Suspect and Nontarget Screening for Contaminants of Emerging Concern in an Urban Estuary.
This study used suspect and nontarget screening with high-resolution mass spectrometry to characterize the occurrence of contaminants of emerging concern (CECs) in the nearshore marine environment of Puget Sound (WA). In total, 87 non-polymeric CECs were identified; those confirmed with reference standards (45) included pharmaceuticals, herbicides, vehicle-related compounds, plasticizers, and flame retardants. Eight polyfluoroalkyl substances were detected; perfluorooctanesulfonic acid (PFOS) concentrations were as high as 72-140 ng/L at one location. Low levels of methamphetamine were detected in 41% of the samples. Transformation products of pesticides were tentatively identified, including two novel transformation products of tebuthiuron. While a hydrodynamic simulation, analytical results, and dilution calculations demonstrated the prevalence of wastewater effluent to nearshore marine environments, the identity and abundance of selected CECs revealed the additional contributions from stormwater and localized urban and industrial sources. For the confirmed CECs, risk quotients were calculated based on concentrations and predicted toxicities, and eight CECs had risk quotients >1. Dilution in the marine estuarine environment lowered the risks of most wastewater-derived CECs, but dilution alone is insufficient to mitigate risks of localized inputs. These findings highlighted the necessity of suspect and nontarget screening and revealed the importance of localized contamination sources in urban marine environments.


A longitudinal analysis of SLE patients treated with rituximab (anti-CD20): factors associated with B lymphocyte recovery.
Identifying factors associated with B lymphocyte depletion and recovery may aid the development of individualized treatment regimens, optimizing therapy for patients with autoimmune disease. In this study, 12 patients with active SLE were monitored at baseline and monthly following treatment with rituximab. The number and phenotype of peripheral blood B lymphocytes, T lymphocytes and natural killer cells were correlated with the extent and longevity of B lymphocyte depletion. This analysis generated three candidate biomarkers for lymphocyte monitoring in patients with autoimmune disease who are treated with rituximab: circulating transitional B cells, the kappa:lambda ratio and natural killer cells. Further refinement of these potential biomarkers may lead to a better understanding of the role of B cells in disease pathogenesis and a more rational use of B cell depletion therapies.


Measuring Antimicrobial Efficacy against Biofilms: a Meta-analysis.
Through a statistical meta-analysis of published data on antimicrobial efficacy against biofilms formed by two common bacterial species, it was concluded that the particular experimental method used is the most important factor determining the outcome of the test. An expected dose-response relationship (greater killing with higher doses or longer treatment times) was observed for data sets derived from a single method but was not observed when data from multiple studies using diverse methods were pooled. Method-specific properties such as the surface area/volume ratio, areal biofilm cell density, and microbial species were shown to influence quantitative measurements of biofilm killing. A better appreciation of the method characteristics that affect antibiofilm efficacy tests could aid decision-making related to investment in research and development and regulatory approvals for biofilm control strategies. The following recommendations are offered to those working in research and development related to biofilm control: (i) report the log reduction, surface area/volume ratio, and biofilm areal cell density; (ii) include data for a benchmark agent, making sure that this agent performs competitively at the dose tested; (iii) measure the dose-response relationship, i.e., make measurements at multiple treatment concentrations or dose durations; and (iv) use a standardized method in addition to research methods.


Immunoglobulin idiotopes expressed by T cells. I. Expression of distinct idiotopes detected by monoclonal antibodies on antigen-specific suppressor T cells.
The idiotopic repertoire expressed by antigen-specific suppressor T cells (Ts) generated by Streptococcus pneumoniae strain R36a (Pn) in BALB/c strain mice was investigated using a panel of five monoclonal anti-idiotopic antibodies against TEPC-15/HOPC-8 myeloma proteins. Previous studies suggested that the anti-idiotopic antibodies recognize distinct idiotopic determinants within the T15 idiotype, and that Pn-reactive B cells express all of those idiotopes as shown by a specific inhibitory effect of the anti-idiotopic antibodies on induction of anti-Pn response in vitro as well as on the mature antibody plaque-forming cells. In this study we asked the question of whether anti-idiotopic (Id) can block the inductive and/or effector phases of generation of Ts which act on the Pn-reactive B cells. The presence of anti-Id during the activation of T cells with Pn did not prevent the generation of Ts. However, suppression mediated by Ts on responder lymphocytes (cultures of spleen cells or B cels) was inhibited (reversed) by four out of five anti-Id. Some of the antibodies recognize hapten (phosphorylcholine)-inhibitable Id in the paratope of Ig whereas others are directed against nonparatopic Id. These data indicate that the antigen receptor on Ts includes VH sequences both within and without the immunoglobulin in paratope, and that the Id repertoir of Ts overlaps with that of B cells.


Risk Factors for 30-Day Mortality in Patients with Methicillin-Resistant Staphylococcus aureus Bloodstream Infections.
Methicillin-resistant Staphylococcus aureus (MRSA) blood stream infections (BSI) are a major health care problem accounting for a large percentage of nosocomial infections. The aim of this study was to identify risk factors associated with 30-day mortality in patients with MRSA BSI. This was a retrospective study performed in Southeast Michigan. Over a 9- year period, a total of 1,168 patients were identified with MRSA BSI. Patient demographics and clinical data were retrieved and evaluated using electronic medical health records. 30-day mortality during the 9-year study period was 16%. Significant risk factors for 30-day mortality were age, cancer, heart disease, neurologic disease, nursing home residence and Charlson score >3 with Odds Ratio (OR) of 1.03 (CI 1.02-1.04), 2.29 (CI 1.40-3.75), 1.78 (CI 1.20-2.63), 1.65 (CI 1.08-2.25), 1.66 (CI 1.02 - 2.70) and 1.86 (CI 1.18 - 2.95) correspondingly. Diabetes mellitus, peripheral vascular disease (PVD), and readmission were protective factors for 30-day mortality with OR of 0.53 (CI 0.36-0.78), 0.46 (CI 0.26-0.84) and 0.13 (CI0.05 - 0.32) respectively. Our study identified significant risk factors for 30-day mortality in patients with MRSA BSI. Interestingly, diabetes mellitus, PVD and readmission were protective effects on 30-day mortality. There was no statistically significant variability in 30-day mortality over the 9-year study period.


Anti-tumour immunity induces aberrant peptide presentation in melanoma.
Extensive tumour inflammation, which is reflected by high levels of infiltrating T cells and interferon-γ (IFNγ) signalling, improves the response of patients with melanoma to checkpoint immunotherapy1,2. Many tumours, however, escape by activating cellular pathways that lead to immunosuppression. One such mechanism is the production of tryptophan metabolites along the kynurenine pathway by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which is induced by IFNγ3-5. However, clinical trials using inhibition of IDO1 in combination with blockade of the PD1 pathway in patients with melanoma did not improve the efficacy of treatment compared to PD1 pathway blockade alone6,7, pointing to an incomplete understanding of the role of IDO1 and the consequent degradation of tryptophan in mRNA translation and cancer progression. Here we used ribosome profiling in melanoma cells to investigate the effects of prolonged IFNγ treatment on mRNA translation. Notably, we observed accumulations of ribosomes downstream of tryptophan codons, along with their expected stalling at the tryptophan codon. This suggested that ribosomes bypass tryptophan codons in the absence of tryptophan. A detailed examination of these tryptophan-associated accumulations of ribosomes-which we term 'W-bumps'-showed that they were characterized by ribosomal frameshifting events. Consistently, reporter assays combined with proteomic and immunopeptidomic analyses demonstrated the induction of ribosomal frameshifting, and the generation and presentation of aberrant trans-frame peptides at the cell surface after treatment with IFNγ. Priming of naive T cells from healthy donors with aberrant peptides induced peptide-specific T cells. Together, our results suggest that IDO1-mediated depletion of tryptophan, which is induced by IFNγ, has a role in the immune recognition of melanoma cells by contributing to diversification of the peptidome landscape.


Local genomic adaptation of coral reef-associated microbiomes to gradients of natural variability and anthropogenic stressors.
Holobionts are species-specific associations between macro- and microorganisms. On coral reefs, the benthic coverage of coral and algal holobionts varies due to natural and anthropogenic forcings. Different benthic macroorganisms are predicted to have specific microbiomes. In contrast, local environmental factors are predicted to select for specific metabolic pathways in microbes. To reconcile these two predictions, we hypothesized that adaptation of microbiomes to local conditions is facilitated by the horizontal transfer of genes responsible for specific metabolic capabilities. To test this hypothesis, microbial metagenomes were sequenced from 22 coral reefs at 11 Line Islands in the central Pacific that together span a wide range of biogeochemical and anthropogenic influences. Consistent with our hypothesis, the percent cover of major benthic functional groups significantly correlated with particular microbial taxa. Reefs with higher coral cover had a coral microbiome with higher abundances of Alphaproteobacteria (such as Rhodobacterales and Sphingomonadales), whereas microbiomes of algae-dominated reefs had higher abundances of Gammaproteobacteria (such as Alteromonadales, Pseudomonadales, and Vibrionales), Betaproteobacteria, and Bacteriodetes. In contrast to taxa, geography was the strongest predictor of microbial community metabolism. Microbial communities on reefs with higher nutrient availability (e.g., equatorial upwelling zones) were enriched in genes involved in nutrient-related metabolisms (e.g., nitrate and nitrite ammonification, Ton/Tol transport, etc.). On reefs further from the equator, microbes had more genes encoding chlorophyll biosynthesis and photosystems I/II. These results support the hypothesis that core microbiomes are determined by holobiont macroorganisms, and that those core taxa adapt to local conditions by selecting for advantageous metabolic genes.


Deciphering the Subtype Differentiation History of SARS-CoV-2 Based on a New Breadth-First Searching Optimized Alignment Method Over a Global Data Set of 24,768 Sequences.
SARS-CoV-2 has caused a worldwide pandemic. Existing research on coronavirus mutations is based on small data sets, and multiple sequence alignment using a global-scale data set has yet to be conducted. Statistical analysis of integral mutations and global spread are necessary and could help improve primer design for nucleic acid diagnosis and vaccine development. Here, we optimized multiple sequence alignment using a conserved sequence search algorithm to align 24,768 sequences from the GISAID data set. A phylogenetic tree was constructed using the maximum likelihood (ML) method. Coronavirus subtypes were analyzed via t-SNE clustering. We performed haplotype network analysis and t-SNE clustering to analyze the coronavirus origin and spread. Overall, we identified 33 sense, 17 nonsense, 79 amino acid loss, and 4 amino acid insertion mutations in full-length open reading frames. Phylogenetic trees were successfully constructed and samples clustered into subtypes. The COVID-19 pandemic differed among countries and continents. Samples from the United States and western Europe were more diverse, and those from China and Asia mainly contained specific subtypes. Clades G/GH/GR are more likely to be the origin clades of SARS-CoV-2 compared with clades S/L/V. Conserved sequence searches can be used to segment long sequences, making large-scale multisequence alignment possible, facilitating more comprehensive gene mutation analysis. Mutation analysis of the SARS-CoV-2 can inform primer design for nucleic acid diagnosis to improve virus detection efficiency. In addition, research into the characteristics of viral spread and relationships among geographic regions can help formulate health policies and reduce the increase of imported cases.


Factors modulating cottongrass seedling growth stimulation to enhanced nitrogen and carbon dioxide: compensatory tradeoffs in leaf dynamics and allocation to meet potassium-limited growth.
Eriophorum vaginatum is a characteristic species of northern peatlands and a keystone plant for cutover bog restoration. Understanding the factors affecting E. vaginatum seedling establishment (i.e. growth dynamics and allocation) under global change has practical implications for the management of abandoned mined bogs and restoration of their C-sequestration function. We studied the responses of leaf dynamics, above- and belowground biomass production of establishing seedlings to elevated CO(2) and N. We hypothesised that nutrient factors such as limitation shifts or dilutions would modulate growth stimulation. Elevated CO(2) did not affect biomass, but increased the number of young leaves in spring (+400 %), and the plant vitality (i.e. number of green leaves/total number of leaves) (+3 %), both of which were negatively correlated to [K(+)] in surface porewater, suggesting a K-limited production of young leaves. Nutrient ratios in green leaves indicated either N and K co-limitation or K limitation. N addition enhanced the number of tillers (+38 %), green leaves (+18 %), aboveground and belowground biomass (+99, +61 %), leaf mass-to-length ratio (+28 %), and reduced the leaf turnover (-32 %). N addition enhanced N availability and decreased [K(+)] in spring surface porewater. Increased tiller and leaf production in July were associated with a doubling in [K(+)] in surface porewater suggesting that under enhanced N production is K driven. Both experiments illustrate the importance of tradeoffs in E. vaginatum growth between: (1) producing tillers and generating new leaves, (2) maintaining adult leaves and initiating new ones, and (3) investing in basal parts (corms) for storage or in root growth for greater K uptake. The K concentration in surface porewater is thus the single most important factor controlling the growth of E. vaginatum seedlings in the regeneration of selected cutover bogs.


Molecular characterization of a novel geranylgeranyl pyrophosphate synthase from Plasmodium parasites.
We present here a study of a eukaryotic trans-prenylsynthase from the malaria pathogen Plasmodium vivax. Based on the results of biochemical assays and contrary to previous indications, this enzyme catalyzes the production of geranylgeranyl pyrophosphate (GGPP) rather than farnesyl pyrophosphate (FPP). Structural analysis shows that the product length is constrained by a hydrophobic cavity formed primarily by a set of residues from the same subunit as the product as well as at least one other from the dimeric partner. Furthermore, Plasmodium GGPP synthase (GGPPS) can bind nitrogen-containing bisphosphonates (N-BPs) strongly with the energetically favorable cooperation of three Mg(2+), resulting in inhibition by this class of compounds at IC(50) concentrations below 100 nM. In contrast, human and yeast GGPPSs do not accommodate a third magnesium atom in the same manner, resulting in their insusceptibility to N-BPs. This differentiation is in part attributable to a deviation in a conserved motif known as the second aspartate-rich motif: whereas the aspartates at the start and end of the five-residue motif in FFPP synthases and P. vivax GGPPSs both participate in the coordination of the third Mg(2+), an asparagine is featured as the last residue in human and yeast GGPPSs, resulting in a different manner of interaction with nitrogen-containing ligands.


In Situ Magic-Angle Spinning 7Li NMR Analysis of a Full Electrochemical Lithium-Ion Battery Using a Jelly Roll Cell Design.
A new in situ magic angle spinning (MAS) 7Li nuclear magnetic resonance (NMR) strategy allowing for the observation of a full lithium-ion cell is introduced. Increased spectral resolution is achieved through a novel jelly roll cell design, which allowed these studies to be performed for the first time under MAS conditions (MAS rate 10 kHz). The state of charge, metallic lithium plating and solid-electrolyte interface (SEI) formation was captured for the first charge/discharge cycle of a full electrochemical cell (LiCoO2/graphite). This strategy can be used to monitor both anode and cathode electrodes concurrently, which is valuable for tracking the lithium distribution in a full cell in real time and may also enable identification of causes of capacity loss that are not readily available from bulk electrochemical analyses, or other post-mortem strategies.


AMP-activated protein kinase (AMPK) is activated in muscle of subjects with type 2 diabetes during exercise.
Insulin-stimulated GLUT4 translocation is impaired in people with type 2 diabetes. In contrast, exercise results in a normal increase in GLUT4 translocation and glucose uptake in these patients. Several groups have recently hypothesized that exercise increases glucose uptake via an insulin-independent mechanism mediated by the activation of AMP-activated protein kinase (AMPK). If this hypothesis is correct, people with type 2 diabetes should have normal AMPK activation in response to exercise. Seven subjects with type 2 diabetes and eight matched control subjects exercised on a cycle ergometer for 45 min at 70% of maximum workload. Biopsies of vastus lateralis muscle were taken before exercise, after 20 and 45 min of exercise, and at 30 min postexercise. Blood glucose concentrations decreased from 7.6 to 4.77 mmol/l with 45 min of exercise in the diabetic group and did not change in the control group. Exercise significantly increased AMPK alpha2 activity 2.7-fold over basal at 20 min in both groups and remained elevated throughout the protocol, but there was no effect of exercise on AMPK alpha1 activity. Subjects with type 2 diabetes had similar protein expression of AMPK alpha1, alpha2, and beta1 in muscle compared with control subjects. AMPK alpha2 was shown to represent approximately two-thirds of the total alpha mRNA in the muscle from both groups. In conclusion, people with type 2 diabetes have normal exercise-induced AMPK alpha2 activity and normal expression of the alpha1, alpha2 and beta1 isoforms. Pharmacological activation of AMPK may be an attractive target for the treatment of type 2 diabetes.


Therapy of encephalopathy with status epilepticus during sleep (ESES/CSWS syndrome): an update.
Electrical status epilepticus in sleep (ESES)/continuous spikes and waves during slow sleep (CSWS) is an age-related, self-limiting disorder characterised by epilepsy with different seizure types, global or selective neuropsychological regression, motor impairment, and a typical EEG pattern of continuous epileptiform activity for more than 85% of non-rapid eye movement (NREM) sleep. Although the first description of ESES/CSWS dates back to 1971, an agreement about the optimal treatment for this condition is still lacking. ESES/CSWS is rare (incidence is 0.2-0.5% of all childhood epilepsies) and no controlled clinical trials have been conducted to establish the efficacy of different antiepileptic drugs; only uncontrolled studies and case reports are reported in the literature. Treatment options for ESES/CSWS include some antiepileptic drugs (valproic acid, ethosuximide, levetiracetam, and benzodiazepines), steroids, immunoglobulins, the ketogenic diet, and surgery (multiple subpial transections). In this study, the comparative value of each of these treatments is reviewed and a personal therapeutic approach is proposed.


Reports of clinical trials should begin and end with up-to-date systematic reviews of other relevant evidence: a status report.
Scientific and ethical justification for new clinical trials requires them to have been designed in the light of scientifically defensible assessments of relevant previous research. Reliable interpretation of the results of new clinical trials entails setting them in the context of updates of the reviews upon which they were deemed scientifically and ethically justifiable. We have shown previously that most reports of randomized trials published in five general medical journals in May 1997 and in May 2001 failed to set their results in the context of the findings from similar research. In the current study, we assess whether there had been progress in this respect in 2005 and also investigate the extent to which reports begin by referring to systematic reviews providing the justification for the new research reported. Assessment of the Introduction and Discussion sections in all reports of randomized trials published during May 2005 in five general medical journals. Reports of randomized trials in five general medical journals. Annals of Internal Medicine, BMJ, JAMA, Lancet and New England Journal of Medicine. None. The inclusion or mention of one or more systematic reviews in the Introduction or Discussion section of each report assessed. We found 18 reports of randomized trials. The Introduction sections referred to systematic reviews in five (27%) of these reports. None of the discussion sections of the 15 reports of trials that were not the first published trials to address the question studied placed the results of the new trial in the context of an updated systematic review of other research. Although reference was made to relevant systematic reviews in five of these 15 reports, there was no integration - quantitative or qualitative - of the results of the new trials in an update of these reviews. In the remaining ten reports there was no evidence that any systematic attempt had been made to set the new results in the context of previous trials. There is no evidence of progress between 1997 and 2005 in the proportion of reports of trials published in general medical journals which discussed new results within the context of up-to-date systematic reviews of relevant evidence from other controlled trials. Although the proportion of trials referring to systematic reviews in Discussion sections has increased, the majority of reports continued to fail even to do this. Similarly, most researchers appear not to have considered a systematic review when designing their trial. Researchers and journal editors do a disservice to the interests of the public and others involved in healthcare decision-making by acquiescing in this situation.


Statistical Significance Versus Clinical Importance of Observed Effect Sizes: What Do P Values and Confidence Intervals Really Represent?
Effect size measures are used to quantify treatment effects or associations between variables. Such measures, of which >70 have been described in the literature, include unstandardized and standardized differences in means, risk differences, risk ratios, odds ratios, or correlations. While null hypothesis significance testing is the predominant approach to statistical inference on effect sizes, results of such tests are often misinterpreted, provide no information on the magnitude of the estimate, and tell us nothing about the clinically importance of an effect. Hence, researchers should not merely focus on statistical significance but should also report the observed effect size. However, all samples are to some degree affected by randomness, such that there is a certain uncertainty on how well the observed effect size represents the actual magnitude and direction of the effect in the population. Therefore, point estimates of effect sizes should be accompanied by the entire range of plausible values to quantify this uncertainty. This facilitates assessment of how large or small the observed effect could actually be in the population of interest, and hence how clinically important it could be. This tutorial reviews different effect size measures and describes how confidence intervals can be used to address not only the statistical significance but also the clinical significance of the observed effect or association. Moreover, we discuss what P values actually represent, and how they provide supplemental information about the significant versus nonsignificant dichotomy. This tutorial intentionally focuses on an intuitive explanation of concepts and interpretation of results, rather than on the underlying mathematical theory or concepts.


The impact of autism spectrum disorder and alexithymia on judgments of moral acceptability.
One's own emotional response toward a hypothetical action can influence judgments of its moral acceptability. Some individuals with autism spectrum disorder (ASD) exhibit atypical emotional processing, and moral judgments. Research suggests, however, that emotional deficits in ASD are due to co-occurring alexithymia, meaning atypical moral judgments in ASD may be due to alexithymia also. Individuals with and without ASD (matched for alexithymia) judged the moral acceptability of emotion-evoking statements and identified the emotion evoked. Moral acceptability judgments were predicted by alexithymia. Crucially, however, this relationship held only for individuals without ASD. While ASD diagnostic status did not directly predict either judgment, those with ASD did not base their moral acceptability judgments on emotional information. Findings are consistent with evidence demonstrating that decision-making is less subject to emotional biases in those with ASD.


Coupler-apodized Bragg-grating add-drop filter.
We demonstrate an apodization technique using tapered coupler gaps in grating-assisted asymmetric couplers, which circumvents the need for tapered waveguide perturbations and enables a higher tolerance to fabrication errors. A high sidelobe suppression ratio of 30 dB has been obtained on the submicrometer silicon-on-insulator platform using a CMOS-compatible photonics process with 193 nm lithography.


Protective effect of Acacia ferruginea against ulcerative colitis via modulating inflammatory mediators, cytokine profile and NF-κB signal transduction pathways.
In the present study, we evaluated the protective effect of A. ferruginea extract against ulcerative colitis (UC). Male Wistar rats received A. ferruginea extract (10 mg/kg body weight) or sulfasalazine (100 mg/kg body weight) for 5 consecutive days before inducing UC via intrarectal acetic acid (3%) administration. Colonic mucosal injury was assessed by macroscopic scoring, vascular permeability testing, and histopathological examination. The mucosal contents of glutathione, lipid peroxidation, superoxide dismutase, and nitric oxide were evaluated as parameters for the redox state. Inflammatory response was determined by measuring inducible nitric oxide synthase (iNOS) and cyclo-oxygenase (COX-2) expression. Myeloperoxidase (MPO), lactate dehydrogenase assay (LDH), tumor necrosis factor (TNF-α), and interleukins (IL-1β and IL-6) were measured using ELISA. Transcription factor profiling of nuclear factor (NF)-κB subunits (p65/p50) was also conducted using ELISA. All of the relevant parameters were altered in rats with UC, and these parameters improved in animals that received A. ferruginea extract. Colonic mucosal injury parallels antioxidant and anti-inflammatory evaluations, and A. ferruginea extract was considered comparable to the standard treatment drug sulfasalazine. Histopathological studies confirmed these findings. A. ferruginea extract inhibited the activation and translocation of transcription factors, that is, NF-κB subunits (p65/p50). The results of our investigation clearly indicate that treatment with A. ferruginea extract exerted a marked protective effect against experimental UC via modulation of oxidant/anti-oxidant balance and inhibition of inflammatory mediators.


Wnt signaling regulates proliferation and differentiation of radial glia in regenerative processes after stab injury in the optic tectum of adult zebrafish.
Zebrafish have superior abilities to generate new neurons in the adult brain and to regenerate brain tissue after brain injury compared with mammals. There exist two types of neural stem cells (NSCs): neuroepithelial-like stem cells (NE) and radial glia (RG) in the optic tectum. We established an optic tectum stab injury model to analyze the function of NSCs in the regenerative condition and confirmed that the injury induced the proliferation of RG, but not NE and that the proliferated RG differentiated into new neurons after the injury. We then analyzed the involvement of Wnt signaling after the injury, using a Wnt reporter line in which canonical Wnt signaling activation induced GFP expression and confirmed that GFP expression was induced specifically in RG after the injury. We also analyzed the expression level of genes related to Wnt signaling, and confirmed that endogenous Wnt antagonist dkk1b expression was significantly decreased after the injury. We observed that Wnt signal inhibitor IWR1 treatment suppressed the proliferation and differentiation of RG after the injury, suggesting that up-regulation of Wnt signaling in RG after the stab injury was required for optic tectum regeneration. We also confirmed that Wnt activation by treatment with GSK3β inhibitor BIO in uninjured zebrafish induced proliferation of RG in the optic tectum. This optic tectum stab injury model is useful for the study of the molecular mechanisms of brain regeneration and analysis of the RG functions in physiological and regenerative conditions.


Evidence for working memory storage operations in perceptual cortex.
Isolating the short-term storage component of working memory (WM) from the myriad of associated executive processes has been an enduring challenge. Recent efforts have identified patterns of activity in visual regions that contain information about items being held in WM. However, it remains unclear (1) whether these representations withstand intervening sensory input and (2) how communication between multimodal association cortex and the unimodal perceptual regions supporting WM representations is involved in WM storage. We present evidence that the features of a face held in WM are stored within face-processing regions, that these representations persist across subsequent sensory input, and that information about the match between sensory input and a memory representation is relayed forward from perceptual to prefrontal regions. Participants were presented with a series of probe faces and indicated whether each probe matched a target face held in WM. We parametrically varied the feature similarity between the probe and target faces. Activity within face-processing regions scaled linearly with the degree of feature similarity between the probe face and the features of the target face, suggesting that the features of the target face were stored in these regions. Furthermore, directed connectivity measures revealed that the direction of information flow that was optimal for performance was from sensory regions that stored the features of the target face to dorsal prefrontal regions, supporting the notion that sensory input is compared to representations stored within perceptual regions and is subsequently relayed forward. Together, these findings indicate that WM storage operations are carried out within perceptual cortex.


Tanycyte Gene Expression Dynamics in the Regulation of Energy Homeostasis.
Animal survival relies on a constant balance between energy supply and energy expenditure, which is controlled by several neuroendocrine functions that integrate metabolic information and adapt the response of the organism to physiological demands. Polarized ependymoglial cells lining the floor of the third ventricle and sending a single process within metabolic hypothalamic parenchyma, tanycytes are henceforth described as key components of the hypothalamic neural network controlling energy balance. Their strategic position and peculiar properties convey them diverse physiological functions ranging from blood/brain traffic controllers, metabolic modulators, and neural stem/progenitor cells. At the molecular level, these functions rely on an accurate regulation of gene expression. Indeed, tanycytes are characterized by their own molecular signature which is mostly associated to their diverse physiological functions, and the detection of variations in nutrient/hormone levels leads to an adequate modulation of genetic profile in order to ensure energy homeostasis. The aim of this review is to summarize recent knowledge on the nutritional control of tanycyte gene expression.


Systemic Cardiac Troponin T Associated With Incident Atrial Fibrillation Among Patients With Suspected Stable Angina Pectoris.
Higher concentrations of cardiac troponin T are associated with coronary artery disease (CAD) and adverse cardiovascular prognosis. The relation with incident atrial fibrillation (AF) is less explored. We studied this association among 3,568 patients evaluated with coronary angiography for stable angina pectoris without previous history of AF. The prospective association between high-sensitivity cardiac troponin T (hs-cTnT) categories (≤3 ng/L; n = 1,694, 4-9; n = 1,085, 10 to 19; n = 614 and 20 to 30; n = 175) and incident AF and interactions with the extent of CAD were studied by Kaplan-Meier plots and Cox regression. Risk prediction improvements were assessed by receiver operating characteristic area under the curve (ROC-AUC) analyses. During median (25 to 75 percentile) 7.3 (6.3 to 8.6) years of follow-up 412 (11.5%) were diagnosed with AF. In a Cox model adjusted for age, gender, body mass index, hypertension, diabetes mellitus, smoking, estimated glomerular filtration rate, and left ventricular ejection fraction, hazard ratios (HRs) (95% confidence intervals [CIs]) were 1.53 (1.16 to 2.03), 2.03 (1.49 to 2.78), and 2.15 (1.40 to 3.31) when comparing the second, third, and fourth to the first hs-cTnT group, respectively (P for trend <0.000001). The strongest association between hs-cTnT levels and incident AF was found among patients without obstructive CAD (Pint = 0.024) and adding hs-cTnT to established AF risk factors improved risk classification slightly (ΔROC 0.006, p = 0.044). In conclusion, in patients with suspected stable angina higher levels of hs-cTnT predicted increased risk of incident AF. This was most pronounced in patients without obstructive CAD suggesting an association not mediated by coronary disease.


Harmonizing behavioral outcomes across studies, raters, and countries: application to the genetic analysis of aggression in the ACTION Consortium.
Aggression in children has genetic and environmental causes. Studies of aggression can pool existing datasets to include more complex models of social effects. Such analyses require large datasets with harmonized outcome measures. Here, we made use of a reference panel for phenotype data to harmonize multiple aggression measures in school-aged children to jointly analyze data from five large twin cohorts. Individual level aggression data on 86,559 children (42,468 twin pairs) were available in five European twin cohorts measured by different instruments. A phenotypic reference panel was collected which enabled a model-based phenotype harmonization approach. A bi-factor integration model in the integrative data analysis framework was developed to model aggression across studies while adjusting for rater, age, and sex. Finally, harmonized aggression scores were analyzed to estimate contributions of genes, environment, and social interaction to aggression. The large sample size allowed adequate power to test for sibling interaction effects, with unique dynamics permitted for opposite-sex twins. The best-fitting model found a high level of overall heritability of aggression (~60%). Different heritability rates of aggression across sex were marginally significant, with heritability estimates in boys of ~64% and ~58% in girls. Sibling interaction effects were only significant in the opposite-sex twin pairs: the interaction effect of males on their female co-twin differed from the effect of females on their male co-twin. An aggressive female had a positive effect on male co-twin aggression, whereas more aggression in males had a negative influence on a female co-twin. Opposite-sex twins displayed unique social dynamics of aggressive behaviors in a joint analysis of a large, multinational dataset. The integrative data analysis framework, applied in combination with a reference panel, has the potential to elucidate broad, generalizable results in the investigation of common psychological traits in children.


[Evolution of the management and outcomes of patients admitted for acute myocardial infarction in France from 1995 to 2000: data from the USIK 1995 and USIC 2000 nationwide registries].
We assessed the in-hospital management and short- and long-term outcomes of two series of patients admitted for acute myocardial infarction, 5 years apart, in France. The most recent cohort was younger and with a less frequent history of cardiac diseases, but was more often diabetic and with anterior infarcts. Five-day mortality significantly improved from 7.7% to 6.1% (P < 0.03) and 1-year survival was also less in the most recent period (15% versus 19%, P < 0.01). Multivariate analyses showed that the period of inclusion (2000 versus 1995) was an independent predictor of both short- and long-term mortality. In analyses restricted to the patients who were alive by day 5, initial treatment with statins was associated with a 38% decrease in the risk of death at 1 year. Likewise, in patients with left ventricular ejection fraction < or = 35%, the early prescription of ACE inhibitors was associated with a 41% reduction in the risk of 1-year mortality. Thus, in the real world setting, a continued decline in 1-year mortality is observed in patients admitted to intensive care units for recent acute myocardial infarction. This goes along with a shift in reperfusion therapy towards a broader use of coronary angioplasty and with an increased use of the early prescription of recognised secondary prevention medications.


Chimeric viruses expressing primary envelope glycoproteins of human immunodeficiency virus type I show increased sensitivity to neutralization by human sera.
We constructed a number of HXB2 viruses chimeric for the gp 120 glycoprotein derived from a number of viable molecular clones obtained from a primary isolate. Comparative biological characterization of the parental primary viruses with the gp 120.HXB2 chimeras demonstrated identical patterns of cell tropism and cytopathicity. Furthermore, both parental and chimeric viruses were insensitive to neutralization by sCD4 and a panel of conformation-dependent monoclonal antibodies, demonstrating that transfer of the gp 120 protein alone was sufficient to confer a "neutralization-resistant" phenotype to the T-cell-adapted clone HXB2. We assessed the contribution of gp 120 epitopes to the neutralizing immune response by comparing the sensitivity of these viruses to neutralization by a panel of sera from HIV-infected individuals. Seven of eleven sera tested were able to neutralize HXB2 and two or more of the chimeric viruses; in contrast, only one serum neutralized more than one of the parental primary virus clones. The association of gp 120-gp41 envelope at the surface of infected PBMC cultures was measured in the presence or absence of soluble CD4. No differences in CD4-induced gp 120 dissociation were seen between the chimeric and parental virus-infected cultures. Since gp 120 conformation appeared the same between primary and chimeric viruses, we suggest that the ability of human sera to neutralize the chimeric viruses may be mediated by epitopes within gp41.


Reflex alpha-adrenergic coronary vasoconstriction during hindlimb static exercise in dogs.
We studied 18 alpha-chloralose-anesthetized dogs to determine if alpha-adrenergic coronary vasoconstriction occurs with hindlimb static exercise. Exercise was elicited by spinal cord ventral nerve root stimulation. Regional coronary blood flow was determined by the radioactive microsphere method. Animals were studied under four experimental conditions: control rest and static exercise, rest and static exercise after beta-adrenergic blockade with propranolol (2 mg/kg), rest and exercise after alpha-adrenergic blockade with phentolamine (.35 mg/kg), and rest and exercise after combined alpha- and beta-adrenergic blockade. Myocardial oxygen consumption during exercise was determined during control and during alpha-adrenergic blockade conditions. Control hindlimb static exercise resulted in significant increases in systolic (10.6%) and diastolic (12.5%) arterial pressures, heart rate (12.2%), and double product (24.6%). Associated with the increased demand for oxygen, myocardial oxygen consumption increased (33.6%) as did left ventricular myocardial flow (29.6%). However, left ventricular coronary vascular resistance was unchanged during static exercise. After beta-adrenergic blockade, systolic (12.2%) and diastolic (11.6%) arterial pressures and double product (10.7%) still increased significantly, but heart rate did not change with static exercise. In contrast, alpha-adrenergic vasoconstriction was unmasked as left (LV) and right (RV) ventricular myocardial blood flow decreased (LV: -30.0%, RV: -25.0%) and coronary vascular resistance increased (LV: 52.5%, RV: 45.3%) with static exercise. Combined alpha- and beta-adrenergic blockade abolished the reduction in myocardial blood flow and the increase in coronary vascular resistance which occurred with static exercise after beta-adrenergic blockade. These data suggest that, during static exercise, reflexes from skeletal muscles can cause alpha-adrenergic coronary artery vasoconstriction.


Drivers' attitudes toward front or rear child passenger belt use and seat belt reminders at these seating positions.
Passengers, especially those in rear seating positions, use seat belts less frequently than drivers. In-vehicle technology can inform drivers when their passengers are unbuckled and encourage passengers to use belts. The current study collected information about drivers' attitudes toward passenger belt use and belt reminders for front passengers and children in back seats. A national telephone survey of 1218 people 18 and older was conducted, of which 477 respondents were drivers who transport a front seat passenger at least once a week and 254 were drivers who transport an 8- to 15-year-old child in the back seat. Respondents were asked about their attitudes toward belt use by their front passengers or rear child passengers and preferences for different passenger belt reminder features. Ninety percent of drivers who regularly transport front seat passengers said that the passengers always use seat belts. Reported belt use was even higher among 8- to 15-year-old children in the back seat (97%). Among the drivers whose children do not always buckle up, about half said their child unbuckled the belt during the trip. Almost every full-time belt use driver (96%) would encourage front passengers to buckle up if not belted, compared to 57 percent of part-time belt users and nonusers. In contrast, nearly every driver who transports children in the back seat would encourage their belt use, regardless of the driver's belt use habits. Most drivers who transport front passengers wanted passenger belt reminders to encourage passengers to buckle up. Most of these drivers wanted a chime/buzzer or warning light or text display and wanted the reminder to last indefinitely. Most drivers who transport child passengers in the rear seat wanted the vehicle to indicate whether child passengers are unbuckled. A large majority of these drivers wanted notifications via a visual diagram of seating positions and belt use, a chime/buzzer, and a warning light or text display. These drivers also wanted the vehicle to provide belt use information until the child buckled up. Many drivers, especially those who always use seat belts, said they would encourage unbuckled passengers to buckle up and supported auditory and visual belt reminders for passengers, particularly for children sitting in the back seat. Front and rear passenger reminders that last indefinitely would be acceptable to most drivers who transport these passengers. An auditory alert may be especially useful to alert drivers to children unbuckling in the back seat during a trip.


Anesthetic management of patients undergoing intracranial bypass procedures.
Cerebral revascularization is used to augment or replace cerebral blood flow in patients at risk of developing cerebral ischemia. These include patients with moyamoya disease, occlusive cerebrovascular disease, skull base tumors, and complex aneurysms. Our aim in this review is to provide a comprehensive update of both surgical and anesthetic aspects of cerebral revascularization procedures. The anesthetic concerns for most patients presenting for different types of bypass procedures are similar and include the maintenance of adequate cerebral perfusion to prevent cerebral ischemia. Patients with complex aneurysms and tumors have additional considerations related to the surgical treatment of the underlying pathology.


Solution structure and dynamics of a calcium binding epidermal growth factor-like domain pair from the neonatal region of human fibrillin-1.
Fibrillin-1 is a mosaic protein mainly composed of 43 calcium binding epidermal growth factor-like (cbEGF) domains arranged as multiple, tandem repeats. Mutations within the fibrillin-1 gene cause Marfan syndrome (MFS), a heritable disease of connective tissue. More than 60% of MFS-causing mutations identified are localized to cbEGFs, emphasizing that the native properties of these domains are critical for fibrillin-1 function. The cbEGF12-13 domain pair is within the longest run of cbEGFs, and many mutations that cluster in this region are associated with severe, neonatal MFS. The NMR solution structure of Ca(2+)-loaded cbEGF12-13 exhibits a near-linear, rod-like arrangement of domains. This observation supports the hypothesis that all fibrillin-1 (cb)EGF-cbEGF pairs, characterized by a single interdomain linker residue, possess this rod-like structure. The domain arrangement of cbEGF12-13 is stabilized by additional interdomain packing interactions to those observed for cbEGF32-33, which may help to explain the previously reported higher calcium binding affinity of cbEGF13. Based on this structure, a model of cbEGF11-15 that encompasses all known neonatal MFS missense mutations has highlighted a potential binding region. Backbone dynamics data confirm the extended structure of cbEGF12-13 and lend support to the hypothesis that a correlation exists between backbone flexibility and cbEGF domain calcium affinity. These results provide important insight into the potential consequences of MFS-associated mutations for the assembly and biomechanical properties of connective tissue microfibrils.


Identification of a small molecule that turns ON the pluripotency gene circuitry in human fibroblasts.
A nontransgenic approach to reprogram mouse somatic cells into induced pluripotent stem cells using only small molecules got achieved to propose a potential clinical-friendly cellular reprogramming strategy. Consequently, the screening and identification of small molecules capable of inducing pluripotency genes in human cells are increasingly a focus of research. Because cellular reprogramming is multifactorial in nature, there is a need for versatile small molecules capable of modulating the complicated gene networks associated with pluripotency. We have developed a targeting small molecule called SAHA-PIP comprising the histone deacetylase inhibitor SAHA and the sequence-specific DNA binding pyrrole-imidazole polyamides for modulating distinct gene networks. Here, we report the identification of a SAHA-PIP termed Ì that could trigger genome-wide epigenetic reprogramming and turn ON the typically conserved core pluripotency gene network. Through independent lines of evidence, we report for the first time a synthetic small molecule inducer that target and activate the OCT-3/4 regulated pluripotency genes in human dermal fibroblasts.


Nursing Diagnoses as Predictors of Hospital Length of Stay: A Prospective Observational Study.
To investigate whether the number of nursing diagnoses on hospital admission is an independent predictor of the hospital length of stay. A prospective observational study was carried out. A sample of 2,190 patients consecutively admitted (from July to December 2014) in four inpatient units (two medical, two surgical) of a 1,547-bed university hospital were enrolled for the study. Data were collected from a clinical nursing information system and the hospital discharge register. Two regression analyses were performed to investigate if the number of nursing diagnoses on hospital admission was an independent predictor of length of stay and length of stay deviation after controlling for patients' sociodemographic characteristics (age, gender), clinical variables (disease groupers, disease severity morbidity indexes), and organizational hospital variables (admitting inpatient unit, modality of admission). The number of nursing diagnoses was shown to be an independent predictor of both the length of stay (β = .15; p < .001) and the length of stay deviation (β = .19; p < .001). The number of nursing diagnoses is a strong independent predictor of an effective hospital length of stay and of a length of stay longer than expected. The systematic inclusion of standard nursing care data in electronic health records can improve the predictive ability on hospital outcomes and describe the patient complexity more comprehensively, improving hospital management efficiency.


Kinetic analysis using low-molecular mass xyloglucan oligosaccharides defines the catalytic mechanism of a Populus xyloglucan endotransglycosylase.
Plant XETs [XG (xyloglucan) endotransglycosylases] catalyse the transglycosylation from a XG donor to a XG or low-molecular-mass XG fragment as the acceptor, and are thought to be important enzymes in the formation and remodelling of the cellulose-XG three-dimensional network in the primary plant cell wall. Current methods to assay XET activity use the XG polysaccharide as the donor substrate, and present limitations for kinetic and mechanistic studies of XET action due to the polymeric and polydisperse nature of the substrate. A novel activity assay based on HPCE (high performance capillary electrophoresis), in conjunction with a defined low-molecular-mass XGO {XG oligosaccharide; (XXXGXXXG, where G=Glcbeta1,4- and X=[Xylalpha1,6]Glcbeta1,4-)} as the glycosyl donor and a heptasaccharide derivatized with ANTS [8-aminonaphthalene-1,3,6-trisulphonic acid; (XXXG-ANTS)] as the acceptor substrate was developed and validated. The recombinant enzyme PttXET16A from Populus tremula x tremuloides (hybrid aspen) was characterized using the donor/acceptor pair indicated above, for which preparative scale syntheses have been optimized. The low-molecular-mass donor underwent a single transglycosylation reaction to the acceptor substrate under initial-rate conditions, with a pH optimum at 5.0 and maximal activity between 30 and 40 degrees C. Kinetic data are best explained by a ping-pong bi-bi mechanism with substrate inhibition by both donor and acceptor. This is the first assay for XETs using a donor substrate other than polymeric XG, enabling quantitative kinetic analysis of different XGO donors for specificity, and subsite mapping studies of XET enzymes.


[Treatment of chronic hepatitis B: adherence and safety].
Second generation nucleos (t) idic analogues result in a complete viral suppression after 48 to 96 weeks of therapy in most patients, regardless of the virus (HBV genotype, wild type or pre-C mutant), the underlying liver disease (cirrhosis or not) or the immune status (mono- or HIV/HBV co-infection). This antiviral efficacy may result in HBe or HBs seroconversion. Its clinical impact is important since inactivation of necroinflammation allows, in the absence of liver comorbidities, a stabilisation then a reversal of fibrosis and cirrhosis, and consequently a decrease in the occurrence of carcinomatous or non-carcinomatous complications. The future issues for long-term anti-HBV therapy will be adherence on the one hand and safety on the other hand. Therapeutic failures are mainly related to poor adherence more than to viral resistance. Adherence of patients has to be optimized by therapeutic education and education of physicians. Long-term safety has to be systematically evaluated. More than the neuromuscular or metabolic side effects (lactic acidosis), the renal and bone-related adverse events have to be monitored, followed-up and anticipated by good clinical practices.


Effects of hyper- and hypoosmolality on whole body protein and glucose kinetics in humans.
To investigate the effect of acute changes of extracellular osmolality on whole body protein and glucose metabolism, we studied 10 male subjects during three conditions: hyperosmolality was induced by fluid restriction and intravenous infusion of hypertonic NaCl [2-5%; (wt/vol)] during 17 h; hypoosmolality was produced by intravenous administration of desmopressin, liberal water drinking, and infusion of hypotonic saline (0.4%); and the isoosmolality study consisted of ad libitum oral water intake by the subjects. Leucine flux ([1-13C]leucine infusion technique), a parameter of whole body protein breakdown, decreased during the hypoosmolality study (P < 0. 02 vs. isoosmolality). The leucine oxidation rate decreased during the hypoosmolality study (P < 0.005 vs. isoosmolality). Metabolic clearance rate of glucose during hyperinsulinemic-euglycemic clamping increased less during the hypoosmolality study than during the isoosmolality study (P < 0.04). Plasma insulin decreased, and plasma nonesterified fatty acids, glycerol, and ketone body concentrations and lipid oxidation increased during the hypoosmolality study. It is concluded that acute alterations of plasma osmolality influence whole body protein, glucose, and lipid metabolism; hypoosmolality results in protein sparing associated with increased lipolysis and lipid oxidation and impaired insulin sensitivity.


Fixed and random effects selection in mixed effects models.
We consider selecting both fixed and random effects in a general class of mixed effects models using maximum penalized likelihood (MPL) estimation along with the smoothly clipped absolute deviation (SCAD) and adaptive least absolute shrinkage and selection operator (ALASSO) penalty functions. The MPL estimates are shown to possess consistency and sparsity properties and asymptotic normality. A model selection criterion, called the IC(Q) statistic, is proposed for selecting the penalty parameters (Ibrahim, Zhu, and Tang, 2008, Journal of the American Statistical Association 103, 1648-1658). The variable selection procedure based on IC(Q) is shown to consistently select important fixed and random effects. The methodology is very general and can be applied to numerous situations involving random effects, including generalized linear mixed models. Simulation studies and a real data set from a Yale infant growth study are used to illustrate the proposed methodology.


Potentially modifiable factors contributing to outcome from acute respiratory distress syndrome: the LUNG SAFE study.
To improve the outcome of the acute respiratory distress syndrome (ARDS), one needs to identify potentially modifiable factors associated with mortality. The large observational study to understand the global impact of severe acute respiratory failure (LUNG SAFE) was an international, multicenter, prospective cohort study of patients with severe respiratory failure, conducted in the winter of 2014 in a convenience sample of 459 ICUs from 50 countries across five continents. A pre-specified secondary aim was to examine the factors associated with outcome. Analyses were restricted to patients (93.1 %) fulfilling ARDS criteria on day 1-2 who received invasive mechanical ventilation. 2377 patients were included in the analysis. Potentially modifiable factors associated with increased hospital mortality in multivariable analyses include lower PEEP, higher peak inspiratory, plateau, and driving pressures, and increased respiratory rate. The impact of tidal volume on outcome was unclear. Having fewer ICU beds was also associated with higher hospital mortality. Non-modifiable factors associated with worsened outcome from ARDS included older age, active neoplasm, hematologic neoplasm, and chronic liver failure. Severity of illness indices including lower pH, lower PaO2/FiO2 ratio, and higher non-pulmonary SOFA score were associated with poorer outcome. Of the 578 (24.3 %) patients with a limitation of life-sustaining therapies or measures decision, 498 (86.0 %) died in hospital. Factors associated with increased likelihood of limitation of life-sustaining therapies or measures decision included older age, immunosuppression, neoplasia, lower pH and increased non-pulmonary SOFA scores. Higher PEEP, lower peak, plateau, and driving pressures, and lower respiratory rate are associated with improved survival from ARDS. ClinicalTrials.gov NCT02010073.


Towards quantitative molecular mapping of cells by Raman microscopy: using AFM for decoupling molecular concentration and cell topography.
Raman micro-spectroscopy (RMS) is a non-invasive technique for imaging live cells in vitro. However, obtaining quantitative molecular information from Raman spectra is difficult because the intensity of a Raman band is proportional to the number of molecules in the sampled volume, which depends on the local molecular concentration and the thickness of the cell. In order to understand these effects, we combined RMS with atomic force microscopy (AFM), a technique that can measure accurately the thickness profile of the cells. Solution-based calibration models for RNA and albumin were developed to create quantitative maps of RNA and proteins in individual fixed cells. The maps were built by applying the solution-based calibration models, based on partial least squares fitting (PLS), on raster-scan Raman maps, after accounting for the local cell height obtained from the AFM. We found that concentrations of RNA in the cytoplasm of mouse neuroprogenitor stem cells (NSCs) were as high as 25 ± 6 mg ml(-1), while proteins were distributed more uniformly and reached concentrations as high as ∼50 ± 12 mg ml(-1). The combined AFM-Raman datasets from fixed cells were also used to investigate potential improvements for normalization of Raman spectral maps. For all Raman maps of fixed cells (n = 10), we found a linear relationship between the scores corresponding to the first component (PC1) and the cell height profile obtained by AFM. We used PC1 scores to reconstruct the relative height profiles of independent cells (n = 10), and obtained correlation coefficients with AFM maps higher than 0.99. Using this normalization method, qualitative maps of RNA and protein were used to obtain concentrations for live NSCs. While this study demonstrates the potential of using AFM and RMS for measuring concentration maps for individual NSCs in vitro, further studies are required to establish the robustness of the normalization method based on principal component analysis when comparing Raman spectra of cells with large morphological differences.


Decoding the grasping intention from electromyography during reaching motions.
Active upper-limb prostheses are used to restore important hand functionalities, such as grasping. In conventional approaches, a pattern recognition system is trained over a number of static grasping gestures. However, training a classifier in a static position results in lower classification accuracy when performing dynamic motions, such as reach-to-grasp. We propose an electromyography-based learning approach that decodes the grasping intention during the reaching motion, leading to a faster and more natural response of the prosthesis. Eight able-bodied subjects and four individuals with transradial amputation gave informed consent and participated in our study. All the subjects performed reach-to-grasp motions for five grasp types, while the elecromyographic (EMG) activity and the extension of the arm were recorded. We separated the reach-to-grasp motion into three phases, with respect to the extension of the arm. A multivariate analysis of variance (MANOVA) on the muscular activity revealed significant differences among the motion phases. Additionally, we examined the classification performance on these phases. We compared the performance of three different pattern recognition methods; Linear Discriminant Analysis (LDA), Support Vector Machines (SVM) with linear and non-linear kernels, and an Echo State Network (ESN) approach. Our off-line analysis shows that it is possible to have high classification performance above 80% before the end of the motion when with three-grasp types. An on-line evaluation with an upper-limb prosthesis shows that the inclusion of the reaching motion in the training of the classifier importantly improves classification accuracy and enables the detection of grasp intention early in the reaching motion. This method offers a more natural and intuitive control of prosthetic devices, as it will enable controlling grasp closure in synergy with the reaching motion. This work contributes to the decrease of delays between the user's intention and the device response and improves the coordination of the device with the motion of the arm.


Work attendance despite headache and its economic impact: a comparison between two workplaces.
To study work attendance despite headache in 2 different workplaces and its economic impact. Literature on the economic impact of headache traditionally has focused on direct costs. Little is known concerning headache experienced at work and its costs due to loss of effectiveness and productivity. We sent a questionnaire to 800 employees in Sweden--400 at a technology company (private employee population) and 400 at a university hospital (public employee population). We attempted to assess the prevalence of headache, work attendance despite the presence of acute headache, and the impact of acute headache upon work effectiveness. Subjects self-scored decreased work effectiveness resulting from headache during the previous 3 months and recorded the number of days at work despite headache. From these data, we estimated the economic loss resulting from headache. The survey response rate was 71.5%. The prevalence of headache was 64% in the private employee population and 78% in the public employee population. Thirty-nine percent of the private employees and 57% of the public employees reported experiencing headache as a result of stress. Fifty percent reported that they went to work despite headache, and the mean number of days at work despite headache, during the previous 3 months, was 6.6 days in the private employee group and 6.1 days in the public employee group. A 25% decrease in work effectiveness was estimated, and, extrapolating from our data, we calculated the cost of lost effectiveness due to headache among employers in Sweden to be approximately 1.4 billion euros a year. The economic burden of headache experienced at work is substantial, suggesting that workplace-based treatment and prevention programs emphasizing stress management may be financially, as well as clinically, advantageous.


Vortices enable the complex aerobatics of peregrine falcons.
The peregrine falcon (Falco peregrinus) is known for its extremely high speeds during hunting dives or stoop. Here we demonstrate that the superior manoeuvrability of peregrine falcons during stoop is attributed to vortex-dominated flow promoted by their morphology, in the M-shape configuration adopted towards the end of dive. Both experiments and simulations on life-size models, derived from field observations, revealed the presence of vortices emanating from the frontal and dorsal region due to a strong spanwise flow promoted by the forward sweep of the radiale. These vortices enhance mixing for flow reattachment towards the tail. The stronger wing and tail vortices provide extra aerodynamic forces through vortex-induced lift for pitch and roll control. A vortex pair with a sense of rotation opposite to that from conventional planar wings interacts with the main wings vortex to reduce induced drag, which would otherwise decelerate the bird significantly during pull-out. These findings could help in improving aircraft performance and wing suits for human flights.


Power and choice: their dynamic interplay in quenching the thirst for personal control.
Power and choice represent two fundamental forces that govern human behavior. Scholars have largely treated power as an interpersonal construct involving control over other individuals, whereas choice has largely been treated as an intrapersonal construct that concerns the ability to select a preferred course of action. Although these constructs have historically been studied separately, we propose that they share a common foundation--that both are rooted in an individual's sense of personal control. Because of this common underlying basis, we hypothesized that power and choice are substitutable; that is, we predicted that the absence of one would increase the desire for the other, which, when acquired, would serve to satisfy the broader need for control. We also predicted that choice and power would exhibit a threshold effect, such that once one source of control had been provided (e.g., power), the addition of the other (e.g., choice) would yield diminishing returns. Six experiments provide evidence supporting these predictions.


In vitro evaluation of novel antisense oligonucleotides is predictive of in vivo exon skipping activity for Duchenne muscular dystrophy.
Targeted splice modulation of pre-mRNA transcripts by antisense oligonucleotides (AOs) can correct the function of aberrant disease-related genes. Duchenne muscular dystrophy (DMD) arises as a result of mutations that interrupt the open-reading frame in the DMD gene encoding dystrophin such that dystrophin protein is absent, leading to fatal muscle degeneration. AOs have been shown to correct this dystrophin defect via exon skipping to yield functional dystrophin protein in animal models of DMD and also in DMD patients via intramuscular administration. To advance this therapeutic method requires increased exon skipping efficiency via an optimized AO sequence, backbone chemistry and additional modifications, and the improvement of methods for evaluating AO efficacy. In the present study, we establish the conditions for rapid in vitro AO screening in H(2)K muscle cells, in which we evaluate the exon skipping properties of a number of known and novel AO chemistries [2'-O-methyl, peptide nucleic acid, phosphorodiamidate morpholino (PMO)] and their peptide-conjugated derivatives and correlate their in vitro and in vivo exon skipping activities. The present study demonstrates that using AO concentrations of 300 nM with analysis at a single time-point of 24 h post-transfection allowed the effective in vitro screening of AO compounds to yield data predictive of in vivo exon skipping efficacy. Peptide-conjugated PMO AOs provided the highest in vitro activity. We also show for the first time that the feasibility of rapid AO screening extends to primary cardiomyocytes. In vitro screening of different AOs within the same chemical class is a reliable method for predicting the in vivo exon skipping efficiency of AOs for DMD.


Association of Daily Step Count and Step Intensity With Mortality Among US Adults.
It is unclear whether the number of steps per day and the intensity of stepping are associated with lower mortality. Describe the dose-response relationship between step count and intensity and mortality. Representative sample of US adults aged at least 40 years in the National Health and Nutrition Examination Survey who wore an accelerometer for up to 7 days ( from 2003-2006). Mortality was ascertained through December 2015. Accelerometer-measured number of steps per day and 3 step intensity measures (extended bout cadence, peak 30-minute cadence, and peak 1-minute cadence [steps/min]). Accelerometer data were based on measurements obtained during a 7-day period at baseline. The primary outcome was all-cause mortality. Secondary outcomes were cardiovascular disease (CVD) and cancer mortality. Hazard ratios (HRs), mortality rates, and 95% CIs were estimated using cubic splines and quartile classifications adjusting for age; sex; race/ethnicity; education; diet; smoking status; body mass index; self-reported health; mobility limitations; and diagnoses of diabetes, stroke, heart disease, heart failure, cancer, chronic bronchitis, and emphysema. A total of 4840 participants (mean age, 56.8 years; 2435 [54%] women; 1732 [36%] individuals with obesity) wore accelerometers for a mean of 5.7 days for a mean of 14.4 hours per day. The mean number of steps per day was 9124. There were 1165 deaths over a mean 10.1 years of follow-up, including 406 CVD and 283 cancer deaths. The unadjusted incidence density for all-cause mortality was 76.7 per 1000 person-years (419 deaths) for the 655 individuals who took less than 4000 steps per day; 21.4 per 1000 person-years (488 deaths) for the 1727 individuals who took 4000 to 7999 steps per day; 6.9 per 1000 person-years (176 deaths) for the 1539 individuals who took 8000 to 11 999 steps per day; and 4.8 per 1000 person-years (82 deaths) for the 919 individuals who took at least 12 000 steps per day. Compared with taking 4000 steps per day, taking 8000 steps per day was associated with significantly lower all-cause mortality (HR, 0.49 [95% CI, 0.44-0.55]), as was taking 12 000 steps per day (HR, 0.35 [95% CI, 0.28-0.45]). Unadjusted incidence density for all-cause mortality by peak 30 cadence was 32.9 per 1000 person-years (406 deaths) for the 1080 individuals who took 18.5 to 56.0 steps per minute; 12.6 per 1000 person-years (207 deaths) for the 1153 individuals who took 56.1 to 69.2 steps per minute; 6.8 per 1000 person-years (124 deaths) for the 1074 individuals who took 69.3 to 82.8 steps per minute; and 5.3 per 1000 person-years (108 deaths) for the 1037 individuals who took 82.9 to 149.5 steps per minute. Greater step intensity was not significantly associated with lower mortality after adjustment for total steps per day (eg, highest vs lowest quartile of peak 30 cadence: HR, 0.90 [95% CI, 0.65-1.27]; P value for trend = .34). Based on a representative sample of US adults, a greater number of daily steps was significantly associated with lower all-cause mortality. There was no significant association between step intensity and mortality after adjusting for total steps per day.


[Kidney and bladder cancers in the elderly].
Kidney and bladder cancers are common in the elderly. Treatments used in younger patients may be considered for the latter, subject to an individual estimation of the/risk-benefit ratio that takes into consideration the geriatric evaluation parameters. Surgery is the only curative treatment for both cancers. Supportive care should be integrated early in comprehensive care to preserve the quality of life of elderly patients with these cancers.


Black tea consumption dose-dependently improves flow-mediated dilation in healthy males.
Flavonoids may protect against cardiovascular disease. Tea is a major source of dietary flavonoids. Studies indicate black tea improves endothelial function but data on arterial haemodynamics, blood pressure (BP) and insulin resistance are equivocal. Inconsistency may be due to flaws in study design or flavonoid doses tested. Further, no study has evaluated the dose-response curve. Our study aimed to test the effects of various doses of black tea on vascular function, BP and insulin resistance. According to a randomized, double-blind, controlled, cross-over design, 19 healthy men were assigned to receive either five treatments with a twice daily intake of black tea (0, 100, 200, 400 and 800 mg tea flavonoids/day) in five periods lasting 1 week each. Black tea dose dependently increased flow-mediated dilation (FMD) from 7.8% (control) to 9.0, 9.1, 9.6 and 10.3% after the different flavonoid doses, respectively (P = 0.0001). Already 100 mg/day (less than 1 cup of tea) increased FMD compared with control (P = 0.0113). FMD improvement after 800 mg/day was significant compared with control (P < 0.0001) but also to 100 mg/day (P = 0.0121) and 200 mg/day (P = 0.0275). Black tea intake decreased office systolic (-2.6 mmHg, P = 0.0007) and diastolic (-2.2 mmHg, P = 0.006) BP as well as stiffness index (P = 0.0159) without changes in other parameters studied. Our study is the first showing black tea ingestion dose dependently improved FMD and decreased peripheral arterial stiffness in healthy volunteers. Our data suggest that worldwide all tea drinkers could benefit from protective cardiovascular effects exerted by tea.


Collapse of resilience patterns in generalized Lotka-Volterra dynamics and beyond.
Recently, a theoretical framework aimed at separating the roles of dynamics and topology in multidimensional systems has been developed [Gao et al., Nature (London) 530, 307 (2016)10.1038/nature16948]. The validity of their method is assumed to hold depending on two main hypotheses: (i) The network determined by the the interaction between pairs of nodes has negligible degree correlations; (ii) the node activities are uniform across nodes on both the drift and the pairwise interaction functions. Moreover, the authors consider only positive (mutualistic) interactions. Here we show the conditions proposed by Gao and collaborators [Nature (London) 530, 307 (2016)10.1038/nature16948] are neither sufficient nor necessary to guarantee that their method works in general and validity of their results are not independent of the model chosen within the class of dynamics they considered. Indeed we find that a new condition poses effective limitations to their framework and we provide quantitative predictions of the quality of the one-dimensional collapse as a function of the properties of interaction networks and stable dynamics using results from random matrix theory. We also find that multidimensional reduction may work also for an interaction matrix with a mixture of positive and negative signs, opening up an application of the framework to food webs, neuronal networks, and social and economic interactions.


Targeting AIDS prevention and treatment toward HIV-1-infected persons. The concept of early intervention.
We propose establishing private and public outpatient facilities where persons with human immunodeficiency virus, type 1 (HIV-1), infection can receive state-of-the-art clinical and behavioral follow-up, treatment, and assistance. The possible advantages of enrolling HIV-1-positive persons into long-term follow-up are early treatment of clinical conditions and resulting gains in life quality and life expectancy, decreased transmission of HIV-1 to uninfected persons, more efficient use of scarce patient-care resources, and improved estimates of the total number of HIV-infected persons. The possible disadvantages of such a program are adverse psychological reactions to knowledge of HIV-1 infection, adverse societal actions against infected persons, and, finally, the economic cost of the program. These facilities, with the proper expertise and safeguards of confidentiality and trust, could prolong and improve the lives of infected persons while preventing infection of others.


Reattachment of endodontically treated lateral incisor with supragingivally complicated crown fracture using fiber-reinforced post.
Re-restoring endodontically treated teeth with complicated crown or crown root fractures is a major challenge for dental practitioners, because they can present difficulties for successful treatment. This report describes the management of supragingivally complicated crown fracture of an endodontically treated maxillary lateral incisor. The involved tooth was restored with the reattachment procedure using light transmitting fiber post. After 11 months, the reattached tooth had a satisfying function, favorable physiological and esthetic outcomes and healthy surrounding periodontal structures.


Relation between body mass index and radiological progression in patients with rheumatoid arthritis.
To determine if there is an influence of body mass index (BMI) on the radiological progression in early and longer duration rheumatoid arthritis (RA). Fifty-four patients with RA were observed in a progressive 2 year followup for radiological progression of joint damage. At the beginning of study, 27 (50%) patients had a duration of complaints less than 6 months, grouped as early RA. BMI at the beginning and end of the study were monitored, together with HLA-DRB1 alleles, initial joint erosions, duration of disease, age, sex, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Outcome was defined as radiographic damage according to yearly increase of Larsen score. Increased radiographic joint damage of patients was significantly correlated with lower BMI at the beginning of the study (r = 0.363, p < 0.05), the presence of initial joint erosions (r = 0.341, p < 0.01), ESR (r = 0.315, p < 0.05), and CRP at study entry (r = 0.427, p < 0.01). Patients with an increase of Larsen score > or = 5.8/year were found to have a lower weight at the beginning of their complaints (BMI 24.8 +/- 4.7 vs 27.8 +/- 3.8; p < 0.05) as well as after the time of observation (BMI 24.6 +/- 3.7 vs 27.6 +/- 4.9; p < 0.05). Stepwise logistic regression analysis revealed a BMI < 27 at the beginning of disease (beta = 2.04, p = 0.003, odds ratio = 7.69), the presence of HLA-DR4 shared epitope (beta = 1.76, p = 0.015, OR 5.82), and joint erosions at study entry (beta = 1.56, p = 0.044, OR 4.78) as significant predictors for rapid joint damage. Together with the presence of HLA-DR4 shared epitope and erosive disease at study entry, a low BMI at the beginning of RA was found in association with higher radiographic progression in RA. Accordingly, BMI could be of interest as a sensitive and inflammation-independent predictor for radiological outcome of RA.


Computational Prediction of Disordered Protein Motifs Using SLiMSuite.
Short linear motifs (SLiMs) are important mediators of interactions between intrinsically disordered regions of proteins and their interaction partners. Here, we detail instructions for the computational prediction of SLiMs in disordered protein regions, using the main tools of the SLiMSuite package: (1) SLiMProb identifies and calculates enrichment of predefined motifs in a set of proteins; (2) SLiMFinder predicts SLiMs de novo in a set of proteins, accounting for evolutionary relationships; (3) QSLiMFinder increases SLiMFinder sensitivity by focusing SLiM prediction on a specific query protein/region; (4) CompariMotif compares predicted SLiMs to known SLiMs or other SLiM predictions to identify common patterns. For each tool, command-line and online server examples are provided. Detailed notes provide additional advice on different applications of SLiMSuite, including batch running of multiple datasets and conservation masking using alignments of predicted orthologues.


Torsion of the optic nerve head is a prominent feature of normal-tension glaucoma.
To compare optic nerve head (ONH) morphology between eyes with normal-tension glaucoma (NTG) and primary open-angle glaucoma (POAG). Seventy-eight NTG patients and 78 POAG patients matched according to age and axial length were analyzed. Optic nerve head tilt and torsion were identified from cross-sectional images of optical coherence tomography. The degree of horizontal, vertical, and maximum ONH tilt and torsion was compared between NTG and POAG eyes, and additional comparisons were based on the presence of myopia and the location of the visual field defect. Logistic regression analysis was used to determine the factors related to the degree of ONH torsion. Vertical (P = 0.610) and horizontal tilt degree (P = 0.746) did not differ between NTG and POAG eyes. However, torsion degree (P = 0.022) differed significantly between NTG and POAG eyes. Direction of vertical tilt (P = 0.040) and torsion (P < 0.001) showed more prevalent superior tilt and torsion in NTG eyes (21.8% and 33.3%, respectively) compared to POAG eyes (10.3% and 10.3%, respectively). Myopic NTG eyes showed greater torsion degree (P = 0.014) than nonmyopic NTG eyes, which was not observed in the comparison between myopic and nonmyopic POAG eyes. Only NTG eyes showed a significant difference in the degree of maximum tilt (P < 0.001) and torsion (P < 0.001) and the direction of vertical tilt (P < 0.001) and torsion (P = 0.010) by the location of visual field defect. Longer axial length, maximum tilt degree, and diagnosis of NTG were the factors related to the degree of ONH torsion. Normal-tension glaucoma eyes had a greater ONH torsion compared to POAG eyes with matched axial length. The direction of the ONH tilt and torsion was related to the location of the visual field defect only in NTG eyes.


Understanding sustainable diets: a descriptive analysis of the determinants and processes that influence diets and their impact on health, food security, and environmental sustainability.
The confluence of population, economic development, and environmental pressures resulting from increased globalization and industrialization reveal an increasingly resource-constrained world in which predictions point to the need to do more with less and in a "better" way. The concept of sustainable diets presents an opportunity to successfully advance commitments to sustainable development and the elimination of poverty, food and nutrition insecurity, and poor health outcomes. This study examines the determinants of sustainable diets, offers a descriptive analysis of these areas, and presents a causal model and framework from which to build. The major determinants of sustainable diets fall into 5 categories: 1) agriculture, 2) health, 3) sociocultural, 4) environmental, and 5) socioeconomic. When factors or processes are changed in 1 determinant category, such changes affect other determinant categories and, in turn, the level of "sustainability" of a diet. The complex web of determinants of sustainable diets makes it challenging for policymakers to understand the benefits and considerations for promoting, processing, and consuming such diets. To advance this work, better measurements and indicators must be developed to assess the impact of the various determinants on the sustainability of a diet and the tradeoffs associated with any recommendations aimed at increasing the sustainability of our food system.


Mesoaxial polydactyly is a major feature in Bardet-Biedl syndrome patients with LZTFL1 (BBS17) mutations.
Ciliopathies are heterogeneous disorders sharing different clinical signs due to a defect at the level of the primary cilia/centrosome complex. Postaxial polydactyly is frequently reported in ciliopathies, especially in Bardet-Biedl syndrome (BBS). Clinical features and genetic results observed in a pair of dizygotic twins with BBS are reported. The following manifestations were present: retinitis pigmentosa, bilateral insertional polydactyly, cognitive impairment and renal dysfunction. X-rays of the hands confirmed the presence of a 4th mesoaxial extra-digit with Y-shaped metacarpal bones. The sequencing of LZTFL1 identified a missense mutation (NM_020347.2: p.Leu87Pro; c.260T>C) and a nonsense mutation (p.Glu260*; c.778G>T), establishing a compound heterozygous status for the twins. A major decrease of LZTFL1 transcript and protein was observed in the patient's fibroblasts. This is the second report of LZTFL1 mutations in BBS patients confirming LZTFL1 as a BBS gene. Interestingly, the only two families reported in literature thus far with LZTFL1 mutations have in common mesoaxial polydactyly, a very uncommon feature for BBS. This special subtype of polydactyly in BBS patients is easily identified on clinical examination and prompts for priority sequencing of LZTFL1 (BBS17).


Maximal release of highly bifidogenic soluble dietary fibers from industrial potato pulp by minimal enzymatic treatment.
Potato pulp is a poorly utilized, high-volume co-processing product resulting from industrial potato starch manufacturing. Potato pulp mainly consists of the tuber plant cell wall material and is particularly rich in pectin, notably galactan branched rhamnogalacturonan I type pectin which has previously been shown to exhibit promising properties as dietary fiber. The objective of this study was to solubilize dietary fibers from potato pulp by a one-step minimal treatment procedure and evaluate the prebiotic potential of the fibers. Statistically designed experiments were conducted to investigate the influence of enzyme type, dosage, substrate level, incubation time, and temperature on the enzyme catalyzed solubilization to define the optimal minimal enzyme treatment for maximal fiber solubilization. The result was a method that within 1 min released 75% [weight/weight (w/w)] dry matter from 1% (w/w) potato pulp treated with 1.0% (w/w) [enzyme/substrate (E/S)] pectin lyase from Aspergillus nidulans and 1.0% (w/w) E/S polygalacturonase from Aspergillus aculeatus at pH 6.0 and 60 °C. Molecular size fractionation of the solubilized fibers revealed two major fractions: one fraction rich in galacturonic acid of 10-100 kDa indicating mainly homogalacturonan, and a fraction >100 kDa rich in galactose, presumably mainly made up of β-1,4-galactan chains of rhamnogalacturonan I. When fermented in vitro by microbial communities derived from fecal samples from three healthy human volunteers, both of the solubilized fiber fractions were more bifidogenic than fructo-oligosaccharides (FOS). Notably the fibers having molecular masses of >100 kDa selectively increased the densities of Bifidobacterium spp. and Lactobacillus spp. 2-3 times more than FOS.


Defective fast inactivation recovery of Nav 1.4 in congenital myasthenic syndrome.
To describe the unique phenotype and genetic findings in a 57-year-old female with a rare form of congenital myasthenic syndrome (CMS) associated with longstanding muscle fatigability, and to investigate the underlying pathophysiology. We used whole-cell voltage clamping to compare the biophysical parameters of wild-type and Arg1457His-mutant Nav 1.4. Clinical and neurophysiological evaluation revealed features consistent with CMS. Sequencing of candidate genes indicated no abnormalities. However, analysis of SCN4A, the gene encoding the skeletal muscle sodium channel Nav 1.4, revealed a homozygous mutation predicting an arginine-to-histidine substitution at position 1457 (Arg1457His), which maps to the channel's voltage sensor, specifically D4/S4. Whole-cell patch clamp studies revealed that the mutant required longer hyperpolarization to recover from fast inactivation, which produced a profound use-dependent current attenuation not seen in the wild type. The mutant channel also had a marked hyperpolarizing shift in its voltage dependence of inactivation as well as slowed inactivation kinetics. We conclude that Arg1457His compromises muscle fiber excitability. The mutant fast-inactivates with significantly less depolarization, and it recovers only after extended hyperpolarization. The resulting enhancement in its use dependence reduces channel availability, which explains the patient's muscle fatigability. Arg1457His offers molecular insight into a rare form of CMS precipitated by sodium channel inactivation defects. Given this channel's involvement in other muscle disorders such as paramyotonia congenita and hyperkalemic periodic paralysis, our study exemplifies how variations within the same gene can give rise to multiple distinct dysfunctions and phenotypes, revealing residues important in basic channel function.


Essential role of the zinc transporter ZIP9/SLC39A9 in regulating the activations of Akt and Erk in B-cell receptor signaling pathway in DT40 cells.
The essential trace element zinc is important for all living organisms. Zinc functions not only as a nutritional factor, but also as a second messenger. However, the effects of intracellular zinc on the B cell-receptor (BCR) signaling pathway remain poorly understood. Here, we present data indicating that the increase in intracellular zinc level induced by ZIP9/SLC39A9 (a ZIP Zrt-/Irt-like protein) plays an important role in the activation of Akt and Erk in response to BCR activation. In DT40 cells, the enhancement of Akt and Erk phosphorylation following BCR activation requires intracellular zinc. To clarify this event, we used chicken ZnT5/6/7-gene-triple-knockout DT40 (TKO) cells and chicken Zip9-knockout DT40 (cZip9KO) cells. The levels of Akt and ERK phosphorylation significantly decreased in cZip9KO cells. In addition, the enzymatic activity of protein tyrosine phosphatase (PTPase) increased in cZip9KO cells. These biochemical events were restored by overexpressing the human Zip9 (hZip9) gene. Moreover, we found that the increase in intracellular zinc level depends on the expression of ZIP9. This observation is in agreement with the increased levels of Akt and Erk phosphorylation and the inhibition of total PTPase activity. We concluded that ZIP9 regulates cytosolic zinc level, resulting in the enhancement of Akt and Erk phosphorylation. Our observations provide new mechanistic insights into the BCR signaling pathway underlying the regulation of intracellular zinc level by ZIP9 in response to the BCR activation.


Attention patterns in children with attention deficit disorder with or without hyperactivity.
The objective of this study was to differentiate the attention patterns associated with attention deficit disorder with or without hyperactivity using continuous performance test (CPT). The diagnoses were based on the DSM-III, III-R, and IV criteria and of the 39 children who participated in the study, 14 had attention deficit disorder with hyperactivity (ADDH) and 11 had attention deficit disorder without hyperactivity (ADDWO), while 14 normal children served as a control group. Attention patterns were examined according to the performance of subjects on the CPT and parental scores on the ADHD Rating Scale, the Child Attention Profile, and the Conners Rating Scale. CPT performances were assessed before and after administration of 10 mg methylphenidate. We found as hypothesized that the CPT differentiated between the ADDH and ADDWO groups. However, contrary to our expectations, the ADDH children made more omission errors than the ADDWO children; they also showed more hyperactivity and impulsivity. The performance of both groups improved to an equal degree after the administration of methylphenidate. It is concluded that different subtypes of the attention deficit disorders are characterized by different attention profiles and that methylphenidate improves scores on test of continuous performance.


Spinal manipulation alters electromyographic activity of paraspinal muscles: a descriptive study.
To examine the effect of spinal manipulation on electromyographic (EMG) activity in areas of localized tight muscle bundles of the low back. Surface EMG activity was collected from 16 participants in 2 chiropractic offices during the 5 to 10 minutes of the treatment protocol. Electrodes were placed over the 2 sites of greatest paraspinal muscle tension as determined by manual palpation. Spinal manipulation was administered to 8 participants using Activator protocol; the other 8 were treated using Diversified protocol. Electromyographic activity decreased by at least 25% after treatment in 24 of the 31 sites that were monitored. There was less than 25% change at 3 sites and more than 25% increase at 4 sites. Multiple distinct increases and decreases were observed in many data plots. The results of this study indicate that manipulation induces a virtually immediate change, usually a reduction, in resting EMG levels in at least some patients with low back pain and tight paraspinal muscle bundles. In some cases, EMG activity increased during the treatment protocol and then usually, but not always, decreased to a level lower than the pretreatment level.


Attention for action in visual working memory.
From the conception of Baddeley's visuospatial sketchpad, visual working memory and visual attention have been closely linked concepts. An attractive model has advocated unity of the two cognitive functions, with attention serving the active maintenance of sensory representations. However, empirical evidence from various paradigms and dependent measures has now firmly established an at least partial dissociation between visual attention and visual working memory maintenance - thus leaving unclear what the relationship between the two concepts is. Moreover, a focus on sensory storage has treated visual working memory as a reflection of the past, with attention as a limiting resource. This view ignores what storage is for: immediate or future action. We argue that rather than serving sensory storage, attention emerges from coupling relevant sensory and action representations within working memory. Importantly, this coupling is bidirectional: First, through recurrent feedback mechanisms, action coupling results in the enhancement of the appropriate sensory memory representation. Under this view, unattended memories are currently not coupled to an action plan, but are not necessarily lost and remain available for future tasks when necessary. Second, through the very same feedback projections, attention serves as the credit assignment mechanism for the action's outcome. When the action is successful, the associated representations are being reinforced, leading to more robust consolidation and more rapid retrieval in the future - thus explaining performance benefits for attended memories without assuming that attention serves as the maintenance mechanism. By firmly grounding VWM in the action system, the new framework integrates a range of behavioural and neurophysiological findings and avoids circularity in explaining the role of attention in working memory.


Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies.
A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease. We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study-specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls. We observed independent associations for 2 single-nucleotide polymorphisms at the ABCG8 locus: rs11887534 (OR, 1.69; 95% confidence interval [CI], 1.54-1.86; P = 2.44 × 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 × 10(-34)). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR, 1.12; 95% CI, 1.08-1.16; P = 6.09 × 10(-11)), rs2547231 in SULT2A1 (encodes a sulfoconjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids) (OR, 1.17; 95% CI, 1.12-1.21; P = 2.24 × 10(-10)), rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 × 10(-10)), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR, 1.11; 95% CI, 1.08-1.15; P = 8.84 × 10(-9)). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were associated positively with gallstone disease risk, whereas the association for the rs1260326 variant was inverse. In this large-scale GWAS of gallstone disease, we identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids.


Anal cancer incidence and mortality in Puerto Rico.
Anal cancer is a rare tumor that is associated with oncogenic HPV genotypes. This study aims to compare the age-standardized rates (ASRs) of anal cancer incidence and mortality in men and women living in Puerto Rico (PR) with those of non-Hispanic whites (NHW), non-Hispanic blacks (NHB), and Hispanics (USH) living in the continental United States (US). ASRs were calculated based on cancer data that came from the PR Cancer Central Registry and from the Surveillance, Epidemiology, and End Results (SEER) program. The age-specific relative risks (RR) and 95% Confidence Interval (95% CI) were estimated using Poisson regression models. Comparing the period of 2001 to 2004 to that of 1992 to 1996, the incidence of anal cancer increased among NHW, NHB, and PR men. In females, an increase in the incidence was observed for all racial groups except for Puerto Rican women. When evaluating findings by age groups, Puerto Rican men younger than 60 years old had a 20% higher incidence of anal cancer than did USH men of the same age strata (RR: 2.20; 95% CI = 1.48-3.29). However, Puerto Rican females had a lower incidence of anal cancer than NHW and NHB women. An increased percent change in mortality was observed only in NHW and NHB men. A decreasing trend was observed in all racial/ethnic groups except for NHW women. Our results support the notion that there are racial/ethnic differences in anal cancer incidence and mortality, with potential disparities among men and women in PR compared with USH men and women. Given the increasing incidence trends in anal cancer, particularly among PR, NHW, and NHB men, further investigation is needed to better elucidate screening practices that can aid in the prevention of anal cancer.