Predictors of subjective recovery from recent-onset psychosis in a developing country: a mixed-methods study.
This study was conducted to: (a) investigate the levels and progress of subjective recovery from recent-onset psychosis; (b) examine its predictive factors and; (c) describe perceived challenges and opportunities affecting recovery. The findings were expected to help inform recovery-oriented psychiatric care in low-income, particularly African, countries. This sequential explanatory mixed-methods study involved 263 service users with recent-onset psychosis from Northwestern Ethiopia. For the quantitative part, a 9-month longitudinal study approach was employed with three time point measurements over 9 months. Predictor variables for subjective recovery from recent-onset psychosis were identified by hierarchical multiple linear regression tests. Following the quantitative survey, individual qualitative interviews were conducted with 19 participants. Interview data were transcribed and thematically analysed. High mean subjective recovery scores were recorded throughout the study (Questionnaire about the Process of Recovery score ranging from 44.17 to 44.65). Quality of life, internalized stigma, disability, hopelessness, satisfaction with social support, and central obesity were significant predictors of subjective recovery across the three time points. Participants' perceived challenges and opportunities affecting their recovery were categorized into four themes. In Ethiopia, a low percentage of individuals with SMIs initiate psychiatric treatment and many discontinue this to attend spiritual healing. In this study, the Ethiopian SMI patients engaged consistently in psychiatric treatment indicated high mean subjective recovery scores. Devising mechanisms to integrate the psychiatric treatment and spiritual healing sectors are suggested. Approaches to improve quality of life, functioning, hope, internalized stigma and provide need-based social support are suggested.


Inertial Sensor-Based Assessment of Central Sensory Integration for Balance After Mild Traumatic Brain Injury.
Optimal balance control requires a complex integration of sensory information from the visual, vestibular, and proprioceptive systems. The goal of this study is to determine if the instrumented modified Clinical Test of Sensory Integration and Balance (mCTSIB) was impaired acutely after mild traumatic brain injury (mTBI) when postural sway under varying sensory conditions was measured with a wearable inertial sensor. Postural sway was assessed in athletes who had sustained a mTBI within the past 2-3 d (n = 38) and control athletes (n = 81). Postural sway was quantified with a wearable inertial sensor (Opal; APDM, Inc.) during four varying sensory conditions of quiet stance: (1) eyes open (EO) firm surface, (2) eyes closed (EC) firm surface, (3) eyes open (EO) foam surface, and (4) eyes closed (EC) foam surface. Sensory reweighting deficits were computed by comparing the postural sway area in eyes closed versus eyes open conditions for firm and foam condition. Postural sway was higher for mTBI compared with the control group during three of the four conditions of instrumented mCTSIB (EO firm, EC firm, and EC foam; p < 0.05). Sensory reweighting deficits were evident for mTBI individuals compared with control group on foam surface (EC firm vs EO firm; p < 0.05) and not on firm surface (EC firm vs EO firm; p = 0.63). The results from this study highlight the importance of detecting postural sway deficits during sensorimotor integration in mild TBI individuals.


Crystal structure at 2.4 A resolution of E. coli serine hydroxymethyltransferase in complex with glycine substrate and 5-formyl tetrahydrofolate.
Serine hydroxymethyltransferase (EC 220.127.116.11), a member of the alpha-class of pyridoxal phosphate enzymes, catalyzes the reversible interconversion of serine and glycine, changing the chemical bonding at the C(alpha)-C(beta) bond of the serine side-chain mediated by the pyridoxal phosphate cofactor. Scission of the C(alpha)-C(beta) bond of serine substrate produces a glycine product and most likely formaldehyde, which reacts without dissociation with tetrahydropteroylglutamate cofactor. Crystal structures of the human and rabbit cytosolic serine hydroxymethyltransferases (SHMT) confirmed their close similarity in tertiary and dimeric subunit structure to each other and to aspartate aminotransferase, the archetypal alpha-class pyridoxal 5'-phosphate enzyme. We describe here the structure at 2.4 A resolution of Escherichia coli serine hydroxymethyltransferase in ternary complex with glycine and 5-formyl tetrahydropteroylglutamate, refined to an R-factor value of 17.4 % and R(free) value of 19.6 %. This structure reveals the interactions of both cofactors and glycine substrate with the enzyme. Comparison with the E. coli aspartate aminotransferase structure shows the distinctions in sequence and structure which define the folate cofactor binding site in serine hydroxymethyltransferase and the differences in orientation of the amino terminal arm, the evolution of which was necessary for elaboration of the folate binding site. Comparison with the unliganded rabbit cytosolic serine hydroxymethyltransferase structure identifies changes in the conformation of the enzyme, similar to those observed in aspartate aminotransferase, that probably accompany the binding of substrate. The tetrameric quaternary structure of liganded E. coli serine hydroxymethyltransferase also differs in symmetry and relative disposition of the functional tight dimers from that of the unliganded eukaryotic enzymes. SHMT tetramers have surface charge distributions which suggest distinctions in folate binding between eukaryotic and E. coli enzymes. The structure of the E. coli ternary complex provides the basis for a thorough investigation of its mechanism through characterization and structure determination of site mutants.


Genome-wide analysis of the Dof transcription factor gene family reveals soybean-specific duplicable and functional characteristics.
The Dof domain protein family is a classic plant-specific zinc-finger transcription factor family involved in a variety of biological processes. There is great diversity in the number of Dof genes in different plants. However, there are only very limited reports on the characterization of Dof transcription factors in soybean (Glycine max). In the present study, 78 putative Dof genes were identified from the whole-genome sequence of soybean. The predicted GmDof genes were non-randomly distributed within and across 19 out of 20 chromosomes and 97.4% (38 pairs) were preferentially retained duplicate paralogous genes located in duplicated regions of the genome. Soybean-specific segmental duplications contributed significantly to the expansion of the soybean Dof gene family. These Dof proteins were phylogenetically clustered into nine distinct subgroups among which the gene structure and motif compositions were considerably conserved. Comparative phylogenetic analysis of these Dof proteins revealed four major groups, similar to those reported for Arabidopsis and rice. Most of the GmDofs showed specific expression patterns based on RNA-seq data analyses. The expression patterns of some duplicate genes were partially redundant while others showed functional diversity, suggesting the occurrence of sub-functionalization during subsequent evolution. Comprehensive expression profile analysis also provided insights into the soybean-specific functional divergence among members of the Dof gene family. Cis-regulatory element analysis of these GmDof genes suggested diverse functions associated with different processes. Taken together, our results provide useful information for the functional characterization of soybean Dof genes by combining phylogenetic analysis with global gene-expression profiling.


Analysis of live cell images: Methods, tools and opportunities.
Advances in optical microscopy, biosensors and cell culturing technologies have transformed live cell imaging. Thanks to these advances live cell imaging plays an increasingly important role in basic biology research as well as at all stages of drug development. Image analysis methods are needed to extract quantitative information from these vast and complex data sets. The aim of this review is to provide an overview of available image analysis methods for live cell imaging, in particular required preprocessing image segmentation, cell tracking and data visualisation methods. The potential opportunities recent advances in machine learning, especially deep learning, and computer vision provide are being discussed. This review includes overview of the different available software packages and toolkits.


Strengthening strategic management approaches to address antimicrobial resistance in global human health: a scoping review.
The development and implementation of national strategic plans is a critical component towards successfully addressing antimicrobial resistance (AMR). This study aimed to review the scope and analytical depth of situation analyses conducted to address AMR in human health to inform the development and implementation of national strategic plans. A systematic search of the literature was conducted to identify all studies since 2000, that have employed a situation analysis to address AMR. The included studies are analysed against frameworks for strategic analysis, primarily the PESTELI (Political, Economic, Sociological, Technological, Ecological, Legislative, Industry) framework, to understand the depth, scope and utility of current published approaches. 10 studies were included in the final review ranging from single country (6) to regional-level multicountry studies (4). 8 studies carried out documentary review, and 3 of these also included stakeholder interviews. 2 studies were based on expert opinion with no data collection. No study employed the PESTELI framework. Most studies (9) included analysis of the political domain and 1 study included 6 domains of the framework. Technological and industry analyses is a notable gap. Facilitators and inhibitors within the political and legislative domains were the most frequently reported. No facilitators were reported in the economic or industry domains but featured inhibiting factors including: lack of ring-fenced funding for surveillance, perverse financial incentives, cost-shifting to patients; joint-stock drug company ownership complicating regulations. The PESTELI framework provides further opportunities to combat AMR using a systematic, strategic management approach, rather than a retrospective view. Future analysis of existing quantitative data with interviews of key strategic and operational stakeholders is needed to provide critical insights about where implementation efforts should be focussed, and also how to build contingency at the strategic level for agile responses to macro-level environmental influences.


Effects of copper nanoparticle exposure on host defense in a murine pulmonary infection model.
Human exposure to nanoparticles (NPs) and environmental bacteria can occur simultaneously. NPs induce inflammatory responses and oxidative stress but may also have immune-suppressive effects, impairing macrophage function and altering epithelial barrier functions. The purpose of this study was to assess the potential pulmonary effects of inhalation and instillation exposure to copper (Cu) NPs using a model of lung inflammation and host defense. We used Klebsiella pneumoniae (K.p.) in a murine lung infection model to determine if pulmonary bacterial clearance is enhanced or impaired by Cu NP exposure. Two different exposure modes were tested: sub-acute inhalation (4 hr/day, 5 d/week for 2 weeks, 3.5 mg/m(3)) and intratracheal instillation (24 hr post-exposure, 3, 35, and 100 μg/mouse). Pulmonary responses were evaluated by lung histopathology plus measurement of differential cell counts, total protein, lactate dehydrogenase (LDH) activity, and inflammatory cytokines in bronchoalveolar lavage (BAL) fluid. Cu NP exposure induced inflammatory responses with increased recruitment of total cells and neutrophils to the lungs as well as increased total protein and LDH activity in BAL fluid. Both inhalation and instillation exposure to Cu NPs significantly decreased the pulmonary clearance of K.p.-exposed mice measured 24 hr after bacterial infection following Cu NP exposure versus sham-exposed mice also challenged with K.p (1.4 × 10(5) bacteria/mouse). Cu NP exposure impaired host defense against bacterial lung infections and induced a dose-dependent decrease in bacterial clearance in which even our lowest dose demonstrated significantly lower clearance than observed in sham-exposed mice. Thus, exposure to Cu NPs may increase the risk of pulmonary infection.


Rat mammary extracellular matrix composition and response to ibuprofen treatment during postpartum involution by differential GeLC-MS/MS analysis.
Breast cancer patients diagnosed within five years following pregnancy have increased metastasis and decreased survival. A hallmark of postpartum biology that may contribute to this poor prognosis is mammary gland involution, involving massive epithelial cell death and dramatic stromal remodeling. Previous studies show pro-tumorigenic properties of extracellular matrix (ECM) isolated from rodent mammary glands undergoing postpartum involution. More recent work demonstrates systemic ibuprofen treatment during involution decreases its tumor-promotional nature. Utilizing a proteomics approach, we identified relative differences in the composition of mammary ECM isolated from nulliparous rats and those undergoing postpartum involution, with and without ibuprofen treatment. GeLC-MS/MS experiments resulted in 20327 peptide identifications that mapped to 884 proteins with a <0.02% false discovery rate. Label-free quantification yielded several ECM differences between nulliparous and involuting glands related to collagen-fiber organization, cell motility and attachment, and cytokine regulation. Increases in known pro-tumorigenic ECM proteins osteopontin, tenascin-C, and laminin-α1 and pro-inflammatory proteins STAT3 and CD68 further identify candidate mediators of breast cancer progression specific to the involution window. With postpartum ibuprofen treatment, decreases in tenascin-C and three laminin chains were revealed. Our data suggest novel ECM mediators of breast cancer progression and demonstrate a protective influence of ibuprofen on mammary ECM composition.


Movement generation with circuits of spiking neurons.
How can complex movements that take hundreds of milliseconds be generated by stereotypical neural microcircuits consisting of spiking neurons with a much faster dynamics? We show that linear readouts from generic neural microcircuit models can be trained to generate basic arm movements. Such movement generation is independent of the arm model used and the type of feedback that the circuit receives. We demonstrate this by considering two different models of a two-jointed arm, a standard model from robotics and a standard model from biology, that each generates different kinds of feedback. Feedback that arrives with biologically realistic delays of 50 to 280 ms turns out to give rise to the best performance. If a feedback with such desirable delay is not available, the neural microcircuit model also achieves good performance if it uses internally generated estimates of such feedback. Existing methods for movement generation in robotics that take the particular dynamics of sensors and actuators into account (embodiment of motor systems) are taken one step further with this approach, which provides methods for also using the embodiment of motion generation circuitry, that is, the inherent dynamics and spatial structure of neural circuits, for the generation of movement.


The Birth and Death of Toxins with Distinct Functions: A Case Study in the Sea Anemone Nematostella.
The cnidarian Nematostella vectensis has become an established lab model, providing unique opportunities for venom evolution research. The Nematostella venom system is multimodal: involving both nematocytes and ectodermal gland cells, which produce a toxin mixture whose composition changes throughout the life cycle. Additionally, their modes of interaction with predators and prey vary between eggs, larvae, and adults, which is likely shaped by the dynamics of the venom system. Nv1 is a major component of adult venom, with activity against arthropods (through specific inhibition of sodium channel inactivation) and fish. Nv1 is encoded by a cluster of at least 12 nearly identical genes that were proposed to be undergoing concerted evolution. Surprisingly, we found that Nematostella venom includes several Nv1 paralogs escaping a pattern of general concerted evolution, despite belonging to the Nv1-like family. Here, we show two of these new toxins, Nv4 and Nv5, are lethal for zebrafish larvae but harmless to arthropods, unlike Nv1. Furthermore, unlike Nv1, the newly identified toxins are expressed in early life stages. Using transgenesis and immunostaining, we demonstrate that Nv4 and Nv5 are localized to ectodermal gland cells in larvae. The evolution of Nv4 and Nv5 can be described either as neofunctionalization or as subfunctionalization. Additionally, the Nv1-like family includes several pseudogenes being an example of nonfunctionalization and venom evolution through birth-and-death mechanism. Our findings reveal the evolutionary history for a toxin radiation and point toward the ecological function of the novel toxins constituting a complex cnidarian venom.


A distinct vesicle population targets membranes and pore complexes to the nuclear envelope in Xenopus eggs.
Extracts from Xenopus eggs capable of nuclear envelope assembly in vitro were fractionated by differential and density gradient centrifugation. Nuclear envelope assembly was found to require soluble components in the cytosol and two distinct particulate fractions, which we have called nuclear envelope precursor fractions A and B (NEP-A and NEP-B). Both NEP-A and NEP-B are sensitive to treatments with trypsin, sodium carbonate, and detergents, but can be distinguished from each other by their sensitivities to high salt and N-ethylmaleimide and by their levels of alpha-glucosidase activity. Vesicles in NEP-B bind to chromatin, whereas those in NEP-A do not. NEP-B may therefore be involved in the targeting of membranes to the surface of the chromatin, whereas NEP-A may provide a pool of vesicles that contributes many of the nuclear envelope membranes. NEP-B may also play a role in the assembly of nuclear pore complexes because the density of nuclear pores in the resulting envelope is dependent on the ratio of NEP-B to NEP-A in the reconstituted extract.


Unilateral unique Lupus tumidus: pathogenetic mystery and diagnostic problem.
Lupus tumidus is a rare immunological disorder whose pathogenesis is not fully understood. Although on the one hand there are some differences in (1) the clinical morphology of lesions, (2) the histopathology picture, as well as in (3) serological profile of lupus tumidus patients at the current moment, the disease is regarded as a subform of chronic cutaneous lupus erythematosus. Differential diagnosis requires the exclusion of many diseases such as Jessner Kanoff lymphocytic infiltration, polymorphous light eruption, and reticular erythematous mucinosis. Differentiation between them is not always easy. The standard treatment regimen of patients with lupus tumidus is based on local and systemic application of corticosteroids, azathioprin, dapsone, mepacrine, chloroquine, and hydroxychloroquine. Modern treatment options include the use of pulsed dye laser, tacrolimus 0.1 % ointment and photophoresis. We present a 42-year-old patient with unilateral atypical form of lupus tumidus who was successfully treated with systematically administration of hydroxychloroquine in combination with sunscreen SPF 50. After a 2-month course of treatment with hydroxychloroquine dosage of 200 mg per day and a break of 3 months between courses, we observed a complete remission.


The long-acting dopamine receptor agonist cabergoline in early Parkinson's disease: final results of a 5-year, double-blind, levodopa-controlled study.
Cabergoline is an ergoline derivative with a very long half-life that allows once-daily administration and the potential for more continuous stimulation of dopaminergic receptors than is possible with other dopamine receptor agonists (DAs). The aim of this study was to evaluate whether the possible advantage resulting from a more sustained dopaminergic effect of cabergoline would translate into delayed onset of motor complications, compared with levodopa, in patients with newly diagnosed Parkinson's disease. This study was a double-blind, multicentre trial that compared cabergoline and levodopa as initial therapy for Parkinson's disease. A total of 419 levodopa-, DA- and selegiline-naive patients with newly diagnosed Parkinson's disease were randomised to receive either cabergoline (n = 211) or levodopa (n = 209). Treatment was titrated to an optimal dose over a period of up to 24 weeks and then continued at this dose until the study endpoint (confirmed motor complications) or up to a maximum of 5 years. At years 1-5, the cabergoline group was receiving cabergoline at average daily doses ranging from 2.8-2.9 mg, with added levodopa at mean daily doses ranging from 322 mg at year 1 to 431 mg at year 5; over the same period, the levodopa group was receiving daily levodopa doses of 784 mg. Thus, patients in the cabergoline group received <50% levodopa than patients in the levodopa group. Motor complications were significantly delayed (p = 0.0175) and occurred less frequently in cabergoline-treated patients than in levodopa-treated patients (22.3% vs 33.7%). Cox model proportional hazards regression analysis showed that the relative risk of developing such complications was >50% lower (0.46; p < 0.001) in the cabergoline group compared with the levodopa group. In particular, development of dyskinesias was markedly delayed in the cabergoline group and occurred in 9.5% of patients compared with 21.2% in the levodopa group (p < 0.001). Among patients not requiring supplemental levodopa, the frequency of motor complications was three times higher with levodopa (15.5% of 110 patients) than with cabergoline (5.3% of 76 patients). Among patients who did need supplemental levodopa, motor complications were more frequent in the levodopa arm (54.1% of 98 patients) than in the cabergoline arm (31.9% of 135 patients). Consistent improvements relative to baseline in average Unified Parkinson's Disease Rating Scale (UPDRS) daily living activities and motor function sections, and in Clinical Global Impression severity of illness and physician- and patient- rated global improvement scores, were seen in both treatment groups, with maximal effects occurring within 2 years. However, levodopa treatment was associated with a significantly (p < 0.001) greater improvement in motor disability (as measured by the UPDRS motor score) over time, with mean values of 13.8 versus 12.9 in the cabergoline versus levodopa arm recorded at 1 year, 18.6 versus 17.2 at 3 years and 19.2 versus 16.3 at 5 years, respectively. While the overall frequency of adverse events was similar in the two groups, the cabergoline-treated group experienced marginally, but not significantly, higher frequencies of nausea, vomiting, dyspepsia and gastritis (37.4% vs 32.2% in the levodopa group) and of dizziness and postural hypotension (31.3% vs 24% in the levodopa group). Cabergoline-treated patients also experienced a significantly higher frequency of peripheral oedema (16.1% vs 3.4%, respectively; p < 0.0001). The cabergoline and levodopa groups had similar rates of sleepiness (17.5% vs 18.3%, respectively) and hallucinations (4.8% vs 4.4%, respectively); in an elderly population subset, hallucinations were reported in 7.1% and 6.5% of patients taking cabergoline and levodopa, respectively. Adverse events generally occurred more frequently in female patients (with the exception of dyskinesias, hyperkinesias and hallucinations, which occurred more frequently in men) and in the elderly. This study showed that, compared with levodopa, initial therapy with cabergoline in patients with Parkinson's disease is associated with a lower risk of response fluctuations at the cost of a marginally reduced symptomatic improvement and some tolerability disadvantages that are mostly limited to a significantly higher frequency of peripheral oedema.


Molecular design toward efficient polymer solar cells with high polymer content.
A novel polythiophene derivative, PBT1, was designed, synthesized, and applied in polymer solar cells (PSCs). This work provides a successful example of using molecular structure as a tool to realize optimal photovoltaic performance with high polymer content, thus enabling the realization of efficient photoabsorption in very thin films. As a result, an efficiency of 6.88% was recorded in a PSC with a 75 nm active layer.


Influence of band selection and target estimation error on the performance of the matched filter in hyperspectral imaging.
The matched filter is a widely used detector in hyperspectral detection applications because of its simplicity and its efficiency in practical situations. We propose to estimate its performance with respect to the number of spectral bands. These spectral bands are selected thanks to a genetic algorithm in order to optimize the contrast between the target and the background in the detection plane. Our band selection method can be used to optimize not only the position but also the linewidth of the spectral bands. The optimized contrast always increases with the number of selected bands. However, in practical situations, the target spectral signature has to be estimated from the image. We show that in the presence of estimation error, the maximum number of bands may not always be the best choice in terms of detection performance.


Cell3: a new vision for study of the endomembrane system in mammalian cells.
The endomembrane system of mammalian cells provides massive capacity for the segregation of biochemical reactions into discrete locations. The individual organelles of the endomembrane system also require the ability to precisely transport material between these compartments in order to maintain cell homeostasis; this process is termed membrane traffic. For several decades, researchers have been systematically identifying and dissecting the molecular machinery that governs membrane trafficking pathways, with the overwhelming majority of these studies being carried out in cultured cells growing as monolayers. In recent years, a number of methodological innovations have provided the opportunity for cultured cells to be grown as 3-dimensional (3D) assemblies, for example as spheroids and organoids. These structures have the potential to better replicate the cellular environment found in tissues and present an exciting new opportunity for the study of cell function. In this mini-review, we summarize the main methods used to generate 3D cell models and highlight emerging studies that have started to use these models to study basic cellular processes. We also describe a number of pieces of work that potentially provide the basis for adaptation for deeper study of how membrane traffic is coordinated in multicellular assemblies. Finally, we comment on some of the technological challenges that still need to be overcome if 3D cell biology is to become a mainstream tool toward deepening our understanding of the endomembrane system in mammalian cells.


CEP63 deficiency promotes p53-dependent microcephaly and reveals a role for the centrosome in meiotic recombination.
CEP63 is a centrosomal protein that facilitates centriole duplication and is regulated by the DNA damage response. Mutations in CEP63 cause Seckel syndrome, a human disease characterized by microcephaly and dwarfism. Here we demonstrate that Cep63-deficient mice recapitulate Seckel syndrome pathology. The attrition of neural progenitor cells involves p53-dependent cell death, and brain size is rescued by the deletion of p53. Cell death is not the result of an aberrant DNA damage response but is triggered by centrosome-based mitotic errors. In addition, Cep63 loss severely impairs meiotic recombination, leading to profound male infertility. Cep63-deficient spermatocytes display numerical and structural centrosome aberrations, chromosome entanglements and defective telomere clustering, suggesting that a reduction in centrosome-mediated chromosome movements underlies recombination failure. Our results provide novel insight into the molecular pathology of microcephaly and establish a role for the centrosome in meiotic recombination.


A computational and conceptual DFT study on the mechanism of hydrogen activation by novel frustrated Lewis pairs.
A computational and conceptual density functional theory (DFT) study on the mechanism of molecular hydrogen activation by a set of three frustrated Lewis pairs (FLPs) was performed at the ωB97X-D/6-311G(d,p) level of theory. A reduced model and other two prototypes derived from experimental data, based on the donor nitrogen and acceptor boron atoms, were used. Analysis based on the energy results, geometries and the global electron density transfer at the TSs made it possible to obtain some interesting conclusions: (i) despite the well-known very low reactivity of molecular hydrogen, the catalytic effectiveness of the three FLPs produces reactions with almost unappreciable activation energies; (ii) the reactions, being exothermic, follow a one-step mechanism via polarised TSs; (iii) there are neither substituent effects on the kinetics nor on the thermodynamics of these reactions; (iv) the activation of molecular hydrogen seems to be attained when the N-B distance in the FLP derivatives is around 2.74 Å; and (v) the proposed FLP model is consistent with the behaviour of the experimental prototypes. Finally, the ability of the three FLPs as efficient catalysts was evaluated studying the hydrogenation of acetylene to yield ethylene.


The effect of atmospheric scintillation on an optical data channel-laser radar and binary communications.
The effects of scintillation on an optical data channel are analyzed and numerical results presented. Scintillation with a log normal distribution typical of atmospheric optical effects is assumed. The analysis is concerned with the target miss probability of a laser radar and the bit error probability of an optical binary communications link. Results are expressed in terms of a loss factor which is the extra number of dB signal-to-noise ratio necessary to keep the performance in the presence of scintillation up to the level achievable in the absence of scintillation. With even moderately weak scintillation large loss factors are encountered. A brief treatment of the effects of normally distributed scintillation is also presented.


New perspectives on the "silo effect": initial comparisons of network structures across public health collaboratives.
We explored to what extent "silos" (preferential partnering) persist in interorganizational boundaries despite advances in working across boundaries. We focused on organizational homophily and resulting silo effects within networks that might both facilitate and impede success in public health collaboratives (PHCs). We analyzed data from 162 PHCs with a series of exponential random graph models to determine the influence of uniform and differential homophily among organizations and to identify the propensity for partnerships with similar organizations. The results demonstrated a low presence (8%) of uniform homophily among networks, whereas a greater number (30%) of PHCs contained varying levels of differential homophily by 1 or more types of organization. We noted that the higher frequency among law enforcement, nonprofits, and public health organizations demonstrated a partner preference with similar organizations. Although we identified only a modest occurrence of partner preference in PHCs, overall success in efforts to work across boundaries might be problematic when public health members (often leaders of PHCs) exhibit the tendency to form silos.


Protein resistance of surfaces prepared by sorption of end-thiolated poly(ethylene glycol) to gold: effect of surface chain density.
Nonspecific protein adsorption generally occurs at the biomaterial-tissue interface and usually has adverse consequences. Thus, surfaces that are protein-resistant are eagerly sought with the expectation that these materials will exhibit improved biocompatibility. Surfaces modified with end-tethered poly(ethylene oxide) (PEO) have been shown to be protein-resistant to some degree. Although the mechanisms are unclear, it has been suggested that chain length, chain density, and chain conformation are important factors. To investigate the effects of PEO chain density, we selected a model system based on the chemisorption of chain-end thiolated PEO to a gold substrate. Chain density was varied by varying PEO solubility (proximity to cloud point) and incubation time in the chemisorption solution. The adsorption of fibrinogen and lysozyme to these surfaces was investigated. It was found that for 750 and 2000 MW PEO layers, resistance to fibrinogen increased with chain density and was maximal at a density of approximately 0.5 chains/nm(2) (80% decrease in adsorption compared to unmodified gold). As PEO chain density increased beyond 0.5/nm(2) adsorption increased. For PEO of 5000 MW the optimal chain density was 0.27/nm(2) and gave only a 60% reduction in fibrinogen adsorption. It is suggested that, at high chain density, the chemisorbed PEO is dehydrated giving a surface that is no longer protein resistant. The PEO-modified surfaces were found also to be resistant to lysozyme adsorption with reductions similar to, if somewhat less than, those for fibrinogen. The fibrinogen to lysozyme molar ratios were within the expected range for close-packed layers of these proteins in their native conformation and were relatively insensitive to PEO chain density and MW. This may suggest that such adsorption as did occur, even at chain densities giving minimum adsorption, may have been on patches of unmodified gold.


Understanding migraine: Potential role of neurogenic inflammation.
Neurogenic inflammation, a well-defined pathophysiologial process is characterized by the release of potent vasoactive neuropeptides, predominantly calcitonin gene-related peptide (CGRP), substance P (SP), and neurokinin A from activated peripheral nociceptive sensory nerve terminals (usually C and A delta-fibers). These peptides lead to a cascade of inflammatory tissue responses including arteriolar vasodilation, plasma protein extravasation, and degranulation of mast cells in their peripheral target tissue. Neurogenic inflammatory processes have long been implicated as a possible mechanism involved in the pathophysiology of various human diseases of the nervous system, respiratory system, gastrointestinal tract, urogenital tract, and skin. The recent development of several innovative experimental migraine models has provided evidence suggestive of the involvement of neuropeptides (SP, neurokinin A, and CGRP) in migraine headache. Antidromic stimulation of nociceptive fibers of the trigeminal nerve resulted in a neurogenic inflammatory response with marked increase in plasma protein extravasation from dural blood vessels by the release of various sensory neuropeptides. Several clinically effective abortive antimigraine medications, such as ergots and triptans, have been shown to attenuate the release of neuropeptide and neurogenic plasma protein extravasation. These findings provide support for the validity of using animal models to investigate mechanisms of neurogenic inflammation in migraine. These also further strengthen the notion of migraine being a neuroinflammatory disease. In the clinical context, there is a paucity of knowledge and awareness among physicians regarding the role of neurogenic inflammation in migraine. Improved understanding of the molecular biology, pharmacology, and pathophysiology of neurogenic inflammation may provide the practitioner the context-specific feedback to identify the novel and most effective therapeutic approach to treatment. With this objective, the present review summarizes the evidence supporting the involvement of neurogenic inflammation and neuropeptides in the pathophysiology and pharmacology of migraine headache as well as its potential significance in better tailoring therapeutic interventions in migraine or other neurological disorders. In addition, we have briefly highlighted the pathophysiological role of neurogenic inflammation in various other neurological disorders.


Vocal economy in vocally trained actresses and untrained female subjects.
Vocally trained actresses are expected to have more vocal economy than nonactresses. Therefore, we hypothesize that there will be differences in the electroglottogram-based voice economy parameter quasi-output cost ratio (QOCR) between actresses and nonactresses. This difference should remain across different levels of intensity. A total of 30 actresses and 30 nonactresses were recruited for this study. Participants from both groups were required to sustain the vowels /a/, /i/, and /u/, in habitual, moderate, and high intensity levels. Acoustic variables such as sound pressure level (SPL), fundamental frequency (F0), and glottal contact quotient (CQ) were obtained. The QOCR was then calculated. There were no significant differences among the groups for QOCR. Positive correlations were observed for QOCR versus SPL and QOCR versus F0 in all intensity levels. Negative correlation was found between QOCR and CQ in all intensity levels. Considering the differences among intensity levels, from habitual to moderate and from moderate to loud, only the CQ did not differ significantly. The QOCR, SPL, and F0 presented significant differences throughout the different intensity levels. The QOCR did not reflect the level of vocal training when comparing trained and nontrained female subjects in the present study. Both groups demonstrated more vocal economy in moderate and high intensity levels owing to more voice output without an increase in glottal adduction.


Alternative splicing due to an intronic SNP in HMSD generates a novel minor histocompatibility antigen.
Here we report the identification of a novel human leukocyte antigen (HLA)-B44-restricted minor histocompatibility antigen (mHA) with expression limited to hematopoietic cells. cDNA expression cloning studies demonstrated that the cytotoxic T lymphocyte (CTL) epitope of interest was encoded by a novel allelic splice variant of HMSD, hereafter designated as HMSD-v. The immunogenicity of the epitope was generated by differential protein expression due to alternative splicing, which was completely controlled by 1 intronic single-nucleotide polymorphism located in the consensus 5' splice site adjacent to an exon. Both HMSD-v and HMSD transcripts were selectively expressed at higher levels in mature dendritic cells and primary leukemia cells, especially those of myeloid lineage. Engraftment of mHA(+) myeloid leukemia stem cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID)/gammac(null) mice was completely inhibited by in vitro preincubation with the mHA-specific CTL clone, suggesting that this mHA is expressed on leukemic stem cells. The patient from whom the CTL clone was isolated demonstrated a significant increase of the mHA-specific T cells in posttransplantation peripheral blood, whereas mHA-specific T cells were undetectable in pretransplantation peripheral blood and in peripheral blood from his donor. These findings suggest that the HMSD-v-encoded mHA (designated ACC-6) could serve as a target antigen for immunotherapy against hematologic malignancies.


Adaptive wavelet Wiener filtering of ECG signals.
In this study, we focused on the reduction of broadband myopotentials (EMG) in ECG signals using the wavelet Wiener filtering with noise-free signal estimation. We used the dyadic stationary wavelet transform (SWT) in the Wiener filter as well as in estimating the noise-free signal. Our goal was to find a suitable filter bank and to choose other parameters of the Wiener filter with respect to the signal-to-noise ratio (SNR) obtained. Testing was performed on artificially noised signals from the standard CSE database sampled at 500 Hz. When creating an artificial interference, we started from the generated white Gaussian noise, whose power spectrum was modified according to a model of the power spectrum of an EMG signal. To improve the filtering performance, we used adaptive setting parameters of filtering according to the level of interference in the input signal. We were able to increase the average SNR of the whole test database by about 10.6 dB. The proposed algorithm provides better results than the classic wavelet Wiener filter.


Total nasal reconstruction: a 6-year experience with the three-stage forehead flap combined with the septal pivot flap.
Several different methods can be applied for repairing total nasal defects. Most of them are based on some common principles and techniques widely accepted and adopted by experienced surgeons. We have been using most of these techniques during the past two decades, however modifying and refining them several times. Our observations and sometimes disappointing experiences led to a concept that has remained unchanged for the past 6 years. It comprises three regular operative steps and sometimes a fourth surgical intervention for repair and refinement. First stage: Reconstruction of the septum using a bipedicled composite septal pivot flap (SPF), of the intranasal lining (INL), and the cover being established by elevating a full-thickness paramedian forehead flap (PMFF). Second stage: Re-elevation of the PMFF, thinning of its layers, and reconstruction of the subsurface framework using autogenous rib cartilage. Third stage: Division of the pedicle and minor corrections. We have been using this technique presented here since 2004 in nine consecutive patients with subtotal to supratotal nasal defects. Seven cases have been repaired completely by now and can be evaluated carefully. With this technique, results have significantly improved and have been stable to date.


The Impact of Glycated Hemoglobin (HbA1c) on Cardiovascular Disease Risk: A Mendelian Randomization Study Using UK Biobank.
Glycated hemoglobin (HbA1c) is positively associated with cardiovascular disease (CVD), although evidence is primarily observational. Mendelian randomization studies have only examined its relation with subtypes of CVD. We examined the relation of HbA1c with CVD and its subtypes in the UK Biobank using Mendelian randomization. We used 38 genetic variants strongly and independently related to HbA1c (n = 123,665) applied to the UK Biobank (n = 392,038). We used inverse variance weighting (IVW) to obtain the associations of HbA1c with CVD, coronary artery disease (CAD), and stroke (overall and stroke subtypes). Sensitivity analyses included Mendelian randomization (MR)-Egger, a weighted median, and exclusion of potentially invalid single nucleotide polymorphisms (SNPs). We also applied the same genetic instruments to CARDIoGRAMplusC4D (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) 1000 Genomes-based genome-wide association study (n = 184,305) as a validation for CAD. In the UK Biobank, HbA1c was not associated with CVD using IVW (odds ratio [OR] 1.11 per %, 95% CI 0.83-1.48). However, HbA1c was associated with increased CAD risk (OR 1.50 per %, 95% CI 1.08-2.11) with directionally consistent results from MR-Egger and weighted median. The positive association with CAD was more pronounced when we excluded potentially invalid SNPs (OR 2.24 per %, 95% CI 1.55-3.25). The positive association was replicated in CARDIoGRAM (OR 1.52 per %, 95% CI 1.03-2.26). The association of HbA1c with stroke and its subtypes was less clear given the low number of cases. HbA1c likely causes CAD. The underlying mechanisms remain to be elucidated.


Attenuation of atherogenic apo B-48-dependent hyperlipidemia and high density lipoprotein remodeling induced by vitamin C and E combination and their beneficial effect on lethal ischemic heart disease in mice.
Atherosclerotic cardiovascular disease is highly prevalent and its underlying pathogenesis involves dyslipidemia including pro-atherogenic high density lipoprotein (HDL) remodeling. Vitamins C and E have been proposed as atheroprotective agents for cardiovascular disease management. However, their effects and benefits on high density lipoprotein function and remodeling are unknown. In this study, we evaluated the role of vitamin C and E on non HDL lipoproteins as well as HDL function and remodeling, along with their effects on inflammation/oxidation biomarkers and atherosclerosis in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice. Mice were pre-treated for 5 weeks before and during atherogenic diet feeding with vitamin C and E added to water and diet, respectively. Compared to a control group, combined vitamin C and E administration reduced serum total cholesterol and triglyceride levels by decreasing apo B-48-containing lipoproteins, remodeled HDL particles by reducing phospholipid as well as increasing PON1 and apo D content, and diminished PLTP activity and levels. Vitamin supplementation improved HDL antioxidant function and lowered serum TNF-α levels. Vitamin C and E combination attenuated atherogenesis and increased lifespan in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice. Vitamin C and E administration showed significant lipid metabolism regulating effects, including HDL remodeling and decreased levels of apoB-containing lipoproteins, in mice. In addition, this vitamin supplementation generated a cardioprotective effect in a murine model of severe and lethal atherosclerotic ischemic heart disease.


Acute Hormonal Responses to High-Intensity Interval Training in Hyperoxia.
This study aimed to compare selected hormonal responses to a single session of high intensity interval training performed with an increased fraction of inspired oxygen (hyperoxia) and under normoxic conditions. Twelve recreationally trained men (age 24 ± 3 years) performed two sessions of high intensity interval training on a cycle ergometer, in randomized order with hyperoxia (4 L·min-1 with a flowrate of 94% O2) and normoxia. Each session consisted of 5 intervals of 3 minutes at 85% of the maximal power output, interspersed by 2 min at 40% of the maximal power output. Serum cortisol, prolactin and vascular endothelial growth factor (VEGF) were assessed both before and immediately after each high intensity interval training session. Statistically significant differences in cortisol were found between hyperoxic and normoxic conditions (p = 0.011), with a significant increase in hyperoxia (61.4 ± 73.2%, p = 0.013, ES = -1.03), but not in normoxia (-1.3 ± 33.5%, p > 0.05, ES = 0.1). Prolactin increased similarly in both hyperoxia (118.1 ± 145.1%, p = 0.019, ES = -0.99) and normoxia (62.14 ± 75.43%, p = 0.005, ES = -0.5). VEGF was not statistically altered in either of the conditions. Our findings indicate that a single session of high intensity interval training in low-dose hyperoxia significantly increased cortisol concentrations in recreationally trained individuals compared to normoxia, while the difference was smaller in prolactin and diminished in VEGF concentrations.


Circulating prolactin levels and Behcet's disease: A meta-analysis.
This study aimed to summarize the current evidence on the relationship between circulating prolactin levels and Behcet's disease (BD). We performed a meta-analysis comparing the serum/plasma prolactin levels in patients with BD with those of controls and performed a subgroup analysis based on ethnicity, disease activity, and sex. Ten articles with a total of 320 patients with BD and 259 controls were included. The prolactin levels were not significantly higher in the BD group than in the control group (SMD=0.208, 95% CI=-0.012-0.428, p=0.064). Stratification by ethnicity indicated no elevation in prolactin level in Turkish patients with BD (SMD=0.127, 95% CI=-0.111-0.366, p=0.295). Stratification by disease activity revealed no elevation in prolactin level in both the active and inactive BD groups compared with the control group (SMD=0.373, 95% CI=-0.095-0.841, p=0.119; SMD=0.055, 95% CI=-0.243-0.354, p=0.717). Stratification by sex revealed no elevation in prolactin level in both the female and male BD groups (SMD=0.031, 95% CI=-0.398-0.460, p=0.888; SMD=0.279, 95% CI=-1.411-1.969, p=0.746). The prolactin levels were not significantly elevated in patients with BD, regardless of the adjustments for age/sex, sample size, or data type evaluated. This meta-analysis of current evidence suggests that circulating prolactin levels may not be higher in patients with BD than in controls.


Hypertension, the Kuna, and the epidemiology of flavanols.
A low sodium diet has often been implicated in the protection of low blood pressure populations from hypertension, but several other dietary factors, including those as yet unidentified, may also be involved. The Kuna Indians of Panama are free of hypertension and cardiovascular disease, but this is changing with migration to urban areas. We compared the indigenous diet of Kuna Indians living on remote islands in Panama (Ailigandi), whose lifestyle is largely hunter-gatherer, with those who have moved to a suburb of Panama City (Vera Cruz). Between April and October 1999, members of a Kuna research team administered a 118-item food frequency questionnaire to133 adult Kuna from Ailigandi and 183 from Vera Cruz. Single 24-hour urine collections and nonfasting blood samples were obtained. The Kuna in Ailigandi reported consuming a 10-fold higher amount of cocoa-containing beverages, 4 times the amount of fish, and twice the amount of fruit as urban Kuna (P<0.05 by t test). Salt added was ample among those living in Ailigandi and Vera Cruz according to both self-report (7.1+/-1.1 and 4.6+/-0.3 tsp weekly) and urinary sodium levels (177+/-9 and 160+/-7 mEq Na/g creatinine), respectively. The low blood pressure of island-dwelling Kuna does not seem to be related to a low salt diet. Among dietary factors that varied among migrating Kuna, the notably higher intake of flavanol-rich cocoa is a potential candidate for further study.


High resolution ion mobility-mass spectrometry for separation and identification of isomeric lipids.
Lipidomics is a particularly difficult analytical challenge due to the number and importance of isomeric species that are known or postulated in biological samples. Current separation and identification techniques are too often insufficiently powerful, slow or ambiguous. High resolution, low field ion mobility coupled to mass spectrometry is shown here to have sufficient performance to represent a new alternative for lipidomics. For the first time, drift-tube ion mobility separation of lipid isomers that differ only in position of the acyl chain, position of the double bond or double bond geometry is demonstrated. Differences in collision cross sections of less than 1% are sufficient for baseline separation. The same level of performance is maintained in complex biological mixtures. More than 130 high-precision reduced mobility and collision cross section values were also determined for a range of lipids. Such data can be the basis of a new lipidomics workflow, as the appropriate libraries are developed.


Evaluations of capsule endoscopy software in reducing the reading time and the rate of false negatives by inexperienced endoscopists.
Capsule endoscopy (CE) is a comfortable for the patients; however, CE review is time-consuming. The aim of this study was (1) to evaluate the effectiveness of the CE software in reducing the CE reading time and the number of false negatives by beginners, and (2) to determine the learning curve for reading CE images. Capsule endoscopic images were captured by Pillcam SB (Given Imaging Ltd, Tokyo, Japan), and analyzed using the proprietary RAPID 5 software. Comparison of CE reading using different software modes: manual mode, automatic mode, and QuickView (QV) mode. Three trainee endoscopists participated as CE readers. Each participant watched CE videos in which positive findings had been predefined by trained endoscopists. Each participant read the same CE record by using one of three different software modes. These were blinded on clinical history of patients. CE reading time was recorded, and the number of false negatives was counted. Each trainee endoscopist read a total of 45 CE videos, in five steps divided into nine videos per step. There was no significant reader associated difference between the results for the different modes. The QV software did miss some positive findings. Therefore, the total number of instances of FN by the software plus the reader in the QV mode was significantly higher than the others. The reading times in the automatic mode and the QV mode were significantly shorter than that in the manual mode. After the second step, the number of instances of false negatives significantly decreased. CE software is useful for reducing the reading time. Experience of approximately 20 CE readings can be considered as the first step to becoming an expert.


Climate change-mediated temperature extremes and insects: From outbreaks to breakdowns.
Insects are among the most diverse and widespread animals across the biosphere and are well-known for their contributions to ecosystem functioning and services. Recent increases in the frequency and magnitude of climatic extremes (CE), in particular temperature extremes (TE) owing to anthropogenic climate change, are exposing insect populations and communities to unprecedented stresses. However, a major problem in understanding insect responses to TE is that they are still highly unpredictable both spatially and temporally, which reduces frequency- or direction-dependent selective responses by insects. Moreover, how species interactions and community structure may change in response to stresses imposed by TE is still poorly understood. Here we provide an overview of how terrestrial insects respond to TE by integrating their organismal physiology, multitrophic, and community-level interactions, and building that up to explore scenarios for population explosions and crashes that have ecosystem-level consequences. We argue that TE can push insect herbivores and their natural enemies to and even beyond their adaptive limits, which may differ among species intimately involved in trophic interactions, leading to phenological disruptions and the structural reorganization of food webs. TE may ultimately lead to outbreak-breakdown cycles in insect communities with detrimental consequences for ecosystem functioning and resilience. Lastly, we suggest new research lines that will help achieve a better understanding of insect and community responses to a wide range of CE.


The Use of a Mobile Application to Teach Concussion-Related Health Knowledge.
Sports-related concussions affect over 280,000 adolescents each year while the general public remains ill-informed about concussions, signs/symptoms, and treatments. Adolescents may be at an increased risk for experiencing adverse physiological and psychological effects from concussions, underscoring the critical need for effective concussion education strategies. While mobile apps are increasingly being used in education and healthcare settings, none were found to offer comprehensive concussion education capable of reaching diverse audiences. The interactive mobile app "Rebound: Beating Concussions" has the potential to be an effective teaching tool for school athletic programs and medical professionals to communicate important concussion-related information to student athletes, parents, and sports coaches. A mixed methods study was used to determine the app's ability to convey information about concussions to student athletes in grades 5 through 12, parents of student athletes, and sports coaches. Concussion knowledge and participant opinions were assessed via a pre/post model and administered before and after app use. Participants demonstrated knowledge gains in the identification of concussion symptoms, treatments, and misconceptions. Additionally, participants demonstrated positive opinions on the content of the app, its relevance to everyday life, and its potential as a teaching tool.


Sumatriptan improves the locomotor activity and neuropathic pain by modulating neuroinflammation in rat model of spinal cord injury.
To investigate the therapeutic effects of sumatriptan in a rat model of spinal cord injury (SCI) and possible anti-inflammatory and analgesic mechanisms underlying this effect. Using an aneurysm mini-clip model of contusive SCI, T9-10 laminectomies were performed for 60 male rats. Animals were divided into six experimental groups (n = 10 per group) as follows: a minocycline administered positive control group, a saline-vehicle negative control group, a sham-operated group, and three experimental groups which received separate doses of sumatriptan (0.1, 0.3 and 1 mg/kg). Behavioural assessments were used to evaluate locomotor activity and neuropathic pain for 28 days. At the end of the study, spinal cord tissues were collected from sacrificed animals for histopathological analysis. Levels of calcitonin gene-related peptide (CGRP) and two pro-inflammatory cytokines (tumor necrosis factor [TNF]-α and interleukin [IL]-1β) were assessed by the enzyme-linked immunosorbent assay (ELISA). Sumatriptan significantly (P < 0.001) improved the locomotor activity in SCI group. Sumatriptan was also more effective than the positive control, i.e. minocycline (0.3 mg/kg). Additionally, sumatriptan and minocycline similarly attenuated the mechanical and thermal allodynia in SCI (P < 0.001). TNF-α, IL-1β and CGRP levels in sumatriptan- and minocycline-treated groups significantly (P < 0.001) decreased compared to controls. Histopathological analysis also revealed a markedly improvement in hemorrhage followed by inflammatory cell invasion, neuronal vacuolation, and cyst formation in both sumatriptan- and minocycline-treated groups compared to control animals. Sumatriptan improves functional recovery from SCI through its anti-inflammatory effects and reducing pro-inflammatory and pain mediators.


Self-perpetuating changes in Sup35 protein conformation as a mechanism of heredity in yeast.
Recently, a novel mode of inheritance has been described in the yeast Saccharomyces cerevisiae. The mechanism is based on the prion hypothesis, which posits that self-perpetuating changes in the conformation of single protein, PrP, underlie the severe neurodegeneration associated with the transmissible spongiform enchephalopathies in mammals. In yeast, two prions, [URE3] and [PSI+], have been identified, but these factors confer unique phenotypes rather than disease to the organism. In each case, the prion-associated phenotype has been linked to alternative conformations of the Ure2 and Sup35 proteins. Remarkably, Ure2 and Sup35 proteins existing in the alternative conformations have the unique capacity to transmit this physical state to the newly synthesized protein in vivo. Thus, a mechanism exists to ensure replication of the conformational information that underlies protein-only inheritance. We have characterized the mechanism by which Sup35 conformational information is replicated in vitro. The assembly of amyloid fibres by a region of Sup35 encompassing the N-terminal 254 amino acids faithfully recapitulates the in vivo propagation of [PSI+]. Mutations that alter [PSI+] inheritance in vivo change the kinetics of amyloid assembly in vitro in a complementary fashion, and lysates from [PSI+] cells, but not [psi-] cells, accelerate assembly in vitro. Using this system we propose a mechanism by which the alternative conformation of Sup35 is adopted by an unstructured oilgomeric intermediate at the time of assembly.


Can oncology recapitulate paleontology? Lessons from species extinctions.
Although we can treat cancers with cytotoxic chemotherapies, target them with molecules that inhibit oncogenic drivers, and induce substantial cell death with radiation, local and metastatic tumours recur, resulting in extensive morbidity and mortality. Indeed, driving a tumour to extinction is difficult. Geographically dispersed species of organisms are perhaps equally resistant to extinction, but >99.9% of species that have ever existed on this planet have become extinct. By contrast, we are nowhere near that level of success in cancer therapy. The phenomena are broadly analogous--in both cases, a genetically diverse population mutates and evolves through natural selection. The goal of cancer therapy is to cause cancer cell population extinction, or at least to limit any further increase in population size, to prevent the tumour burden from overwhelming the patient. However, despite available treatments, complete responses are rare, and partial responses are limited in duration. Many patients eventually relapse with tumours that evolve from cells that survive therapy. Similarly, species are remarkably resilient to environmental change. Paleontology can show us the conditions that lead to extinction and the characteristics of species that make them resistant to extinction. These lessons could be translated to improve cancer therapy and prognosis.


Hepatic Krüppel-like factor 16 (KLF16) targets PPARα to improve steatohepatitis and insulin resistance.
Impaired hepatic fatty acids oxidation results in lipid accumulation and redox imbalance, promoting the development of fatty liver diseases and insulin resistance. However, the underlying pathogenic mechanism is poorly understood. Krüppel-like factor 16 (KLF16) is a transcription factor that abounds in liver. We explored whether and by what mechanisms KLF16 affects hepatic lipid catabolism to improve hepatosteatosis and insulin resistance. KLF16 expression was determined in patients with non-alcoholic fatty liver disease (NAFLD) and mice models. The role of KLF16 in the regulation of lipid metabolism was investigated using hepatocyte-specific KLF16-deficient mice fed a high-fat diet (HFD) or using an adenovirus/adeno-associated virus to alter KLF16 expression in mouse primary hepatocytes (MPHs) and in vivo livers. RNA-seq, luciferase reporter gene assay and ChIP analysis served to explore the molecular mechanisms involved. KLF16 expression was decreased in patients with NAFLD, mice models and oleic acid and palmitic acid (OA and PA) cochallenged hepatocytes. Hepatic KLF16 knockout impaired fatty acid oxidation, aggravated mitochondrial stress, ROS burden, advancing hepatic steatosis and insulin resistance. Conversely, KLF16 overexpression reduced lipid deposition and improved insulin resistance via directly binding the promoter of peroxisome proliferator-activated receptor α (PPARα) to accelerate fatty acids oxidation and attenuate mitochondrial stress, oxidative stress in db/db and HFD mice. PPARα deficiency diminished the KLF16-evoked protective effects against lipid deposition in MPHs. Hepatic-specific PPARα overexpression effectively rescued KLF16 deficiency-induced hepatic steatosis, altered redox balance and insulin resistance. These findings prove that a direct KLF16-PPARα pathway closely links hepatic lipid homeostasis and redox balance, whose dysfunction promotes insulin resistance and hepatic steatosis.


Meta-analysis of genome-wide linkage studies in BMI and obesity.
The objective was to provide an overall assessment of genetic linkage data of BMI and BMI-defined obesity using a nonparametric genome scan meta-analysis. We identified 37 published studies containing data on over 31,000 individuals from more than >10,000 families and obtained genome-wide logarithm of the odds (LOD) scores, non-parametric linkage (NPL) scores, or maximum likelihood scores (MLS). BMI was analyzed in a pooled set of all studies, as a subgroup of 10 studies that used BMI-defined obesity, and for subgroups ascertained through type 2 diabetes, hypertension, or subjects of European ancestry. Bins at chromosome 13q13.2- q33.1, 12q23-q24.3 achieved suggestive evidence of linkage to BMI in the pooled analysis and samples ascertained for hypertension. Nominal evidence of linkage to these regions and suggestive evidence for 11q13.3-22.3 were also observed for BMI-defined obesity. The FTO obesity gene locus at 16q12.2 also showed nominal evidence for linkage. However, overall distribution of summed rank p values <0.05 is not different from that expected by chance. The strongest evidence was obtained in the families ascertained for hypertension at 9q31.1-qter and 12p11.21-q23 (p < 0.01). Despite having substantial statistical power, we did not unequivocally implicate specific loci for BMI or obesity. This may be because genes influencing adiposity are of very small effect, with substantial genetic heterogeneity and variable dependence on environmental factors. However, the observation that the FTO gene maps to one of the highest ranking bins for obesity is interesting and, while not a validation of this approach, indicates that other potential loci identified in this study should be investigated further.


[Concurrent infections by two dengue virus serotypes during an outbreak in northwestern Peru, 2008].
To establish the existence of concurrent infections by different dengue virus (DENV) serotypes in an outbreak in the Northwestern in Peru during 2008. 73 serum samples from patients with dengue were analyzed during an outbreak that occurred in Northwestern in Peru between May and June 2008. Molecular biology techniques were used to serotype the DENV, thus, firstly the viral RNA viral was extracted using Viral QIAamp RNA mini kit (Qiagen, Valencia, California, USA), then the viral cDNA fragments were reverse transcripted and amplified by means of the Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) and the RT-Nested PCR region techniques and finally, genetic sequencing of the viral cDNA fragments were performed using the Big Dye Terminator v.3,1 kit. The 73 dengue cases presented infections by different serotypes: 34 (46.6%) by DENV-3, 29 (39.7%) by DENV-1, 4 (5.5%) by DENV-4, and 6 (8.2%) concurrent infections by DENV-1 and DENV-3. The most frequent clinical manifestations observed among dengue patients were fever and headache (100%), myalgia (94.5%), ocular pain (83.6%), arthralgia (78.1%), shivers (63.0%), nausea/vomiting (38.4%), positive tourniquet test (30.1%), and rash (20.5%). All patients with concurrent infections presented light clinical course of dengue fever (DF) except one patient who had moderate hemorrhagic manifestations. This is the first Peruvian report of patients with concurrent infections of two DENV serotypes without severe clinical manifestations.


Interaction of tetraspan(in) TM4SF5 with CD44 promotes self-renewal and circulating capacities of hepatocarcinoma cells.
Tumor metastasis involves circulating and tumor-initiating capacities of metastatic cancer cells. Epithelial-mesenchymal transition (EMT) is related to self-renewal capacity and circulating tumor cell (CTC) characteristics for tumor metastasis. Although tumor metastasis is a life-threatening, complicated process that occurs through circulation of tumor cells, mechanistic aspects of self-renewal and circulating capacities have been largely unknown. Hepatic transmembrane 4 L six family member 5 (TM4SF5) promotes EMT for malignant growth and migration, so it was rationalized that TM4SF5, as a hepatocellular carcinoma (HCC) biomarker, might be important for metastatic potential. Here, self-renewal capacity by TM4SF5 was mechanistically explored using hepatocarcinoma cells with or without TM4SF5 expression, and we explored whether they became CTCs using mouse liver-orthotopic model systems. We found that TM4SF5-dependent sphere growth correlated with CD24(-) , aldehyde dehydrogenase (ALDH) activity, as well as a physical association between CD44 and TM4SF5. Interaction between TM4SF5 and CD44 was through their extracellular domains with N-glycosylation modifications. TM4SF5/CD44 interaction activated proto-oncogene tyrosine-protein kinase Src (c-Src)/signal transducer and activator of transcription 3 (STAT3)/Twist-related protein 1 (Twist1)/B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi1) signaling for spheroid formation, whereas disturbing the interaction, expression, or activity of any component in this signaling pathway inhibited spheroid formation. In serial xenografts using 200∼5,000 cells per injection, TM4SF5-positive tumors exhibited subpopulations with locally increased CD44 expressions, supporting for tumor cell differentiation. TM4SF5-positive, but not TM4SF5- or CD44-knocked-down, cells were identified circulating in blood 4-6 weeks after orthotopic liver injection using in vivo laser scanning endomicroscopy. Anti-TM4SF5 reagent blocked their metastasis to distal intestinal organs. TM4SF5 promotes self-renewal and CTC properties supported by TM4SF5(+) /CD44(+(TM4SF5-bound)) /ALDH(+) /CD24(-) markers during HCC metastasis.


Toward Heisenberg-limited spectroscopy with multiparticle entangled states.
The precision in spectroscopy of any quantum system is fundamentally limited by the Heisenberg uncertainty relation for energy and time. For N systems, this limit requires that they be in a quantum-mechanically entangled state. We describe a scalable method of spectroscopy that can potentially take full advantage of entanglement to reach the Heisenberg limit and has the practical advantage that the spectroscopic information is transferred to states with optimal protection against readout noise. We demonstrate our method experimentally with three beryllium ions. The spectroscopic sensitivity attained is 1.45(2) times as high as that of a perfect experiment with three non-entangled particles.


The NACSTOP Trial: A Multicenter, Cluster-Controlled Trial of Early Cessation of Acetylcysteine in Acetaminophen Overdose.
Historically, intravenous acetylcysteine has been delivered at a fixed dose and duration of 300 mg/kg over 20 to 21 hours to nearly every patient deemed to be at any risk for hepatotoxicity following acetaminophen overdose. We investigated a 12-hour treatment regimen for selected low-risk patients. This was a multicenter, open-label, cluster-controlled trial at six metropolitan emergency departments. We enrolled subjects following single or staggered acetaminophen overdose with normal serum alanine transaminase (ALT) and creatinine on presentation and at 12 hours, and less than 20 mg/L acetaminophen at 12 hours. Patients were allocated to intervention (250 mg/kg over 12-hour) or control (300 mg/kg over 20-hour) regimens by site. The primary outcome was incidence of "hepatic injury" 20 hours following initiation of acetylcysteine treatment, defined as ALT doubling and peak ALT greater than 100 IU/L, indicating the need for further antidotal treatment. Secondary outcomes included incidence of hepatotoxicity (ALT > 1,000 IU/L), peak international normalized ratio (INR), and adverse drug reactions. Of the 449 acetaminophen overdoses receiving acetylcysteine, 100 were recruited to the study. Time to acetylcysteine (median 7 hours [interquartile ratio 6,12] versus 7 hours [6,10]) and initial acetaminophen (124 mg/L [58,171] versus 146 mg/L [66,204]) were similar between intervention and control groups. There was no difference in ALT (18 IU/L [13,22] versus 16 IU/L [13,21]) or INR (1.2 versus 1.2) 20 hours after starting acetylcysteine between groups. No patients developed hepatic injury or hepatotoxicity in either group (odds ratio 1.0 [95% confidence interval 0.02, 50]). No patients represented with liver injury, none died, and 96 of 96 were well at 14-day telephone follow-up. Conclusion: Discontinuing acetylcysteine based on laboratory testing after 12 hours of treatment is feasible and likely safe in selected patients at very low risk of liver injury from acetaminophen overdose.


The development and evaluation of a large-scale self-referral CBT-I intervention for men who have insomnia: an exploratory study.
Whilst effective psychological treatments such as CBT-I have been developed for insomnia, few services provide CBT-I and awareness of CBT-I is low among referrers. In addition, men tend to seek help less frequently for their insomnia than women. This paper describes the development and evaluation of psycho-educational CBT-I workshops, each for up to 25 people, and designed to be acceptable to men. The CBT-I programme was based on Morin and Espie (2003), and adapted into a self-referral one-day workshop format designed specifically to improve access. Workshops were held on Saturdays in leisure centres. A one group pretest-posttest design was used and assessments were collected before and 6 weeks after each workshop. Over a 6-month period, 74 men self-referred, and attended the Introductory Talks preceding the workshops. Of these, 49.3% had never sought help from their GP, 66.2% suffered from clinical insomnia (ISI) and 61.6% were experiencing elevated depression symptoms (BDI over 10). At follow-up, the workshops were found to be effective in reducing insomnia and depression. Satisfaction ratings with the workshops were very high. Given these promising results, further work is now proposed for a larger controlled study with a longer-term follow-up.


Exercise-induced changes in urinary water and mineral output during the menstrual cycle.
This study monitors changes in urinary excretion of water and minerals before and after exercise in pre-menopausal women and in those using oral contraception. Resting urine flow rate was lower and sodium output significantly higher (p less than 0.02) during the normal post-menstrual phase than during other phases of the cycle. These changes were unrelated to glomerular filtration rate and might impede maximal performance. After exercise an oliguria and hyponatriuresis were most pronounced during the menstrual phase. In addition the resting urinary output of calcium and magnesium were unrelated to normal oestrogenic and progestegenic cyclic surges. Amongst oral contraceptive users, resting excretion of water, minerals and creatinine were all significantly lower than general menstrual cycle values (p less than 0.01) and further reductions in salts and water output occurred with exercise. Basal calcium and magnesium excretion rates were significantly lower than general menstrual cycle values (p less than 0.05). Renal conservation of water and salts for 'pill' takers may affect renal homeostasis. The consequences of mineral retention are unknown.


Decoding and reprogramming fungal iterative nonribosomal peptide synthetases.
Nonribosomal peptide synthetases (NRPSs) assemble a large group of structurally and functionally diverse natural products. While the iterative catalytic mechanism of bacterial NRPSs is known, it remains unclear how fungal NRPSs create products of desired length. Here we show that fungal iterative NRPSs adopt an alternate incorporation strategy. Beauvericin and bassianolide synthetases have the same C1-A1-T1-C2-A2-MT-T2a-T2b-C3 domain organization. During catalysis, C3 and C2 take turns to incorporate the two biosynthetic precursors into the growing depsipeptide chain that swings between T1 and T2a/T2b with C3 cyclizing the chain when it reaches the full length. We reconstruct the total biosynthesis of beauvericin in vitro by reacting C2 and C3 with two SNAC-linked precursors and present a domain swapping approach to reprogramming these enzymes for peptides with altered lengths. These findings highlight the difference between bacterial and fungal NRPS mechanisms and provide a framework for the enzymatic synthesis of non-natural nonribosomal peptides.


Exercise training enhances leg vasodilatory capacity of 65-yr-old men and women.
To determine whether extremity vasodilatory capacity may be augmented in older persons by endurance exercise training, lower leg blood flow and conductance were characterized plethysmographically at rest and during maximal hyperemia in 9 men and 10 women aged 64 +/- 3 (SD) yr before and after 31 +/- 6 wk of walking and jogging at 70-90% of maximal oxygen uptake for 45 min 3-5 days/wk. Maximal oxygen uptake expressed as milliliters per kilogram per minute improved 25% in men and 21% in women (P less than 0.01). Maximal leg blood flow and conductance increased in all nine men by an average of 39 +/- 33 (P less than 0.001) and 42 +/- 44% (P less than 0.004), respectively. Results were more variable in women and achieved unequivocal statistical significance only for maximal blood flow (+33 +/- 54% for blood flow and +29 +/- 55% for conductance; P less than 0.02 and P = 0.05, respectively). Body weight and skinfold adiposity declined in both sexes (P less than 0.05). Enhancement of vasodilatory capacity was related to weight loss in men and adipose tissue loss in women (r = 0.61 and 0.51, respectively; P less than 0.05). There were no significant changes in exercise capacity, body weight, or maximal blood flow in four male and three female controls aged 66 +/- 4 yr. Thus adaptability of the lower limb circulation to endurance exercise training is retained to at least age 65 yr.


Lewis acid-promoted [2 + 2] cycloadditions of alkenes with aryl ketenes.
A method for the [2 + 2] cycloaddition of aryl ketenes and alkenes is presented. The process involves the in situ generation of a ketene in the presence of a Lewis acid. The utility of products is demonstrated towards the synthesis of a common scaffold found in several natural product families.


Maturity onset diabetes of the young is not linked to the insulin gene.
Maturity onset diabetes of the young is inherited as an autosomal dominant condition. Two families with the disease were studied to determine whether the inheritance of this type of diabetes was linked to the insulin gene. A cloned insulin gene probe was hybridised to DNA from the family members and the insulin gene on each chromosome identified by a different fragment length polymorphism. The results showed no linkage between the insulin gene and the inheritance of maturity onset diabetes of the young.


Integrating evolution into ecological modelling: accommodating phenotypic changes in agent based models.
Evolutionary change is a characteristic of living organisms and forms one of the ways in which species adapt to changed conditions. However, most ecological models do not incorporate this ubiquitous phenomenon. We have developed a model that takes a 'phenotypic gambit' approach and focuses on changes in the frequency of phenotypes (which differ in timing of breeding and fecundity) within a population, using, as an example, seasonal breeding. Fitness per phenotype calculated as the individual's contribution to population growth on an annual basis coincide with the population dynamics per phenotype. Simplified model variants were explored to examine whether the complexity included in the model is justified. Outputs from the spatially implicit model underestimated the number of individuals across all phenotypes. When no phenotype transitions are included (i.e. offspring always inherit their parent's phenotype) numbers of all individuals are always underestimated. We conclude that by using a phenotypic gambit approach evolutionary dynamics can be incorporated into individual based models, and that all that is required is an understanding of the probability of offspring inheriting the parental phenotype.


The next 10 years for tuberculosis vaccines: do we have the right plans in place?
The control of TB is a global health priority. Over the last decade, considerable progress has been made in the field of TB vaccines with numerous vaccine candidates entering the clinic and two candidates now in Phase IIb efficacy trials. Nevertheless, the lack of predictive animal models and biomarkers of TB vaccine efficacy prevents rational vaccine down-selection and necessitates prolonged and expensive clinical efficacy trials in target populations. Advances in molecular technology and progress in the development of human as well as animal mycobacterial challenge models make the identification of one or more immune correlates of protection a genuine prospect over the next decade. Moreover, the increasing pace, extent and coordination of global research efforts in TB promises to broaden understanding and inform the next generation of vaccine candidates against TB as well as related globally important pathogens.


Beyond volume: hospital-based healthcare technology as a predictor of mortality for cardiovascular patients in Korea.
To examine whether hospital-based healthcare technology is related to 30-day postoperative mortality rates after adjusting for hospital volume of cardiovascular surgical procedures.This study used the National Health Insurance Service-Cohort Sample Database from 2002 to 2013, which was released by the Korean National Health Insurance Service. A total of 11,109 cardiovascular surgical procedure patients were analyzed. The primary analysis was based on logistic regression models to examine our hypothesis.After adjusting for hospital volume of cardiovascular surgical procedures as well as for all other confounders, the odds ratio (OR) of 30-day mortality in low healthcare technology hospitals was 1.567-times higher (95% confidence interval [CI] = 1.069-2.297) than in those with high healthcare technology. We also found that, overall, cardiovascular surgical patients treated in low healthcare technology hospitals, regardless of the extent of cardiovascular surgical procedures, had the highest 30-day mortality rate.Although the results of our study provide scientific evidence for a hospital volume-mortality relationship in cardiovascular surgical patients, the independent effect of hospital-based healthcare technology is strong, resulting in a lower mortality rate. As hospital characteristics such as clinical pathways and protocols are likely to also play an important role in mortality, further research is required to explore their respective contributions.


Recurrent MLK4 Loss-of-Function Mutations Suppress JNK Signaling to Promote Colon Tumorigenesis.
MLK4 is a member of the mixed-lineage family of kinases that regulate the JNK, p38, and ERK kinase signaling pathways. MLK4 mutations have been identified in various human cancers, including frequently in colorectal cancer, where their function and pathobiological importance have been uncertain. In this study, we assessed the functional consequences of MLK4 mutations in colon tumorigenesis. Biochemical data indicated that a majority of MLK4 mutations are loss-of-function (LOF) mutations that can exert dominant-negative effects. In seeking to understand the abrogated activity of these mutants, we elucidated a new MLK4 catalytic domain structure. To determine whether MLK4 is required to maintain tumorigenic phenotypes, we reconstituted its signaling axis in colon cancer cells harboring MLK4-inactivating mutations. We found that restoring MLK4 activity reduced cell viability, proliferation, and colony formation in vitro and delayed tumor growth in vivo. Mechanistic investigations established that restoring the function of MLK4 selectively induced the JNK pathway and its downstream targets, cJUN, ATF3, and the cyclin-dependent kinase inhibitors CDKN1A and CDKN2B. Our work indicates that MLK4 is a novel tumor-suppressing kinase harboring frequent LOF mutations that lead to diminished signaling in the JNK pathway and enhanced proliferation in colon cancer.


Systematic revision of the avian family Cisticolidae based on a multi-locus phylogeny of all genera.
The avian taxon Cisticolidae includes c. 110 species which are distributed throughout the tropical and subtropical parts of the Old World. We estimated the phylogeny of 47 species representing all genera assumed to be part of Cisticolidae based on sequence data from two mitochondrial and two nuclear markers, in total 3495bp. Bayesian inference and maximum likelihood analyses resulted in a generally well-supported phylogeny which clarified the position of several previously poorly known taxa. The placement of Drymocichla, Malcorus, Micromacronus, Oreophilais, Phragmacia, Phyllolais, Poliolais and Urorhipis in Cisticolidae is corroborated, whereas Rhopophilus and Scotocerca are removed from Cisticolidae. Urorhipis and Heliolais are placed in the genus Prinia whereas Prinia burnesii is shown to be part of Timaliidae, and is placed in the genus Laticilla. Although not recovered by all single loci independently, four major clades were identified within Cisticolidae, and one of these is here described as a new taxon (Neomixinae).


Morphogenesis and aggressiveness of cervix carcinoma.
The regular nutritional intake of an expectant mother clearly affects the weight development of the fetus. Assuming the growth of the fetus follows a deterministic growth law, like a logistic equation, albeit dependent on the nutritional intake, the ideal solution is usually determined by the birth-weight being pre-assigned, for example, as a percentage of the mother's average weight. This problem can then be specified as an optimal control problem with the daily intake as the control, which appears in a Michaelis-Menten relationship, for which there are well-developed procedures to follow. The best solution is determined by requiring minimum total intake under which the preassigned birth weight is reached. The algorithm has been generalized to the case where the fetal weight depends in a detailed way on the cumulative intake, suitably discounted according to the history. The optimality system is derived and then solved numerically using an iterative method for the specific values of parameter. The procedure is generic and can be adapted to any growth law and any parameterisation obtained by the detailed physiology.


Barriers to gene exchange in hybridizing field crickets: the role of male courtship effort and cuticular hydrocarbons.
Pre-zygotic barriers often involve some form of sexual selection, usually interpreted as female choice, as females are typically the choosier sex. However, males typically show some mate preferences, which are increasingly reported. Here we document previously uncharacterized male courtship behavior (effort and song) and cuticular hydrocarbon (CHC) profiles in the hybridizing crickets Gryllus firmus and G. pennsylvanicus. These two species exhibit multiple barriers to gene exchange that act throughout their life history, including a behavioral barrier that results in increased time to mate in heterospecific pairs. We demonstrated that male mate choice (as courtship effort allocation) plays a more important role in the prezygotic behavioral barrier than previously recognized. In gryllids females ultimately decide whether or not to mate, yet we found males were selective by regulating courtship effort intensity toward the preferred (conspecific) females. Females were also selective by mating with more intensely courting males, which happened to be conspecifics. We report no differences in courtship song between the two species and suggest that the mechanism that allows males to act differentially towards conspecific and heterospecific females is the cuticular hydrocarbon (CHC) composition. CHC profiles differed between males and females of both species, and there were clear differences in CHC composition between female G. firmus and G. pennsylvanicus but not between the males of each species. Although many barriers to gene exchange are known in this system, the mechanism behind the mate recognition leading to reduced heterospecific mating remains unknown. The CHC profiles might be the phenotypic cue that allow males to identify conspecifics and thus to adjust their courtship intensity accordingly, leading to differential mating between species.


Linkage analysis of candidate genes in autoimmune thyroid disease: 1. Selected immunoregulatory genes. International Consortium for the Genetics of Autoimmune Thyroid Disease.
Graves' and Hashimoto's diseases are autoimmune thyroid diseases in which the genetic contribution is complex. For this reason, identification of necessary susceptibility genes has been difficult. However, a number of immunoregulatory genes have been implicated by association studies, including: CTLA-4, a recently described protein involved in antigen presentation, located on chromosome 2q33; the T-cell receptor V alpha and V beta gene complexes, located on 14q11 and 7q35, respectively; and the Ig gene complex (IgH), located on 15q11. We used polymorphic microsatellite markers located within these genes, or gene complexes, to test for linkage (rather than association), to each of these candidates. Using markers within the loci allowed us to assume a fixed recombination fraction of 0.01 in the tested model. Three hundred eight subjects from 48 multiplex families were studied, with 142 affected subjects. Using this set of families, we have previously shown evidence of linkage with a major susceptibility locus for Graves' disease (GD-1) on 14q24.3-31, with a maximum lod (logarithm + odds) score of 2.1, at a penetrance of 80% and with a dominant mode of inheritance. In the present study, we obtained consistently negative lod scores for each of the candidate genes, assuming either dominant or recessive modes of inheritance. These data, therefore, showed evidence against linkage with all the candidate genes. Unlike association studies, linkage analyses detect major genetic influences on disease susceptibility exerted by the linked loci. The lack of linkage for the immunoregulatory genes that were studied indicated, therefore, that they were not major contributors to disease etiology.


A biphasic memory curve in the chambered nautilus, Nautilus pompilius L. (Cephalopoda: Nautiloidea).
Cephalopods are an exceptional taxon for examining the competing influences of ecology and evolutionary history on brain and behaviour. Coleoid cephalopods (octopuses, cuttlefishes and squids) have evolved specialised brains containing dedicated learning and memory centres, and rely on plastic behaviours to hunt prey effectively and communicate intricate visual displays. Their closest living relative, the primitive nautilus, is the sole remnant of an ancient lineage that has persisted since the Cambrian. Nautilus brains are the simplest among the extant cephalopods, and the absence of dedicated learning and memory regions may represent an ancestral condition. It is assumed that the absence of these regions should limit memory storage and recall in nautilus, but this assumption has never been tested. Here we describe the first evidence of learning and memory in chambered nautilus (Nautilus pompilius). Using a Pavlovian conditioning paradigm, we demonstrate that chambered nautilus exhibits temporally separated short- and long-term memory stores, producing a characteristic biphasic memory curve similar to that of cuttlefishes. Short-term memory persisted for less than 1 h post-training, whereas long-term memory was expressed between 6 and 24 h after training. Despite lacking the dedicated neural regions that support learning and memory in all other extant cephalopods, nautilus expressed a similar memory profile to coleoids. Thus the absence of these regions in the nautilus brain does not appear to limit memory expression, as hypothesised. Our results provide valuable insights into the evolution of neural structures supporting memory.


'Names will never hurt us': A qualitative exploration of çapulcu identity through the eyes of Gezi Park protesters.
While there is a wealth of literature on how and why people engage in collective action, there has been comparably less focus on the way identities that have emerged (as compared to how they are consolidated or politicized) through crowd action are understood and explained by those who carry those identities, as well as the particular importance of norm formation and adherence in this process. The Gezi Park protests in Turkey allowed studying exactly how a newly created identity - çapulcu identity [Turkish for looters] - can be perceived by the protesters. The present study utilizes a qualitative approach to explore how the çapulcu identity was understood by people who participated in the Gezi Park protests, as well as the norms and prototypes associated with that identity. More specifically, we investigated perceptions of (1) the defining characteristics of a new identity (i.e., meaning of çapulcu), (2) prototypicality (i.e., typical çapulcu), (3) expectations of çapulcu behaviour in terms of social norms, and (4) out-group definitions (i.e., differentiating a çapulcu from a non-çapulcu). We used a survey with open-ended questions to explore çapulcu identity and analysed the data from 196 participants using qualitative content analysis. Results highlighted the important defining characteristics of çapulcu identity, how this identity is positioned in relation to the newly created out-group (i.e., government supporters), and social norms based on this newly created identity. We discuss the meanings of identity characteristics and social norms in the political context of Turkey in relation to existing collective action models, as well as why we need to examine identities that come about during protests qualitatively.


Association of protein kinase A and protein phosphatase 2B with a common anchoring protein.
Specificity of protein kinases and phosphatases may be achieved through compartmentalization with preferred substrates. In neurons, adenosine 3', 5'-monophosphate (cAMP)-dependent protein kinase (PKA) is localized at postsynaptic densities by association of its regulatory subunit with an A kinase anchor protein, AKAP79. Interaction cloning experiments demonstrated that AKAP79 also binds protein phosphatase 2B, or calcineurin (CaN). A ternary complex of PKA, AKAP, and CaN was isolated from bovine brain, and colocalization of the kinase and the phosphatase was established in neurites of cultured hippocampal neurons. The putative CaN-binding domain of AKAP79 is similar to that of the immunophilin FKBP-12, and AKAP79 inhibited CaN phosphatase activity. These results suggest that both PKA and CaN are targeted to subcellular sites by association with a common anchor protein and thereby regulate the phosphorylation state of key neuronal substrates.


Molecular mechanisms of renal blood flow autoregulation.
Diabetes and hypertension are the leading causes of chronic kidney disease and their incidence is increasing at an alarming rate. Both are associated with impairments in the autoregulation of renal blood flow (RBF) and greater transmission of fluctuations in arterial pressure to the glomerular capillaries. The ability of the kidney to maintain relatively constant blood flow, glomerular filtration rate (GFR) and glomerular capillary pressure is mediated by the myogenic response of afferent arterioles working in concert with tubuloglomerular feedback that adjusts the tone of the afferent arteriole in response to changes in the delivery of sodium chloride to the macula densa. Despite intensive investigation, the factors initiating the myogenic response and the signaling pathways involved in the myogenic response and tubuloglomerular feedback remain uncertain. This review focuses on current thought regarding the molecular mechanisms underlying myogenic control of renal vascular tone, the interrelationships between the myogenic response and tubuloglomerular feedback, the evidence that alterations in autoregulation of RBF contributes to hypertension and diabetes-induced nephropathy and the identification of vascular therapeutic targets for improved renoprotection in hypertensive and diabetic patients.


Electro-acupuncture reverses nerve growth factor abundance in experimental polycystic ovaries in the rat.
Polycystic ovary syndrome (PCOS) remains one of the most common causes of anovulation in women of reproductive age. There is some evidence that nerve growth factor (NGF) is involved in the pathogenesis of PCOS. Therefore, seeking the pathogenesis of PCOS is important for controlling fertility. In traditional Oriental Medicine, acupuncture has been used for the function of ovaries. The present study was designed to determine whether electro-acupuncture (EA) could affect experimentally induced polycystic ovary (PCO) in the rat. The two acupoints Sp-6 and E-128 were stimulated to test for efficacy in the protein expression of NGF. Polycystic ovaries were induced by a single injection of estradiol valerate (4 mg i.m.). During the experimental period of 8 weeks, some of the rats were treated with EA twice weekly; this group was compared with a vehicle-treated control group and an estradiol-injected group not subjected to EA. At day 60, the protein expression of NGF was examined by immunohistochemistry in the ovaries, the adrenal glands and some parts of the brain. The estradiol treatment induced a clear PCO appearance, and was associated with a robust increase in NGF expression in the ovaries, the adrenal glands and the brain. EA treatment partly reversed the NGF abundance, particularly in the ovaries, but not in the brain. Our data show that EA affects the NGF involvement in ovarian dysfunction.