulthood--over and above the incidence of such symptoms and conduct problems during adolescence--among a sample of female adolescents in residential care. This study used data from a longitudinal study. The sample was composed of 89 adolescent females who were first interviewed at time of admission in a residential center (M(age)=15.33 years, SD=1.31) and later in young adulthood (M(age)=19.27, SD=1.55). At time 1, trauma-related symptoms were assessed with the Trauma Symptom Checklist for Children and conduct problems with a composite measure. At time 2, child maltreatment was assessed retrospectively with the Childhood Trauma Questionnaire, and trauma-related symptoms were reassessed with the Trauma Symptom Inventory-2. Results indicated that child maltreatment, especially emotional abuse and neglect, was related to anxious arousal, depression, and anger in emerging adulthood. This study showed that females from our sample often reported different types of maltreatment during childhood and that these traumatic experiences were significantly associated with poor adult psychological functioning.


Efficacy of red propolis hydro-alcoholic extract in controlling Streptococcus mutans biofilm build-up and dental enamel demineralization.
The efficacy of a red propolis hydro-alcoholic extract (RP) in controlling Streptococcus mutans biofilm colonization was evaluated. The effect of RP on dental demineralization was also investigated. Chemical composition was determined by High Performance Liquid Chromatography (HPLC). Minimum Inhibitory and Bactericidal Concentration (MIC and MBC, respectively) were investigated against Streptococcus mutans (ATCC 25175). The cytotoxic potential of 3% RP in oral fibroblasts was observed after 1 and 3 min. Bovine dental enamel blocks (N = 24) were used for S. mutans biofilm formation (48 h), simulating 'feast or famine' episodes. Blocks/biofilms were exposed 2×/day, for 3 days, to a cariogenic challenge with sucrose 10% (5 min) and treated (1 min) with: 0.85% saline solution (negative control), 0.12% Chlorhexidine (CHX, positive control for biofilm colonization), 0.05% Sodium Fluoride (NaF, positive control to avoid demineralization) and 3% RP. Biofilms were assessed for viability (CFU/mL), and to observe the concentration of soluble and insoluble extracellular polysaccharides (SEPS and IEPS). Dental demineralization was assessed by the percentage of surface hardness loss (%SHL) and through polarized light microscopy (PLM). The RP presented 4.0 pH and ºBrix = 4.8. The p-coumaric acid (17.2 μg/mL) and luteolin (15.23 μg/mL) were the largest contents of phenolic acids and flavonoids, respectively. MIC and MBC of RP were 293 μg/mL and 1172 μg/mL, respectively. The 3% RP showed 43% of viably cells after 1 min. Lower number (p < 0.05) of viable bacteria (CFU/mL) was observed after CHX (1.8 × 105) followed by RP (1.8 × 107) treatments. The lowest concentration (μg/CFU) of SEPS (12.6) and IEPS (25.9) was observed in CHX (p < 0.05) followed by RP (17.1 and 54.3), and both differed from the negative control (34.4 and 63.9) (p < 0.05). Considering the %SHL, all groups differed statistically (p < 0.05) from the negative control (46.6%); but NaF (13.9%), CHX (20.1%) and RP (20.7%) did not differ among them (p > 0.05). After all treatments, suggestive areas of caries lesions were observed by PLM, which were lower for CHX and NaF. The 3% RP reduced S. mutans colonization, decreased concentration of extracellular polysaccharides and reduced dental enamel demineralization.


The Role of Mentors in Early Intervention Referrals: Overlooked Views of Pediatric Residency Training Directors.
Objectives There continues to be a pressing need to increase referrals to family-centered early intervention (EI) for more eligible infants and toddlers with inadequate consideration for the role of senior, mentoring professionals. Methods To address a dearth in our understanding, a subset of Pediatric Residency Training Directors shared views on EI, referral, and relevant training efforts. Results Participating directors primarily reported limited understanding of EI. Greater knowledge of family-focused EI correlated with its perceived helpfulness (r = .420; p = .021), which positively correlated with referring a child to EI. Despite 67% of the sample viewing pediatricians as 'most important' in screenings and EI referrals, residents were perceived as only somewhat aware of EI referral and services, and only somewhat aware of differences between clinic options and Part C EI. Although nearly all respondents noted minimal EI exposure during training, only 43% felt this amount was 'inadequate/insufficient'. The sample was fairly evenly divided in being 'extremely' or 'somewhat' interested in communicating with state EI leaders. Conclusions for Practice This preliminary analysis describes perceptions among senior medical professionals who may influence referrals via mentoring, training, and interdisciplinary collaboration. Findings inform next steps in terms of research, improving education for directors and residents, and collaborative information-sharing to bolster family-centered EI referrals to improve child and family outcomes.


Variability in Time and Space of Meloidogyne incognita Fall Population Density in Cotton Fields.
Three cotton fields infested with Meloidogyne incognita were intensively sampled in the fall for 3 years (1996 to 1998) to determine if intensive sampling for M. incognita, for which spatial location is important, was necessary every year in a continuous cotton system. Two composite soil samples (20 cores each), taken over an area covering one-third of the field length and two rows wide, were averaged to represent that area (row-location combination). Each field (except one) had 24 areas assayed for changes in M. incognita population density (Pf) over a 3-year period. At all three sites, Pf was higher during fall 1998 than fall 1996. There were no differences in Pf between rows within a year or between years (no. row x year interaction) at any of the sites. At all three sites, there was a consistent difference each year in Pf among locations in a field (no. year x location interaction). At each area, M. incognital/500 cm(3) was labeled for one of four Pf classes: <250, 250 to 999, 1,000 to 2,499, and >/= 2,500. Management of root-knot nematode would likely be altered as classification changed. The areas that were reclassified by two classes or more after 1 and 2 years ranged from 0 to 29% and 25 to 54%, respectively. The risk of underestimating Pf of M. incognita was higher in one site 2 years after the initial intensive sampling procedure, whereas in another site there was little change in Pf 2 years after initial sampling. Sampling frequency will need to be decided on a field-by-field basis.


Time discounting for primary rewards.
Previous research, involving monetary rewards, found that limbic reward-related areas show greater activity when an intertemporal choice includes an immediate reward than when the options include only delayed rewards. In contrast, the lateral prefrontal and parietal cortex (areas commonly associated with deliberative cognitive processes, including future planning) respond to intertemporal choices in general but do not exhibit sensitivity to immediacy (McClure et al., 2004). The current experiments extend these findings to primary rewards (fruit juice or water) and time delays of minutes instead of weeks. Thirsty subjects choose between small volumes of drinks delivered at precise times during the experiment (e.g., 2 ml now vs 3 ml in 5 min). Consistent with previous findings, limbic activation was greater for choices between an immediate reward and a delayed reward than for choices between two delayed rewards, whereas the lateral prefrontal cortex and posterior parietal cortex responded similarly whether choices were between an immediate and a delayed reward or between two delayed rewards. Moreover, relative activation of the two sets of brain regions predicts actual choice behavior. A second experiment finds that when the delivery of all rewards is offset by 10 min (so that the earliest available juice reward in any choice is 10 min), no differential activity is observed in limbic reward-related areas for choices involving the earliest versus only more delayed rewards. We discuss implications of this finding for differences between primary and secondary rewards.


Expression patterns of sulfatase genes in the developing mouse embryo.
Mammalian sulfatase enzymes participate in various processes, such as hormone regulation, lysosomal degradation and modulation of several signaling pathways. The sulfatase gene family consists of 14 members in mice and 17 in humans. Mutations of at least eight members are associated with human disorders, with main disease manifestations in the nervous system and skeleton. Despite their biological significance, little is known about their expression during embryonic development, especially for the more recently discovered gene family members. By in situ hybridization, we compared the expression patterns of nine sulfatases: ArsB, ArsG, ArsI, ArsJ, Galns, Gns, Ids, Sulf1, and Sulf2 in midgestation mouse embryos. Of interest, overlapping expression domains of several sulfatases could be detected in the developing central nervous system, eye, skeleton, and inner organs. Moreover, novel expression patterns for ArsG in choroid plexus, ArsI in hypertrophic chondrocytes and ArsJ in joints were identified.


Risk factors for ventilator-associated pneumonia in infants and children: a cross-sectional cohort study.
The epidemiology of ventilator-associated pneumonia is well described for adults, but little information is available on risk factors for this disease in children. To identify predisposing factors for ventilator-associated pneumonia in children. A cross-sectional prospective cohort study of 96 patients in a 9-bed pediatric intensive care unit was performed. Variables examined were demographic characteristics, inpatient care, medications, nutrition, invasive procedures, and characteristics of mechanical ventilation. Data were analyzed by using Pearson χ(2) analysis, Fisher exact and Mann-Whitney tests, odds ratios, and forward stepwise logistic regression. Occurrence of ventilator-associated pneumonia correlated positively with use of nasoenteral tubes (odds ratio, 5.278; P < .001), intermittent administration of nutritional formula (odds ratio, 6.632; P = .005), emergency reintubation (odds ratio, 2.700; P = .02), use of vasoactive drugs (odds ratio, 5.108; P = .009), duration of mechanical ventilation (P < .001), and length of stay in the pediatric intensive care unit (P < .001) and in the hospital (P = .01). Use of vasoactive drugs, presence of a nasoenteral tube, and duration of stay in the pediatric intensive care unit were independent risk factors for ventilator-associated pneumonia.


Advancing the Sustainability of US Agriculture through Long-Term Research.
Agriculture in the United States must respond to escalating demands for productivity and efficiency, as well as pressures to improve its stewardship of natural resources. Growing global population and changing diets, combined with a greater societal awareness of agriculture's role in delivering ecosystem services beyond food, feed, fiber, and energy production, require a comprehensive perspective on where and how US agriculture can be sustainably intensified, that is, made more productive without exacerbating local and off-site environmental concerns. The USDA's Long-Term Agroecosystem Research (LTAR) network is composed of 18 locations distributed across the contiguous United States working together to integrate national and local agricultural priorities and advance the sustainable intensification of US agriculture. We explore here the concept of sustainable intensification as a framework for defining strategies to enhance production, environmental, and rural prosperity outcomes from agricultural systems. We also elucidate the diversity of factors that have shaped the past and present conditions of cropland, rangeland, and pastureland agroecosystems represented by the LTAR network and identify priorities for research in the areas of production, resource conservation and environmental quality, and rural prosperity. Ultimately, integrated long-term research on sustainable intensification at the national scale is critical to developing practices and programs that can anticipate and address challenges before they become crises.


Frontal eye fields control attentional modulation of alpha and gamma oscillations in contralateral occipitoparietal cortex.
Covertly directing visuospatial attention produces a frequency-specific modulation of neuronal oscillations in occipital and parietal cortices: anticipatory alpha (8-12 Hz) power decreases contralateral and increases ipsilateral to attention, whereas stimulus-induced gamma (>40 Hz) power is boosted contralaterally and attenuated ipsilaterally. These modulations must be under top-down control; however, the control mechanisms are not yet fully understood. Here we investigated the causal contribution of the human frontal eye field (FEF) by combining repetitive transcranial magnetic stimulation (TMS) with subsequent magnetoencephalography. Following inhibitory theta burst stimulation to the left FEF, right FEF, or vertex, participants performed a visual discrimination task requiring covert attention to either visual hemifield. Both left and right FEF TMS caused marked attenuation of alpha modulation in the occipitoparietal cortex. Notably, alpha modulation was consistently reduced in the hemisphere contralateral to stimulation, leaving the ipsilateral hemisphere relatively unaffected. Additionally, right FEF TMS enhanced gamma modulation in left visual cortex. Behaviorally, TMS caused a relative slowing of response times to targets contralateral to stimulation during the early task period. Our results suggest that left and right FEF are causally involved in the attentional top-down control of anticipatory alpha power in the contralateral visual system, whereas a right-hemispheric dominance seems to exist for control of stimulus-induced gamma power. These findings contrast the assumption of primarily intrahemispheric connectivity between FEF and parietal cortex, emphasizing the relevance of interhemispheric interactions. The contralaterality of effects may result from a transient functional reorganization of the dorsal attention network after inhibition of either FEF.


Unintended consequences of incentive provision for behaviour change and maintenance around childbirth.
Financial (positive or negative) and non-financial incentives or rewards are increasingly used in attempts to influence health behaviours. While unintended consequences of incentive provision are discussed in the literature, evidence syntheses did not identify any primary research with the aim of investigating unintended consequences of incentive interventions for lifestyle behaviour change. Our objective was to investigate perceived positive and negative unintended consequences of incentive provision for a shortlist of seven promising incentive strategies for smoking cessation in pregnancy and breastfeeding. A multi-disciplinary, mixed-methods approach included involving two service-user mother and baby groups from disadvantaged areas with experience of the target behaviours as study co-investigators. Systematic reviews informed the shortlist of incentive strategies. Qualitative semi-structured interviews and a web-based survey of health professionals asked open questions on positive and negative consequences of incentives. The participants from three UK regions were a diverse sample with and without direct experience of incentive interventions: 88 pregnant women/recent mothers/partners/family members; 53 service providers; 24 experts/decision makers and interactive discussions with 63 conference attendees. Maternity and early years health professionals (n = 497) including doctors, midwives, health visitors, public health and related staff participated in the survey. Qualitative analysis identified ethical, political, cultural, social and psychological implications of incentive delivery at population and individual levels. Four key themes emerged: how incentives can address or create inequalities; enhance or diminish intrinsic motivation and wellbeing; have a positive or negative effect on relationships with others within personal networks or health providers; and can impact on health systems and resources by raising awareness and directing service delivery, but may be detrimental to other health care areas. Financial incentives are controversial and generated emotive and oppositional responses. The planning, design and delivery of future incentive interventions should evaluate unexpected consequences to inform the evidence for effectiveness, cost-effectiveness and future implementation.


Yes-associated protein is not an independent prognostic marker in breast cancer.
The development of tissue microarray (TMA) technology has provided the opportunity to perform analyses of tissue samples on a large scale in an uniform fashion. This study was designed with the use of TMA to explore the Yes-associated protein (YAP) status in breast cancer. YAP expression in tumor and tumor-free samples from 94 patients with primary breast cancer was analyzed by TMA. The clinicopathological data for age, estrogen receptor status, histological grading and TNM staging were also collected. There were 29 patients (30.8%) with 1(+) expression, in YAP, 59 patients (62.8%) with 2(+) expression and 6 (6.4%) with 3(+) expression. There was no significant relationship between YAP expression and the other clinicopathological variables. By multivariate analysis, YAP expression failed to produce any significant relationship with the overall survival rate. YAP expression is not an independent prognostic factor in patients with breast cancer.