Automated Multi-Atlas Segmentation of Hippocampal and Extrahippocampal Subregions in Alzheimer's Disease at 3T and 7T: What Atlas Composition Works Best?
Multi-atlas segmentation, a popular technique implemented in the Automated Segmentation of Hippocampal Subfields (ASHS) software, utilizes multiple expert-labelled images ("atlases") to delineate medial temporal lobe substructures. This multi-atlas method is increasingly being employed in early Alzheimer's disease (AD) research, it is therefore becoming important to know how the construction of the atlas set in terms of proportions of controls and patients with mild cognitive impairment (MCI) and/or AD affects segmentation accuracy. To evaluate whether the proportion of controls in the training sets affects the segmentation accuracy of both controls and patients with MCI and/or early AD at 3T and 7T. We performed cross-validation experiments varying the proportion of control subjects in the training set, ranging from a patient-only to a control-only set. Segmentation accuracy of the test set was evaluated by the Dice similarity coeffiecient (DSC). A two-stage statistical analysis was applied to determine whether atlas composition is linked to segmentation accuracy in control subjects and patients, for 3T and 7T. The different atlas compositions did not significantly affect segmentation accuracy at 3T and for patients at 7T. For controls at 7T, including more control subjects in the training set significantly improves the segmentation accuracy, but only marginally, with the maximum of 0.0003 DSC improvement per percent increment of control subject in the training set. ASHS is robust in this study, and the results indicate that future studies investigating hippocampal subfields in early AD populations can be flexible in the selection of their atlas compositions.


Functionality of patients with post-stroke hemiplegia: Does serum folate level matter?
This study aims to investigate the possible effects of folate on the functional outcomes of patients with post-stroke hemiplegia. Between January 2012 and March 2015, a total of 80 patients with hemiplegia (51 males, 29 females; mean age 60.3±13.2 years; range, 19 to 95 years) at least three months post-stroke were included in this study. Serum folate levels (ng/mL), Brunnstrom recovery stages of the lower limb, and Functional Ambulation Category (FAC) scores were recorded. All patients were divided into two groups according to the Brunnstrom stages (Category I; Stage 1-3 and Category II; Stage 4-6) and FAC scores (non-functional ambulatory; score 0-2, functional ambulatory; score 3-5). The mean serum folate level of the patient group was 6.8±2.8 ng/mL. Serum folate levels differed significantly between the Brunnstrom categories with lower levels in patients with poorer motor recovery (Category I) (p=0.047). Folate levels were also lower in non- functional ambulatory patients than those in patients with functional ambulation (p=0.046). Lower serum folate levels are associated with poorer ambulation potential and impaired lower limb motor recovery in patients with post-stroke hemiplegia.


EEG-based Brain-Computer Interfaces for people with Disorders of Consciousness: Features and applications. A systematic review.
Disorders of Consciousness (DoC) are clinical conditions following a severe acquired brain injury (ABI) characterized by absent or reduced awareness, known as coma, Vegetative State (VS)/Unresponsive Wakefulness Syndrome (VS/UWS), and Minimally Conscious State (MCS). Misdiagnosis rate between VS/UWS and MCS is attested around 40% due to the clinical and behavioral fluctuations of the patients during bedside consciousness assessments. Given the large body of evidence that some patients with DoC possess "covert" awareness, revealed by neuroimaging and neurophysiological techniques, they are candidates for intervention with brain-computer interfaces (BCIs). The aims of the present work are (i) to describe the characteristics of BCI systems based on electroencephalography (EEG) performed on DoC patients, in terms of control signals adopted to control the system, characteristics of the paradigm implemented, classification algorithms and applications (ii) to evaluate the performance of DoC patients with BCI. The search was conducted on Pubmed, Web of Science, Scopus and Google Scholar. The PRISMA guidelines were followed in order to collect papers published in english, testing a BCI and including at least one DoC patient. Among the 527 papers identified with the first run of the search, 27 papers were included in the systematic review. Characteristics of the sample of participants, behavioral assessment, control signals employed to control the BCI, the classification algorithms, the characteristics of the paradigm, the applications and performance of BCI were the data extracted from the study. Control signals employed to operate the BCI were: P300 (N = 19), P300 and Steady-State Visual Evoked Potentials (SSVEP; hybrid system, N = 4), sensorimotor rhythms (SMRs; N = 5) and brain rhythms elicited by an emotional task (N = 1), while assessment, communication, prognosis, and rehabilitation were the possible applications of BCI in DoC patients. Despite the BCI is a promising tool in the management of DoC patients, supporting diagnosis and prognosis evaluation, results are still preliminary, and no definitive conclusions may be drawn; even though neurophysiological methods, such as BCI, are more sensitive to covert cognition, it is suggested to adopt a multimodal approach and a repeated assessment strategy.


Validating module network learning algorithms using simulated data.
In recent years, several authors have used probabilistic graphical models to learn expression modules and their regulatory programs from gene expression data. Despite the demonstrated success of such algorithms in uncovering biologically relevant regulatory relations, further developments in the area are hampered by a lack of tools to compare the performance of alternative module network learning strategies. Here, we demonstrate the use of the synthetic data generator SynTReN for the purpose of testing and comparing module network learning algorithms. We introduce a software package for learning module networks, called LeMoNe, which incorporates a novel strategy for learning regulatory programs. Novelties include the use of a bottom-up Bayesian hierarchical clustering to construct the regulatory programs, and the use of a conditional entropy measure to assign regulators to the regulation program nodes. Using SynTReN data, we test the performance of LeMoNe in a completely controlled situation and assess the effect of the methodological changes we made with respect to an existing software package, namely Genomica. Additionally, we assess the effect of various parameters, such as the size of the data set and the amount of noise, on the inference performance. Overall, application of Genomica and LeMoNe to simulated data sets gave comparable results. However, LeMoNe offers some advantages, one of them being that the learning process is considerably faster for larger data sets. Additionally, we show that the location of the regulators in the LeMoNe regulation programs and their conditional entropy may be used to prioritize regulators for functional validation, and that the combination of the bottom-up clustering strategy with the conditional entropy-based assignment of regulators improves the handling of missing or hidden regulators. We show that data simulators such as SynTReN are very well suited for the purpose of developing, testing and improving module network algorithms. We used SynTReN data to develop and test an alternative module network learning strategy, which is incorporated in the software package LeMoNe, and we provide evidence that this alternative strategy has several advantages with respect to existing methods.


Acculturation and self-rated health among Arctic indigenous peoples: a population-based cross-sectional study.
Acculturation is for indigenous peoples related to the process of colonisation over centuries as well as the on-going social transition experienced in the Arctic today. Changing living conditions and lifestyle affect health in numerous ways in Arctic indigenous populations. Self-rated health (SRH) is a relevant variable in primary health care and in general public health assessments and monitoring. Exploring the relationship between acculturation and SRH in indigenous populations having experienced great societal and cultural change is thus of great importance. The principal method in the Survey of Living Conditions in the Arctic (SLiCA) was standardised face-to-face interviews using a questionnaire. Very high overall participation rates of 83% were obtained in Greenland and Alaska, whilst a more conventional rate of 57% was achieved in Norway. Acculturation was conceptualised as certain traditional subsistence activities being of lesser importance for people's ethnic identity, and poorer spoken indigenous language ability (SILA). Acculturation was included in six separate gender- and country-specific ordinal logistic regressions to assess qualitative effects on SRH. Multivariable analyses showed that acculturation significantly predicted poorer SRH in Greenland. An increased subsistence score gave an OR of 2.32 (P<0.001) for reporting poorer SRH among Greenlandic men, while an increased score for Greenlandic women generated an OR of 1.71 (P=0.01). Poorer SILA generated an OR of 1.59 in men (p=0.03). In Alaska, no evidence of acculturation effects was detected among Iñupiaq men. Among Iñupiaq women, an increased subsistence score represented an increased odds of 73% (p=0.026) for reporting poorer SRH. No significant effects of acculturation on SRH were detected in Norway. This study shows that aggregate acculturation is a strong risk factor for poorer SRH among the Kalaallit of Greenland and female Iñupiat of Alaska, but our cross-sectional study design does not allow any conclusion with regard to causality. Limitations with regard to wording, categorisations, assumed cultural differences in the conceptualisation of SRH, and confounding effects of health care use, SES and discrimination, make it difficult to appropriately assess how strong this effect is though.


Knocking down mitochondrial iron transporter (MIT) reprograms primary and secondary metabolism in rice plants.
Iron (Fe) is an essential micronutrient for plant growth and development, and its reduced bioavailability strongly impairs mitochondrial functionality. In this work, the metabolic adjustment in the rice (Oryza sativa) mitochondrial Fe transporter knockdown mutant (mit-2) was analysed. Biochemical characterization of purified mitochondria from rice roots showed alteration in the respiratory chain of mit-2 compared with wild-type (WT) plants. In particular, proteins belonging to the type II alternative NAD(P)H dehydrogenases accumulated strongly in mit-2 plants, indicating that alternative pathways were activated to keep the respiratory chain working. Additionally, large-scale changes in the transcriptome and metabolome were observed in mit-2 rice plants. In particular, a strong alteration (up-/down-regulation) in the expression of genes encoding enzymes of both primary and secondary metabolism was found in mutant plants. This was reflected by changes in the metabolic profiles in both roots and shoots of mit-2 plants. Significant alterations in the levels of amino acids belonging to the aspartic acid-related pathways (aspartic acid, lysine, and threonine in roots, and aspartic acid and ornithine in shoots) were found that are strictly connected to the Krebs cycle. Furthermore, some metabolites (e.g. pyruvic acid, fumaric acid, ornithine, and oligosaccharides of the raffinose family) accumulated only in the shoot of mit-2 plants, indicating possible hypoxic responses. These findings suggest that the induction of local Fe deficiency in the mitochondrial compartment of mit-2 plants differentially affects the transcript as well as the metabolic profiles in root and shoot tissues.


Patient Engagement as Measured by Inpatient Portal Use: Methodology for Log File Analysis.
Inpatient portals (IPPs) have the potential to increase patient engagement and satisfaction with their health care. An IPP provides a hospitalized patient with similar functions to those found in outpatient portals, including the ability to view vital signs, laboratory results, and medication information; schedule appointments; and communicate with their providers. However, IPPs may offer additional functions such as meal planning, real-time messaging with the inpatient care team, daily schedules, and access to educational materials relevant to their specific condition. In practice, IPPs have been developed as websites and tablet apps, with hospitals providing the required technology as a component of care during the patient's stay. This study aimed to describe how inpatients are using IPPs at the first academic medical center to implement a system-wide IPP and document the challenges and choices associated with this analytic process. We analyzed the audit log files of IPP users hospitalized between January 2014 and January 2016. Data regarding the date/time and duration of interactions with each of the MyChart Bedside modules (eg, view lab results or medications and patient schedule) and activities (eg, messaging the provider and viewing educational videos) were captured as part of the system audit logs. The development of a construct to describe the length of time associated with a single coherent use of the tool-which we call a session-provides a foundational unit of analysis. We defined frequency as the number of sessions a patient has during a given provision day. We defined comprehensiveness in terms of the percentage of functions that an individual uses during a given provision day. The analytic process presented data challenges such as length of stay and tablet-provisioning factors. This study presents data visualizations to illustrate a series of data-cleaning issues. In the presence of these robust approaches to data cleaning, we present the baseline usage patterns associated with our patient panel. In addition to frequency and comprehensiveness, we present considerations of median data to mitigate the effect of outliers. Although other studies have published usage data associated with IPPs, most have not explicated the challenges and choices associated with the analytic approach deployed within each study. Our intent in this study was to be somewhat exhaustive in this area, in part, because replicability requires common metrics. Our hope is that future researchers in this area will avail themselves of these perspectives to engage in critical assessment moving forward.


Dietary-related and physical activity-related predictors of obesity in children: a 2-year prospective study.
This observational study examined cross-sectional and 24-month longitudinal associations of physical activity and dietary behaviors with change in BMI and percent body fat among children aged 6–9 years old. Data were from the control group (n = 271; 48% Latino) of a community-based childhood obesity prevention program. Assessments were conducted at baseline and at 24 months and included height and weight, bioelectrical impedance–derived percent body fat, and 10 physical activity and dietary behaviors measured via parent report of their child. Cross-sectional analysis of variances (ANOVA) (normal weight, overweight, obese) and longitudinal mixed-effects linear regression models were used to investigate the relation of each physical activity and dietary behavior with BMI and percent body fat. At baseline, obese children engaged in less physical activity and more sedentary behavior than normal-weight children (p < 0.05). Increased physical activity (p < 0.01) and number of breakfasts eaten with family (p < 0.05) were associated with decreased BMI z-score and percent body fat. Decreased sedentary behavior and sugar-sweetened beverage consumption were associated with decreased percent body fat (p < 0.05) but not BMI. In this cohort of 271 children, increased physical activity and eating breakfast with family and reduced screen-based sedentary behaviors and sugar-sweetened beverage consumption were associated with more favorable trends in adiposity. Therefore, attention to these behaviors may be of particular importance. Results also suggest that future studies should include percent body fat as an outcome for a more precise assessment of the association of behavior with adiposity.


Use of fluorescent-based amplified fragment length polymorphism to resolve phylogenetic relationships of Colchicum species from Turkey.
The study of phylogenetic relationships between 14 Colchicum taxa spread throughout Turkey was performed using a fluorescent-based amplified fragment length polymorphism (AFLP) technique. Five primer pair combinations were used in AFLP reactions. The data set was analyzed statistically using the NTSYS 2.1 software, and the neighbor-joining and maximum parsimony methods were implemented to generate phylogenetic trees. These analyses clustered the samples into 3 main clades. Both the neighbor-joining and maximum parsimony analyses resulted in similar topologies. Furthermore, supporting the phylogenetic trees, a similar grouping of 14 taxa was generated by principal component analysis. The AFLP analysis with 5 primer combinations was carried out to assess 14 taxa. Fragment sizes ranged from 54 to 462 bp in length for each primer combination. The average was 166 fragments per primer pair, primer B2 generated the highest number of bands (200), and primer B3 produced the lowest number of bands (112). A total of 834 polymorphic bands were scored. The cophenetic correlation coefficient between the data matrix and the cophenetic matrix for AFLP data was 0.72. Based on this molecular data, we concluded that the genetic diversity among these Turkish accessions is relatively high.


Haplotype matching in large cohorts using the Li and Stephens model.
The Li and Stephens model, which approximates the coalescent describing the pattern of variation in a population, underpins a range of key tools and results in genetics. Although highly efficient compared to the coalescent, standard implementations of this model still cannot deal with the very large reference cohorts that are starting to become available, and practical implementations use heuristics to achieve reasonable runtimes. Here I describe a new, exact algorithm ('fastLS') that implements the Li and Stephens model and achieves runtimes independent of the size of the reference cohort. Key to achieving this runtime is the use of the Burrows-Wheeler transform, allowing the algorithm to efficiently identify partial haplotype matches across a cohort. I show that the proposed data structure is very similar to, and generalizes, Durbin's positional Burrows-Wheeler transform.


Hypoxia is present in murine atherosclerotic plaques and has multiple adverse effects on macrophage lipid metabolism.
Human atherosclerotic plaques contain large numbers of cells deprived of O(2). In murine atherosclerosis, because the plaques are small, it is controversial whether hypoxia can occur. To examine if murine plaques contain hypoxic cells, and whether hypoxia regulates changes in cellular lipid metabolism and gene expression in macrophages. Aortic plaques from apolipoprotein-E-deficient mice were immunopositive for hypoxia-inducible transcription factor (HIF-1α) and some of its downstream targets. Murine J774 macrophages rendered hypoxic demonstrated significant increases in cellular sterol and triglycerides. The increase in sterol content in hypoxic macrophages correlated with elevated 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase activity and mRNA levels. In addition, when macrophages were incubated with cholesterol complexes, hypoxic cells accumulated 120% more cholesterol, predominately in the free form. Cholesterol-efflux assays showed that hypoxia significantly decreased efflux mediated by ATP-binding cassette subfamily A member 1 (ABCA1), whose sub cellular localization was altered in both J774 and primary macrophages. Furthermore, in vivo expression patterns of selected genes from cells in hypoxic regions of murine plaques were similar to those from J774 and primary macrophages incubated in hypoxia. The hypoxia-induced accumulation of sterol and decreased cholesterol efflux was substantially reversed in vitro by reducing the expression of the hypoxia-inducible transcription factor, HIF-1α. Hypoxic regions are present in murine plaques. Hypoxic macrophages have increased sterol content due to the induction of sterol synthesis and the suppression of cholesterol efflux, effects that are in part mediated by HIF-1α.


Mixture Effects of 3 Mechanistically Different Steroidogenic Disruptors (Prochloraz, Genistein, and Ketoconazole) in the H295R Cell Assay.
Mixture effects of 3 model endocrine disruptors, prochloraz, ketoconazole, and genistein, on steroidogenesis were tested in the adrenocortical H295R cell line. Seven key steroid hormones (pregnenolone, progesterone, dehydroepiandrosterone, androstenedione, testosterone, estrone, and 17β-estradiol) were analyzed using gas chromatography and tandem mass spectrometry (GC-MS/MS) to investigate the effects throughout the steroidogenic pathway. Current modeling approaches often rely on models assuming compounds acting independently and that the individual effects in some way can be summarized to predict a mixture effect. In H295R cells with an intact steroidogenic pathway, such assumptions may not be feasible. The purpose of this study was therefore to evaluate whether effects of a mixture with differing modes of action followed or deviated from additivity (concentration addition) and whether the H295R cell line was suitable for evaluating mixture toxicity of endocrine disruptors with different modes of action. The compounds were chosen because they interfere with steroidogenesis in different ways. They all individually decrease the concentrations of the main sex steroids downstream but exert different effects upstream in the steroidogenic pathway. Throughout the study, we observed lowest observed effect concentrations of mixtures at levels 2 to 10 times higher than the predicted EC(50), strongly indicating antagonistic effects. The results demonstrate that chemical analysis combined with the H295R cell assay is a useful tool also for studying how mixtures of endocrine disruptors with differing modes of action interfere with the steroidogenic pathway and that existing models like concentration addition are insufficient in such cases. Furthermore, for end points where compounds exert opposite effects, no relevant models are available.


Blood and islet phenotypes indicate immunological heterogeneity in type 1 diabetes.
Studies in type 1 diabetes indicate potential disease heterogeneity, notably in the rate of β-cell loss, responsiveness to immunotherapies, and, in limited studies, islet pathology. We sought evidence for different immunological phenotypes using two approaches. First, we defined blood autoimmune response phenotypes by combinatorial, multiparameter analysis of autoantibodies and autoreactive T-cell responses in 33 children/adolescents with newly diagnosed diabetes. Multidimensional cluster analysis showed two equal-sized patient agglomerations characterized by proinflammatory (interferon-γ-positive, multiautoantibody-positive) and partially regulated (interleukin-10-positive, pauci-autoantibody-positive) responses. Multiautoantibody-positive nondiabetic siblings at high risk of disease progression showed similar clustering. Additionally, pancreas samples obtained post mortem from a separate cohort of 21 children/adolescents with recently diagnosed type 1 diabetes were examined immunohistologically. This revealed two distinct types of insulitic lesions distinguishable by the degree of cellular infiltrate and presence of B cells that we termed "hyper-immune CD20Hi" and "pauci-immune CD20Lo." Of note, subjects had only one infiltration phenotype and were partitioned by this into two equal-sized groups that differed significantly by age at diagnosis, with hyper-immune CD20Hi subjects being 5 years younger. These data indicate potentially related islet and blood autoimmune response phenotypes that coincide with and precede disease. We conclude that different immunopathological processes (endotypes) may underlie type 1 diabetes, carrying important implications for treatment and prevention strategies.


Recommendations on Fecal Immunochemical Testing to Screen for Colorectal Neoplasia: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer.
The use of the fecal occult blood test (FOBT) for colorectal cancer (CRC) screening is supported by randomized trials demonstrating effectiveness in cancer prevention and widely recommended by guidelines for this purpose. The fecal immunochemical test (FIT), as a direct measure of human hemoglobin in stool has a number of advantages relative to conventional FOBT and is increasingly used relative to that test. This review summarizes current evidence for FIT in colorectal neoplasia detection and the comparative effectiveness of FIT relative to other commonly used CRC screening modalities. Based on evidence, guidance statements on FIT application were developed and quality metrics for program implementation proposed.


Nicotinamide N-methyltransferase overexpression is associated with Akt phosphorylation and indicates worse prognosis in patients with nasopharyngeal carcinoma.
Nicotinamide N-methyltransferase (NNMT) is overexpressed in many human cancers and is associated with poor prognosis. Akt (also known as protein kinase B) is an evolutionarily conserved serine/threonine kinase, serving as a downstream effector of the phosphatidylinositol 3-kinase signaling pathway. NNMT was first identified as a differentially upregulated gene in nasopharyngeal cancer tissues through data mining from published transcriptomic databases. Since no prior study has attempted to evaluate the clinical significance of NNMT or phosphorylated Akt (pAkt) expression in nasopharyngeal cancer, this study explores their expression in a large cohort of patients with nasopharyngeal cancer. The study included 124 nasopharyngeal cancer patients who were free of distant metastasis at initial diagnosis. Pathological slides were reviewed and clinical findings collected. We evaluated the expression of NNMT and pAkt immunohistochemically, stratified them into two groups (high and low expression) and examined the correlation with disease-specific survival (DSS), metastasis-free survival (MeFS), local recurrence-free survival (LRFS), and various clinicopathological factors. NNMT expression was significantly positively associated with pAkt expression. The high expression of both markers was significantly associated with an increment of tumor stage (p = 0.006 and p = 0.006, respectively). High expression of NNMT correlated significantly with a more aggressive clinical course and a significantly shorter DSS. Furthermore, NNMT expression and pAkt expression were strongly predictive of MeFS (p = 0.008; p = 0.0063) and LRFS (p = 0.005; p = 0.0125). In multivariate analysis, high expression of NNMT remained as a robust prognosticator for both end points evaluated. It independently portended inferior DSS (p = 0.02, HR = 1.976) and worse MeFS (p = 0.029, HR = 2.022) after tumor stage (p = 0.033, HR = 2.150; p = 0.028, HR = 2.942, for DSS and LRFS, respectively). We found NNMT positively correlated with pAkt expression and was independent adverse prognosticators of patient survival. NNMT therefore has potential utility as an indicator for prognosis, predicting treatment response to chemotherapy or radiation therapy, and even as a therapeutic target in the future.


Diversity and adaptation in rodent copulatory behavior.
Copulatory patterns of muroid rodents provide an ideal locus for comparative behavioral research. Such patterns are highly stereotyped within and between the individuals of a given species, variable across species, readily elicited in the laboratory, and of great biological significance. Detailed behavioral comparisons of a broad range of muroid species have revealed extensive behavioral diversity that was not anticipated from research confined to laboratory rats. Various muroid species display postejaculatory compulations without sperm transfer, locking, thrusting, and other behavioral patterns. This behavioral diversity appears not to be the result of a simple linear pattern of evolutionary history. Rather, patterns appear to have evolved repeatedly in response to particular selective pressures acting on particular species. While understanding of the adaptive significance of these behavioral patterns remains rudimentary, important beginnings have been made.


The temporal and spatial development of vascularity in a healing displaced fracture.
Underlying vascular disease is an important pathophysiologic factor shared among many co-morbid conditions associated with poor fracture healing, such as diabetes, obesity, and age. Determining the temporal and spatial patterns of revascularization following a fracture is essential for devising therapeutic strategies to augment this critical reparative process. Seminal studies conducted in the last century have investigated the pattern of vascularity in bone following a fracture. The consensus model culminating from these classical studies depicts a combination of angiogenesis emanating from both the intact intramedullary and periosteal vasculature. Subsequent to the plethora of experimental fracture angiography in the early to mid-20th century there has been a paucity of reports describing the pattern of revascularization of a healing fracture. Consequently the classical model of revascularization of a displaced fracture has remained largely unchanged. Here, we have overcome the limitations of animal fracture models performed in the above described classical studies by combining novel techniques of bone angiography and a reproducible murine femur fracture model to demonstrate for the first time the complete temporal and spatial pattern of revascularization in a displaced/stabilized fracture. These studies were designed specifically to i) validate the classical model of fracture revascularization of a displaced/stabilized fracture, ii) assess the association between intramedullary and periosteal angiogenesis and iii) elucidate the expression of VEGF/VEGF-R in relation to the classical model. From the studies, in conjunction with classic studies of angiogenesis during fracture repair, we propose a novel model (see abstract graphic) that defines the process of bone revascularization subsequent to injury to guide future approaches to enhance fracture healing. This new model validates and advances the classical model by providing evidence that during the process of revascularization of a displaced fracture 1) periosteal angiogenesis occurs in direct communication with the remaining intact intramedullary vasculature as a result of a vascular shunt and 2) vascular union occurs through an intricate interplay between intramembranous and endochondral VEGF/VEGF-R mediated angiogenesis.


Ocean acidification reduces coral recruitment by disrupting intimate larval-algal settlement interactions.
Ecology Letters (2012) 15: 338-346 ABSTRACT: Successful recruitment in shallow reef ecosystems often involves specific cues that connect planktonic invertebrate larvae with particular crustose coralline algae (CCA) during settlement. While ocean acidification (OA) can reduce larval settlement and the abundance of CCA, the impact of OA on the interactions between planktonic larvae and their preferred settlement substrate are unknown. Here, we demonstrate that CO2 concentrations (800 and 1300 μatm) predicted to occur by the end of this century significantly reduce coral (Acropora millepora) settlement and CCA cover by ≥ 45%. The CCA important for inducing coral settlement (Titanoderma spp., Hydrolithon spp.) were the most deleteriously affected by OA. Surprisingly, the only preferred settlement substrate (Titanoderma) in the experimental controls was avoided by coral larvae as pCO2 increased, and other substrata selected. Our results suggest OA may reduce coral population recovery by reducing coral settlement rates, disrupting larval settlement behaviour, and reducing the availability of the most desirable coralline algal species for successful coral recruitment.


Exploiting members of the BAHD acyltransferase family to synthesize multiple hydroxycinnamate and benzoate conjugates in yeast.
BAHD acyltransferases, named after the first four biochemically characterized enzymes of the group, are plant-specific enzymes that catalyze the transfer of coenzyme A-activated donors onto various acceptor molecules. They are responsible for the synthesis in plants of a myriad of secondary metabolites, some of which are beneficial for humans either as therapeutics or as specialty chemicals such as flavors and fragrances. The production of pharmaceutical, nutraceutical and commodity chemicals using engineered microbes is an alternative, green route to energy-intensive chemical syntheses that consume petroleum-based precursors. However, identification of appropriate enzymes and validation of their functional expression in heterologous hosts is a prerequisite for the design and implementation of metabolic pathways in microbes for the synthesis of such target chemicals. For the synthesis of valuable metabolites in the yeast Saccharomyces cerevisiae, we selected BAHD acyltransferases based on their preferred donor and acceptor substrates. In particular, BAHDs that use hydroxycinnamoyl-CoAs and/or benzoyl-CoA as donors were targeted because a large number of molecules beneficial to humans belong to this family of hydroxycinnamate and benzoate conjugates. The selected BAHD coding sequences were synthesized and cloned individually on a vector containing the Arabidopsis gene At4CL5, which encodes a promiscuous 4-coumarate:CoA ligase active on hydroxycinnamates and benzoates. The various S. cerevisiae strains obtained for co-expression of At4CL5 with the different BAHDs effectively produced a wide array of valuable hydroxycinnamate and benzoate conjugates upon addition of adequate combinations of donors and acceptor molecules. In particular, we report here for the first time the production in yeast of rosmarinic acid and its derivatives, quinate hydroxycinnamate esters such as chlorogenic acid, and glycerol hydroxycinnamate esters. Similarly, we achieved for the first time the microbial production of polyamine hydroxycinnamate amides; monolignol, malate and fatty alcohol hydroxycinnamate esters; tropane alkaloids; and benzoate/caffeate alcohol esters. In some instances, the additional expression of Flavobacterium johnsoniae tyrosine ammonia-lyase (FjTAL) allowed the synthesis of p-coumarate conjugates and eliminated the need to supplement the culture media with 4-hydroxycinnamate. We demonstrate in this study the effectiveness of expressing members of the plant BAHD acyltransferase family in yeast for the synthesis of numerous valuable hydroxycinnamate and benzoate conjugates.


Fluorescence imaging of nanoscale domains in polymer blends using stochastic optical reconstruction microscopy (STORM).
High-resolution fluorescence techniques that provide spatial resolution below the diffraction limit are attractive new methods for structural characterization of nanostructured materials. For the first time, we apply the super-resolution technique of Stochastic Optical Reconstruction Microscopy (STORM), to characterize nanoscale structures within polymer blend films. The STORM technique involves temporally separating the fluorescence signals from individual labeled polymers, allowing their positions to be localized with high accuracy, yielding a high-resolution composite image of the material. Here, we describe the application of the technique to demixed blend films of polystyrene (PS) and poly(methyl methacrylate) (PMMA), and find that STORM provides comparable structural characteristics as those determined by Atomic Force Microscopy (AFM) and scanning electron microscopy (SEM), but with all of the advantages of a far-field optical technique.


Sucrose-induced translational repression of plant bZIP-type transcription factors.
Sugars as signalling molecules exert control on the transcription of many plant genes. Sugar signals also alter mRNA and protein stability. Increased sucrose concentrations specifically repress translation of the S-class basic region leucine zipper (bZIP) type transcription factor AtbZIP11/ATB2. This sucrose-induced repression of translation (SIRT) depends on translation of a highly conserved upstream open reading frame (uORF) in the 5' UTR of the gene. This conserved uORF is exclusively encoded in 5' UTRs of several plant S-class bZIP transcription factors. Arabidopsis homologues of ATB2/AtbZIP11, which harbour the conserved uORF, also show SIRT. Therefore, SIRT emerges as a general sucrose translational control mechanism of a group of transcription factors. SIRT might be part of a sucrose-specific signalling pathway, controlling expression of plant bZIP transcription factor genes.


[Hormones, autocrine and paracrine regulators of tumor growth in osteosarcoma].
The data on 300 patients, aged 14-56, treated at the Center's Clinic have been evaluated. They include findings on androgen metabolism, basal level of secretion of sex steroid hormones in blood serum and their receptors in tumor, blood concentrations of sex steroids, binding globulin and pituitary hormones, arachidonic acid metabolism, expression of epidermal growth factor and its receptors and ligands, soluble Fas-antigen, vascular endothelial growth factor as well as calmodulin and cAMP levels in sarcoma. New trends of research in pathogenetic methods of treatment of osteosarcomas used in practice of oncology have been identified. Among them are androgen metabolism regulation, correction of the cyclooxygenase pathway of arachidonic acid metabolism, expression of epidermal growth factor and its ligands and neoangiogenesis in tumor.


Blue again: perturbational effects of antidepressants suggest monoaminergic homeostasis in major depression.
Some evolutionary researchers have argued that current diagnostic criteria for major depressive disorder (MDD) may not accurately distinguish true instances of disorder from a normal, adaptive stress response. According to disorder advocates, neurochemicals like the monoamine neurotransmitters (serotonin, norepinephrine, and dopamine) are dysregulated in major depression. Monoamines are normally under homeostatic control, so the monoamine disorder hypothesis implies a breakdown in homeostatic mechanisms. In contrast, adaptationist hypotheses propose that homeostatic mechanisms are properly functioning in most patients meeting current criteria for MDD. If the homeostatic mechanisms regulating monoamines are functioning properly in these patients, then oppositional tolerance should develop with prolonged antidepressant medication (ADM) therapy. Oppositional tolerance refers to the forces that develop when a homeostatic mechanism has been subject to prolonged pharmacological perturbation that attempt to bring the system back to equilibrium. When pharmacological intervention is discontinued, the oppositional forces cause monoamine levels to overshoot their equilibrium levels. Since depressive symptoms are under monoaminergic control, this overshoot should cause a resurgence of depressive symptoms that is proportional to the perturbational effect of the ADM. We test this prediction by conducting a meta-analysis of ADM discontinuation studies. We find that the risk of relapse after ADM discontinuation is positively associated with the degree to which ADMs enhance serotonin and norepinephrine in prefrontal cortex, after controlling for covariates. The results are consistent with oppositional tolerance, and provide no evidence of malfunction in the monoaminergic regulatory mechanisms in patients meeting current diagnostic criteria for MDD. We discuss the evolutionary and clinical implications of our findings.


Mechanical impact and articular cartilage.
Mechanical impact forces on articular cartilage can cause substantial damage. Car accidents, falls, and sports injuries have a tremendous effect on the U.S. and world populations, both in terms of economic and quality of life costs. While the effects of impact forces are known to be damaging, tolerance levels of cartilage to these forces and the mechanobiologic sequelae are still mostly unknown. Impact studies can be difficult to compare to each other due to the complex array of mechanical factors that are involved in a single impact. Previous work includes mathematical models, acute effects of impact, and in vivo and explant models of impact. These experiments have found that articular cartilage has a threshold above which impact forces are damaging, though this threshold is likely dependent on many factors, both genetic and environmental. This type of damage has been shown to vary according to the severity of the impact, from leaving the articular cartilage surface intact to fracture of the subchondral bone. Some studies have initiated investigations into ways to ameliorate the injurious response to impact, which may allow some patients to avoid the ensuing cartilage degeneration and osteoarthritis. Much work remains to be performed in understanding the genetic and biochemical response to impact. The goal of this research is to eventually decrease the incidence of posttraumatic arthritis and possibly even delay primary osteoarthritis, which can be achieved by using a robust testing design that includes morphological, biomechanical, quantitative biochemical, and genetic characterization of a model system for articular cartilage impact. This model system can then be used to test treatments to prevent degenerative changes in articular cartilage.


Validation of the Whooley questions for antenatal depression and anxiety among low-income women in urban South Africa.
In South Africa, approximately 40% of women suffer from depression during pregnancy. Although perinatal depression and anxiety are significant public health problems impacting maternal and infant morbidity and mortality, no routine mental health screening programmes exist in the country. A practical, accurate screening tool is needed to identify cases in these busy, resource-scarce settings. A convenience sample of 145 women between 22 and 28 weeks gestation was recruited from Rahima Moosa Hospital antenatal clinic in Johannesburg. All women completed a biographical interview, the Edinburgh Postnatal Depression Scale (EPDS), the Whooley questions and a structured clinical interview. The results demonstrate the sensitivity and specificity of the Whooley questions and the EPDS in identifying depression, anxiety and stress disorders of varying severity. The importance of personal, social and cultural context in influencing the content and expression of these common perinatal conditions was also identified. The validity of the Whooley questions in the context of urban South Africa, and the importance of ensuring clinical interviews to supplement any screening tools, is emphasised.


Clinical study of Duogastrone in the treatment of duodenal ulcers.
This study confirms the preliminary reports that Duogastrone effectively controls the symptoms of duodenal ulceration and appears to hasten healing. In a double-blind trial, 14 patients with active duodenal ulcers were treated with Duogastrone capsules, one four times daily, half-an-hour before meals, while a comparable control group of 14 patients was treated similarly with a placebo containing magnesium trisilicate. Treatment continued for 12 weeks with clinical assessments fortnightly and a radiological assessment at the start and at the end of treatment. Only one of the 14 patients receiving Duogastrone did not respond. The remaining 13 showed marked clinical improvement with complete relief of pain and ceased to require supplementary antacids. Radiological evidence of healing or marked improvement was seen in eight of the 14 patients. None of the patients in the control group showed any marked improvement either of pain or tenderness and no changes were detectable by radiology. Patients in this group showed no reduction in their demand for supplementary antacids to relieve symptoms. No significant side effects were encountered. It is concluded that Duogastrone accelerates the healing of duodenal ulcer in ambulant patients and affords a much greater and more rapid relief of symptoms than does magnesium trisilicate.


A general implementation of TMLE for longitudinal data applied to causal inference in survival analysis.
In many randomized controlled trials the outcome of interest is a time to event, and one measures on each subject baseline covariates and time-dependent covariates until the subject either drops-out, the time to event is observed, or the end of study is reached. The goal of such a study is to assess the causal effect of the treatment on the survival curve. We present a targeted maximum likelihood estimator of the causal effect of treatment on survival fully utilizing all the available covariate information, resulting in a double robust locally efficient substitution estimator that will be consistent and asymptotically linear if either the censoring mechanism is consistently estimated, or if the maximum likelihood based estimator is already consistent. In particular, under the independent censoring assumption assumed by current methods, this TMLE is always consistent and asymptotically linear so that it provides valid confidence intervals and tests. Furthermore, we show that when both the censoring mechanism and the initial maximum likelihood based estimator are mis-specified, and thus inconsistent, the TMLE exhibits stability when inverse probability weighted estimators and double robust estimating equation based methods break down The TMLE is used to analyze the Tshepo study, a study designed to evaluate the efficacy, tolerability, and development of drug resistance of six different first-line antiretroviral therapies. Most importantly this paper presents a general algorithm that may be used to create targeted maximum likelihood estimators of a large class of parameters of interest for general longitudinal data structures.


Improving the dietary intake of under nourished older people in residential care homes using an energy-enriching food approach: a cluster randomised controlled study.
To examine whether the nutritional status of aged undernourished residents in care could be improved through dietary modification to increase energy intake but not portion size. A 12-week cluster randomised controlled trial was carried out in 21 residential care homes. Participants comprised undernourished residents with a body mass index (BMI) <18.5 kg m(-2) . All menus were analysed to evaluate nutrient provision. Energy and macronutrient intakes of undernourished residents were estimated using 3-day weighed food intake diaries. Those resident in homes randomised to intervention had their usual meals enriched with energy-dense foods to a maximum of +1673 kJ day(-1) . Of 445 residents screened, 41 (9%) had a BMI <18.5 kg m(-2) and entered the study. Despite adequate food provision, energy and macronutrient intakes were below UK dietary reference values. Mean (SEM) energy intake increased [+556 (372) kJ, P = 0.154] in residents allocated to intervention but fell in those residents in 'control homes' receiving usual care [-151 (351) kJ, P = 0.676]. Weight change [+1.3 (0.53) kg, P = 0.03] was seen in intervention residents but not in controls [-0.2 (1.5) kg, P = 0.536]. Between-group differences for changes in weight and energy intake were not significant (P = 0.08 and 0.20, respectively). Six residents allocated to the intervention increased their BMI >18.5 kg m(-2) (P = 0.018). Achieving weight gain in frail older people is difficult. These results suggest that enriching food could help address undernutrition and slow chronic weight loss. Interventions of a longer duration are needed to confirm or exclude the value of food enrichment.


Effects of adjunctive N-acetylcysteine on depressive symptoms: Modulation by baseline high-sensitivity C-reactive protein.
Outcomes in a RCTs of 12 weeks of theclinical efficacy of N-acetylcysteine (NAC) as an adjunctive treatment on depression and anxiety symptoms and its effects on high-sensitivity C-reactive protein (hs-CRP) levels. A wide array of measures were made. The 17-item version of the Hamilton Depression Rating Scale (HDRS17); the Hamilton Anxiety Rating Scale (HAM-A); Sheehan Disability Scale; Quality of Life; Clinical Global Impression (CGI); anthropometrics measures; and vital signs and biochemical laboratory. There were no significant differences among the groups regarding demographic, clinical features, use of medication, metabolic syndrome and comorbidities. From baseline to week 12, individuals receiving NAC, versus placebo, had a statistically significant reduction in depressive symptoms on HDRS17 (p < 0.01) and anxiety symptoms on HAM-A (p = 0.04), but only for individuals with levels of hs-CRP > 3 mg/L at baseline. Individuals receiving NAC with baseline levels of hs-CRP > 3 mg/L, had more significant reduction in uric acid levels compared to individuals with baseline levels of hs-CRP ≤ 3 mg/L on week 12. Participants receiving placebogained significantly more weight during the 12 weeks for baseline levels of hs-CRP ≤ 3 mg/L and hs-CRP > 3 mg/L, and individuals receiving NAC in both groups did not have significant weight change during the 12 weeks. No individuals were withdrawn from the study because of adverse event. NAC group exhibited significantly greater reduction on hs-CRP levels than placebo group from baseline to week 12. clinicaltrials.gov Identifier; NCT02252341.


Seven surprises in the TCR-centred regulation of immune responsiveness in an autoimmune system.
Self-reactivity is potentially so devastating to the organism that a variety of regulatory devices have evolved to control it. One broadly used strategy is that employing the processed T cell receptor (TCR) as a target for TCR-specific regulatory cells. In several autoimmune models, feedback regulation employing both CD4+ and CD8+ T cells of TCR specificity can be shown to occur and to account for remission from the transient disease state, or for its prevention. We will focus here on the experimental autoimmune encephalomyelitis (EAE) model in the B10.PL (H-2u) mouse. In this model, the acetylated 1-9 N-terminal antigenic determinant from myelin basic protein (MBP) induces a transient paralytic disease owing to the activation of self-directed, high-affinity, CD4+ T cells. Although the response is multiclonal, a particularly aggressive member of this repertoire, bearing a Vbeta8.2,Jbeta2.7 receptor, which we have termed a 'driver clone', appears to be largely responsible for the disease process. A CD4+ T cell directed against a TCR determinant in the framework region of the Vbeta chain, and a CD8+ T cell directed against an upstream, distinct framework determinant, both of which are necessary for regulation, bring about a reversal of the disease process. To accomplish this, there must be a Th1 milieu during the induction of regulation, which is provided in part by the CD4+ regulatory cells themselves. To act as a target, the Vbeta8.2 MBP-reactive T cell must be activated, and the Th1 driver clone(s) is down-regulated via apoptotic killing, leaving a group of Th2, MBP-specific clones of weak affinity, which themselves may help in perpetuating long-term regulation. Similar results are also found in the collagen arthritis and NOD diabetes models.


Truncated Conjugate Gradient: An Optimal Strategy for the Analytical Evaluation of the Many-Body Polarization Energy and Forces in Molecular Simulations.
We introduce a new class of methods, denoted as Truncated Conjugate Gradient(TCG), to solve the many-body polarization energy and its associated forces in molecular simulations (i.e. molecular dynamics (MD) and Monte Carlo). The method consists in a fixed number of Conjugate Gradient (CG) iterations. TCG approaches provide a scalable solution to the polarization problem at a user-chosen cost and a corresponding optimal accuracy. The optimality of the CG-method guarantees that the number of the required matrix-vector products are reduced to a minimum compared to other iterative methods. This family of methods is non-empirical, fully adaptive, and provides analytical gradients, avoiding therefore any energy drift in MD as compared to popular iterative solvers. Besides speed, one great advantage of this class of approximate methods is that their accuracy is systematically improvable. Indeed, as the CG-method is a Krylov subspace method, the associated error is monotonically reduced at each iteration. On top of that, two improvements can be proposed at virtually no cost: (i) the use of preconditioners can be employed, which leads to the Truncated Preconditioned Conjugate Gradient (TPCG); (ii) since the residual of the final step of the CG-method is available, one additional Picard fixed point iteration ("peek"), equivalent to one step of Jacobi Over Relaxation (JOR) with relaxation parameter ω, can be made at almost no cost. This method is denoted by TCG-n(ω). Black-box adaptive methods to find good choices of ω are provided and discussed. Results show that TPCG-3(ω) is converged to high accuracy (a few kcal/mol) for various types of systems including proteins and highly charged systems at the fixed cost of four matrix-vector products: three CG iterations plus the initial CG descent direction. Alternatively, T(P)CG-2(ω) provides robust results at a reduced cost (three matrix-vector products) and offers new perspectives for long polarizable MD as a production algorithm. The T(P)CG-1(ω) level provides less accurate solutions for inhomogeneous systems, but its applicability to well-conditioned problems such as water is remarkable, with only two matrix-vector product evaluations.


DNA Base Excision Repair: The Achilles' Heel of Tumour Cells and their Microenvironment?
Our current understanding of cancer suggests that every tumour has individual features. Approaches to cancer treatment require thorough comprehension of the mechanisms triggering genomic instability and protecting cancer cells from therapeutic treatments. Base excision repair (BER) is a frontline DNA repair system that is responsible for maintaining genome integrity. The BER pathway prevents the occurrence of disease, including cancer, by constantly repairing DNA base lesions and DNA single strand breaks caused by endogenous and exogenous mutagens. BER is an important DNA repair system for cancer cell survival, as it can affect both chemoand radio-resistance of tumours. Variations in BER capacity are likely responsible for a number of cases of sporadic cancer and may also modulate cancer sensitivity and resistance to therapeutic treatments. For these reasons, it is broadly accepted that targeting BER enzymes might be a promising approach to personalised anti-cancer therapy. However, recent advances in both treatment strategies and the comprehension of cancer development call for a better understanding of the consequences of BER inhibition. Indeed, the impact on both the tumour microenvironment and healthy tissues is still unclear. This review will summarise the current status of the approaches exploiting BER targeting, describing the most promising small molecule inhibitors and synthetic lethality strategies, as well as potential limitations of these approaches.


Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures.
Genetic variants identified by genome-wide association studies explain only a modest proportion of heritability, suggesting that meaningful associations lie 'hidden' below current thresholds. Here, we integrate information from association studies with epigenomic maps to demonstrate that enhancers significantly overlap known loci associated with the cardiac QT interval and QRS duration. We apply functional criteria to identify loci associated with QT interval that do not meet genome-wide significance and are missed by existing studies. We demonstrate that these 'sub-threshold' signals represent novel loci, and that epigenomic maps are effective at discriminating true biological signals from noise. We experimentally validate the molecular, gene-regulatory, cellular and organismal phenotypes of these sub-threshold loci, demonstrating that most sub-threshold loci have regulatory consequences and that genetic perturbation of nearby genes causes cardiac phenotypes in mouse. Our work provides a general approach for improving the detection of novel loci associated with complex human traits.


Minocycline restores sAPPα levels and reduces the late histopathological consequences of traumatic brain injury in mice.
Traumatic brain injury (TBI) induces both focal and diffuse lesions that are concurrently responsible for the ensuing morbidity and mortality and for which no established treatment is available. It has been recently reported that an endogenous neuroprotector, the soluble form α of the amyloid precursor protein (sAPPα), exerts neuroprotective effects following TBI. However, the emergent post-traumatic neuroinflammatory environment compromises sAPPα production and may promote neuronal degeneration and consequent brain atrophy. Hence, the aim of this study was to examine the effects of the anti-inflammatory drug minocycline on sAPPα levels, as well as on long-term histological consequences post-TBI. The weight-drop model was used to induce TBI in mice. Minocycline or its vehicle were administered three times: at 5 min (90 mg/kg, i.p.) and at 3 and 9 h (45 mg/kg, i.p.) post-TBI. The levels of sAPPα, the extent of brain atrophy, and reactive gliosis were evaluated by ELISA, cresyl violet, and immunolabeling of GFAP and CD11b, respectively. Our results revealed a post-TBI sAPPα decrease that was significantly attenuated by minocycline. Additionally, corpus callosum and striatal atrophy, ventriculomegaly, astrogliosis, and microglial activation were observed at 3 months post-TBI. All the above consequences were significantly reduced by minocycline. In conclusion, inhibition of the acute phase of post-TBI neuroinflammation was associated with the sparing of sAPPα and the protection of brain tissue in the long-term, emphasizing the potential role of minocycline as an effective treatment for TBI.


Subsistence and the evolution of religion.
We present a cross-cultural analysis showing that the presence of an active or moral High God in societies varies generally along a continuum from lesser to greater technological complexity and subsistence productivity. Foragers are least likely to have High Gods. Horticulturalists and agriculturalists are more likely. Pastoralists are most likely, though they are less easily positioned along the productivity continuum. We suggest that belief in moral High Gods was fostered by emerging leaders in societies dependent on resources that were difficult to manage and defend without group cooperation. These leaders used the concept of a supernatural moral enforcer to manipulate others into cooperating, which resulted in greater productivity. Reproductive success would accrue most to such leaders, but the average reproductive success of all individuals in the society would also increase with greater productivity. Supernatural enforcement of moral codes maintained social cohesion and allowed for further population growth, giving one society an advantage in competition with others.


Single cell migration profiling on a microenvironmentally tunable hydrogel microstructure device that enables stem cell potency evaluation.
Cell migration is a key function in a myriad of physiological events and disease conditions. Efficient, quick and descriptive profiling of migration behaviour in response to different treatments or conditions is highly desirable in a series of applications, ranging from fundamental studies of the migration mechanism to drug discovery and cell therapy. This investigation applied the use of methacrylamide gelatin (GelMA) to microfabricate migration lanes based on GelMA hydrogel with encapsulated migration stimuli and structural stability under culture medium conditions, providing the possibility of tailoring the microenvironment during cell-based assays. The actual device provides 3D topography, cell localization and a few step protocol, allowing the quick evaluation and quantification of individual migrated distances of a cell sample by an ImageJ plugin for automated microscopy processing. The detailed profiling of migration behaviour given by the new device has demonstrated a broader assay sensitivity compared to other migration assays and higher versatility to study cell migration in different settings of applications. In this study, parametric information extracted from the migration profiling was successfully used to develop predictive models of immunosuppressive cell function that could be applied as a potency test for mesenchymal stem cells.


Chiral plasmonic DNA nanostructures with switchable circular dichroism.
Circular dichroism spectra of naturally occurring molecules and also of synthetic chiral arrangements of plasmonic particles often exhibit characteristic bisignate shapes. Such spectra consist of peaks next to dips (or vice versa) and result from the superposition of signals originating from many individual chiral objects oriented randomly in solution. Here we show that by first aligning and then toggling the orientation of DNA-origami-scaffolded nanoparticle helices attached to a substrate, we are able to reversibly switch the optical response between two distinct circular dichroism spectra corresponding to either perpendicular or parallel helix orientation with respect to the light beam. The observed directional circular dichroism of our switchable plasmonic material is in good agreement with predictions based on dipole approximation theory. Such dynamic metamaterials introduce functionality into soft matter-based optical devices and may enable novel data storage schemes or signal modulators.


Surgical repair of cartilage defects of the patella.
The structure and biomechanical forces on the patellar joint challenges researchers to define an ideal method for resurfacing the patellar cartilage. The articular surface of the patella presents variability between individuals, and has various minor articulations that bear partial or total compressive, shear, and combined forces during movement. Surgical techniques for the repair of patellar cartilage defects have evolved from cumulative advances in basic science and technology. Such surgeries include the techniques that promote either fibrocartilage formation or hyalinelike cartilage formation. Techniques promoting the formation of fibrocartilage yield short-term solutions because fibrocartilage lacks the durability and the mechanical properties of articular hyaline cartilage. Currently, there is no ideal method for the repair of patellar cartilage defects; all methods are considered experimental. Additional controlled and randomized clinical studies with large series of patients and long-term followup are required.


Tunable multi-wavelength SOA based linear cavity dual-output port fiber laser using Lyot-Sagnac loop mirror.
We propose and demonstrate a simple dual port tunable from the C- to the L-band multi-wavelength fiber laser based on a SOA designed for C-band operation and fiber loop mirrors. The laser incorporates a polarization maintaining fiber in one of the fiber loop mirrors and delivers multi-wavelength operation at 9 laser lines with a wavelength separation of ~2.8 nm at room temperature. We show that the number of lasing wavelengths increases with the increase of the bias current of the SOA. Wavelength tunability from the C to L-band is achieved by exploiting the gain compression of a SOA. Stable multi-wavelength operation is achieved at room temperature without temperature compensation techniques, with measured power and the wavelength stability within < ±0.5 dB and ±0.1 nm, respectively.


Senses of care: Embodying inequality and sustaining personhood in the home care of older adults in Chicago.
In paid home care-one of the fastest-growing occupations in the United States-low-wage workers help elderly clients living in their own homes remain independent by embodying and then reproducing the elders' lifetimes of experience. Exploring the bodily and moral consequences of everyday home care practices in Chicago, I show that in this context, sustaining independent personhood depended on and intensified unequal social relations. To sustain clients' personhood, workers developed a deeply embodied empathy that enabled them to imagine and re-create the elders' social and sensory worlds. Home care practices involved unreciprocated circulations of bodily experience that led some workers to feel that the needs and preferences of their clients took priority over their own comfort and well-being. Care workers' bodily practices thus became one way in which social hierarchies shaped individual subjectivities and came to seem morally legitimate.


Selective tuning for contrast in macaque area V4.
Visually responsive neurons typically exhibit a monotonic-saturating increase of firing with luminance contrast of the stimulus and are able to adapt to the current spatiotemporal context by shifting their selectivity, therefore being perfectly suited for optimal contrast encoding and discrimination. Here we report the first evidence of the existence of neurons showing selective tuning for contrast in area V4d of the behaving macaque (Macaca mulatta), i.e., narrow bandpass filter neurons with peak activity encompassing the whole range of visible contrasts and pronounced attenuation at contrasts higher than the peak. Crucially, we found that contrast tuning emerges after a considerable delay from stimulus onset, likely reflecting the contribution of inhibitory mechanisms. Selective tuning for luminance contrast might support multiple functions, including contrast identification and the attentive selection of low contrast stimuli.


Solvent-assisted lipid self-assembly at hydrophilic surfaces: factors influencing the formation of supported membranes.
As a simple and efficient technique, the solvent-assisted lipid bilayer (SALB) formation method offers a versatile approach to fabricating a planar lipid bilayer on solid supports. Corresponding mechanistic aspects and the role of various governing parameters remain, however, to be better understood. Herein, we first scrutinized the effect of lipid concentration (0.01 to 5 mg/mL) and solvent type (isopropanol, n-propanol, or ethanol) on SALB formation on silicon oxide in order to identify optimal conditions for this process. The obtained fluid-phase lipid layers on silicon oxide were investigated by using the quartz crystal microbalance with dissipation monitoring, epifluorescence microscopy, and atomic force microscopy. The experimental results indicate that, in alcohol, lipid attachment to the substrate is reversible and reaches equilibrium in accordance with the bulk lipid concentration. During the solvent-exchange step, the water fraction increases and the deposited lipids are converted into planar bilayer fragments, along with the concurrent adsorption and rupture of micelles within an optimal lipid concentration range. In addition, fluid-phase lipid bilayers were successfully formed on other substrates (e.g., chrome, indium tin oxide, and titanium oxide) that are largely intractable to conventional methods (e.g., vesicle fusion). Moreover, gel-phase lipid bilayers were fabricated as well. Depending on the phase state of the lipid bilayer during fabrication, the corresponding adlayer mass varied by approximately 20% between the fluid- and gel-phase states in a manner which is consistent with the molecular packing of lipids in the two arrangements. Taken together, our findings help to explain the mechanistic details of SALB formation, optimize the corresponding procedure, and demonstrate the general utility for fabricating gel- and fluid-phase planar lipid bilayers.


Deconstruction of the Ras switching cycle through saturation mutagenesis.
Ras proteins are highly conserved signaling molecules that exhibit regulated, nucleotide-dependent switching between active and inactive states. The high conservation of Ras requires mechanistic explanation, especially given the general mutational tolerance of proteins. Here, we use deep mutational scanning, biochemical analysis and molecular simulations to understand constraints on Ras sequence. Ras exhibits global sensitivity to mutation when regulated by a GTPase activating protein and a nucleotide exchange factor. Removing the regulators shifts the distribution of mutational effects to be largely neutral, and reveals hotspots of activating mutations in residues that restrain Ras dynamics and promote the inactive state. Evolutionary analysis, combined with structural and mutational data, argue that Ras has co-evolved with its regulators in the vertebrate lineage. Overall, our results show that sequence conservation in Ras depends strongly on the biochemical network in which it operates, providing a framework for understanding the origin of global selection pressures on proteins.


Characterization of cell subpopulations expressing progenitor cell markers in porcine cardiac valves.
Valvular interstitial cells (VICs) are the main population of cells found in cardiac valves. These resident fibroblastic cells play important roles in maintaining proper valve function, and their dysregulation has been linked to disease progression in humans. Despite the critical functions of VICs, their cellular composition is still not well defined for humans and other mammals. Given the limited availability of healthy human valves and the similarity in valve structure and function between humans and pigs, we characterized porcine VICs (pVICs) based on expression of cell surface proteins and sorted a specific subpopulation of pVICs to study its functions. We found that small percentages of pVICs express the progenitor cell markers ABCG2 (~5%), NG2 (~5%) or SSEA-4 (~7%), whereas another subpopulation (~5%) expresses OB-CDH, a type of cadherin expressed by myofibroblasts or osteo-progenitors. pVICs isolated from either aortic or pulmonary valves express most of these protein markers at similar levels. Interestingly, OB-CDH, NG2 and SSEA-4 all label distinct valvular subpopulations relative to each other; however, NG2 and ABCG2 are co-expressed in the same cells. ABCG2(+) cells were further characterized and found to deposit more calcified matrix than ABCG2(-) cells upon osteogenic induction, suggesting that they may be involved in the development of osteogenic VICs during valve pathology. Cell profiling based on flow cytometry and functional studies with sorted primary cells provide not only new and quantitative information about the cellular composition of porcine cardiac valves, but also contribute to our understanding of how a subpopulation of valvular cells (ABCG2(+) cells) may participate in tissue repair and disease progression.


Stumbling over iron rice bowls: the quest for integrated continuing care for the elderly.
Chappell and Hollander "offer an evidence-based policy prescription to meet the challenges …[of] an aging society." The fallacies of apocalyptic demography are briskly dismissed; their message is that decades of solid evidence support the critical importance of an integrated system of continuing care for the chronically ill elderly, both health services and home support. But the paper loses focus with discussions of "ageism", the compression of morbidity, and healthy communities. The authors might have explored why (as they argue) public policy has retreated from their prescription in recent decades. That prescription would require either a re-allocation of resources (incomes) away from politically well-entrenched interests, or simply more money. Neither appears currently promising.


Effects of vandetanib on adenoma formation in a dextran sodium sulphate enhanced Apc(MIN/+) mouse model.
The Apc(MIN/+) mouse is a well-characterised model of intestinal tumourigenesis in which animals develop macroscopically detectable adenomas. However, most of the adenomas are formed in the small intestine and resolution of events in the colon, the most relevant site for human disease, is limited. Inducing colitis with dextran sodium sulphate (DSS) can selectively enhance the development of lesions in the colon. We demonstrated that a DSS pre-treatment is well tolerated and effective at inducing colon adenomas in an Apc(MIN/+) mouse model. We then investigated the effect of inhibiting vascular endothelial growth factor (VEGFR)- and epidermal growth factor receptor (EGFR)-dependent signalling pathways on the development of adenomas induced in DSS-pretreated (DSS/Apc(MIN/+)) or non-DSS-pretreated (Apc(MIN/+)) mice using vandetanib (ZD6474), a potent and selective inhibitor of VEGFR and EGFR tyrosine kinase activity. Eight-week old Apc(MIN/+) mice were given either drinking water or 1.8% DSS and then vandetanib (ZD6474) (50 mg/kg/day) or vehicle by oral gavage for 28 days and sacrificed 24 h after the last dose and assessed for adenoma formation in the intestines. DSS pre-treatment was well tolerated and significantly enhanced formation of adenomas in the colon of control Apc(MIN/+) mice. Vandetanib treatment significantly reduced adenoma formation in the small intestine by 68% (P=0.001) and the colon by 77% (from 13.8 to 3.1, P=0.01) of DSS-pretreated Apc(MIN/+) mice. In the Apc(MIN/+) group, vandetanib also reduced the mean number of adenomas in the small intestine by 76% (P<0.001) and in the colon by 60% (from 3.9 to 1.5, P=0.1). DSS-pre-treatment increased the resolution of the model, allowing us to confirm statistically significant effects of vandetanib on the development and growth of colon adenomas in the Apc(MIN/+) mouse. Moreover these preclinical data provide a rationale for studying the effects of vandetanib in early stages of intestinal cancer in the clinic.


Crizotinib inhibits metabolic inactivation of gemcitabine in c-Met-driven pancreatic carcinoma.
Pancreatic ductal adenocarcinoma (PDAC) remains a major unsolved health problem. Most drugs that pass preclinical tests fail in these patients, emphasizing the need of improved preclinical models to test novel anticancer strategies. Here, we developed four orthotopic mouse models using primary human PDAC cells genetically engineered to express firefly- and Gaussia luciferase, simplifying the ability to monitor tumor growth and metastasis longitudinally in individual animals with MRI and high-frequency ultrasound. In these models, we conducted detailed histopathologic and immunohistochemical analyses on paraffin-embedded pancreatic tissues and metastatic lesions in liver, lungs, and lymph nodes. Genetic characteristics were compared with the originator tumor and primary tumor cells using array-based comparative genomic hybridization, using frozen specimens obtained by laser microdissection. Notably, the orthotopic human xenografts in these models recapitulated the phenotype of human PDACs, including hypovascular and hypoxic areas. Pursuing genomic and immunohistochemical evidence revealed an increased copy number and overexpression of c-Met in one of the models; we examined the preclinical efficacy of c-Met inhibitors in vitro and in vivo. In particular, we found that crizotinib decreased tumor dimension, prolonged survival, and increased blood and tissue concentrations of gemcitabine, synergizing with a cytidine deaminase-mediated mechanism of action. Together, these more readily imaged orthotopic PDAC models displayed genetic, histopathologic, and metastatic features similar to their human tumors of origin. Moreover, their use pointed to c-Met as a candidate therapeutic target in PDAC and highlighted crizotinib and gemcitabine as a synergistic combination of drugs warranting clinical evaluation for PDAC treatment.


Dynamic optical properties of collagen-based tissue during ArF excimer laser ablation.
Various attenuation mechanisms affecting the absorption of ArF excimer laser light in collagenous tissues have been studied. Temporal distortion of the laser pulse reflected from the cornea has been observed over a range of incident pulse fluences including the ablation threshold. Reflected pulse shortening begins near the ablation threshold and advances with increasing fluence. The measurement of laser light scattered 30 degrees off specular axis from collagen gel targets indicates that the reflected-pulse distortion is partially a result of scattering. Collagen film transmission studies show an increase in 193-nm light transmission in ablation conditions. These nonlinear attenuation mechanisms may impact significantly on the photoablation process.


Beneficial Effects of Apple Vinegar on Hyperglycemia and Hyperlipidemia in Hypercaloric-Fed Rats.
The main objective of this study is to determine the effects of apple vinegar on the metabolic changes caused by hypercaloric diet in Wistar rats. Apple vinegar was first analyzed to find out the total acidity, the polyphenolic and flavonoid contents, the total antioxidant capacity, and the free radical scavenging activity. In vivo study on adult male and female Wistar rats was conducted by administering a drink containing either 10% D-glucose or water (control) for five weeks. Apple vinegar is administered daily by gavage (2 mL/kg) to rats fed D-glucose for 5 weeks. The results showed that the polyphenolic content in apple vinegar was 148.02 ± 10.16 mg GAE/100 mL, flavonoid content was 22.93 ± 0.73 QE/100 mL, and total antioxidant capacity was 13.4 ± 0.47 mg AAE/100 mL. Free radical IC50 apple vinegar scavenging activity (DPPH) was 0.74 ± 0.154 μL/mL. The total acidity was (3.24 ± 0.02 mg AAE/100 mL). The treatment during five weeks with D-glucose leads to increased plasma glucose, lipid profile, hepatic enzyme levels, urea, and creatinine. Simultaneous treatment with apple vinegar improves the parameters studied. These results clearly show that the daily consumption of vinegar can reduce the rise in blood sugar and lipid profile induced by hypercaloric diet in rats. Therefore, the use of apple vinegar would have a very beneficial effect in the prevention of metabolic disorders caused by high-caloric food.


Mapping invasive species risks with stochastic models: a cross-border United States-Canada application for Sirex noctilio fabricius.
Nonindigenous species have caused significant impacts to North American forests despite past and present international phytosanitary efforts. Though broadly acknowledged, the risks of pest invasions are difficult to quantify as they involve interactions between many factors that operate across a range of spatial and temporal scales: the transmission of invading organisms via various pathways, their spread and establishment in new environments. Our study presents a stochastic simulation approach to quantify these risks and associated uncertainties through time in a unified fashion. We outline this approach with an example of a forest pest recently detected in North America, Sirex noctilio Fabricius. We simulate new potential entries of S. noctilio as a stochastic process, based on recent volumes of marine shipments of commodities from countries where S. noctilio is established, as well as the broad dynamics of foreign marine imports. The results are then linked with a spatial model that simulates the spread of S. noctilio within the geographical distribution of its hosts (pines) while incorporating existing knowledge about its behavior in North American landscapes. Through replications, this approach yields a spatial representation of S. noctilio risks and uncertainties in a single integrated product. The approach should also be appealing to decisionmakers, since it accounts for projected flows of commodities that may serve as conduits for pest entry. Our 30-year forecasts indicate high establishment probability in Ontario, Quebec, and the northeastern United States, but further southward expansion of S. noctilio is uncertain, ultimately depending on the impact of recent international treatment standards for wood packing materials.


Do we need zinc to think?
Chelatable Zn(2+), which is found in the synaptic vesicles of certain glutamatergic neurons in several regions of the forebrain, is released during neuronal activity. Zn(2+) exhibits numerous effects on ligand-gated and voltage-dependent ion channels, and released Zn(2+) is therefore likely able to modulate synaptic transmission. The physiologically relevant actions of Zn(2+), however, have remained unclear. Recent research exploiting improved Zn(2+)-sensitive optical probes has suggested some intriguing effects for synaptically released Zn(2+), including heterosynaptic regulation of N-methyl-D-aspartate (NMDA) receptor function, and a novel role as a trans-synaptic second messenger that may enter postsynaptic neurons to modulate various signal transduction pathways.


Pemetrexed Monotherapy as Salvage Treatment in Patients with Metastatic Colorectal Cancer Refractory to Standard Chemotherapy: A Phase II Single-arm Prospective Trial.
Background: We designed a single-arm, open-label phase II study to determine the efficacy and toxicity of pemetrexed monotherapy with vitamin supplementation in patients with refractory colorectal cancer (CRC) that failed to respond to standard treatments including 5-fluorouracil, oxaliplatin, and irinotecan with or without biologic agents. Methods: Patients were treated with pemetrexed 500 mg/m2 on day 1 every 3 weeks, with folic acid and vitamin B12 supplementation. Treatment was continued until disease progression or intolerable toxicity. Between June 2016 and October 2016, 24 patients were enrolled in this study. Results: One patient withdrew consent, leaving a total of 23 patients for evaluation. The median age of the patients was 54.0 years (range, 23.0 to 67.0), and the median ECOG performance status was 1 (1-2). The median number of previous systemic chemotherapies was 3 (range, 2 to 5). There was no patient with complete response (CR) or partial response (PR). However, stable disease was observed in 10 patients (43.4%) and maintained more than 6 months in 7 of 10 patients. The median progression-free survival was 1.6 months (95% CI, 1.1-2.0) and the median overall survival was 9.8 months (95% CI, 5.9-13.6). Grade 3 treatment-related adverse events occurred in one patient with elevated liver enzymes and hematologic adverse event of grade 2 anemia was observed in one patient. There were no cases of dose reduction or treatment-related deaths and all toxicities were manageable. Conclusions: Pemetrexed monotherapy showed moderate disease control and acceptable toxicity profile as salvage therapy for refractory CRC.


Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models.
Autosomal dominant forms of familial Alzheimer's disease (FAD) are associated with increased production of the amyloid beta peptide, Abeta42, which is derived from the amyloid protein precursor (APP). In FAD, as well as in sporadic forms of the illness, Abeta peptides accumulate abnormally in the brain in the form of amyloid plaques. Here, we show that overexpression of FAD(717V-->F)-mutant human APP in neurons of transgenic mice decreases the density of presynaptic terminals and neurons well before these mice develop amyloid plaques. Electrophysiological recordings from the hippocampus revealed prominent deficits in synaptic transmission, which also preceded amyloid deposition by several months. Although in young mice, functional and structural neuronal deficits were of similar magnitude, functional deficits became predominant with advancing age. Increased Abeta production in the context of decreased overall APP expression, achieved by addition of the Swedish FAD mutation to the APP transgene in a second line of mice, further increased synaptic transmission deficits in young APP mice without plaques. These results suggest a neurotoxic effect of Abeta that is independent of plaque formation.


Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway.
Keap1 is a BTB-Kelch protein that functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex. Keap1 targets its substrate, the Nrf2 transcription factor, for ubiquitination and subsequent degradation by the 26 S proteasome. Inhibition of Keap1-dependent ubiquitination of Nrf2 increases steady-state levels of Nrf2 and enables activation of cytoprotective Nrf2-dependent genes. In this report, we demonstrate that Keap1 and three other BTB-Kelch proteins, including GAN1, ENC1, and Sarcosin, are ubiquitinated by a Cul3-dependent complex. Ubiquitination of Keap1 is markedly increased in cells exposed to quinone-induced oxidative stress, occurs in parallel with inhibition of Keap1-dependent ubiquitination of Nrf2, and results in decreased steady-state levels of Keap1, particularly in cells that are unable to synthesize glutathione. Degradation of Keap1 is independent of the 26 S proteasome, because inhibitors of the 26 S proteasome do not prevent loss of Keap1 following exposure of cells to quinone-induced oxidative stress. Our results suggest that a switch from substrate to substrate adaptor ubiquitination is a critical regulatory step that controls steady-state levels of both BTB-Kelch substrate adaptor proteins and their cognate substrates.


Poly(ADP-ribosyl)ation associated changes in CTCF-chromatin binding and gene expression in breast cells.
CTCF is an evolutionarily conserved and ubiquitously expressed architectural protein regulating a plethora of cellular functions via different molecular mechanisms. CTCF can undergo a number of post-translational modifications which change its properties and functions. One such modifications linked to cancer is poly(ADP-ribosyl)ation (PARylation). The highly PARylated CTCF form has an apparent molecular mass of 180 kDa (referred to as CTCF180), which can be distinguished from hypo- and non-PARylated CTCF with the apparent molecular mass of 130 kDa (referred to as CTCF130). The existing data accumulated so far have been mainly related to CTCF130. However, the properties of CTCF180 are not well understood despite its abundance in a number of primary tissues. In this study we performed ChIP-seq and RNA-seq analyses in human breast cells 226LDM, which display predominantly CTCF130 when proliferating, but CTCF180 upon cell cycle arrest. We observed that in the arrested cells the majority of sites lost CTCF, whereas fewer sites gained CTCF or remain bound (i.e. common sites). The classical CTCF binding motif was found in the lost and common, but not in the gained sites. The changes in CTCF occupancies in the lost and common sites were associated with increased chromatin densities and altered expression from the neighboring genes. Based on these results we propose a model integrating the CTCF130/180 transition with CTCF-DNA binding and gene expression changes. This study also issues an important cautionary note concerning the design and interpretation of any experiments using cells and tissues where CTCF180 may be present.


A cognitive model of tinnitus and hyperacusis; a clinical tool for patient information, appeasement and assessment.
Tinnitus and hyperacusis are both aggravating audiological symptoms. Their underlying mechanisms are not fully understood, but the pathophysiology involves a central mechanism rather than a peripheral one. There is no curative treatment. A review of the available research on tinnitus and auditory processing was conducted to connect insights gained from different approaches to the subject; this resulted in the development of a holistic view of both conditions. In this view, the chronic course of the symptoms is pathological and attributed to a stress-related lack of habituation. This article adds to the literature on tinnitus and hyperacusis by presenting a schematic model of the cognitive mechanisms which can be used clinically in patient information sessions which are geared towards provide reassurance and encouraging the development of coping skills. In cooperation with the patient, the model can also help in the identification of underlying pathology. Future aims of study are suggested, elaborating on the role of tinnitus and hyperacusis in normal auditory processing and on the value of insight. Finally, parallels are drawn between tinnitus and positive symptom syndromes in neuropsychiatry and some of its modern visions on their treatment.


Clinical experience with and analytical confirmation of "bath salts" and "legal highs" (synthetic cathinones) in the United States.
Recently, there has been a worldwide rise in the popularity and abuse of synthetic cathinones. In 2009 and 2010, a significant rise in the abuse of a new group of synthetic cathinones was reported in Western Europe. In 2010, the rapid emergence of a new drug of abuse, referred to as bath salts or "legal high," occurred in the USA. The growing number of cases along with the alarming severity of the effects caused by the abuse of these substances prompted significant concern from both healthcare providers and legal authorities. We report the experience of the first 8 months of two regional poison centers after the emergence of a new group of substances of abuse. This was a retrospective case series of patients reported to two poison centers with exposures to bath salts. Additionally, 15 "product samples" were obtained and analyzed for drug content using GC/MS. There were 236 patients of which 184 (78%) were male. Age range was 16-64 years (mean 29 years, SD 9.4). All cases were intentional abuse. There were 37 separate "brand" names identified. Clinical effects were primarily neurological and cardiovascular and included: agitation (n = 194), combative behavior (n = 134), tachycardia (n = 132), hallucinations (n = 94), paranoia (n = 86), confusion (n = 83), chest pain (n = 40), myoclonus (n = 45), hypertension (n = 41), mydriasis (n = 31), CPK elevations (n = 22), hypokalemia (n = 10), and blurred vision (n = 7). Severe medical outcomes included death (n = 1), major (n = 8), and moderate (n = 130). Therapies included benzodiazepines (n = 125), antipsychotics (n = 47), and propofol (n = 10). Primary dispositions of patients were: 116 (49%) treated and released from ED, 50 (21%) admitted to critical care, 29 (12%) admitted to psych, and 28 (12%) lost to follow up. Nineteen patients had blood and/or urine analyzed using GC/MS. MDPV was detected in 13 of 17 live patients (range 24-241 ng/mL, mean 58 ng/mL). The four samples with no drug detected, reported last use of bath salts >20 h prior to presentation. Three of five patients had MDPV detected in urine (range 34-1386 ng/mL, mean 856 ng/mL). No mephedrone or methylone was detected in any sample. Quantitative analysis performed on postmortem samples detected MDPV in blood at 170 ng/mL and in urine at 1400 ng/mL. No other synthetic cathinones were detected. This is the first report of MDPV exposures with quantitative blood level confirmation. Clinical effects displayed a sympathomimetic syndrome, including psychotic episodes often requiring sedation, movement disorders, and tachycardia. Within 8 months of their appearance, 16 states had added synthetic cathinones to the controlled substances list as a Schedule I drug. We report the emergence of a new group of substances of abuse in the USA, known as bath salts, with quantitative results in 18 patients. State and federal authorities used timely information from poison centers on the bath salt outbreak during investigations to help track the extent of use and the effects occurring from these new drugs. Close collaboration between state authorities and poison centers enhanced a rapid response, including legislation.


Smoking as a weight-control strategy among adolescent girls and young women: a reconsideration.
Many studies have reported that adolescent girls and young women smoke to control their weight. The majority of these studies are cross-sectional and report on correlational data from quantitative surveys. This article presents data from ethnographic interviews with 60 smokers, interviewed in high school and in follow-up interviews at age 21. Contrary to previous research, this study found little evidence for the sustained use of smoking as a weight-control strategy. In high school, smokers were no more likely than nonsmokers to be trying to lose weight. In the follow-up study, 85 percent of informants replied that they had never smoked as a way to control their weight. One-half of informants at age 21 believed that smoking as a weight-control strategy would be ineffective, while the other one-half had no idea whether it would work or not. Researchers need to exert caution in propagating the idea that smoking is commonly used as a conscious and sustained weight-control strategy among adolescent females and young women.


Near-wall dynamics of concentrated hard-sphere suspensions: comparison of evanescent wave DLS experiments, virial approximation and simulations.
In this article we report on a study of the near-wall dynamics of suspended colloidal hard spheres over a broad range of volume fractions. We present a thorough comparison of experimental data with predictions based on a virial approximation and simulation results. We find that the virial approach describes the experimental data reasonably well up to a volume fraction of ϕ≈ 0.25 which provides us with a fast and non-costly tool for the analysis and prediction of evanescent wave DLS data. Based on this we propose a new method to assess the near-wall self-diffusion at elevated density. Here, we qualitatively confirm earlier results [Michailidou, et al., Phys. Rev. Lett., 2009, 102, 068302], which indicate that many-particle hydrodynamic interactions are diminished by the presence of the wall at increasing volume fractions as compared to bulk dynamics. Beyond this finding we show that this diminishment is different for the particle motion normal and parallel to the wall.


Learning gene functional classifications from multiple data types.
In our attempts to understand cellular function at the molecular level, we must be able to synthesize information from disparate types of genomic data. We consider the problem of inferring gene functional classifications from a heterogeneous data set consisting of DNA microarray expression measurements and phylogenetic profiles from whole-genome sequence comparisons. We demonstrate the application of the support vector machine (SVM) learning algorithm to this functional inference task. Our results suggest the importance of exploiting prior information about the heterogeneity of the data. In particular, we propose an SVM kernel function that is explicitly heterogeneous. In addition, we describe feature scaling methods for further exploiting prior knowledge of heterogeneity by giving each data type different weights.


Distinct physiological effects of β1- and β2-adrenoceptors in mouse ventricular myocytes: insights from a compartmentalized mathematical model.
The β1- and β2-adrenergic signaling systems play different roles in the functioning of cardiac cells. Experimental data show that the activation of the β1-adrenergic signaling system produces significant inotropic, lusitropic, and chronotropic effects in the heart, whereas the effects of the β2-adrenergic signaling system is less apparent. In this paper, a comprehensive compartmentalized experimentally based mathematical model of the combined β1- and β2-adrenergic signaling systems in mouse ventricular myocytes is developed to simulate the experimental findings and make testable predictions of the behavior of the cardiac cells under different physiological conditions. Simulations describe the dynamics of major signaling molecules in different subcellular compartments; kinetics and magnitudes of phosphorylation of ion channels, transporters, and Ca2+ handling proteins; modifications of action potential shape and duration; and [Ca2+]i and [Na+]i dynamics upon stimulation of β1- and β2-adrenergic receptors (β1- and β2-ARs). The model reveals physiological conditions when β2-ARs do not produce significant physiological effects and when their effects can be measured experimentally. Simulations demonstrated that stimulation of β2-ARs with isoproterenol caused a marked increase in the magnitude of the L-type Ca2+ current, [Ca2+]i transient, and phosphorylation of phospholamban only upon additional application of pertussis toxin or inhibition of phosphodiesterases of type 3 and 4. The model also made testable predictions of the changes in magnitudes of [Ca2+]i and [Na+]i fluxes, the rate of decay of [Na+]i concentration upon both combined and separate stimulation of β1- and β2-ARs, and the contribution of phosphorylation of PKA targets to the changes in the action potential and [Ca2+]i transient.