Sleep Duration and Health-Related Quality of Life in Predialysis CKD.
Sleep duration has been associated with cardiometabolic risk and mortality. The health-related quality of life represents a patient's comprehensive perception of health and is accepted as a health outcome. We examined the relationship between sleep duration and health-related quality of life in predialysis CKD. In this cross-sectional study, data from 1910 adults with CKD enrolled in the Korean Cohort Study for Outcome in Patients with CKD were analyzed. Health-related quality of life was assessed with the physical component summary and mental component summary of the Short Form-36 Health Survey. Low health-related quality of life was defined as a Short Form-36 Health Survey score >1 SD below the mean. Using a generalized additive model and multivariable logistic regression analysis, the relationship between self-reported sleep duration and health-related quality of life was examined. Seven-hour sleepers showed the highest health-related quality of life. We found an inverted U-shaped relationship between sleep duration and health-related quality of life as analyzed by a generalized additive model. In multivariable logistic analysis, short sleepers (≤5 h/d) had lower health-related quality of life (odds ratio, 3.23; 95% confidence interval, 1.86 to 5.60 for the physical component summary; odds ratio, 2.37; 95% confidence interval, 1.43 to 3.94 for the mental component summary), and long sleepers (≥9 h/d) had lower health-related quality of life (odds ratio, 2.80; 95% confidence interval, 1.55 to 5.03 for the physical component summary; odds ratio, 2.08; 95% confidence interval, 1.20 to 3.60 for the mental component summary) compared with 7-hour sleepers. Sleep duration had a significant U-shaped association with low health-related quality of life. These findings suggest that short or long sleep duration is independently associated with low health-related quality of life in adults with CKD.


Ecocultural basis of cognition: farmers and fishermen are more holistic than herders.
It has been proposed that social interdependence fosters holistic cognition, that is, a tendency to attend to the broad perceptual and cognitive field, rather than to a focal object and its properties, and a tendency to reason in terms of relationships and similarities, rather than rules and categories. This hypothesis has been supported mostly by demonstrations showing that East Asians, who are relatively interdependent, reason and perceive in a more holistic fashion than do Westerners. We examined holistic cognitive tendencies in attention, categorization, and reasoning in three types of communities that belong to the same national, geographic, ethnic, and linguistic regions and yet vary in their degree of social interdependence: farming, fishing, and herding communities in Turkey's eastern Black Sea region. As predicted, members of farming and fishing communities, which emphasize harmonious social interdependence, exhibited greater holistic tendencies than members of herding communities, which emphasize individual decision making and foster social independence. Our findings have implications for how ecocultural factors may have lasting consequences on important aspects of cognition.


Presence of functional dendritic cells in patients chronically infected with hepatitis C virus.
The absence of expanded numbers of hepatitis C virus (HCV)-reactive CD8(+) T lymphocytes (CTLs) in patients chronically infected with HCV has led to the investigation of dendritic cell (DC) function in this population as a potential cause for this defect. Several studies have shown evidence for impaired monocyte-derived DCs in chronically infected patients. As it is difficult to reconcile these data with the fact that patients with chronic HCV are immune competent, we re-evaluated this finding, carefully assessing phenotypic markers and functional activity of patient DCs as compared with noninfected controls. In contrast to these prior studies, DCs from 13 of 13 chronic HCV patients expressed typical maturation markers. These mature DCs were capable of priming allogeneic T lymphocytes, as well as stimulating influenza-specific memory T cells. This finding is consistent with clinical and immunologic data that the deficit in the patient's immune repertoire is HCV-specific and suggests that refined models are required for understanding the role of DCs in HCV pathogenesis.


Endoplasmic reticulum-located PDAT1-2 from castor bean enhances hydroxy fatty acid accumulation in transgenic plants.
Ricinoleic acid (12-hydroxy-octadeca-9-enoic acid) is a major unusual fatty acid in castor oil. This hydroxy fatty acid is useful in industrial materials. This unusual fatty acid accumulates in triacylglycerol (TAG) in the seeds of the castor bean (Ricinus communis L.), even though it is synthesized in phospholipids, which indicates that the castor plant has an editing enzyme, which functions as a phospholipid:diacylglycerol acyltransferase (PDAT) that is specific to ricinoleic acid. Transgenic plants containing fatty acid Δ12-hydroxylase encoded by the castor bean FAH12 gene produce a limited amount of hydroxy fatty acid, a maximum of around 17% of TAGs present in Arabidopsis seeds, and this unusual fatty acid remains in phospholipids of cell membranes in seeds. Identification of ricinoleate-specific PDAT from castor bean and manipulation of the phospholipid editing system in transgenic plants will enhance accumulation of the hydroxy fatty acid in transgenic seeds. The castor plant has three PDAT genes; PDAT1-1 and PDAT2 are homologs of PDAT, which are commonly found in plants; however, PDAT1-2 is newly grouped as a castor bean-specific gene. PDAT1-2 is expressed in developing seeds and localized in the endoplasmic reticulum, similar to FAH12, indicating its involvement in conversion of ricinoleic acid into TAG. PDAT1-2 significantly enhances accumulation of total hydroxy fatty acid up to 25%, with a significant increase in castor-like oil, 2-OH TAG, in seeds of transgenic Arabidopsis, which is an identification of the key gene for oilseed engineering in production of unusual fatty acids.


The correlation between the imaging characteristics of hamstring injury and time required before returning to sports: a literature review.
Injuries to the hamstring muscles are common in athletes. Track and field, Australian football, American football and soccer are examples of sports where hamstring injuries are the most common. The purpose of this study was to investigate whether there is a correlation between a hamstring injury prognosis and its characteristics of imaging parameters. The literature search was performed in the databases PubMed and CINAHL, and eleven articles were included. Seven out of the 11 articles showed a correlation between the size of the hamstring injury and length of time required before returning to sports. Different authors have reported contrasting results about length of time required before returning to sports due to location of injury within specific muscle. Majority of the articles found hamstring strain correlated to an extended amount of time required before returning to sports.


The role of left-right symmetry in the encodement of spatial orientations.
Three experiments investigated a hypothesis, suggested by studies of the difficulties of discriminating between shapes forming symmetrical pairs, that spatial orientations of thin flat plates (lamellae) may be encoded in a plane, the encodement consisting of two enantiomorphs. The results indicated that participants encoded the spatial orientation of lamellar stimuli in terms of the difference in cogency between their two enantiomorphic elements (Expt 1). The difference in the cogency of the two enantiomorphs is related to the orientation of the plane containing the lamellar stimulus with respect to the participant's fronto-parallel plane (Expt 2). The two possible orientations of a lamella which yield the same difference of cogency, but which differ in spatial orientation (e.g. lamella 'b' set at 30 degrees or set at 150 degrees) are distinguished by the manner in which the two enantiomorphic elements are arranged with respect to their axis of symmetry (Expt 3). The results suggest that the orientation of a lamella may be encoded as a two-dimensional representation and hence that three dimensions may be encoded by two by means of enantiomorphs. Implications of this finding for the encodements of three-dimensional solids, wherein pronounced contours may fulfil the same role as do the edges of lamella, are discussed briefly.


Mucosal T cells regulate Paneth and intermediate cell numbers in the small intestine of T. spiralis-infected mice.
Secretions of Paneth, intermediate and goblet cells have been implicated in innate intestinal host defense. We have investigated the role of T cells in effecting alterations in small intestinal epithelial cell populations induced by infection with the nematode Trichinella spiralis. Small intestinal tissue sections from euthymic and athymic (nude) mice, and mice with combined deficiency in T-cell receptor beta and delta genes [TCR(beta/delta)-/-] infected orally with T. spiralis larvae, were examined by electron microscopy and after histochemical and lineage-specific immunohistochemical staining. Compared with uninfected controls, Paneth and intermediate cell numbers increased significantly in infected euthymic and nude mice but not infected TCR(beta/delta)-/- mice. Transfer of mesenteric lymph node cells before infection led to an increase in Paneth and intermediate cells in TCR(beta/delta)-/- mice. In infected euthymic mice, Paneth cells and intermediate cells expressed cryptdins (alpha-defensins) but not intestinal trefoil factor (ITF), and goblet cells expressed ITF but not cryptdins. In conclusion, a unique, likely thymic-independent population of mucosal T cells modulates innate small intestinal host defense in mice by increasing the number of Paneth and intermediate cells in response to T. spiralis infection.


Contribution of the Nordic School of Public Health to the public mental health research field: a selection of research initiatives, 2007-2014.
The field of public mental health has been defined by an expert group convened by the Nordic School of Public Health (NHV) as encompassing the experience, occurrence, distribution and trajectories of positive mental health and mental health problems and their determinants; mental health promotion and prevention of mental disorders; as well as mental health system policies, governance and organization. The mental health priorities of the Nordic Council of Ministers in 2010 signalled a mutual Nordic exchange of knowledge in the following thematic areas: child and adolescent mental health; working life and mental health; mental health in older people; strengthening the role of primary care in mental health service provision; stronger involvement of users and carers; and reduction of use of coercion in psychiatric care. Efforts to realize these priorities included commissioning the Nordic Research Academy for Mental Health, an NHV-based network of research institutions with a common interest in mental health research across the Nordic countries, to develop, organize and follow-up projects on public mental health. The research initiatives included mental health policy analysis, register-based research and research focused on the users' perspective in a Nordic context, as well as EU-level research policy analysis. The public mental health research conducted at the NHV highlighted the complexity of mental health and emphasized that the broad determinants of mental health need to be increasingly addressed in both public health research and practice. For example, health promotion actions, improved access to health care, a healthy alcohol policy and prevention of suicides and violence are all needed to reduce the life expectancy gap - a red flag indicator of public health inequalities. By exchanging knowledge and best practice, the collaboration between the Nordic countries contributes to the welfare of the region. The expertise and traditions developed at the NHV are of significant importance in this work.


Caring for a common future: medical schools' social accountability.
ORIGINS AND CONTEXT: The concept of 'the social accountability of medical schools' is moving from the peripheral preoccupation of a few to a more central concern of medical schools themselves. Born of concerns about the professionalism and relevance of both the institutions and their graduates, it is seen increasingly as an urgent call to focus the considerable social resources vested in academic health science institutions on addressing the priority health concerns of the societies they serve. For a profession embedded in an ethos of service, this would seem an obvious transition. However, as with any movement towards transformative change, it runs the risk of being more mantra and rhetoric than mandate and responsibility. NEEDED RESPONSE: Proceeding from the assumption that good intentions alone are not enough, this paper seeks to outline the historical development and some current expression of the concept throughout the world. The sadly divergent wealth and health status of modern societies calls for very different actions by medical schools across the spectrum from the least endowed to the wealthiest of schools. In a profession claiming centuries of cohesive commitment to the welfare of others, it is increasingly urgent that the current generation of medical educators converge on a relevant set of principles and coherent activities. TOOLS FOR THE TASK: While recognising that they are closely intertwined, the paper outlines the difference between the social accountability of the institutions themselves and the social accountability of the graduates they produce. It outlines both individual examples and the international initiatives that are fostering and facilitating institutional collaborations to bring both progress and optimism to this daunting task. It provides connections to practical resources for those who are committed to that task. Other papers in this series add further practical insights into the central role that medical educators must play if we are to fulfil the responsibilities we carry with the privilege of our profession.


Discovery of All Three Types in Cartilaginous Fishes Enables Phylogenetic Resolution of the Origins and Evolution of Interferons.
Interferons orchestrate host antiviral responses in jawed vertebrates. They are categorized into three classes; IFN1 and IFN3 are the primary antiviral cytokine lineages, while IFN2 responds to a broader variety of pathogens. The evolutionary relationships within and between these three classes have proven difficult to resolve. Here, we reassess interferon evolution, considering key phylogenetic pitfalls including taxon sampling, alignment quality, model adequacy, and outgroup choice. We reveal that cartilaginous fishes, and hence the jawed vertebrate ancestor, possess(ed) orthologs of all three interferon classes. We show that IFN3 groups sister to IFN1, resolve the origins of the human IFN3 lineages, and find that intronless IFN3s emerged at least three times. IFN2 genes are highly conserved, except for IFN-γ-rel, which we confirm resulted from a teleost-specific duplication. Our analyses show that IFN1 phylogeny is highly sensitive to phylogenetic error. By accounting for this, we describe a new backbone IFN1 phylogeny that implies several IFN1 genes existed in the jawed vertebrate ancestor. One of these is represented by the intronless IFN1s of tetrapods, including mammalian-like repertoires of reptile IFN1s and a subset of amphibian IFN1s, in addition to newly-identified intron-containing shark IFN1 genes. IFN-f, previously only found in teleosts, likely represents another ancestral jawed vertebrate IFN1 family member, suggesting the current classification of fish IFN1s into two groups based on the number of cysteines may need revision. The providence of the remaining fish IFN1s and the coelacanth IFN1s proved difficult to resolve, but they may also be ancestral jawed vertebrate IFN1 lineages. Finally, a large group of amphibian-specific IFN1s falls sister to all other IFN1s and was likely also present in the jawed vertebrate ancestor. Our results verify that intronless IFN1s have evolved multiple times in amphibians and indicate that no one-to-one orthology exists between mammal and reptile IFN1s. Our data also imply that diversification of the multiple IFN1s present in the jawed vertebrate ancestor has occurred through a rapid birth-death process, consistent with functional maintenance over a 450-million-year host-pathogen arms race. In summary, this study reveals a new model of interferon evolution important to our understanding of jawed vertebrate antiviral immunity.


Immunogenicity and reactivity of novel Mycobacterium avium subsp. paratuberculosis PPE MAP1152 and conserved MAP1156 proteins with sera from experimentally and naturally infected animals.
Mycobacterium avium subsp. paratuberculosis causes Johne's disease (JD) in ruminants. Development of genetic tools and completion of the M. avium subsp. paratuberculosis genome sequencing project have expanded the opportunities for antigen discovery. In this study, we determined the seroreactivities of two proteins encoded at the 5' and 3' regions of the MAP1152-MAP1156 gene cluster. MAP1152 encodes a PPE protein, and MAP1156 encodes a diacylglycerol acyltransferase involved in triglyceride metabolism and classified in the uncharacterized protein family UPF0089. Recombinant MAP proteins were overproduced and purified from Escherichia coli as maltose-binding protein (MBP) fusions. Immunoblotting analysis indicated that both MAP1152 and MAP1156 displayed reactivity against sera of mice and rabbits immunized with live M. avium subsp. paratuberculosis cells and against samples from naturally infected cattle. In immunoblot assays, MAP1156 yielded a stronger positive signal than MAP1152 against sera from cattle with JD. An enzyme-linked immunosorbent assay for the recombinant proteins was developed and used to test preclassified positive and negative serum samples from naturally infected and noninfected cattle. Samples, with one exception, displayed no seroreactivity against the MBP-LacZ fusion protein (P > 0.05), the negative-control antigen. MAP1152 displayed seroreactivity against all positive sera but no seroreactivity to the negative sera (P < 0.01). MAP1156 displayed stronger and more variable reactivity than MAP1152, but significant differences were observed between noninfected and infected cattle (P < 0.05). Otherwise, degrees of reactivity followed the same trend as the positive reference antigen. In conclusion, both proteins are immunogenic in mice and rabbits, and M. avium subsp. paratuberculosis-infected cattle mount a humoral response to both MAP1152 and MAP1156 cross-reactive epitopes. These findings have potential applications to diagnostics, vaccine production, and elucidation of the immunopathogenesis of JD.


Energy Model of Neuron Activation.
On the basis of the neurophysiological strength-duration (amplitude-duration) curve of neuron activation (which relates the threshold amplitude of a rectangular current pulse of neuron activation to the pulse duration), as well as with the use of activation energy constraint (the threshold curve corresponds to the energy threshold of neuron activation by a rectangular current pulse), an energy model of neuron activation by a single current pulse has been constructed. The constructed model of activation, which determines its spectral properties, is a bandpass filter. Under the condition of minimum-phase feature of the neuron activation model, on the basis of Hilbert transform, the possibilities of phase-frequency response calculation from its amplitude-frequency response have been considered. Approximation to the amplitude-frequency response by the response of the Butterworth filter of the first order, as well as obtaining the pulse response corresponding to this approximation, give us the possibility of analyzing the efficiency of activating current pulses of various shapes, including analysis in accordance with the energy constraint.


Cardiopulmonary resuscitation on television: are we miseducating the public?
Out-of-hospital cardiac arrest survival rates in the UK are poor, and non-medically trained individuals have been identified to perform substandard cardiopulmonary resuscitation (CPR). Millions watch televised medical dramas and, for many, these comprise their only education on CPR. This study aims to investigate the quality of CPR portrayed on these programmes and whether this has an effect on public knowledge. Prospective observational study of 30 consecutive episodes of three popular medical dramas. Public knowledge of CPR and viewing habits were assessed with a survey of non-medically trained personnel. 90 episodes were reviewed with 39 resuscitation attempts shown. Chest compression rates varied from 60 to 204 compressions per minute with a median of 122 (95% CI 113 to 132). Depth varied from 1.5 to 7.5 cm with a median of 3 (3.15-4.31). Rate and depth were significantly different from the UK Resuscitation Council Guidelines (2010) (p<0.05, t-test). Survey participants (n=160, 80% response rate) documented what they thought was the correct rate and depth of chest compressions and were scored accordingly. Those who documented watching medical dramas regularly scored significantly worse than those who watched occasionally (p<0.05, Mann-Whitney test). Televised medical dramas depict CPR inaccurately and laypersons may be less well informed about the correct technique the more they tune into these programmes. While there may be other confounding variables, given the popularity of television medical dramas, the poor depiction may be significantly contributing to poor public CPR knowledge and represent a potential new avenue of public education.


Proliferation signal inhibitors and post-transplant malignancies in heart transplantation: practical clinical management questions.
Although malignancy is a major threat to long-term survival of heart transplant (HT) recipients, clear strategies to manage immunosuppression in these patients are lacking. Several lines of evidences support the hypothesis of an anticancer effect of proliferation signal inhibitors (PSIs: mammalian target of rapamycin [mTOR] inhibitors) in HT recipients. This property may arise from PSI's ability to replace immunosuppressive therapies that promote cancer progression, such as calcineurin inhibitors or azathioprine, and/or through their direct biological actions in preventing tumor development and progression. Given the lack of randomized studies specifically exploring these issues in the transplant setting, a collaborative group reviewed current literature and personal clinical experience to reach a consensus aimed to provide practical guidance for the clinical conduct in HT recipients with malignancy, or at high risk of malignancy, with a special focus on advice relevant to potential role of PSIs.


Current approach to down-staging of hepatocellular carcinoma prior to liver transplantation.
Orthotopic liver transplantation is currently the best curative treatment for hepatocellular carcinoma within conventional Milan criteria. Recent data have suggested that modest expansion of tumor size limits could still preserve acceptable long-term recurrence-free survival. Down-staging of hepatocellular carcinoma initially exceeding conventional criteria for transplantation provides a unique perspective on tumor biology in that those with more favorable tumor biology are more likely to be successfully down-staged and do well after transplantation. This article reviews the principles and published data on down-staging of hepatocellular carcinoma prior to orthotopic liver transplantation. Several groups have examined the use of loco-regional therapy such as chemoembolization and radiofrequency ablation for tumor down-staging before Orthotopic liver transplantation. According to the latest results from the University of California, San Francisco involving 61 patients with hepatocellular carcinoma exceeding Milan criteria but meeting specific criteria for tumor size and number, 70% were successfully down-staged to within Milan criteria by an intention-to-treat analysis, with no posttransplant recurrence and a 4-year posttransplant survival of 92%. Strictly defined upper limits of tumor size and number for patient inclusion, as well as criteria for response to loco-regional therapy, are essential in achieving excellent posttransplant outcome following tumor down-staging.


Lavandula angustifolia Essential Oil and Linalool Counteract Social Aversion Induced by Social Defeat.
Many vegetable extracts, essential oils, and their main constituents are active on the Central Nervous System (CNS). In fact, they have been used as sedatives, hypnotics, or tranquilizers for their activity in treating CNS disorders. In this research, we studied the possible activities of Lavandula angustifolia (LA) essential oil and of its main constituent, linalool, as anti-stress compounds on anxiety and social interaction and their in vitro effects on proteins (pERK and PKA) involved in the transmission of the signal. An acute intraperitoneal injection of linalool (100 mg/kg) and of LA essential oil (200 mg/kg) reduced motor activity without any anxiolytic effect, but significantly increased social interaction. Stressed mice, after being exposed to a social defeat encounter, showed heightened anxiety and social avoidance. Acute administration of LA essential oil blocked stress-induced anxiety, while linalool showed no effects. However, both compounds were capable of reversing social aversion, acting as antidepressant agents. Our results showed that linalool inhibits pERK and PKA expression in the SH-SY5Y cell, but no effect was detected with the LA essential oil. Therefore, the LA essential oil and linalool may be considered as useful alternative tools to the available traditional treatments for social stress-induced mental illnesses.


Visual cortex development in the ferret. I. Genesis and migration of visual cortical neurons.
The production of ferret visual cortical neurons was studied using 3H-thymidine autoradiography. The genesis of cortical neurons begins on or slightly before embryonic day 20 (E20) of the 41 d gestational period, continues postnatally until 2 weeks after birth (P14), and follows an inside-out radial gradient with neurons for the deeper cortical layers being generated before those for the superficial layers. Layer I neurons are generated both early (E20-E30) and late (P1-P14) in the period of cortical neurogenesis and, thus, provide at least a partial exception to the inside-out gradient of cortical neurogenesis. Tangential gradients of cortical neurogenesis extend across areas 17 and 18 in both the anterior-to-posterior and lateral-to-medial directions. Neither of these gradients bears a meaningful relationship to the cortical representation of the visual field. Most infragranular and granular layer neurons are generated prenatally, while most supragranular layer neurons are produced postnatally. Neurons destined for a given layer are produced over a period of several days, and the neurons generated on any given day contribute to the formation of 2 or more cortical layers. In general, prenatally generated neurons complete their migration in 1 week or less, while most postnatally generated neurons require approximately 2 weeks to complete their migration.


High Expression of Stromal Cell-Derived Factor 1 (SDF-1) and NF-κB Predicts Poor Prognosis in Cervical Cancer.
BACKGROUND SDF-1 and NF-κB are associated with the prognosis of a wide range of cancers, but their value in cervical cancer remains controversial. The aim of this study was to investigate the expression of SDF-1and NF-κB in cervical cancer and their significance in clinical prognosis. MATERIAL AND METHODS The expression of SDF-1and NF-κB in 105 formalin-fixed, paraffin-embedded cervical cancer tissues and the adjacent tissues was examined by immunohistochemistry (IHC). The results were semi-quantitatively scored and analyzed by chi-square test. The overall survival times (OS) were collected by follow-up and analyzed by Kaplan-Meier analysis. RESULTS The expression level of both SDF-1and NF-κB in cervical cancer are higher than that in the adjacent tissues (P<0.05). SDF-1 expression are correlated with tumor size and FIGO histology grade (P<0.05). NF-κB expression are correlated with tumor size and FIGO histology grade, and lymph node metastasis (LNM) status (P<0.05). The patients with a positive expression of SDF-1or NF-κB tended to have much shorter survival time than patients with negative expression. In addition, multivariate Cox regression analysis demonstrated that SDF-1 expression and lymph node metastasis are independent predictors of the OS in cervical cancer patients. CONCLUSIONS The expression of SDF-1 is significantly associated with tumor size and FIGO histology grade. The expression of NF-κB is significantly associated with tumor size, FIGO histology grade, and lymph node metastasis. The positive SDF-1or NF-κB expression is significantly correlated with poor prognosis. These may be valuable biomarkers for the prognosis and the potential therapeutic targets of cervical cancer.


The cerebral embolism evoked by intra-arterial delivery of allogeneic bone marrow mesenchymal stem cells in rats is related to cell dose and infusion velocity.
Intra-arterial cell infusion is an efficient delivery route with which to target organs such as the ischemic brain. However, adverse events including microembolisms and decreased cerebral blood flow were recently reported after intra-arterial cell delivery in rodent models, raising safety concerns. We tested the hypothesis that cell dose, infusion volume, and velocity would be related to the severity of complications after intra-arterial cell delivery. In this study, 38 rats were subjected to a sham middle cerebral artery occlusion (sham-MCAO) procedure before being infused with allogeneic bone-marrow mesenchymal stem cells at different cell doses (0 to 1.0 × 10(6)), infusion volumes (0.5 to 1.0 ml), and infusion times (3 to 6 minutes). An additional group (n = 4) was infused with 1.0 × 10(6) cells labeled with iron oxide for in vivo tracking of cells. Cells were infused through the external carotid artery under laser Doppler flowmetry monitoring 48 hours after sham-MCAO. Magnetic resonance imaging (MRI) was performed 24 hours after cell infusion to reveal cerebral embolisms or hemorrhage. Limb placing, cylinder, and open field tests were conducted to assess sensorimotor functions before the rats were perfused for histology. A cell dose-related reduction in cerebral blood flow was noted, as well as an increase in embolic events and concomitant lesion size, and sensorimotor impairment. In addition, a low infusion velocity (0.5 ml/6 minutes) was associated with high rate of complications. Lesions on MRI were confirmed with histology and corresponded to necrotic cell loss and blood-brain barrier leakage. Particularly cell dose but also infusion velocity contribute to complications encountered after intra-arterial cell transplantation. This should be considered before planning efficacy studies in rats and, potentially, in patients with stroke.


What are the barriers to initiating end-of-life conversations with patients in the last year of life?
Improving end of life care is a national imperative. Unsatisfactory care persists particularly in acute hospitals, with shortcomings, variability in communication and advance care planning identified as fundamental issues. This review explored the literature to identify what is known about the barriers to initiating end-of-life conversations with patients from the perspective of doctors and nurses in the acute hospital setting. Six electronic databases were searched for potentially relevant records published between 2008 and 2015. Studies were included if the authors reported on barriers to discussing end of life with families or patients as described by doctors or nurses in hospital settings, excluding critical care. Of 1267 potentially relevant records, 12 were included in the review. Although there is limited high-quality evidence available, several barriers were identified. Recurrent themes within the literature related to a lack of education and training, difficulty in prognostication, cultural differences and perceived reluctance of the patient or family. This study illustrated that, in addressing barriers to communication, consideration needs to be extended to include how to embed good communication practice between patients and health professionals into the culture of this setting. Board level commitment is required to raise awareness of, and familiarity with, policies and protocols concerning communication and end-of-life care. Communication training should include practical skills and tools, opportunities to explore the personal beliefs of practitioners and managing their emotions, opportunities to analyse the local organisational (physical and social environment) and team barriers.


Chiriquitoxin, a new tool for mapping ionic channels.
Chiriquitoxin is a new natural analog of tetrodotoxin in which the -CH2OH group on C6 has been replaced with a yet unidentified group consisting of 104 mass units. It is unique in being the only known stable analog to be equally potent as tetrodotoxin in blocking the sodium channel. It additionally interferes with the delayed rectifier (potassium) channel. In frog skeletal muscle, it significantly reduced the outward current while abolishing the inward current. It also slows the fast repolarization of the action potential and obliterates the voltage response characteristic of delayed rectification to large outward currents. It completes the tetrodotoxin for the same membrane binding site, thereby suggesting that the same molecule interferes with both the sodium and the potassium channels. A new working hypothesis is proposed in which tetrodotoxin and chiriquitoxin are postulated to bind to a membrane receptor located in the outside surface of the muscle fiber membrane. From the structure of tetrodotoxin and a presumed structure of chiriquitoxin, the Na+ and K+ channels have been estimated to be separated from each other by not less than 5 A nor much more than 15 A.


SMARCAD1 is an ATP-dependent stimulator of nucleosomal H2A acetylation via CBP, resulting in transcriptional regulation.
Histone acetylation plays a pivotal role in transcriptional regulation, and ATP-dependent nucleosome remodeling activity is required for optimal transcription from chromatin. While these two activities have been well characterized, how they are coordinated remains to be determined. We discovered ATP-dependent histone H2A acetylation activity in Drosophila nuclear extracts. This activity was column purified and demonstrated to be composed of the enzymatic activities of CREB-binding protein (CBP) and SMARCAD1, which belongs to the Etl1 subfamily of the Snf2 family of helicase-related proteins. SMARCAD1 enhanced acetylation by CBP of H2A K5 and K8 in nucleosomes in an ATP-dependent fashion. Expression array analysis of S2 cells having ectopically expressed SMARCAD1 revealed up-regulated genes. Using native genome templates of these up-regulated genes, we found that SMARCAD1 activates their transcription in vitro. Knockdown analysis of SMARCAD1 and CBP indicated overlapping gene control, and ChIP-seq analysis of these commonly controlled genes showed that CBP is recruited to the promoter prior to SMARCAD1. Moreover, Drosophila genetic experiments demonstrated interaction between SMARCAD1/Etl1 and CBP/nej during development. The interplay between the remodeling activity of SMARCAD1 and histone acetylation by CBP sheds light on the function of chromatin and the genome-integrity network.


Ultra-rapid prototyping of flexible, multi-layered microfluidic devices via razor writing.
The fabrication of microfluidic devices is often still a time-consuming and costly process. Here we introduce a very simple and cheap microfabrication process based on "razor writing", also termed xurography, for the ultra-rapid prototyping of microfluidic devices. Thin poly(dimethylsiloxane) (PDMS) membranes are spin-coated on flexible plastic foil and cut into user-defined shapes with a bench-top cutter plotter. The PDMS membranes can then be assembled into desirable microdevices via plasma bonding. The plastic foil allows manipulation of exceptionally thin (30-300 μm) PDMS layers and can be readily peeled after fabrication. This versatile technique can be used to produce a wide variety of microfluidic device prototypes within just a few hours.


KEYLINK: towards a more integrative soil representation for inclusion in ecosystem scale models-II: model description, implementation and testing.
New knowledge on soil structure highlights its importance for hydrology and soil organic matter (SOM) stabilization, which however remains neglected in many wide used models. We present here a new model, KEYLINK, in which soil structure is integrated with the existing concepts on SOM pools, and elements from food web models, that is, those from direct trophic interactions among soil organisms. KEYLINK is, therefore, an attempt to integrate soil functional diversity and food webs in predictions of soil carbon (C) and soil water balances. We present a selection of equations that can be used for most models as well as basic parameter intervals, for example, key pools, functional groups' biomasses and growth rates. Parameter distributions can be determined with Bayesian calibration, and here an example is presented for food web growth rate parameters for a pine forest in Belgium. We show how these added equations can improve the functioning of the model in describing known phenomena. For this, five test cases are given as simulation examples: changing the input litter quality (recalcitrance and carbon to nitrogen ratio), excluding predators, increasing pH and changing initial soil porosity. These results overall show how KEYLINK is able to simulate the known effects of these parameters and can simulate the linked effects of biopore formation, hydrology and aggregation on soil functioning. Furthermore, the results show an important trophic cascade effect of predation on the complete C cycle with repercussions on the soil structure as ecosystem engineers are predated, and on SOM turnover when predation on fungivore and bacterivore populations are reduced. In summary, KEYLINK shows how soil functional diversity and trophic organization and their role in C and water cycling in soils should be considered in order to improve our predictions on C sequestration and C emissions from soils.


Perfect blackbody radiation from a graphene nanostructure with application to high-temperature spectral emissivity measurements.
We report the successful fabrication of a novel type of blackbody material based on a graphene nanostructure. We demonstrate that the graphene nanostructure not only shows a low reflectance comparable to that of a carbon nanotube array but also shows an extremely high heat resistance at temperatures greater than 2500 K. The graphene nanostructure, which has an emissivity higher than 0.99 over a wide range of wavelengths, behaves as a standard blackbody material; therefore, the radiation spectrum and the temperature can be precisely measured in a simple manner. Here, the spectral emissivities of tungsten and tantalum are experimentally obtained using this ideal blackbody material and are compared to previously reported spectra. We clearly demonstrate the existence of a temperature-independent fixed point of emissivity at a certain wavelength. Both the spectral emissivity as a function of temperature and the cross-over point in the emissivity spectrum are well described by the complex dielectric function based on the Lorentz-Drude model with the phonon-scattering effect.


Multiple Quality Control Mechanisms in the ER and TGN Determine Subcellular Dynamics and Salt-Stress Tolerance Function of KORRIGAN1.
Among many glycoproteins within the plant secretory system, KORRIGAN1 (KOR1), a membrane-anchored endo-β-1,4-glucanase involved in cellulose biosynthesis, provides a link between N-glycosylation, cell wall biosynthesis, and abiotic stress tolerance. After insertion into the endoplasmic reticulum, KOR1 cycles between the trans-Golgi network (TGN) and the plasma membrane (PM). From the TGN, the protein is targeted to growing cell plates during cell division. These processes are governed by multiple sequence motifs and also host genotypes. Here, we investigated the interaction and hierarchy of known and newly identified sorting signals in KOR1 and how they affect KOR1 transport at various stages in the secretory pathway. Conventional steady-state localization showed that structurally compromised KOR1 variants were directed to tonoplasts. In addition, a tandem fluorescent timer technology allowed for differential visualization of young versus aged KOR1 proteins, enabling the analysis of single-pass transport through the secretory pathway. Observations suggest the presence of multiple checkpoints/branches during KOR1 trafficking, where the destination is determined based on KOR1's sequence motifs and folding status. Moreover, growth analyses of dominant PM-confined KOR1-L48L49→A48A49 variants revealed the importance of active removal of KOR1 from the PM during salt stress, which otherwise interfered with stress acclimation.


Radiation tolerance in the eutardigrade Richtersius coronifer.
Tardigrades have a reputation of being extremely tolerant to extreme environmental conditions including tolerance to ionizing radiation while in a desiccated, anhydrobiotic state. However, the evidence for radio-tolerance in tardigrades is based on only one previous report, and there is an obvious need for complementary studies. In this paper we report an investigation on radio-tolerance in desiccated and hydrated specimens of the eutardigrade Richtersius coronifer. Groups of 30 - 50 tardigrades were exposed to gamma-radiation at doses between 1.0 - 9.0 (anhydrobiotic animals) or 0.5 - 5.0 (hydrated animals) kGy and the animals were followed until all were dead. Radiation tolerance of both desiccated and hydrated tardigrades was studied. Both desiccated and hydrated animals irradiated with 0.5 and 1 kGy did not deviate in survival from the control groups. Animals from all exposed groups underwent their moulting and egg production cycle, but at decreasing frequency for doses above 1 kGy. No eggs laid by irradiated animals hatched, while eggs laid by controls did so. Our study suggests that radiation tolerance in tardigrades is not due to biochemical protectants connected with the desiccated state. Rather, cryptobiotic tardigrades may rely on efficient mechanisms of DNA repair, the nature of which is currently unknown.


Manuka honey-impregnated dressings in the treatment of neuropathic diabetic foot ulcers.
In this study, we investigate the effect of manuka honey-impregnated dressings (MHID) on the healing of neuropathic diabetic foot ulcers (NDFU). A total of 63 Caucasians, type 2 diabetic patients followed up in the diabetic foot outpatient clinic comprised the study population. Patients were randomised in two groups as follows: group I patients were treated with MHID and group II patients were treated with conventional dressings (CD). The patients were followed up on a weekly basis for 16 weeks. Mean healing time was 31 ± 4 days in group I versus 43 ± 3 days in group II (P < 0·05). In group I patients 78·13% of ulcers became sterile during the first week versus 35·5% in group II patients; the corresponding percentages for weeks 2, 4 and 6 were 15·62% versus 38·7%, 6·25% versus 12·9% and 0% versus 12·9% respectively. The percent of ulcers healed did not differ significantly between groups (97% for MHID and 90% for CD). MHID represent an effective treatment for NDFU leading to a significant reduction in the time of healing and rapid disinfection of ulcers.


Chemical Proteomics Maps Brain Region Specific Activity of Endocannabinoid Hydrolases.
The biosynthetic and catabolic enzymes of the endocannabinoids tightly regulate endocannabinoid-mediated activation of the cannabinoid CB1 receptor. Monitoring the activities of these endocannabinoid hydrolases in different brain regions is, therefore, key to gaining insight into spatiotemporal control of CB1 receptor-mediated physiology. We have employed a comparative chemical proteomics approach to quantitatively map the activity profile of endocannabinoid hydrolases in various mouse brain regions at the same time. To this end, we used two different activity-based probes: fluorophosphonate-biotin (FP-biotin), which quantifies FAAH, ABHD6, and MAG-lipase activity, and MB108, which detects DAGL-α, ABHD4, ABHD6, and ABHD12. In total, 32 serine hydrolases were evaluated in the frontal cortex, hippocampus, striatum, and cerebellum. Comparison of endocannabinoid hydrolase activity in the four brain regions revealed that FAAH activity was highest in the hippocampus, and MAGL activity was most pronounced in the frontal cortex, whereas DAGL-α was most active in the cerebellum. Comparison of the activity profiles with a global proteomics data set revealed pronounced differences. This could indicate that post-translational modification of the endocannabinoid hydrolases is important to regulate their activity. Next, the effect of genetic deletion of the CB1 receptor was studied. No difference in the enzymatic activity was found in the cerebellum, striatum, frontal cortex, and hippocampus of CB1 receptor knockout animals compared to wild type mice. Our results are in line with previous reports and indicate that the CB1 receptor exerts no regulatory control over the basal production and degradation of endocannabinoids and that genetic deletion of the CB1 receptor does not induce compensatory mechanisms in endocannabinoid hydrolase activity.


Emergency contraception for newly arrested women: evidence for an unrecognized public health opportunity.
Incarceration affords an opportunity to provide health care to populations with limited access to care. Women in this population are at high risk for experiencing unintended pregnancies. It is not known what proportion of these women engage in unprotected intercourse in the days prior to incarceration and therefore may benefit from being offered emergency contraception upon their arrest to decrease their risk of unintended pregnancies. We sought to describe the proportion and characteristics of newly arrested women who are eligible for and interested in taking emergency contraception by conducting a cross-sectional study in an urban county jail booking facility. A 63-item survey was administered to women ages 18-44 within 24 h of being arrested in San Francisco. Eighty-four (29%) women were eligible for emergency contraception. Of these, 48% indicated a willingness to take emergency contraception if offered. Half of the women eligible for emergency contraception expressed ambivalent attitudes about pregnancy. Women who had taken emergency contraception in the past were more likely to say they would accept it (45%) than women who had never used it (25%, p = .05). The strongest predictor of willingness to take emergency contraception was not having a misperception about its safety, efficacy, or mechanism of action (RR = 1.9, 95% CI 1.2-3.0). Seventy-one percent of all women indicated that they would accept an advance supply of emergency contraception upon release from jail. Emergency contraception counseling and provision should be offered to newly arrested women as a key reproductive and public health intervention for a traditionally marginalized, high-risk population.


Disruption of the Rev3l-encoded catalytic subunit of polymerase zeta in mice results in early embryonic lethality.
Polymerase zeta (Pol zeta) is an error-prone DNA polymerase [1], which in yeast is involved in trans-lesion synthesis (TLS) and is responsible for most of the ultraviolet (UV) radiation-induced and spontaneous mutagenesis [2-4]. Pol zeta consists of three subunits: REV1, a deoxycytidyl-transferase [5]; REV7, of unclear function [6]; and REV3, the catalytic subunit. REV3 alone is sufficient to carry out TLS, but association with REV1 and REV7 enhances its activity [5, 7]. Experiments using human cells treated with UV radiation indicate also that mammalian Pol zeta is involved in TLS [7]. The peculiar mutagenic activity of Pol zeta [4,7,8] suggests a possible role in somatic hypermutation of immunoglobulin (Ig) genes [9]. Here, we report that, unlike in yeast where the REV3 gene is not essential for life [4], disruption of the mouse homologue (Rev3l) resulted in early embryonic lethality. In Rev3l(-/-) embryos, no haematopoietic cells other than erythrocytes could be identified in the yolk sac. Rev3l(-/-) haematopoietic precursors were unable to expand in vitro and no haematopoietic cells could be derived from the intraembryonic haematogenic compartment (splanchnopleura). Fibroblasts could not be derived from the Rev3l(-/-) embryos, and Rev3l(-/-) embryonic stem (ES) cells could not be obtained. This is the first evidence that an enzyme involved in TLS is critical for mammalian development.


Burr-hole Irrigation with Closed-system Drainage for the Treatment of Chronic Subdural Hematoma: A Meta-analysis.
There is controversy among neurosurgeons regarding whether irrigation or drainage is necessary for achieving a lower revision rate for the treatment of chronic subdural hematoma (CSDH) using burr-hole craniostomy (BHC). Therefore, we performed a meta-analysis of all available published reports. Multiple electronic health databases were searched to identify all studies published between 1989 and June 2012 that compared irrigation and drainage. Data were processed by using Review Manager 5.1.6. Effect sizes are expressed as pooled odds ratio (OR) estimates. Due to heterogeneity between studies, we used the random effect of the inverse variance weighted method to perform the meta-analysis. Thirteen published reports were selected for this meta-analysis. The comprehensive results indicated that there were no statistically significant differences in mortality or complication rates between drainage and no drainage (P > 0.05). Additionally, there were no differences in recurrence between irrigation and no irrigation (P > 0.05). However, the difference between drainage and no drainage in recurrence rate reached statistical significance (P < 0.01). The results from this meta-analysis suggest that burr-hole surgery with closed-system drainage can reduce the recurrence of CSDH; however, irrigation is not necessary for every patient.


A family of transcripts encoding water channel proteins: tissue-specific expression in the common ice plant.
Seawater-strength salt stress of the ice plant (Mesembryanthemum crystallinum) initially results in wilting, but full turgor is restored within approximately 2 days. We are interested in a mechanistic explanation for this behavior and, as a requisite for in-depth biochemical studies, have begun to analyze gene expression changes in roots coincident with the onset of stress. cDNAs that suggested changes in mRNA amount under stress were found; their deduced amino acid sequences share homologies with proteins of the Mip (major intrinsic protein) gene family and potentially encode aquaporins. One transcript, MipB, was found only in root RNA, whereas two other transcripts, MipA and MipC, were detected in roots and leaves. Transcript levels of MipB were of low abundance. All transcripts declined initially during salt stress but later recovered to at least prestress level. The most drastic decline was in MipA and MipC transcripts. MipA mRNA distribution in roots detected by in situ hybridization indicated that the transcript was present in all cells in the root tip. In the expansion zone of the root where vascular bundles differentiate, MipA transcript amounts were most abundant in the endodermis. In older roots, which had undergone secondary growth, MipA was highly expressed in cell layers surrounding individual xylem strands. MipA was also localized in leaf vascular tissue and, in lower amounts, in mesophyll cells. Transcripts for MipB seemed to be present exclusively in the tip of the root, in a zone before and possibly coincident with the development of a vascular system. MipA- and MipB-encoded proteins expressed in Xenopus oocytes led to increased water permeability. mRNA fluctuations of the most highly expressed MipA and MipC coincided with turgor changes in leaves under stress. As the leaves regained turgor, transcript levels of these water channel proteins increased.


Metabolic activity affects the response of single cells to a nutrient switch in structured populations.
Microbes live in ever-changing environments where they need to adapt their metabolism to different nutrient conditions. Many studies have characterized the response of genetically identical cells to nutrient switches in homogeneous cultures; however, in nature, microbes often live in spatially structured groups such as biofilms where cells can create metabolic gradients by consuming and releasing nutrients. Consequently, cells experience different local microenvironments and vary in their phenotype. How does this phenotypic variation affect the ability of cells to cope with nutrient switches? Here, we address this question by growing dense populations of Escherichia coli in microfluidic chambers and studying a switch from glucose to acetate at the single-cell level. Before the switch, cells vary in their metabolic activity: some grow on glucose, while others cross-feed on acetate. After the switch, only few cells can resume growth after a period of lag. The probability to resume growth depends on a cells' phenotype prior to the switch: it is highest for cells cross-feeding on acetate, while it depends in a non-monotonic way on the growth rate for cells growing on glucose. Our results suggest that the strong phenotypic variation in spatially structured populations might enhance their ability to cope with fluctuating environments.


Anticlastogenic effect of Ginkgo biloba extract in Graves' disease patients receiving radioiodine therapy.
Chromosomal damage, as assessed by clastogenic factors (CFs) and micronuclei (MN) appearance, after radioiodine therapy of Graves' disease has been reported. Our objective was to evaluate the effect of Ginkgo biloba extract (EGb 761) supplementation on the time course (up to 120 d) of CFs and MN appearance in lymphocytes from patients with Graves' disease after iodine-131 ((131)I) therapy. Patients were randomly assigned to EGb 761 or placebo, in a blinded manner. In the placebo group, MN increased early (P < 0.001) after (131)I, peaking at the 21st day (P = 0.0003) and declining thereafter. In EGb 761-treated patients, MN increased early (P < 0.05), while returning toward baseline value thereafter. Therefore, mean MN increment was significantly higher in the placebo group as compared with EGb 761-treated patients (P < 0.01). Moreover, an early (P < 0.0001) and sustained (up to 35 d; P < 0.001) MN increase induced by CFs was observed in the placebo group. Conversely, in EGb 761-treated patients, MN increase induced by CFs never reached the statistical significance; therefore, the mean of the MN increments was significantly lower than in placebo (P < 0.05). A significant positive correlation between MN maximum increment and the bone marrow dose was observed in the placebo group only (P = 0.03). No significant difference was observed in clinical outcome between the two groups. EGb 761 supplementation neutralized genotoxic damage induced by radioiodine treatment, without affecting the clinical outcome. Although (131)I therapy is generally safe, our data suggest that Gingko biloba extracts may prevent genetic effects of radioiodine therapy for hyperthyroid Graves' disease.


Skin microbiome correlates with bioclimate and Batrachochytrium dendrobatidis infection intensity in Brazil's Atlantic Forest treefrogs.
In Brazil's Atlantic Forest (AF) biodiversity conservation is of key importance since the fungal pathogen Batrachochytrium dendrobatidis (Bd) has led to the rapid loss of amphibian populations here and worldwide. The impact of Bd on amphibians is determined by the host's immune system, of which the skin microbiome is a critical component. The richness and diversity of such cutaneous bacterial communities are known to be shaped by abiotic factors which thus may indirectly modulate host susceptibility to Bd. This study aimed to contribute to understanding the environment-host-pathogen interaction determining skin bacterial communities in 819 treefrogs (Anura: Hylidae and Phyllomedusidae) from 71 species sampled across the AF. We investigated whether abiotic factors influence the bacterial community richness and structure on the amphibian skin. We further tested for an association between skin bacterial community structure and Bd co-occurrence. Our data revealed that temperature, precipitation, and elevation consistently correlate with richness and diversity of the skin microbiome and also predict Bd infection status. Surprisingly, our data suggest a weak but significant positive correlation of Bd infection intensity and bacterial richness. We highlight the prospect of future experimental studies on the impact of changing environmental conditions associated with global change on environment-host-pathogen interactions in the AF.


Behavioural evidence for polychromatic ultraviolet sensitivity in mantis shrimp.
Stomatopod crustaceans are renowned for their elaborate visual systems. Their eyes contain a plethora of photoreceptors specialized for chromatic and polarization detection, including several that are sensitive to varying wavelength ranges and angles of polarization within the ultraviolet (UV) range (less than 400 nm). Behavioural experiments have previously suggested that UV photoreception plays a role in stomatopod communication, but these experiments have only manipulated the entire UV range. Here, using a behavioural approach, we examine UV vision in the stomatopod Haptosquilla trispinosa Using binary trained choice assays as well as innate burrow-choice experiments, we assessed the ability of H. trispinosa to detect and respond to narrow-band LED stimuli peaking near 314 nm (UVB) versus 379 nm (UVA) in wavelength. We find that H. trispinosa can discriminate these stimuli and appears to display an aversive reaction to UVB light, suggesting segregated behavioural responses to stimuli within the UV range. Furthermore, we find that H. trispinosa can discriminate stimuli peaking near 379 nm versus 351 nm in wavelength, suggesting that their wavelength discrimination in the UV is comparable to their performance in the human-visible range.


Cloning and characterization of two human VIP1-like inositol hexakisphosphate and diphosphoinositol pentakisphosphate kinases.
Eukaryotes possess numerous inositol phosphate (IP) and diphosphoinositol phosphate (PP-IPs or inositol pyrophosphates) species that act as chemical codes important for intracellular signaling pathways. Production of IP and PP-IP molecules occurs through several classes of evolutionarily conserved inositol phosphate kinases. Here we report the characterization of a human inositol hexakisphosphate (IP6) and diphosphoinositol pentakisphosphate (PP-IP5 or IP7) kinase with similarity to the yeast enzyme Vip1, a recently identified IP6/IP7 kinase (Mulugu, S., Bai, W., Fridy, P. C., Bastidas, R. J., Otto, J. C., Dollins, D. E., Haystead, T. A., Ribeiro, A. A., and York, J. D. (2007) Science 316, 106-109). Recombinant human VIP1 exhibits in vitro IP6 and IP7 kinase activities and restores IP7 synthesis when expressed in mutant yeast. Expression of human VIP1 in HEK293T cells engineered to produce high levels of IP7 results in dramatic increases in bisdiphosphoinositol tetrakisphosphate (PP2-IP4 or IP8). Northern blot analysis indicates that human VIP1 is expressed in a variety of tissues and is enriched in skeletal muscle, heart, and brain. The subcellular distribution of tagged human VIP1 is indicative of a cytoplasmic non-membrane localization pattern. We also characterized human and mouse VIP2, an additional gene product with nearly 90% similarity to VIP1 in the kinase domain, and observed both IP6 and IP7 kinase activities. Our data demonstrate that human VIP1 and VIP2 function as IP6 and IP7 kinases that act along with the IP6K/Kcs1-class of kinases to convert IP6 to IP8 in mammalian cells, a process that has been found to occur in response to various stimuli and signaling events.


Disruption of a maize 9-lipoxygenase results in increased resistance to fungal pathogens and reduced levels of contamination with mycotoxin fumonisin.
Plant oxylipins, produced via the lipoxygenase (LOX) pathway, function as signals in defense and development. In fungi, oxylipins are potent regulators of mycotoxin biosynthesis and sporogenesis. Previous studies showed that plant 9-LOX-derived fatty acid hydroperoxides induce conidiation and mycotoxin production. Here, we tested the hypothesis that oxylipins produced by the maize 9-LOX pathway are required by pathogens to produce spores and mycotoxins and to successfully colonize the host. Maize mutants were generated in which the function of a 9-LOX gene, ZmLOX3, was abolished by an insertion of a Mutator transposon in its coding sequence, which resulted in reduced levels of several 9-LOX-derived hydroperoxides. Supporting our hypothesis, conidiation and production of the mycotoxin fumonisin B1 by Fusarium verticillioides were drastically reduced in kernels of the lox3 mutants compared with near-isogenic wild types. Similarly, conidia production and disease severity of anthracnose leaf blight caused by Colletotrichum graminicola were significantly reduced in the lox3 mutants. Moreover, lox3 mutants displayed increased resistance to southern leaf blight caused by Cochliobolus heterostrophus and stalk rots caused by both F. verticillioides and C. graminicola. These data strongly suggest that oxylipin metabolism mediated by a specific plant 9-LOX isoform is required for fungal pathogenesis, including disease development and production of spores and mycotoxins.


Carbohydrate antigen 125: an emerging prognostic risk factor in acute heart failure?
To assess whether circulating levels of carbohydrate antigen 125 (CA125) predict subsequent 6-month all-cause mortality in patients after the index hospitalisation for acute heart failure (HF). Prospective cohort study at a single teaching centre in Spain. 529 consecutive patients with acute HF admitted in a single university centre were analysed. In addition to the traditional clinical information, CA125 (U/ml) was measured during the early course of hospitalisation. The independent association between baseline CA125 and mortality was assessed with Cox regression analysis. The follow-up was limited to 6 months. 349 (66%) patients showed serum levels of CA125 >35 U/ml (established cut-off point value). At a 6-month follow-up, 89 (16.8%) deaths were identified. A positive trend between mortality and CA125 quartiles was observed; 3.8%, 15.2%, 22% and 26.5% of deaths occurred from quartile 1 to 4 of CA125 (p<0.001). Likewise, a monotonic, ascending trend in the risk ratios was estimated from the multivariable Cox model. Compared with the first quartile of CA125, the HRs (95% CI) for the second, third and fourth quartiles were 3.25 (1.20 to 8.79), 4.91 (1.88 to 12.85) and 8.41 (3.24 to 21.79), respectively. Serum levels of CA125 obtained in patients admitted with a diagnosis of acute HF was shown to be an independent predictor of mortality up to the 6-month follow-up.


A mutant with aberrant extracellular LcrV-YscF interactions fails to form pores and translocate Yop effector proteins but retains the ability to trigger Yop secretion in response to host cell contact.
The plasmid-encoded type three secretion system (TTSS) of Yersinia spp. is responsible for the delivery of effector proteins into cells of the innate immune system, where these effectors disrupt the target cells' activity. Successful translocation of effectors into mammalian cells requires Yersinia to both insert a translocon into the host cell membrane and sense contact with host cells. To probe the events necessary for translocation, we investigated protein-protein interactions among TTSS components of the needle-translocon complex using a chemical cross-linking-based approach. We detected extracellular protein complexes containing YscF, LcrV, and YopD that were dependent upon needle formation. The formation of these complexes was evaluated in a secretion-competent but translocation-defective mutant, the YscFD28AD46A strain (expressing YscF with the mutations D28A and D46A). We found that one of the YscF and most of the LcrV and YopD cross-linked complexes were nearly absent in this mutant. Furthermore, the YscFD28AD46A strain did not support YopB insertion into mammalian membranes, supporting the idea that the LcrV tip complex is required for YopB insertion and translocon formation. However, the YscFD28AD46A strain did secrete Yops in the presence of host cells, indicating that a translocation-competent tip complex is not required to sense contact with host cells to trigger Yop secretion. In conclusion, in the absence of cross-linkable LcrV-YscF interactions, translocon insertion is abolished, but Yersinia still retains the ability to sense cell contact.


The role of Tenascin C in the lymphoid progenitor cell niche.
Hemopoietic stem cells (HSCs) are extrinsically controlled by the bone marrow (BM) microenvironment. Mice devoid of the extracellular matrix molecule Tenascin-C (TNC) were reported to develop normally. The current study explores the relationship between TNC and hemopoiesis, from HSCs within their niche to maturing progenitors in alternate niches. Although the absence of TNC did not alter the size of the BM stem cell pool, we report decreased thymic T cell progenitors with redistribution to other lymphoid organs, suggesting an anchoring role for TNC. TNC did not play an essential role in stem and progenitor cell homing to BM, but significantly altered lymphoid primed progenitor cell homing. These cells express the TNC receptor, integrin α9β1, with the same reduced homing evident in the absence of this integrin. The absence of TNC also resulted in an increased proportion and number of mature circulating T cells. In addition, the absence of TNC significantly impaired hemopoietic reconstitution after transplant and increased stem and progenitor cell mobilization. In summary, our analysis revealed unidentified roles for TNC in hemopoiesis: in lineage commitment of thymic T cell progenitors, peripheral T cell migration, and hemopoietic reconstitution.


Differential postnatal development of catecholamine and serotonin inputs to identified neurons in prefrontal cortex of rhesus monkey.
The monoaminergic innervation of cerebral cortex has long been implicated in its development. Methods now exist to examine catecholamine and serotonin inputs to identified neurons in the cerebral cortex. We have quantified such inputs on pyramidal and nonpyramidal cells in prefrontal cortex of rhesus monkeys ranging in age from 2 weeks to 10 years. Individual layer III neurons were filled with Lucifer yellow and double-immunostained with axons containing either tyrosine hydroxylase (TH) or 5-hydroxytryptamine (5-HT). The filled cells were reconstructed, and putative appositions between the axons and dendritic spines and shafts were quantified at high magnification using light microscopy. The density of catecholamine appositions on pyramidal neurons matures slowly, reaching only half the adult level by 6 months of age and thereafter rising gradually to adult levels by 2 years of age. By contrast, the density of serotonin appositions on pyramidal cells reaches the adult level before the second week after birth. The average adult pyramidal neuron in layer III of area 9m receives three times stronger input from catecholaminergic than from serotoninergic axons. The overall density of both inputs to interneurons does not appear to change during postnatal development. Selective changes in the TH innervation of pyramidal cells against a backdrop of constant TH innervation of interneurons suggest that the balance between excitation and inhibition may change developmentally in the prefrontal cortex. By contrast, 5-HT innervation of both types of neurons remains relatively constant over the age range studied.


Biomarkers in Barrett esophagus.
Barrett esophagus is a premalignant condition that may progress to adenocarcinoma. The risk of developing cancer has been estimated to be approximately 1 in 250 patient-years of observation; however, there appear to be subsets of patients at much higher risk. Risk stratification has previously been determined by histological identification of dysplasia. Several new biomarkers are being tested to help clinicians better determine the risk of cancer development. Although none of these biomarkers has been proven in a prospective study to predict the onset of cancer, they have been correlated with cancer development. Most of these are factors that have been associated with cancer development in other organs. These include assessment of cell proliferation, expression of cyclooxygenase 2, growth factors and oncogenes, secretory factors, cell cycle proteins, adhesion molecules, and aneuploidy and other genetic abnormalities. In addition to their role as potential cancer biomarkers, these factors have increasingly been reported as surrogate markers to monitor the effectiveness of conservative treatments for Barrett esophagus. In this article, biological markers are reviewed for their relevance in Barrett esophagus. Although most biological markers need to be evaluated further and, for most, prospective follow-up studies are lacking, at present abnormal ploidy status, P16 and P53 gene abnormalities, or allelic losses are the most extensively documented.


Process and outcome evaluation of an organizational-level stress management intervention in Switzerland.
This field study evaluates the process and outcome of an organizational-level stress management intervention (SMI) in eight companies, taking into account the lessons learned from previous evaluation research. It utilizes the RE-AIM evaluation framework to capture the Reach and Adoption of the intervention in the companies, the appraisal of the Implementation process and the project's Effectiveness and Maintenance with a range of qualitative and quantitative methods. It applies an adapted research design in the context of a field study involving entire organizations, retrospectively assigning study participants to comparison groups. The results of a longitudinal analysis (n = 1400) showed that the SMI had a positive impact on the participants' job demands and resources, when controlled for baseline levels. Qualitative data analysis revealed that the companies had built capacities for ongoing health promotion and showed what issues must be borne in mind when implementing such projects. The study also showed that participation in such interventions alone does not suffice to achieve the desired impact, but that the individual participants' appraisal of the intervention and the collective involvement of the teams must be further researched to fully understand how change occurs.


Mathematical modeling: bridging the gap between concept and realization in synthetic biology.
Mathematical modeling plays an important and often indispensable role in synthetic biology because it serves as a crucial link between the concept and realization of a biological circuit. We review mathematical modeling concepts and methodologies as relevant to synthetic biology, including assumptions that underlie a model, types of modeling frameworks (deterministic and stochastic), and the importance of parameter estimation and optimization in modeling. Additionally we expound mathematical techniques used to analyze a model such as sensitivity analysis and bifurcation analysis, which enable the identification of the conditions that cause a synthetic circuit to behave in a desired manner. We also discuss the role of modeling in phenotype analysis such as metabolic and transcription network analysis and point out some available modeling standards and software. Following this, we present three case studies-a metabolic oscillator, a synthetic counter, and a bottom--up gene regulatory network--which have incorporated mathematical modeling as a central component of synthetic circuit design.


Parallel line scanning ophthalmoscope for retinal imaging.
A parallel line scanning ophthalmoscope (PLSO) is presented using a digital micromirror device (DMD) for parallel confocal line imaging of the retina. The posterior part of the eye is illuminated using up to seven parallel lines, which were projected at 100 Hz. The DMD offers a high degree of parallelism in illuminating the retina compared to traditional scanning laser ophthalmoscope systems utilizing scanning mirrors. The system operated at the shot-noise limit with a signal-to-noise ratio of 28 for an optical power measured at the cornea of 100 μW. To demonstrate the imaging capabilities of the system, the macula and the optic nerve head of a healthy volunteer were imaged. Confocal images show good contrast and lateral resolution with a 10°×10° field of view.


[Mixed-aetiology extensive ulcers of the crus: postthrombotic disease and gangrenous pyoderma].
Gangrenous pyoderma (GP) is a rare infectious disease typically manifesting itself by utterly painful crural ulcers. Currently, the disease is considered to be most likely of an autoimmune origin. The author presents herein a case report describing key diagnostic and treatment decisions regarding a 30-year-old woman suffering from extensive crural ulcers. Of special interest was the finding that this patient's ultrasonographic duplex scanning showed the signs corresponding to postthrombotic disease. However, conventional treatment of venous trophic ulcers turned out inefficient. The woman was diagnosed as having GP. Topical therapy with corticosteroid drugs (combined with autodermoplasty and compression therapy) made it possible to achieve complete epithelisation of ulcers. Thus, should conventional treatment of venous trophic ulcers result in the patient's failure to respond properly, it is necessary to take into consideration the probability of gangrenous pyoderma.


Synthesis of selective agonists for the α7 nicotinic acetylcholine receptor with in situ click-chemistry on acetylcholine-binding protein templates.
The acetylcholine-binding proteins (AChBPs), which serve as structural surrogates for the extracellular domain of nicotinic acetylcholine receptors (nAChRs), were used as reaction templates for in situ click-chemistry reactions to generate a congeneric series of triazoles from azide and alkyne building blocks. The catalysis of in situ azide-alkyne cycloaddition reactions at a dynamic subunit interface facilitated the synthesis of potentially selective compounds for nAChRs. We investigated compound sets generated in situ with soluble AChBP templates through pharmacological characterization with α7 and α4β2 nAChRs and 5-hydroxytryptamine type 3A receptors. Analysis of activity differences between the triazole 1,5-syn- and 1,4-anti-isomers showed a preference for the 1,4-anti-triazole regioisomers among nAChRs. To improve nAChR subtype selectivity, the highest-potency building block for α7 nAChRs, i.e., 3α-azido-N-methylammonium tropane, was used for additional in situ reactions with a mutated Aplysia californica AChBP that was made to resemble the ligand-binding domain of the α7 nAChR. Fourteen of 50 possible triazole products were identified, and their corresponding tertiary analogs were synthesized. Pharmacological assays revealed that the mutated binding protein template provided enhanced selectivity of ligands through in situ reactions. Discrete trends in pharmacological profiles were evident, with most compounds emerging as α7 nAChR agonists and α4β2 nAChR antagonists. Triazoles bearing quaternary tropanes and aromatic groups were most potent for α7 nAChRs. Pharmacological characterization of the in situ reaction products established that click-chemistry synthesis with surrogate receptor templates offered novel extensions of fragment-based drug design that were applicable to multisubunit ion channels.


Do Additional Features Help or Hurt Category Learning? The Curse of Dimensionality in Human Learners.
The curse of dimensionality, which has been widely studied in statistics and machine learning, occurs when additional features cause the size of the feature space to grow so quickly that learning classification rules becomes increasingly difficult. How do people overcome the curse of dimensionality when acquiring real-world categories that have many different features? Here we investigate the possibility that the structure of categories can help. We show that when categories follow a family resemblance structure, people are unaffected by the presence of additional features in learning. However, when categories are based on a single feature, they fall prey to the curse, and having additional irrelevant features hurts performance. We compare and contrast these results to three different computational models to show that a model with limited computational capacity best captures human performance across almost all of the conditions in both experiments.


(Dis-)Harmony in movement: effects of musical dissonance on movement timing and form.
While the origins of consonance and dissonance in terms of acoustics, psychoacoustics and physiology have been debated for centuries, their plausible effects on movement synchronization have largely been ignored. The present study aimed to address this by investigating whether, and if so how, consonant/dissonant pitch intervals affect the spatiotemporal properties of regular reciprocal aiming movements. We compared movements synchronized either to consonant or to dissonant sounds and showed that they were differentially influenced by the degree of consonance of the sound presented. Interestingly, the difference was present after the sound stimulus was removed. In this case, the performance measured after consonant sound exposure was found to be more stable and accurate, with a higher percentage of information/movement coupling (tau coupling) and a higher degree of movement circularity when compared to performance measured after the exposure to dissonant sounds. We infer that the neural resonance representing consonant tones leads to finer perception/action coupling which in turn may help explain the prevailing preference for these types of tones.


Factors influencing the filtration performance of homemade face masks.
The outbreak of the COVID-19 pandemic is causing a shortage of personal protective equipment (PPE) across the world. As a public health response to control the pandemic, wearing homemade face coverings has been proven as a resort to protect both the wearer and others from droplets and aerosols transmission. Although aerosols and droplets can be removed through these non-medical materials with a series of filtration mechanisms, their filtration performances have not been evaluated in detail. Moreover, many factors, such as the fabric properties and the method of usage, also affect filtration performance. In this study, the size-dependent filtration performances of non-medical materials as candidates for face coverings were evaluated comprehensively. The flow resistance across these filter materials, an indicator of breathability, was also examined. The effect of materials properties, washing and drying cycles, and triboelectric effect on particle filtration was also studied. Results showed that the filtration efficiency varied considerably from 5-50% among fabrics materials due to the material properties, such as density and microscopic structure of the materials. Microfiber cloth demonstrated the highest efficiency among the tested materials. In general, fabric materials with higher grams per square meter (GSM) show higher particle filtration efficiency. The results on washing and drying fabric materials indicated decent reusability for fabric materials. The triboelectric charge could increase the filtration performance of the tested fabric materials, but this effect diminishes soon due to the dissipation of charges, meaning that triboelectric charging may not be effective in manufacturing homemade face coverings.


Mesophyll diffusion conductance to CO2: an unappreciated central player in photosynthesis.
Mesophyll diffusion conductance to CO(2) is a key photosynthetic trait that has been studied intensively in the past years. The intention of the present review is to update knowledge of g(m), and highlight the important unknown and controversial aspects that require future work. The photosynthetic limitation imposed by mesophyll conductance is large, and under certain conditions can be the most significant photosynthetic limitation. New evidence shows that anatomical traits, such as cell wall thickness and chloroplast distribution are amongst the stronger determinants of mesophyll conductance, although rapid variations in response to environmental changes might be regulated by other factors such as aquaporin conductance. Gaps in knowledge that should be research priorities for the near future include: how different is mesophyll conductance among phylogenetically distant groups and how has it evolved? Can mesophyll conductance be uncoupled from regulation of the water path? What are the main drivers of mesophyll conductance? The need for mechanistic and phenomenological models of mesophyll conductance and its incorporation in process-based photosynthesis models is also highlighted.


Association of the MscI polymorphism of the dopamine D3 receptor gene with tardive dyskinesia in schizophrenia.
In 112 schizophrenic patients previously treated with typical neuroleptics, we investigated the putative role of the dopamine D3 receptor gene (DRD3) in tardive dyskinesia (TD). Patients were assessed for TD severity using the Abnormal Involuntary Movement Scale (AIMS) and were subsequently genotyped for the MscI polymorphism that identifies a serine to glycine substitution in DRD3. A modified analysis of covariance model, which incorporated several clinical risk factors for TD, was utilized to detect differences in TD severity among the various genotypic groups. The glycine allele of DRD3 was found to be associated with typical neuroleptic-induced TD (F[2,95] = 8.25, p < .0005). Higher mean AIMS scores were found in patients homozygous for the glycine variant of the DRD3 gene, as compared to both heterozygous and serine homozygous patients. Although replication is necessary, this finding supports a role for the dopamine D3 receptor in the pathogenesis of TD.


Elimination of Guinea Worm Disease in Ethiopia; Current Status of the Disease's, Eradication Strategies and Challenges to the End Game.
Dracunculiasis, also named Guinea Worm Disease (GWD), is one of the Neglected Tropical Diseases (NTDs) caused by a parasitic nematode known as Dracunculus medinensis and has been known since antiquity as 'fiery serpent' from Israelites. It is transmitted to humans via drinking contaminated water containing infective copepods. Given, its feasibility for eradication, the Guinea Worm Eradication Program (GWEP) was launched in 1980 with the aim of eradicating the disease. Since its inception, GWEP has made an extraordinary progress in interrupting transmission. Globally, the number of reported cases reduced from 3.5 million in 20 countries in 1986 to only 22 cases in 2015 from only four countries namely South Sudan, Mali, Chad and Ethiopia. Since Mali has interrupted transmission of GWD in 2016, currently, the disease remains endemic in only three sub-Saharan African countries namely, South Sudan, Chad and Ethiopia. Each endemic country has its own national Guinea Worm Eradication Program. In Ethiopia, the Ethiopian Dracunculiasis Eradication Program (EDEP) which was established in 1993 has made remarkable move towards interruption of disease transmission and now the endgame is fast approaching. The EDEP with support mainly from The Carter Center, WHO, and UNICEF has reduced GWD by more than 99% from 1994 to 2015. In 2015, only 3 indigenous cases in humans and 14 in animals (13 in dogs and 1 in baboon) were reported. In 2016, 3 human cases, 14 dogs and 2 baboon infections were reported.. Refugee influx from the Republic of South Sudan (RSS), increased animal infections with unknown role in transmission of Dracunculiasis, the presence of hard to reach communities and lack of safe water sources in remote non-village areas remain among important challenges at this final stage of GWD eradication in Ethiopia. This paper reviews progress made towards Guinea Worm Eradication with a focus on the experience of the Ethiopian Dracunculiasis Eradication Program (EDEP), and intervention strategies that need further intensification to realize the endgame. Eradication strategies encompassing community education for behavioral change including raising awareness towards cash reward for reporting Guniea Worm Disease (GWD) and animal infection, case containment, surveillance systems, provision of safe water supply, and ABATE chemical application are discussed. It also summarizes challenges the end game faces and recommendations to strengthen the eradication effort.


Blood transfusion is associated with infection and increased resource utilization in combat casualties.
Combat casualty care has made significant advances in recent years, including administration of blood products in far-forward locations. However, recent studies have shown blood transfusion to be a significant risk factor for infection and increased resource utilization in critically injured patients. We therefore sought to investigate the incidence of blood transfusion and its association with infection and resource utilization in combat casualties. Prospective data were collected and retrospectively reviewed on 210 critically injured patients admitted to the USNS Comfort over a 7-week period during the 2003 assault phase of Operation Iraqi Freedom. Patients were stratified by age, gender, and injury severity score (ISS). Multivariate regression analyses were used to assess blood transfusion and hematocrit (HCT) as independent risk factors for infection and intensive care unit (ICU) admission controlling for age, gender, and ISS. The study cohort had a mean age of 30 +/- 2 years, a mean ISS of 14 +/- 3, 84 per cent were male, and 88 per cent sustained penetrating trauma. Blood transfusion was required in 44 per cent (n = 93) of the study cohort. Transfused patients had a higher ISS (18 +/- 4 vs. 10 +/- 3, P < 0.01), a higher pulse rate (105 +/- 4 vs. 93 +/- 3, P < 0.0001), and a lower admission HCT (27 +/- 1 vs. 33 +/- 2, P < 0.0001) compared with patients not transfused. Patients receiving blood transfusion had an increased infection rate (69% vs. 18%, P < 0.0001), ICU admission rate (52% vs. 21%, P < 0.0001), and ICU length of stay (6.7 +/- 2.1 days vs. 1.4 +/- 0.5 days, P < 0.0001) compared with nontransfused patients. However, there was no significant difference in mortality between transfused and nontransfused patients. Multivariate binomial regression analysis identified blood transfusion and HCT as independent risk factors for infection (P < 0.01) and blood transfusion as an independent risk factor for ICU admission (P < 0.05). Combat casualties have a high incidence of blood transfusion. Blood transfusion is an independent risk factor for infection and increased resource utilization. Therefore, consideration should be given to the use of alternative blood substitutes and recombinant human erythropoietin in the treatment and management of combat casualties.


Fast dynamic ventilation MRI of hyperpolarized 129 Xe using spiral imaging.
To develop and optimize a rapid dynamic hyperpolarized 129 Xe ventilation (DXeV) MRI protocol and investigate the feasibility of capturing pulmonary signal-time curves in human lungs. Spiral k-space trajectories were designed with the number of interleaves Nint = 1, 2, 4, and 8 corresponding to voxel sizes of 8 mm, 5 mm, 4 mm, and 2.5 mm, respectively, for field of view = 15 cm. DXeV images were acquired from a gas-flow phantom to investigate the ability of Nint = 1, 2, 4, and 8 to capture signal-time curves. A finite element model was constructed to investigate gas-flow dynamics corroborating the experimental signal-time curves. DXeV images were also carried out in six subjects (three healthy and three chronic obstructive pulmonary disease subjects). DXeV images and numerical modelling of signal-time curves permitted the quantification of temporal and spatial resolutions for different numbers of spiral interleaves. The two-interleaved spiral (Nint = 2) was found to be the most time-efficient to obtain DXeV images and signal-time curves of whole lungs with a temporal resolution of 624 ms for 13 slices. Signal-time curves were well matched in three healthy volunteers. The Spearman's correlations of chronic obstructive pulmonary disease subjects were statistically different from three healthy subjects (P < 0.05). The Nint = 2 spiral demonstrates the successful acquisition of DXeV images and signal-time curves in healthy subjects and chronic obstructive pulmonary disease patients. Magn Reson Med 79:2597-2606, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.


Characterization of a Bioactive Peptide T14 in the Human and Rodent Substantia Nigra: Implications for Neurodegenerative Disease.
The substantia nigra is generally considered to show significant cell loss not only in Parkinson's but also in Alzheimer's disease, conditions that share several neuropathological traits. An interesting feature of this nucleus is that the pars compacta dopaminergic neurons contain acetylcholinesterase (AChE). Independent of its enzymatic role, this protein is released from pars reticulata dendrites, with effects that have been observed in vitro, ex vivo and in vivo. The part of the molecule responsible for these actions has been identified as a 14-mer peptide, T14, cleaved from the AChE C-terminus and acting at an allosteric site on alpha-7 nicotinic receptors, with consequences implicated in neurodegeneration. Here, we show that free T14 is co-localized with tyrosine hydroxylase in rodent pars compacta neurons. In brains with Alzheimer's pathology, the T14 immunoreactivity in these neurons increases in density as their number decreases with the progression of the disease. To explore the functional implications of raised T14 levels in the substantia nigra, the effect of exogenous peptide on electrically evoked neuronal activation was tested in rat brain slices using optical imaging with a voltage-sensitive dye (Di-4-ANEPPS). A significant reduction in the activation response was observed; this was blocked by the cyclized variant of T14, NBP14. In contrast, no such effect of the peptide was seen in the striatum, a region lacking the T14 target, alpha-7 receptors. These findings add to the accumulating evidence that T14 is a key signaling molecule in neurodegenerative disorders and that its antagonist NBP14 has therapeutic potential.


Re-assessing the diversity of negative strand RNA viruses in insects.
The spectrum of viruses in insects is important for subjects as diverse as public health, veterinary medicine, food production, and biodiversity conservation. The traditional interest in vector-borne diseases of humans and livestock has drawn the attention of virus studies to hematophagous insect species. However, these represent only a tiny fraction of the broad diversity of Hexapoda, the most speciose group of animals. Here, we systematically probed the diversity of negative strand RNA viruses in the largest and most representative collection of insect transcriptomes from samples representing all 34 extant orders of Hexapoda and 3 orders of Entognatha, as well as outgroups, altogether representing 1243 species. Based on profile hidden Markov models we detected 488 viral RNA-directed RNA polymerase (RdRp) sequences with similarity to negative strand RNA viruses. These were identified in members of 324 arthropod species. Selection for length, quality, and uniqueness left 234 sequences for analyses, showing similarity to genomes of viruses classified in Bunyavirales (n = 86), Articulavirales (n = 54), and several orders within Haploviricotina (n = 94). Coding-complete genomes or nearly-complete subgenomic assemblies were obtained in 61 cases. Based on phylogenetic topology and the availability of coding-complete genomes we estimate that at least 20 novel viral genera in seven families need to be defined, only two of them monospecific. Seven additional viral clades emerge when adding sequences from the present study to formerly monospecific lineages, potentially requiring up to seven additional genera. One long sequence may indicate a novel family. For segmented viruses, cophylogenies between genome segments were generally improved by the inclusion of viruses from the present study, suggesting that in silico misassembly of segmented genomes is rare or absent. Contrary to previous assessments, significant virus-host codivergence was identified in major phylogenetic lineages based on two different approaches of codivergence analysis in a hypotheses testing framework. In spite of these additions to the known spectrum of viruses in insects, we caution that basing taxonomic decisions on genome information alone is challenging due to technical uncertainties, such as the inability to prove integrity of complete genome assemblies of segmented viruses.


A universal gene expression system for fungi.
Biotechnological production of fuels, chemicals and proteins is dependent on efficient production systems, typically genetically engineered microorganisms. New genome editing methods are making it increasingly easy to introduce new genes and functionalities in a broad range of organisms. However, engineering of all these organisms is hampered by the lack of suitable gene expression tools. Here, we describe a synthetic expression system (SES) that is functional in a broad spectrum of fungal species without the need for host-dependent optimization. The SES consists of two expression cassettes, the first providing a weak, but constitutive level of a synthetic transcription factor (sTF), and the second enabling strong, at will tunable expression of the target gene via an sTF-dependent promoter. We validated the SES functionality in six yeast and two filamentous fungi species in which high (levels beyond organism-specific promoters) as well as adjustable expression levels of heterologous and native genes was demonstrated. The SES is an unprecedentedly broadly functional gene expression regulation method that enables significantly improved engineering of fungi. Importantly, the SES system makes it possible to take in use novel eukaryotic microbes for basic research and various biotechnological applications.


Personalized knowledge to reduce the risk of stroke (PERKS-International): Protocol for a randomized controlled trial.
Theoretically, most strokes could be prevented through the management of modifiable risk factors. The Stroke Riskometer™ mobile phone application (hereon "The App") uses an individual's data to provide personalized information and advice to reduce their risk of stroke. To determine the effect of The App on a combined cardiovascular risk score (Life's Simple 7®, LS7) of modifiable risk factors at 6 months post-randomization. PERKS-International is a Phase III, multicentre, prospective, pragmatic, open-label, single-blinded endpoint, two-arm randomized controlled trial (RCT). Inclusion criteria are as follows: age ⩾ 35 and ⩽75 years; ⩾2 LS7 risk factors; smartphone ownership; no history of stroke/myocardial infarction/cognitive impairment/terminal illness. The intervention group (IG) will be provided with The App, and the usual care group (UCG) is provided with generic online information about risk factors, but not be informed about The App. Face-to-face assessments will be conducted at baseline and 6 months, and online at 3 and 12 months. The RCT includes a process and economic evaluation. The primary outcome is a difference in the mean change in LS7 (seven individual items: blood pressure, cholesterol, glucose, body mass index (BMI), smoking, physical activity, and diet) from baseline to 6 months post-randomization with intention-to-treat analysis. Secondary outcomes include: change in individual LS7 items, quality of life; stroke awareness, adverse events; health service use; and costs. Based on pilot data, 790 participants (395 IG, 395 UCG) will be required to provide 80% power (two-sided α = 0.05) to detect a mean difference in the LS7 of ⩾0.40 (SD 1.61) in IG compared to 0.01 (SD 1.44) in the UCG at 6 months post-randomization. Stroke is largely preventable. This study will provide evidence of the effectiveness of a mobile app to reduce stroke risk. ACTRN12621000211864.