Mutational analysis of the phototransduction pathway of Chlamydomonas reinhardtii.
Chlamydomonas has two photobehavioral responses, phototaxis and photoshock. Rhodopsin is the photoreceptor for these responses and the signal transduction process involves transmembrane Ca2+ fluxes. This causes transient changes in flagellar beating, ultimately resulting in phototaxis or photoshock. To identify components that make up this signal transduction pathway, we generated nonphototactic strains by insertional mutagenesis. Seven new phototaxis genes were identified (ptx2-ptx8); alleles of six of these are tagged by the transforming DNA and therefore should be easily cloned. To order the mutants in the pathway, we characterized them electrophysiologically, behaviorally, and structurally, ptx5, ptx6, and ptx7 have normal light-induced photoreceptor currents (PRC) and flagellar currents (FC) but their pattern of swimming does not change in the normal manner when the intraflagellar Ca2+ concentration is decreased, suggesting that they have defects in the ability of their axonemes to respond to changes in Ca2+ concentration. ptx2 and ptx8 lack the FC but have normal PRCs, suggesting that they are defective in the flagellar Ca2+ channel or some factor that regulates it. ptx4 mutants have multiple eye-spots. ptx3 mutants are defective in a component essential for phototaxis but bypassed during photoshock; this component appears to be located downstream of the PRC but upstream of the axoneme.


Management strategies for trace organic chemicals in water - A review of international approaches.
To ensure an appropriate management of potential health risks and uncertainties from the release of trace organic chemicals (TOrCs) into the aqueous environment, many countries have evaluated and implemented strategies to manage TOrCs. The aim of this study was to evaluate existing management strategies for TOrCs in different countries to derive and compare underlying core principles and paradigms and to develop suggestions for more holistic management strategies to protect the environment and drinking water supplies from the discharge of undesired TOrCs. The strategies in different industrial countries were summarized and subsequently compared with regards to three particular questions: 1) Do the approaches different countries have implemented manage all or only specific portions of the universe of chemicals; 2) What implementation and compliance strategies are used to manage aquatic and human health risk and what are their pros and cons; and 3) How are site-specific watershed differences being addressed? While management strategies of the different countries target similar TOrCs, the programs differ in several important aspects, including underlying principles, the balance between aquatic or human health protection, implementation methods, and financing mechanisms used to fund regulatory programs.


A Moderated Mediation Model of HIV-Related Stigma, Depression, and Social Support on Health-Related Quality of Life among Incarcerated Malaysian Men with HIV and Opioid Dependence.
Although it is well established that HIV-related stigma, depression, and lack of social support are negatively associated with health-related quality of life (HRQoL) among people living with HIV (PLH), no studies to date have examined how these psychosocial factors interact with each other and affect HRQoL among incarcerated PLH. We, therefore, incorporated a moderated mediation model (MMM) to explore whether depression mediates the effect of HIV-related stigma on HRQoL as a function of the underlying level of social support. Incarcerated HIV-infected men with opioid dependence (N = 301) were recruited from the HIV units in Kajang prison in Malaysia. Participants completed surveys assessing demographic characteristics, HIV-related stigma, depression, social support, and HRQoL. Results showed that the effect of HIV-related stigma on HRQoL was mediated via depression (a1:β = 0.1463, p < 0.001; b1:β = -0.8392, p < 0.001), as demonstrated by the two-tailed significance test (Sobel z = -3.8762, p < 0.001). Furthermore, the association between social support and HRQoL was positive (β = 0.4352, p = 0.0433), whereas the interaction between HIV-related stigma and depression was negatively associated with HRQOL (β = -0.0317, p = 0.0133). This indicated that the predicted influence of HIV-related stigma on HRQoL via depression had negative effect on HRQoL for individuals with low social support. The results suggest that social support can buffer the negative impact of depression on HRQoL and highlights the need for future interventions to target these psychosocial factors in order to improve HRQoL among incarcerated PLH.


Molecular mechanisms of G0/G1 cell-cycle arrest and apoptosis induced by terfenadine in human cancer cells.
Terfenadine (TF), a highly potent histamine H1 receptor antagonist, has been shown to exert no significant central nervous system side effects in clinically effective doses. In this study, we demonstrated that TF induced significant growth inhibition of human cancer cells, including Hep G2, HT 29, and COLO 205 cells, through induction of G(0)/G(1) phase cell-cycle arrest. The minimal dose of TF induced significant G(0)/G(1) arrest in these cells was 1-3 microM. The protein levels of p53, p21/Cip1, and p27/Kip1 were significantly elevated, whereas the kinase activities of cyclin-dependent kinase 2 (CDK2) and CDK4 were inhibited simultaneously in the TF-treated cells. On the other hand, significant apoptosis, but not G(0)/G(1) arrest, was induced in the HL 60 (p53-null) or Hep 3B (with deleted p53) cells when treated with TF (3-5 microM). To clarify the roles of p21/Cip1 and p27/Kip1 protein expression, which was involved in G(0)/G(1) arrest and apoptosis induced by TF in human cancer cells, antisense oligodeoxynucleotides (ODNs) specific to p21/Cip1 and p27/Kip1 were used, and the expression of the p21/Cip1 and p27/Kip1 were monitored by immunoblotting analysis. Our data demonstrated that the percentage of the apoptotic cells detected by annexin V/PI analysis in the TF-treated group was clearly attenuated by pretreatment with p27/Kip1-specific ODNs. These results indicated that p27/Kip1 (but not p21/Cip1) protein indeed played a critical role in the TF-induced apoptosis. We also demonstrated that the TF-induced G(0)/G(1) cell-cycle arrest effect was not reversed by TF removal, and this growth inhibition lasted for at least 7 d. Importantly, the occurrence of apoptosis and cell growth arrest was not observed in the TF-treated normal human fibroblast, even at a dose as high as 25 microM. Our study showed the molecular mechanisms for TF-induced cell growth inhibition and the occurrence of apoptosis in human cancer cells.


Shifting anaerobic to aerobic metabolism stimulates apoptosis through modulation of redox balance: potential intervention in the pathogenesis of postoperative adhesions.
To compare the effect of shifting anaerobic to aerobic metabolism on key regulators of oxidative stress, including extracellular superoxide dismutase (SOD3), inducible nitric oxide synthase (iNOS), and its product, nitric oxide (NO), as well as mitochondrial potential (Δψm) and apoptosis in fibroblasts established from normal peritoneum and adhesion tissues. Prospective, experimental study. University medical center. Fibroblasts established from normal peritoneum and adhesion tissues from the same patients. Treatment with dichloroacetate (0, 20, 40, and 80 μg/mL, 24 hours). The expression of SOD3, iNOS, and NO levels were measured utilizing real-time reverse transcription-polymerase chain reaction and Greiss assay. The Δψm was evaluated by the JC-1 Mitochondrial Membrane Potential Assay. Apoptosis was determined by caspase-3 activity and TUNEL assays. Data were analyzed using SPSS 19.0. Mixed model repeated-measures analysis of variance was used with a Bonferroni correction. Significant interactions were analyzed with independent sample t tests. Dichloroacetate increased apoptosis, SOD3 messenger RNA, iNOS messenger RNA, and NO levels in fibroblasts from peritoneum and adhesions. There was enhanced Δψm adhesion as compared with normal peritoneal fibroblasts. Creating oxidative stress by exposure by hypoxia markedly increased Δψm in fibroblasts from normal peritoneum to levels observed in adhesions; dichloroacetate protected against the effects of hypoxia. Anaerobic metabolism and oxidative stress are associated with the development of the adhesion phenotype, which manifests decreased apoptosis. Dichloroacetate induces adhesion fibroblasts to undergo apoptosis via modulation of redox homeostasis. These findings may provide targets for therapeutic treatment for reduction of profibrotic disorders, including postoperative adhesions.


GPR183-Oxysterol Axis in Spinal Cord Contributes to Neuropathic Pain.
Neuropathic pain is a debilitating public health concern for which novel non-narcotic therapeutic targets are desperately needed. Using unbiased transcriptomic screening of the dorsal horn spinal cord after nerve injury we have identified that Gpr183 (Epstein-Barr virus-induced gene 2) is upregulated after chronic constriction injury (CCI) in rats. GPR183 is a chemotactic receptor known for its role in the maturation of B cells, and the endogenous ligand is the oxysterol 7α,25-dihydroxycholesterol (7α,25-OHC). The role of GPR183 in the central nervous system is not well characterized, and its role in pain is unknown. The profile of commercially available probes for GPR183 limits their use as pharmacological tools to dissect the roles of this receptor in pathophysiological settings. Using in silico modeling, we have screened a library of 5 million compounds to identify several novel small-molecule antagonists of GPR183 with nanomolar potency. These compounds are able to antagonize 7α,25-OHC-induced calcium mobilization in vitro with IC50 values below 50 nM. In vivo intrathecal injections of these antagonists during peak pain after CCI surgery reversed allodynia in male and female mice. Acute intrathecal injection of the GPR183 ligand 7α,25-OHC in naïve mice induced dose-dependent allodynia. Importantly, this effect was blocked using our novel GPR183 antagonists, suggesting spinal GPR183 activation as pronociceptive. These studies are the first to reveal a role for GPR183 in neuropathic pain and identify this receptor as a potential target for therapeutic intervention. SIGNIFICANCE STATEMENT: We have identified several novel GPR183 antagonists with nanomolar potency. Using these antagonists, we have demonstrated that GPR183 signaling in the spinal cord is pronociceptive. These studies are the first to reveal a role for GPR183 in neuropathic pain and identify it as a potential target for therapeutic intervention.


Correlated structure of neuronal firing in macaque visual cortex limits information for binocular depth discrimination.
Variability in cortical neural activity potentially limits sensory discriminations. Theoretical work shows that information required to discriminate two similar stimuli is limited by the correlation structure of cortical variability. We investigated these information-limiting correlations by recording simultaneously from visual cortical areas primary visual cortex (V1) and extrastriate area V4 in macaque monkeys performing a binocular, stereo depth discrimination task. Within both areas, noise correlations on a rapid temporal scale (20-30 ms) were stronger for neuron pairs with similar selectivity for binocular depth, meaning that these correlations potentially limit information for making the discrimination. Between-area correlations (V1 to V4) were different, being weaker for neuron pairs with similar tuning and having a slower temporal scale (100+ ms). Fluctuations in these information-limiting correlations just prior to the detection event were associated with changes in behavioral accuracy. Although these correlations limit the recovery of information about sensory targets, their impact may be curtailed by integrative processing of signals across multiple brain areas.NEW & NOTEWORTHY Correlated noise reduces the stimulus information in visual cortical neurons during experimental performance of binocular depth discriminations. The temporal scale of these correlations is important. Rapid (20-30 ms) correlations reduce information within and between areas V1 and V4, whereas slow (>100 ms) correlations between areas do not. Separate cortical areas appear to act together to maintain signal fidelity. Rapid correlations reduce the neuronal signal difference between stimuli and adversely affect perceptual discrimination.


Differential Protein Expression Marks the Transition From Infection With Opisthorchis viverrini to Cholangiocarcinoma.
Parts of Southeast Asia have the highest incidence of intrahepatic cholangiocarcinoma (CCA) in the world because of infection by the liver fluke Opisthorchis viverrini (Ov). Ov-associated CCA is the culmination of chronic Ov-infection, with the persistent production of the growth factors and cytokines associated with persistent inflammation, which can endure for years in Ov-infected individuals prior to transitioning to CCA. Isobaric labeling and tandem mass spectrometry of liver tissue from a hamster model of CCA was used to compare protein expression profiles from inflammed tissue (Ovinfected but not cancerous) versus cancerous tissue (Ov-induced CCA). Immunohistochemistry and immunoblotting were used to verify dysregulated proteins in the animal model and in human tissue. We identified 154 dysregulated proteins that marked the transition from Ov-infection to Ov-induced CCA, i.e. proteins dysregulated during carcinogenesis but not Ov-infection. The verification of dysregulated proteins in resected liver tissue from humans with Ov-associated CCA showed the numerous parallels in protein dysregulation between human and animal models of Ov-induced CCA. To identify potential circulating markers for CCA, dysregulated proteins were compared with proteins isolated from exosomes secreted by a human CCA cell line (KKU055) and 27 proteins were identified as dysregulated in CCA and present in exosomes. These data form the basis of potential diagnostic biomarkers for human Ov-associated CCA. The profile of protein dysregulation observed during chronic Ovinfection and then in Ov-induced CCA provides insight into the etiology of an infection-induced inflammation-related cancer.


Serum lipid response to introducing ghee as a partial replacement for mustard oil in the diet of healthy young Indians.
Ghee (clarified butter) has generally been assumed to be hypercholesterolaemic on the basis of its composition but there is hardly any study to support or refute the assumption. The present study was conducted on sixty-three healthy, young, physically active adult volunteers (52 male, 11 female). The study design was that of a randomized controlled trial with a parallel design. After a lead-in period of 2 wk, the subjects were randomly divided into two groups, Group A (n = 30; 25 male, 5 female) and Group B (n = 33; 27 male, 6 female). Group A (experimental) consumed for 8 wk a diet in which ghee provided 10% of the energy intake. The only other visible fat in the diet was mustard oil, and total energy from fats was 25% of the energy intake. Group B (control) consumed for 8 wk a similar diet except that all visible fat came from mustard oil. The serum total cholesterol level showed a significant rise in the experimental group at 4 wk; the rise persisted at 8 wk. A similar rise was also seen in HDL cholesterol. Hence the total cholesterol/HDL cholesterol ratio did not show any significant change. In the control group, there was a trend towards a fall in LDL cholesterol but the change was not significant. The study does not indicate any adverse effect of ghee on lipoprotein profile. However, more studies are needed on older subjects, hyperlipidaemic subjects, and on subjects following less healthy lifestyles before the results of this study can be extrapolated to the general population.


Telling the truth about genomics.
Issues about communication in genomics have moved out of the clinic and into the public arena. Scientists other than clinicians are confronted by calls for public engagement. Genomics gives rise to these demands partly because it inevitably raises the three basic questions of philosophy as outlined by Kant: What can I know? What ought I to do? What may I hope? Genomics on its own cannot answer these questions. In relation to what can be known, its answer is at best partial. Nor can the ought question be settled by science. In fact, science is criticized for reducing options while claiming to be neutral in the pursuit of knowledge. The answer to the ought question is crucially related to the hope question in so far as this deals with issues about the point of human life generally. The role of public engagement in relation to all these questions may have different objectives. It is argued that there is more of a place for it in relation to the hope question than is commonly recognized, and in particular with regard to the role of science, which could benefit from developing a service ideal in the sense found in discussions of professional ethics.


The experience of physical activity and the transition to retirement: a systematic review and integrative synthesis of qualitative and quantitative evidence.
The transition to retirement has been recognised as a critical turning point for physical activity (PA). In an earlier systematic review of quantitative studies, retirement was found to be associated with an increase in recreational PA but with a decrease in PA among retirees from lower occupational groups. To gain a deeper understanding of the quantitative review findings, qualitative evidence on experiences of and views on PA around the transition to retirement was systematically reviewed and integrated with the quantitative review findings. 19 electronic databases were searched and reference lists were checked, citations tracked and journals hand-searched to identify qualitative studies on PA around the transition to retirement, published between January 1980 and August 2010 in any country or language. Independent quality appraisal, data extraction and evidence synthesis were carried out by two reviewers using a stepwise thematic approach. The qualitative findings were integrated with those of the existing quantitative systematic review using a parallel synthesis approach. Five qualitative studies met the inclusion criteria. Three overarching themes emerged from the synthesis of these studies: these related to retirees' broad concepts of PA, the motives for and the challenges to PA in retirement. Integrative synthesis of the qualitative findings with the quantitative evidence offered several potential explanations for why adults might engage in more recreational PA after the transition to retirement. These included expected health benefits, lifelong PA patterns, opportunities for socialising and personal challenges, and the desire for a new routine. A decrease in PA among retirees from lower occupational groups might be explained by a lack of time and a perceived low personal value of recreational PA. To encourage adoption and maintenance of PA after retirement, interventions should promote health-related and broader benefits of PA. Interventions for retirees from lower occupational groups should take account of busy post-retirement lifestyles and the low personal value that might be attributed to recreational PA. Future research should address predictors of maintenance of recreational PA after the transition to retirement, the broader benefits of PA, and barriers to PA among retirees from lower occupational groups.


Honey Combination Therapies for Skin and Wound Infections: A Systematic Review of the Literature.
Topical application of medical grade honey is recommended for the clinical management of wound infections. The suitability of honey as a wound healing agent is largely due to its antibacterial activity, immune modulatory properties, and biocompatibility. Despite the usefulness of honey in wound healing, chronic wound infections continue to be a global problem requiring new and improved therapeutic interventions. Several recent studies have investigated the effects of combining honey with other therapies or agents with the aim of finding more efficacious treatments. In this systematic review, the database PubMed was used to carry out a search of the scientific literature on the combined effects of honey and other therapies on antimicrobial activity and wound and skin healing. The search revealed that synergistic or additive antimicrobial effects were observed in vitro when honey was combined with antibiotics, bacteriophages, antimicrobial peptides, natural agents, eg, ginger or propolis and other treatment approaches such as the use of chitosan hydrogel. Outcomes depended on the type of honey, the combining agent or treatment and the microbial species or strain. Improved wound healing was also observed in vivo in mice when honey was combined with laser therapy or bacteriophage therapy. More clinical studies in humans are required to fully understand the effectiveness of honey combination therapies for the treatment of skin and wound infections.


Patients with abnormal sperm parameters have an increased sex chromosome aneuploidy rate in peripheral leukocytes.
Patients with oligoasthenoteratozoospermia (OAT) and normal karyotypes have an increased sperm aneuploidy rate. This may be due to an altered intratesticular environment that affects the chromosomal segregation mechanism(s). Alternatively, it may be due to a generalized meiotic and mitotic abnormality. In this case, patients with abnormal spermatogenesis should also have an increased somatic cell aneuploidy rate. To test this hypothesis, we evaluated peripheral leukocyte aneuploidy rate in patients with spermatogenic impairment. In all, 38 patients were enrolled, of whom 20 had OAT, 15 non-obstructive azoospermia and three Y chromosome (Yq) microdeletions (AZF). Eight healthy normozoospermic men with proven fertility were recruited as controls. Conventional karyotype analysis, AZF microdeletion evaluation and triple-colour FISH for chromosomes X, Y and 12 were conducted in all patients and controls. A total of 1000 lymphocytes were scored for each patient and control. All patients and controls had a normal karyotype. Sex chromosome aneuploidy rates in peripheral lymphocytes was significantly higher in patients with OAT (0.74+/-0.09%), azoospermia (1.15+/-0.15%) or Yq microdeleted (1.54+/-0.40%), compared with controls (0.15+/-0.03%) (P <0.05). Patients with OAT, azoospermia or Yq microdeletions had a slight, but significant, increase of sex chromosome aneuploidy rate in lymphocytes, suggesting the presence of a generalized defective cell division mechanism. In contrast with recent observations, Yq microdeletions do not seem to predispose to a higher number of malsegregation events in somatic cells compared with patients with azoospermia.


1,1-Bis(3'-indolyl)-1-(p-biphenyl)methane inhibits basal-like breast cancer growth in athymic nude mice.
1,1-Bis (3'-indolyl)-1-(p-biphenyl) methane (CDIM9) has been identified as a new peroxisome proliferator-activated receptor (PPAR)-gamma agonist that exhibits both receptor dependent and independent antitumor activities. CDIM9 has not previously been studied with respect to its effects against basal-like breast cancer. Our goal in the present study was to investigate the anti-basal-like breast tumor activity of CDIM9 in vitro and in vivo. The effects of CDIM9 on cell protein and DNA syntheses were determined in basal-like breast cancer MDA-MB231 and BT549 cells in vitro. Maximum tolerated dose and dose-limited toxicity were determined in BalB/c mice, and antitumor growth activities were assessed in MDA-MB231 basal-like breast tumor xenografts in athymic nude mice. CDIM9 exhibited selective cell cytotoxicity and anti-proliferation effects on basal-like breast cancer lines. In MDA-MB231 cell, CDIM9 induced caveolin-1 and p27 expression, which was significantly downregulated by co-treatment with the PPAR-gamma antagonist GW9662. Nonsteroidal anti-inflammatory drug-activated gene-1 and activating transcription factor-3 were upregulated by CDIM9 through a PPAR-gamma independent pathway. CDIM9 (40 mg/kg daily, intraperitoneally, for 35 days) inhibited the growth of subcutaneous MDA-MB231 tumor xenografts by 87%, and produced a corresponding decrease in proliferation index. Nearly half of the treated mice (46%) had complete durable remissions, confirmed by histology. The growth of an established tumor was inhibited by CDIM9 treatment (64 mg/kg daily, intraperitoneally, for 10 days), with a mean tumor growth inhibition of 67% as compared with controls. CDIM9 induced increases in tumor caveolin-1 and p27 in vivo, which may contribute to its antitumor activity in basal-like breast cancer. CDIM9 showed potent antiproliferative effects on basal-like breast cancer cell in tissue culture and dramatic growth inhibition in animal models at safe doses. These findings justify further development of this drug for treatment of basal-like breast cancer.


Quantifying the unquantifiable: why Hymenoptera, not Coleoptera, is the most speciose animal order.
We challenge the oft-repeated claim that the beetles (Coleoptera) are the most species-rich order of animals. Instead, we assert that another order of insects, the Hymenoptera, is more speciose, due in large part to the massively diverse but relatively poorly known parasitoid wasps. The idea that the beetles have more species than other orders is primarily based on their respective collection histories and the relative availability of taxonomic resources, which both disfavor parasitoid wasps. Though it is unreasonable to directly compare numbers of described species in each order, the ecology of parasitic wasps-specifically, their intimate interactions with their hosts-allows for estimation of relative richness. We present a simple logical model that shows how the specialization of many parasitic wasps on their hosts suggests few scenarios in which there would be more beetle species than parasitic wasp species. We couple this model with an accounting of what we call the "genus-specific parasitoid-host ratio" from four well-studied genera of insect hosts, a metric by which to generate extremely conservative estimates of the average number of parasitic wasp species attacking a given beetle or other insect host species. Synthesis of our model with data from real host systems suggests that the Hymenoptera may have 2.5-3.2× more species than the Coleoptera. While there are more described species of beetles than all other animals, the Hymenoptera are almost certainly the larger order.


Behavioral and biochemical dissociation of arousal and homeostatic sleep need influenced by prior wakeful experience in mice.
Sleep is regulated by homeostatic mechanisms, and the low-frequency power in the electroencephalogram (delta power) during non-rapid eye movement sleep reflects homeostatic sleep need. Additionally, sleep is limited by circadian and environmentally influenced arousal. Little is known, however, about the underlying neural substrates for sleep homeostasis and arousal and about the potential link between them. Here, we subjected C57BL/6 mice to 6 h of sleep deprivation using two different methods: gentle handling and continual cage change. Both groups were deprived of sleep to a similar extent (>99%), and, as expected, the delta power increase during recovery sleep was quantitatively similar in both groups. However, in a multiple sleep latency test, the cage change group showed significantly longer sleep latencies than the gentle handling group, indicating that the cage change group had a higher level of arousal despite the similar sleep loss. To investigate the possible biochemical correlates of these behavioral changes, we screened for arousal-related and sleep need-related phosphoprotein markers from the diencephalon. We found that the abundance of highly phosphorylated forms of dynamin 1, a presynaptic neuronal protein, was associated with sleep latency in the multiple sleep latency test. In contrast, the abundance of highly phosphorylated forms of N-myc downstream regulated gene 2, a glial protein, was increased in parallel with delta power. The changes of these protein species disappeared after 2 h of recovery sleep. These results suggest that homeostatic sleep need and arousal can be dissociated behaviorally and biochemically and that phosphorylated N-myc downstream regulated gene 2 and dynamin 1 may serve as markers of homeostatic sleep need and arousal, respectively.


Dynamic balance and ankle injury odds: a prospective study in 196 Dutch physical education teacher education students.
The aim of this study was to investigate whether dynamic balance, measured with the anterior component of the Star Excursion Balance Test (SEBT-ANT), is a risk factor for ankle injuries in physical education teacher education (PETE) students. A prospective monocentre study in first-year PETE students. A total of 196 subjects, of which 137 men (70%) and 59 women (30%). This study consisted of measures of the SEBT-ANT at baseline (September 2015) and an injury registration procedure during a follow-up period (September 2015-June 2016). The association between the SEBT-ANT score and subsequent ankle injury was analysed with generalised estimating equations analysis at the leg level. Men and women had an average SEBT-ANT score of, respectively, 65.1% and 67.7% of leg length. In 20 (15%) subjects, the first injured body site involved the ankle. Across all participants, a below average SEBT-ANT score was not associated with increased ankle injury odds (OR OR=2.43, 95% CI: 0.94 to 6.29, p=0.07). In men, a below average SEBT-ANT score indicated sevenfold increased odds for ankle injury (OR=7.06, 95% CI: 1.43 to 34.92, p=0.02). In women, this relationship was not significant (OR=0.72, 95% CI: 0.19 to 2.71, p=0.62). Below average normalised SEBT-ANT scores were associated with sevenfold likelihood for ankle injuries in men. In contrast, no relationship was found for the SEBT-ANT score and ankle injuries in woman. These results may provide directions for the implementation of screening tools, as part of an injury prevention programme, to identify male PETE students with an increased likelihood for ankle injuries.


Low surface expression of B7-1 (CD80) is an immunoescape mechanism of colon carcinoma.
Artificially enforced expression of CD80 (B7-1) and CD86 (B7-2) on tumor cells renders them more immunogenic by triggering the CD28 receptor on T cells. The enigma is that such B7s interact with much higher affinity with CTLA-4 (CD152), an inhibitory receptor expressed by activated T cells. We show that unmutated CD80 is spontaneously expressed at low levels by mouse colon carcinoma cell lines and other transplantable tumor cell lines of various tissue origins. Silencing of CD80 by interfering RNA led to loss of tumorigenicity of CT26 colon carcinoma in immunocompetent mice, but not in immunodeficient Rag-/- mice. CT26 tumor cells bind CTLA-4Ig, but much more faintly with a similar CD28Ig chimeric protein, thus providing an explanation for the dominant inhibitory effects on tumor immunity displayed by CD80 at that expression level. Interestingly, CD80-negative tumor cell lines such as MC38 colon carcinoma and B16 melanoma express CD80 at dim levels during in vivo growth in syngeneic mice. Therefore, low CD80 surface expression seems to give an advantage to cancer cells against the immune system. Our findings are similar with the inhibitory role described for the dim CD80 expression on immature dendritic cells, providing an explanation for the low levels of CD80 expression described in various human malignancies.


The localization of heparin-binding fragments on human C4b-binding protein.
C4b-binding protein (C4BP) is a multimeric plasma protein, which regulates the classical pathway of the C system. C4BP interacts with C C4b on a domain located in a 48-kDa chymotryptic fragment. We now demonstrate that C4BP contains heparin-binding fragments, which are located within the C4b binding domain. We have used an assay using heparin coupled to Sepharose CL-6B to show that 125I-C4BP binds to heparin in a time-dependent, saturable, and reversible manner. Binding could be inhibited by purified 48-kDa fragments and direct binding on the 48-kDa fragments to heparin-Sepharose was demonstrated by SDS-PAGE. mAb against native C4BP and the isolated 160-kDa central core fragment were evaluated for their ability to block the binding of 125I-C4BP to heparin and C4b. The relative efficacy of mAb against intact C4BP in blocking C4BP binding to heparin-Sepharose was similar to that for blocking 125I-C4BP binding to C4b. In addition, heparin blocked the binding of 125I-C4BP to C4b and vice versa. It is therefore likely that the heparin-binding fragments are localized on or close to the C4b-binding site of C4BP.


Active optics and modified-Rumsey wide-field telescopes: MINITRUST demonstrators with vase- and tulip-form mirrors.
Wide-field astronomy requires the development of larger aperture telescopes. The optical properties of a three-mirror modified-Rumsey design provide significant advantages when compared to other telescope designs: (i) at any wavelength, the design has a flat field and is anastigmatic; (ii) the system is extremely compact, i.e., it is almost four times shorter than a Schmidt. Compared to the equally compact flat-field Ritchey-Chrétien with a doublet-lens corrector, as developed for the Sloan digital sky survey-and which requires the polishing of six optical surfaces-the proposed modified-Rumsey design requires only a two-surface polishing and provides a better imaging quality. All the mirrors are spheroids of the hyperboloid type. Starting from the classical Rumsey design, it is shown that the use of all eight available free parameters allows the simultaneous aspherization of the primary and tertiary mirrors by active optics methods from a single deformable substrate. The continuity conditions between the primary and the tertiary hyperbolizations are achieved by an intermediate narrow ring of constant thickness that is not optically used. After the polishing of a double vase form in a spherical shape, the primary-tertiary hyperbolizations are achieved by in situ stressing. The tulip-form secondary is hyperbolized by stress polishing. Other active optics alternatives are possible for a space telescope. The modified-Rumsey design is of interest for developing large space- and ground-based survey telescopes in UV, visible, or IR ranges, such as currently demonstrated with the construction of identical telescopes MINITRUST-1 and -2, f/5-2 degrees field of view. Double-pass optical tests show diffraction-limited images.


Thalamocortical maturation in mice is influenced by body weight.
The emergence of the whisker-related patterning of the barrel cortex during the first postnatal week is a frequently assessed feature of rodent cortical development and has been used extensively to screen for effects of genetic mutations on neural development in mice. As alterations in body weight often accompany genetic mutations, we asked whether body weight itself might affect the progression of barrel cortex development in wildtype C57/BL6 mice. The body weight varied considerably between as well as within litters, and could differ by a factor of up to 1.6 between littermates. The establishment of the periphery-related and barrel patterning was assessed at postnatal (P days) 4 and 6 using cytochrome oxidase and Nissl staining. We found that only 20% of the mouse pups had an established thalamocortical afferent pattern in the barrel cortex at P4 (4 out of 21 brains), while the majority of the pups showed a well-established pattern at P6 (13 of 16 brains). At both ages the more developed barrel structure was found in the heavier littermates. Conversely, no periphery-related pattern was apparent in the somatosensory cortex at either P4 or P6 below a critical body weight of 2.6 g and 2.0 g, respectively. These findings may have implications for the interpretation of developmental changes in the barrel cortex of genetically modified mice.


Do-Not-Resuscitate Status Is Associated With Increased Mortality But Not Morbidity.
Do-not-resuscitate (DNR) orders instruct medical personnel to forego cardiopulmonary resuscitation in the event of cardiopulmonary arrest, but they do not preclude surgical management. Several studies have reported that DNR status is an independent predictor of 30-day mortality; however, the etiology of increased mortality remains unclear. We hypothesized that DNR patients would demonstrate increased postoperative mortality, but not morbidity, relative to non-DNR patients undergoing the same procedures. Using the American College of Surgeons National Surgical Quality Improvement Program database for 2007-2013, we performed a retrospective analysis to compare DNR and non-DNR cohorts matched by the most common procedures performed in DNR patients. We employed univariable and multivariable logistic regression to characterize patterns of care in the perioperative period as well as identify independent risk factors for increased mortality and assess for the presence of "failure to rescue." The most common procedures performed on DNR patients were emergent and centered on immediate symptom relief. When adjusting for preoperative factors, DNR patients were still found to have increased incidence of postoperative mortality (odds ratio 2.54 [2.29-2.82], P < .001) but not postoperative morbidity at 30 days. In addition, cardiopulmonary resuscitative measures and unplanned intubation were found to be less frequent in the DNR cohort. These findings suggest that increased mortality is the result of adherence to goals of care rather than "failure to rescue."


Effect of Engineered Nanoparticles on Enhancement of Composite Properties Relevant to Oilfield Applications.
Materials with enhanced properties permitting operations under increasingly harsh conditions such as high pressure, high temperature, high salinity, and sour environments are in critical need for the oil industry. The recent progress in composite materials has been facilitated by engineered nanoparticles dispersed or in situ generated in different matrix media. The cases representing examples considered in this paper include elastomers filled with carbon nanotubes, both in as-received and surface-functionalized compositions; metal matrix composites with added diamond nanoparticles; and scintillating glass ceramic nanocomposites. New nanocomposite materials prepared, characterized, and tested demonstrate enhanced mechanical and optical properties, as well as improved thermal and chemical stability, in line with requirements for demanding oilfield applications.


Predictors of Loss to follow-up in Patients Living with HIV/AIDS after Initiation of Antiretroviral Therapy.
Long-term regular follow up of ART is an important component of HIV care. Patients who are lost to follow-up (LTFU) while on treatment compromise their own health and the long-term success of ART programs. This study was aimed at determining the incidence and risk factors for LTFU in HIV patients on ART at ART clinic of Mizan-Aman General Hospital, Ethiopia. A retrospective cohort study of 2133 people living with HIV/AIDS and attending an ART clinic between 2005 and 2013 was undertaken. LTFU was defined as not taking an ART refill for a period of 3 months or longer from the last attendance for refill and not yet classified as 'dead' or 'transferred-out'. The log-rank test was used to measure differences in time to LTFU between groups and Cox proportional hazards modeling was used to measure predictors of LTFU. Of 2133 patients, 53.9% were female. The mean (SD) age of the cohort was 31.5 (8.0), 16 (2.2), and 3.8 (3.0) years for adults, adolescents, and children, respectively. Around 574 (26.7%) patients were defined as LTFU. The cumulative incidence of LTFU was 8.8 (95% CIs 8.1-9.6) per 1000 person months. Patients with regimen substitution (HR 5.2; 95% CIs 3.6-7.3), non-isoniazid (INH) prophylaxis (HR 3.7; 95% CIs 2.3-6.2), adolescent (HR 2.1; 95% CIs 1.3-3.4), and had a baseline CD4 count < 200 cells/mm(3) (HR 1.7, 95% CIs 1.3-2.2) were at higher risk of LTFU. WHO clinical stage III (HR 0.6; 95% CIs 0.4-0.9) and IV (HR 0.8; 95% CIs 0.6-1.0) patients at entry were less likely to be LTFU than clinical stage I patients. There was no significant difference in risk of LTFU in males and females. Overall, these data suggested that LTFU in this study was high. Patients phase of life, drug related factors, and clinical stages were associated with LTFU in this study. Effective control measures in the at-risk population need to be implemented to improve retention.


Oscillations in biochemical reaction networks arising from pairs of subnetworks.
Biochemical reaction models show a variety of dynamical behaviors, such as stable steady states, multistability, and oscillations. Biochemical reaction networks with generalized mass action kinetics are represented as directed bipartite graphs with nodes for species and reactions. The bipartite graph of a biochemical reaction network usually contains at least one cycle, i.e., a sequence of nodes and directed edges which starts and ends at the same species node. Cycles can be positive or negative, and it has been shown that oscillations can arise as a result of either a positive cycle or a negative cycle. In earlier work it was shown that oscillations associated with a positive cycle can arise from subnetworks with an odd number of positive cycles. In this article we formulate a similar graph-theoretic condition, which generalizes the negative cycle condition for oscillations. This new graph-theoretic condition for oscillations involves pairs of subnetworks with an even number of positive cycles. An example of a calcium reaction network with generalized mass action kinetics is discussed in detail.


THEMIS: Two Models, Different Thresholds.
THEMIS, a recently identified T-lineage-restricted protein, is the founding member of a large metazoan protein family. Gene inactivation studies have revealed a critical requirement for THEMIS during thymocyte positive selection, implicating THEMIS in signaling downstream of the T cell antigen receptor (TCR), but the mechanistic underpinnings of THEMIS function have remained elusive. A previous model posited that THEMIS prevents thymocytes from inappropriately crossing the positive/negative selection threshold by dampening TCR signaling. However, new data suggest an alternative model where THEMIS enhances TCR signaling enabling thymocytes to reach the threshold for positive selection, avoiding death by neglect. We review the data supporting each model and conclude that the preponderance of evidence favors an enhancing function for THEMIS in TCR signaling.


Effect of coenzyme Q10 as an antioxidant in beta-thalassemia/Hb E patients.
Thalassemia is a group of genetic disorders resulting from different mutations in the globin gene complex and leading to an imbalance in globin synthesis. Unmatched globin chains are less stable and susceptible to oxidation. Patients with beta-thalassemia/HbE are prone to increased oxidative stress as indicated by increased lipid peroxidation product, malondialdehyde (MDA), partly because of the presence of iron in the form of heme and hemichromes released from excess globin chains and excess iron deposition in various tissues. The level of antioxidant such as glutathione is markedly decreased while activities of antioxidant enzymes including superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH-Px) are increased. We have recently found that the levels of coenzyme Q(10) (CoQ(10)) are also very low in thalassemia. We therefore evaluated the oxidative stress and the antioxidants in these patients before and after supplementation with 100 mg CoQ(10) daily for 6 months. The results showed that the plasma level of CoQ(10) significantly increased and the oxidative stress decreased as the level of MDA declined. The administration of CoQ(10) led to significant improvement of biochemical parameters of antioxidant enzymes. The antioxidant supplementation will be beneficial for thalassemia patients as adjunct therapy to increase their quality of life.


Early versus late parenteral nutrition in critically ill, term neonates: a preplanned secondary subgroup analysis of the PEPaNIC multicentre, randomised controlled trial.
Previous randomised studies showed that withholding parenteral nutrition for 1 week of critical illness was superior to early initiation (<24-48 h) of parenteral nutrition in children and adults. However, neonates are considered more susceptible to macronutrient deficits. We investigated the effect of withholding parenteral nutrition for 1 week in critically ill, term neonates. We previously did a randomised, controlled study (PEPaNIC) of children aged up to 17 years admitted to paediatric intensive-care units (ICUs) in three hospitals in Belgium, Canada, and the Netherlands randomly assigned (1:1) to either standard care of parenteral nutrition initiated early within 24 h of admission to an ICU or late parenteral nutrition (where supplemental parenteral nutrition was withheld for 1 week after admission to the ICU). In this preplanned, secondary subanalysis of PEPaNIC, we looked at data from critically ill, term neonate participants (gestational age ≥37 weeks) aged up to 28 days (studied in overlapping age groups of ≤4 weeks, ≤1 week, and <1 day-ie, age at admission). In both the early parenteral nutrition and late parenteral nutrition groups, enteral nutrition was initiated as soon as possible and increased according to local protocols. Outcome assessors and investigators not directly involved in the paediatric ICU were not informed of treatment allocation. The primary endpoints were incidence of new infections and duration of paediatric ICU dependency (quantified as the number of days in the paediatric ICU and likelihood of earlier live discharge from the ICU), analysed based on intention to treat. Multivariable analyses were adjusted for the following risk factors: centre, Paediatric Logistic Organ Dysfunction score, Paediatric Index of Mortality 2 score, diagnosis group, and weight-for-age Z scores on admission. Secondary safety outcomes were mortality (at 90 days, during the intervention, in the paediatric ICU, and in the hospital) and hypoglycaemic incidents during the intervention. All patients in the respective groups were included in the safety analysis. Between June 18, 2012, and July 27, 2015, we included 209 participants in this substudy, 145 of whom were aged up to and including 1 week and 45 aged younger than 1 day. In neonates aged up to and including 4 weeks, late parenteral nutrition increased the likelihood of earlier live discharge from the paediatric ICU compared with early parenteral nutrition (adjusted hazard ratio [HR] 1·61, 95% CI 1·19-2·20; p=0·0021) but did not affect the risk of infection. The risk of infection in neonates aged up to and including 1 week and younger than 1 day was lower with late parenteral nutrition than with early parenteral nutrition (adjusted odds ratios [OR] 0·36, 95% CI 0·15-0·83, p=0·017; and 0·10, 0·01-0·64, p=0·015, respectively). For neonates aged up to and including 1 week, the likelihood of an earlier live discharge from the ICU was higher with late parenteral nutrition (adjusted HR 1·69, 95% CI 1·16-2·46; p=0·0063). For neonates younger than 1 day, adjusted HR was 1·95 (95% CI 0·93-4·12; p=0·078). Mortality at all studied timepoints was similar between the groups for all ages; however, in neonates aged up to and including 4 weeks and aged up to and including 1 week, the risk of hypoglycaemia was higher with late parenteral nutrition (23% vs 14%; adjusted OR 3·05, 95% CI 1·27-7·35, p=0·013; and 24% vs 14%; 3·57, 1·23-10·45, p=0·019, respectively. In critically ill, term neonates, withholding parenteral nutrition for 1 week was clinically superior to standard care of initiating parenteral nutrition within 24 h for short-term outcomes. However, withholding parenteral nutrition for 1 week significantly increased the risk of developing hypoglycaemia, which necessitates long-term follow-up of these children before late parenteral nutrition can be confidently recommended for this vulnerable patient group. Flemish Agency for Innovation through Science and Technology, Methusalem-Programme Flemish Government, European Research Council, Fonds NutsOhra, Stichting Agis-Zorginnovatie, and the Sophia Research-Foundation.


Biogenesis of membrane-bound and secreted immunoglobulins. II. Two forms of the human alpha chain translated in vitro and processed in vivo as distinct polypeptide chains.
Structural differences between alpha m (ther heavy chain of membrane IgA) and alpha s (the heavy chain of secretory IgA) were investigated. Messenger RNA from the human B lymphoblastoid line 32a.1, expressing both membrane and secretory IgA, was translated in a wheat germ cell-free system, resulting in the synthesis of two primary translation products for the alpha chain, that differed in molecular weight. In vivo pulse and pulse-chase experiments demonstrated that two early biosynthetic forms of the alpha chain were subsequently modified to yield three intracellular forms. As shown by endo-beta-N-acetylglucosaminidase H (endo H) treatment, these forms represent two alpha polypeptide chains, with varying compositions of N-linked oligosaccharides. Of the two forms of the alpha chain remaining after endo H treatment, only the form with the lowest molecular weight was associated with cells after long chase periods. The possible significance of this difference from the results with mu and delta chains is discussed. These results indicate that alpha m is distinguished from an alpha s by a difference in both primary structure and intracellular processing. The functional consequences of this distinction, previously shown for the heavy chain of membrane IgM (micrometer) and heavy chain of secretory IgM (microseconds), may reflect a principle common to the secretory and membrane forms of all immunoglobulin heavy chain classes.


Comparative analysis of expressed sequence tags from three castes and two life stages of the termite Reticulitermes flavipes.
Termites (Isoptera) are eusocial insects whose colonies consist of morphologically and behaviorally specialized castes of sterile workers and soldiers, and reproductive alates. Previous studies on eusocial insects have indicated that caste differentiation and behavior are underlain by differential gene expression. Although much is known about gene expression in the honey bee, Apis mellifera, termites remain relatively understudied in this regard. Therefore, our objective was to assemble an expressed sequence tag (EST) data base for the eastern subterranean termite, Reticulitermes flavipes, for future gene expression studies. Soldier, worker, and alate caste and two larval cDNA libraries were constructed, and approximately 15,000 randomly chosen clones were sequenced to compile an EST data base. Putative gene functions were assigned based on a BLASTX Swissprot search. Categorical in silico expression patterns for each library were compared using the R-statistic. A significant proportion of the ESTs of each caste and life stages had no significant similarity to those in existing data bases. All cDNA libraries, including those of non-reproductive worker and soldier castes, contained sequences with putative reproductive functions. Genes that showed a potential expression bias among castes included a putative antibacterial humoral response and translation elongation protein in soldiers and a chemosensory protein in alates. We have expanded upon the available sequences for R. flavipes and utilized an in silico method to compare gene expression in different castes of an eusocial insect. The in silico analysis allowed us to identify several genes which may be differentially expressed and involved in caste differences. These include a gene overrepresented in the alate cDNA library with a predicted function of neurotransmitter secretion or cholesterol absorption and a gene predicted to be involved in protein biosynthesis and ligase activity that was overrepresented in the late larval stage cDNA library. The EST data base and analyses reported here will be a valuable resource for future studies on the genomics of R. flavipes and other termites.


Priapism in Homozygous Sickle Cell Disease: A 40-year Study of the Natural History.
To describe the incidence, pattern, and outcome of priapism in homozygous sickle cell (SS) disease. Regular review, for periods up to 40 years, was done of all 162 males with SS disease detected during the screening of 100 000 consecutive non-operative deliveries at the main government maternity hospital in Kingston, Jamaica, between June 1973 and December 1981. Priapism occurred in 52 (32.7%) patients overall, the incidence rising steeply in late adolescence to 32% by age 20 years and a cumulative incidence of nearly 60% of patients by age 40 years. Many cases were elicited only on direct questioning because of embarrassment and the lack of realization that priapism complicates SS disease. Initial events were recurrent stuttering episodes in 39 patients, a single short-term event in six patients and a major attack (more than six hours) in seven patients. Erectile function was preserved in almost all patients with simple stuttering or single events. Major attacks (> 6 hours) occurred in 17 patients, preceded by stuttering episodes in nine, by a single event in one, and occurring de novo in seven. In these, erectile function was unknown in five, deemed satisfactory in five (sometimes improving over three years), weak in three and impotence persisted in four (two with major attacks three and six months previously). A history of stuttering priapism should be routinely enquired and prophylactic measures used if attacks exceed once weekly. Major events generally result in short-term impotence, but the late recovery of erectile function cautions against the early insertion of penile prostheses.


Using the PfEMP1 head structure binding motif to deal a blow at severe malaria.
Plasmodium falciparum (Pf) malaria causes 200 million cases worldwide, 8 million being severe and complicated leading to ∼1 million deaths and ∼100,000 abortions annually. Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) has been implicated in cytoadherence and infected erythrocyte rosette formation, associated with cerebral malaria; chondroitin sulphate-A attachment and infected erythrocyte sequestration related to pregnancy-associated malaria and other severe forms of disease. An endothelial cell high activity binding peptide is described in several of this ∼300 kDa hypervariable protein's domains displaying a conserved motif (GACxPxRRxxLC); it established H-bonds with other binding peptides to mediate red blood cell group A and chondroitin sulphate attachment. This motif (when properly modified) induced PfEMP1-specific strain-transcending, fully-protective immunity for the first time in experimental challenge in Aotus monkeys, opening the way forward for a long sought-after vaccine against severe malaria.


Nanoparticle Enhancement Cascade for Sensitive Multiplex Measurements of Biomarkers in Complex Fluids with Surface Plasmon Resonance Imaging.
There is a large unmet need for reliable biomarker measurement systems for clinical application. Such systems should meet challenging requirements for large scale use, including a large dynamic detection range, multiplexing capacity, and both high specificity and sensitivity. More importantly, these requirements need to apply to complex biological samples, which require extensive quality control. In this paper, we present the development of an enhancement detection cascade for surface plasmon resonance imaging (SPRi). The cascade applies an antibody sandwich assay, followed by neutravidin and a gold nanoparticle enhancement for quantitative biomarker measurements in small volumes of complex fluids. We present a feasibility study both in simple buffers and in spiked equine synovial fluid with four cytokines, IL-1β, IL-6, IFN-γ, and TNF-α. Our enhancement cascade leads to an antibody dependent improvement in sensitivity up to 40 000 times, resulting in a limit of detection as low as 50 fg/mL and a dynamic detection range of more than 7 logs. Additionally, measurements at these low concentrations are highly reliable with intra- and interassay CVs between 2% and 20%. We subsequently showed this assay is suitable for multiplex measurements with good specificity and limited cross-reactivity. Moreover, we demonstrated robust detection of IL-6 and IL-1β in spiked undiluted equine synovial fluid with small variation compared to buffer controls. In addition, the availability of real time measurements provides extensive quality control opportunities, essential for clinical applications. Therefore, we consider this method is suitable for broad application in SPRi for multiplex biomarker detection in both research and clinical settings.


Viewing facial expressions of pain engages cortical areas involved in the direct experience of pain.
Recent neuroimaging and neuropsychological work has begun to shed light on how the brain responds to the viewing of facial expressions of emotion. However, one important category of facial expression that has not been studied on this level is the facial expression of pain. We investigated the neural response to pain expressions by performing functional magnetic resonance imaging (fMRI) as subjects viewed short video sequences showing faces expressing either moderate pain or, for comparison, no pain. In alternate blocks, the same subjects received both painful and non-painful thermal stimulation. Facial expressions of pain were found to engage cortical areas also engaged by the first-hand experience of pain, including anterior cingulate cortex and insula. The reported findings corroborate other work in which the neural response to witnessed pain has been examined from other perspectives. In addition, they lend support to the idea that common neural substrates are involved in representing one's own and others' affective states.


Discontinuities in soil strength contribute to destabilization of nutrient-enriched creeks.
In a whole-ecosystem, nutrient addition experiment in the Plum Island Sound Estuary (Massachusetts), we tested the effects of nitrogen enrichment on the carbon and nitrogen contents, respiration, and strength of marsh soils. We measured soil shear strength within and across vegetation zones. We found significantly higher soil percent organic matter, carbon, and nitrogen in the long-term enriched marshes and higher soil respiration rates with longer duration of enrichment. The soil strength was similar in magnitude across depths and vegetation zones in the reference creeks, but showed signs of significant nutrient-mediated alteration in enriched creeks where shear strength at rooting depths of the low marsh-high marsh interface zone was significantly lower than at the sub-rooting depths or in the creek bank vegetation zone. To more closely examine the soil strength of the rooting (10-30 cm) and sub-rooting (40-60 cm) depths in the interface and creek bank vegetation zones, we calculated a vertical shear strength differential between these depths. We found significantly lower differentials in shear strength (rooting depth < sub-rooting depths) in the enriched creeks and in the interface zones. The discontinuities in the vertical and horizontal shear strength across the enriched marshes may contribute to observed fracturing and slumping occurring in the marsh systems. Tide gauge data also showed a pattern of rapid sea level rise for the period of the study, and changes in plant distribution patterns were indicative of increased flooding. Longer exposure times to nutrient-enriched waters and increased hydraulic energy associated with sea level rise may exacerbate creek bank sloughing. Additional research is needed, however, to better understand the interactions of nutrient enrichment and sea level rise on soil shear strength and stability of tidal salt marshes.


Participatory Training to Improve Safety and Health in Small Construction Sites in Some Countries in Asia: Development and Application of the WISCON Training Program.
A participatory training program, Work Improvement in Small Construction Sites, was developed to provide practical support measures to the small construction sector. Managers and workers from selected small sites were interviewed about their occupational safety and health risks. The Work Improvement in Small Construction Sites training program comprised a 45-item action checklist, photos, and illustrations showing local examples and group work methods. Pilot training workshops were carried out with workers and employers in Cambodia, Laos, Mongolia, Thailand, and Vietnam. Participants subsequently planned, and using locally available low-cost materials, implemented their own improvements such as hand-made hand trucks to carry heavy materials, removal of projecting nails from timber materials, and fences to protect roof workers from falling. Local Work Improvement in Small Construction Sites trainers consisting of government officials, workers, employers, and nongovernment organization representatives were then trained to implement the Work Improvement in Small Construction Sites training widely. Keys to success were easy-to-apply training tools aiming at immediate, low-cost improvements, and collaboration with various local people's networks.


Mediodorsal and visual thalamic connectivity differ in schizophrenia and bipolar disorder with and without psychosis history.
Empirical and theoretical studies implicate thalamocortical circuits in schizophrenia, supported by emerging resting-state functional connectivity studies (rs-fcMRI). Similar but attenuated alterations were found in bipolar disorder (BD). However, it remains unknown if segregated loops within thalamocortical systems show distinct rs-fcMRI alterations in schizophrenia. For instance, the mediodorsal (MD) nucleus, known to project to prefrontal networks, may be differently altered than the lateral geniculate nucleus (LGN), known to project to the occipital cortex. Also, it remains unknown if these circuits show different patterns of alterations in BD as a function of psychosis history, which may be associated with a more severe clinical course. We addressed these questions in 90 patients with chronic schizophrenia and 73 remitted BD patients (33 with psychosis history) matched to 146 healthy comparison subjects. We hypothesized that the MD vs LGN would show dissociations across diagnostic groups. We found that MD and LGN show more qualitative similarities than differences in their patterns of dysconnectivity in schizophrenia. In BD, patterns qualitatively diverged between thalamic nuclei although these effects were modest statistically. BD with psychosis history was associated with more severe dysconnectivity, particularly for the MD nucleus. Also, the MD nucleus showed connectivity reductions with the cerebellum in schizophrenia but not in BD. Results suggest dissociations for thalamic nuclei across diagnoses, albeit carefully controlling for medication is warranted in future studies. Collectively, these findings have implications for designing more precise neuroimaging-driven biomarkers that can identify common and divergent large-scale network perturbations across psychiatric diagnoses with shared symptoms.


The epistemic integrity of scientific research.
We live in a world in which scientific expertise and its epistemic authority become more important. On the other hand, the financial interests in research, which could potentially corrupt science, are increasing. Due to these two tendencies, a concern for the integrity of scientific research becomes increasingly vital. This concern is, however, hollow if we do not have a clear account of research integrity. Therefore, it is important that we explicate this concept. Following Rudolf Carnap's characterization of the task of explication, this means that we should develop a concept that is (1) similar to our common sense notion of research integrity, (2) exact, (3) fruitful, and (4) as simple as possible. Since existing concepts do not meet these four requirements, we develop a new concept in this article. We describe a concept of epistemic integrity that is based on the property of deceptiveness, and argue that this concept does meet Carnap's four requirements of explication. To illustrate and support our claims we use several examples from scientific practice, mainly from biomedical research.


Empathy-based counterspeech can reduce racist hate speech in a social media field experiment.
Despite heightened awareness of the detrimental impact of hate speech on social media platforms on affected communities and public discourse, there is little consensus on approaches to mitigate it. While content moderation-either by governments or social media companies-can curb online hostility, such policies may suppress valuable as well as illicit speech and might disperse rather than reduce hate speech. As an alternative strategy, an increasing number of international and nongovernmental organizations (I/NGOs) are employing counterspeech to confront and reduce online hate speech. Despite their growing popularity, there is scant experimental evidence on the effectiveness and design of counterspeech strategies (in the public domain). Modeling our interventions on current I/NGO practice, we randomly assign English-speaking Twitter users who have sent messages containing xenophobic (or racist) hate speech to one of three counterspeech strategies-empathy, warning of consequences, and humor-or a control group. Our intention-to-treat analysis of 1,350 Twitter users shows that empathy-based counterspeech messages can increase the retrospective deletion of xenophobic hate speech by 0.2 SD and reduce the prospective creation of xenophobic hate speech over a 4-wk follow-up period by 0.1 SD. We find, however, no consistent effects for strategies using humor or warning of consequences. Together, these results advance our understanding of the central role of empathy in reducing exclusionary behavior and inform the design of future counterspeech interventions.


Improving Ambulation and Minimizing Disability with Therapeutic Plasma Exchange in a Stiff-person Syndrome Patient with Recurrent Falls.
Stiff-person syndrome (SPS) is a rare, autoimmune, neuromuscular disorder that manifests with axial and proximal muscle stiffness, rigidity, and painful muscle spasms, often causing progressive disability due to limited movement. First-line therapies comprise symptomatic management with γ-aminobutyric acid-modulating drugs such as benzodiazepines and baclofen. Patients resistant to these treatments are often given intravenous immunoglobulin (IVIg). Severe disease refractory to first-line therapy and IVIg may be treated with therapeutic plasma exchange (TPE) or immunomodulatory agents such as rituximab. Current evidence derived from case reports and case series has shown that roughly half of SPS patients treated with TPE report benefits. Here, we report the case of a 68-year-old man with a 20-year history of severe SPS and recurrent falls who was admitted to the emergency department for a traumatic hip fracture. He had significant rigidity in the axial and extremity muscles with persistent spasms of the quadriceps femoris muscle. Postoperatively, he was unable to participate in physical therapy (PT) due to these symptoms. He previously failed treatment with diazepam, baclofen, and monthly IVIg. Under our care, he underwent seven TPE treatments. By the end of treatment, he reported significant improvement in mobility with a resolution of muscle spasms and was able to be discharged to inpatient rehabilitation. This suggests that TPE may offer an effective, safe treatment modality for patients with severe refractory SPS that may significantly improve mobility and disability associated with the disease.


Maclaurin-series method for calculating dispersion in arrayed-waveguide grating multiplexers.
We present a Maclaurin-series method for calculating the dispersion from phase error and amplitude distributions in arrayed waveguide grating (AWG) multiplexers. By using this method, we can easily derive the intercept, the gradient, and the curvature of the dispersion in the center frequency region of a passband. A third-order Maclaurin series was calculated by using the measured phase error and amplitude distributions of AWGs having a channel frequency spacing of 12.5 GHz. The calculated results are in good agreement with the dispersions measured with an optical network analyzer. We also discuss the physical effect of the phase error on dispersion by assuming certain limited cases.


Comparative in situ analyses of cell wall matrix polysaccharide dynamics in developing rice and wheat grain.
Cell wall polysaccharides of wheat and rice endosperm are an important source of dietary fibre. Monoclonal antibodies specific to cell wall polysaccharides were used to determine polysaccharide dynamics during the development of both wheat and rice grain. Wheat and rice grain present near synchronous developmental processes and significantly different endosperm cell wall compositions, allowing the localisation of these polysaccharides to be related to developmental changes. Arabinoxylan (AX) and mixed-linkage glucan (MLG) have analogous cellular locations in both species, with deposition of AX and MLG coinciding with the start of grain filling. A glucuronoxylan (GUX) epitope was detected in rice, but not wheat endosperm cell walls. Callose has been reported to be associated with the formation of cell wall outgrowths during endosperm cellularisation and xyloglucan is here shown to be a component of these anticlinal extensions, occurring transiently in both species. Pectic homogalacturonan (HG) was abundant in cell walls of maternal tissues of wheat and rice grain, but only detected in endosperm cell walls of rice in an unesterified HG form. A rhamnogalacturonan-I (RG-I) backbone epitope was observed to be temporally regulated in both species, detected in endosperm cell walls from 12 DAA in rice and 20 DAA in wheat grain. Detection of the LM5 galactan epitope showed a clear distinction between wheat and rice, being detected at the earliest stages of development in rice endosperm cell walls, but not detected in wheat endosperm cell walls, only in maternal tissues. In contrast, the LM6 arabinan epitope was detected in both species around 8 DAA and was transient in wheat grain, but persisted in rice until maturity.


Are there subgroups within the autistic spectrum? A cluster analysis of a group of children with autistic spectrum disorders.
Comprehensive data on the developmental history and current behaviours of a large sample of high-functioning individuals with diagnoses of autism, Asperger's syndrome, or other related disorder were collected via parent interviews. This provided the basis for a taxonomic analysis to search for subgroups. Most participants also completed theory of mind tasks. Three clusters or subgroups were obtained; these differed on theory of mind performance and on verbal abilities. Although subgroups were identified which bore some relationship to clinical differentiation of autistic, Asperger syndrome, and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) cases, the nature of the differences between them appeared strongly related to ability variables. Examination of the kinds of behaviours that differentiated the groups suggested that a spectrum of autistic disorders on which children differ primarily in term of degrees of social and cognitive impairments could explain the findings.


Low vision magnifiers--their optical parameters and methods for prescribing.
Information provided by manufacturers of low vision magnifiers is usually insufficient to allow the clinician to predict accurately the resolution improvement that patients may be expected to achieve. We have measured and tabulated the key optical parameters of 92 stand magnifiers and 53 hand-held magnifiers. For the fixed focus stand magnifiers, the image location and the equivalent power of the lens system have been determined and the enlargement ratio has been derived. For each magnifier, 3 different eye-to-lens distances (2.5, 10, and 25 cm) have been considered and, for each of these, the Equivalent Viewing Distance (EVD), the eye-to-image distance, and the theoretically predicted field width have been computed. The EVD is useful in predicting resolution performance because, for a given patient, the visual resolution limit will be directly proportional to the EVD. The eye-to-image distances allow the clinician to consider whether the patient will be in satisfactory focus or whether adjustments need to be made to the power of any reading addition. The stand magnifiers are listed in order of the EVD they give when the eye is a moderate (10 cm) distance from the magnifier. For the hand-held magnifiers, the equivalent powers have been measured. The EVD for a hand-held magnifier will be the same as the equivalent focal length of the magnifier if the lens is used so that the image is at or close to infinity. The tables include supplementary information on the size of the magnifier lenses and whether the magnifiers incorporate battery, electric, incandescent, or halogen lighting systems. Examples are presented to illustrate how the tables might be used in the selection of magnifiers to meet the resolution and other needs of individual patients.


Evaluating trauma care: the TRISS method. Trauma Score and the Injury Severity Score.
Evaluation of trauma care must be an integral part of any system designed for care of seriously injured patients. However, outcome review should offer comparability to national standards or norms. The TRISS method offers a standard approach for evaluating outcome of trauma care. Anatomic, physiologic, and age characteristics are used to quantify probability of survival as related to severity of injury. TRISS offers a means of case identification for quality assurance review on a local basis, as well as a means of comparison of outcome for different populations of trauma patients. Methods for calculating statistics associated with TRISS are presented. The Z and M statistics are explained with the nonstatistician in mind. We feel this article is a source for those interested in developing or upgrading trauma care evaluation.


Developing a comprehensive time series of GDP per capita for 210 countries from 1950 to 2015.
Income has been extensively studied and utilized as a determinant of health. There are several sources of income expressed as gross domestic product (GDP) per capita, but there are no time series that are complete for the years between 1950 and 2015 for the 210 countries for which data exist. It is in the interest of population health research to establish a global time series that is complete from 1950 to 2015. We collected GDP per capita estimates expressed in either constant US dollar terms or international dollar terms (corrected for purchasing power parity) from seven sources. We applied several stages of models, including ordinary least-squares regressions and mixed effects models, to complete each of the seven source series from 1950 to 2015. The three US dollar and four international dollar series were each averaged to produce two new GDP per capita series. Nine complete series from 1950 to 2015 for 210 countries are available for use. These series can serve various analytical purposes and can illustrate myriad economic trends and features. The derivation of the two new series allows for researchers to avoid any series-specific biases that may exist. The modeling approach used is flexible and will allow for yearly updating as new estimates are produced by the source series. GDP per capita is a necessary tool in population health research, and our development and implementation of a new method has allowed for the most comprehensive known time series to date.


Cortisol stimulates cell cycle activity in the cardiomyocyte of the sheep fetus.
The role of cortisol in regulating cardiac myocyte growth in the near-term fetal sheep is unknown. We hypothesized that cortisol would suppress cardiomyocyte proliferation and stimulate cardiomyocyte binucleation and enlargement, signs of terminal differentiation. Cardiomyocyte dimensions and percent binucleation were determined in isolated cardiac myocytes from seven cortisol-treated and seven control fetuses; percentage of myocytes positive for Ki-67 was determined in an additional four cortisol-treated and four control hearts. Cortisol was infused into the circumflex coronary artery at subpressor rates (0.5 microg/kg.min, 7 d). Cortisol infusion had no hemodynamic effects, compared with controls or pretreatment conditions. Cortisol treatment increased heart weight (44.0 +/- 8.7 g vs. control, 34.9 +/- 9.1 g, P < 0.05). Heart to body weight ratio was greater in treated hearts, compared with controls (10.3 +/- 1.9 vs. 7.7 +/- 0.9 g/kg, P < 0.01). Ventricular myocyte length, width, and percent binucleation were not different between groups. The proportion of treated myocytes in the cell cycle staining for Ki-67 was higher in the left ventricle (5.5 +/- 0.1 vs. 2.7 +/- 0.4%, P < 0.005) and right ventricle (4.4 +/- 0.4 vs. 3.7 +/- 0.7%, P < 0.05), compared with controls. Wet weight to dry weight ratios from cortisol-treated and control hearts were not different. In conclusion, whereas cortisol infused into the fetal sheep heart has no effect on cardiomyocyte size or maturational state, it stimulates entry of cardiomyocytes in the cell cycle. Thus, increases in fetal heart mass associated with subpressor doses of cortisol are due to cardiomyocyte proliferation and not hypertrophic growth.


Introduction to neutron stimulated emission computed tomography.
Neutron stimulated emission computed tomography (NSECT) is presented as a new technique for in vivo tomographic spectroscopic imaging. A full implementation of NSECT is intended to provide an elemental spectrum of the body or part of the body being interrogated at each voxel of a three-dimensional computed tomographic image. An external neutron beam illuminates the sample and some of these neutrons scatter inelastically, producing characteristic gamma emission from the scattering nuclei. These characteristic gamma rays are acquired by a gamma spectrometer and the emitting nucleus is identified by the emitted gamma energy. The neutron beam is scanned over the body in a geometry that allows for tomographic reconstruction. Tomographic images of each element in the spectrum can be reconstructed to represent the spatial distribution of elements within the sample. Here we offer proof of concept for the NSECT method, present the first single projection spectra acquired from multi-element phantoms, and discuss potential biomedical applications.


Sympathetic stimulation produces a greater increase in both transmural and spatial dispersion of repolarization in LQT1 than LQT2 forms of congenital long QT syndrome.
The study compared the influence of sympathetic stimulation on transmural and spatial dispersion of repolarization between LQT1 and LQT2 forms of congenital long QT sYndrome (LQTS). Cardiac events are more associated with sympathetic stimulation in LQT1 than in LQT2 or LQT3 syndrome. Experimental studies have suggested that the interval between Tpeak and Tend (Tp-e) in the electrocardiogram (ECG) reflects transmural dispersion of repolarization across the ventricular wall. We recorded 87-lead body-surface ECGs before and after epinephrine infusion (0.1 microg/kg/min) in 13 LQT1, 6 LQT2, and 7 control patients. The Q-Tend (QT-e), Q-Tpeak (QT-p), and Tp-e were measured automatically from 87-lead ECGs, corrected by Bazett's method (QTc-e, QTc-p, Tcp-e), and averaged among all 87-leads and among 24-leads, which reflect the potential from the left ventricular free wall. As an index of spatial dispersion of repolarization, the dispersion of QTc-e (QTc-eD) and QTc-p (QTc-pD) were obtained among 87-leads and among 24-leads, and were defined as the interval between the maximum and the minimum of the QTc-e and the QTc-p, respectively. Epinephrine significantly increased the mean QTc-e but not the mean QTc-p, resulting in a significant increase in the mean Tcp-e in both LQT1 and LQT2, but not in control patients. The epinephrine-induced increases in the mean QTc-e and Tcp-e were larger in LQT1 than in LQT2, and were more pronounced when the averaged data were obtained from 24-leads than from 87-leads. Epinephrine increased the maximum QTc-e but not the minimum QTc-e, producing a significant increase in the QTc-eD in both LQT1 and LQT2 patients, but not in control patients. The increase in the QTc-eD was larger in LQT1 than in LQT2 patients. Our data suggest that sympathetic stimulation produces a greater increase in both transmural and spatial dispersion of repolarization in LQT1 than in LQT2 syndrome, and this may explain why LQT1 patients are more sensitive to sympathetic stimulation.


Dry powder aerosols generated by standardized entrainment tubes from alternative sugar blends: 3. Trehalose dihydrate and D-mannitol carriers.
The relationship between physicochemical properties of drug/carrier blends and aerosol drug powder delivery was evaluated. Four pulmonary drugs each representing the major pulmonary therapeutic classes and with a different pharmacological action were employed. Specifically, the four pulmonary drugs were albuterol sulfate, ipratropium bromide monohydrate, disodium cromoglycate, and fluticasone propionate. The two carrier sugars, each representing a different sugar class, were D-mannitol and trehalose dihydrate. Dry powder aerosols (2%, w/w, drug in carrier) delivered using standardized entrainment tubes (SETs) were characterized by twin-stage liquid impinger. The fine particle fraction (FPF) was correlated with SET shear stress, tau(s), and the maximum fine particle fraction (FPF(max)) was correlated with a deaggregation constant, k(d), by using a powder aerosol deaggregation equation (PADE) by nonlinear and linear regression analyses applied to pharmaceutical inhalation aerosol systems in the solid state. For the four pulmonary drugs representing the major pulmonary therapeutic classes and two chemically distinct pulmonary sugar carriers (non-lactose types) aerosolized with SETs having well-defined shear stress values, excellent correlation and predictive relationships were demonstrated for the novel and rigorous application of PADE for dry powder inhalation aerosol dispersion within a well-defined shear stress range, in the context of pulmonary drug/sugar carrier physicochemical and interfacial properties.


The basal interstitial nucleus (BIN) of the cerebellum provides diffuse ascending inhibitory input to the floccular granule cell layer.
The basal interstitial nucleus (BIN) in the white matter of the vestibulocerebellum has been defined more than three decades ago, but has since been largely ignored. It is still unclear which neurotransmitters are being used by BIN neurons, how these neurons are connected to the rest of the brain and what their activity patterns look like. Here, we studied BIN neurons in a range of mammals, including macaque, human, rat, mouse, rabbit, and ferret, using tracing, immunohistological and electrophysiological approaches. We show that BIN neurons are GABAergic and glycinergic, that in primates they also express the marker for cholinergic neurons choline acetyl transferase (ChAT), that they project with beaded fibers to the glomeruli in the granular layer of the ipsilateral floccular complex, and that they are driven by excitation from the ipsilateral and contralateral medio-dorsal medullary gigantocellular reticular formation. Systematic analysis of codistribution of the inhibitory synapse marker VIAAT, BIN axons, and Golgi cell marker mGluR2 indicate that BIN axon terminals complement Golgi cell axon terminals in glomeruli, accounting for a considerable proportion ( > 20%) of the inhibitory terminals in the granule cell layer of the floccular complex. Together, these data show that BIN neurons represent a novel and relevant inhibitory input to the part of the vestibulocerebellum that controls compensatory and smooth pursuit eye movements.


Use of Non-Prescription Remedies by Ghanaian Human Immunodeficiency Virus-Positive Persons on Antiretroviral Therapy.
Inappropriate use of non-prescription remedies by persons living with human immunodeficiency virus (PLHIV) may result in adverse events or potentiate non-adherence to prescribed medications. This study investigated the use of non-prescription remedies among PLHIV receiving antiretroviral therapy (ART) from four treatment centers in southern Ghana. A mixed method design using quantitative and qualitative methods was used. This article focuses on the quantitative survey of 540 respondents. Univariate analysis was used to generate descriptive tabulations of key variables. Bivariate analysis and logistic regression modeling, respectively, produced unadjusted and adjusted associations between background attributes of PLHIV and the use of non-prescription remedies. A p-value of < 0.05 was considered statistically significant. All analyses were performed using IBM SPSS Statistics for Windows, Version 20.0. One out of three respondents reported the use of non-prescription remedies at least once within 3 months of the survey. Most of these were locally made and included "Angel natural bitters, concoctions from the Christian prayer centers, garlic, and mahogany syrups." These remedies were used concomitantly with antiretroviral medications (ARVs)-46% or administered with ARVs but at different times during the day (43%). Some of the remedies were reportedly prescribed by health workers, or self-initiated during periods of ARVs shortage. Others took them based on their perception of their efficacy. Bivariate level analysis identified ART clinic site, place of residence, and ARV adherence monitoring to be significantly associated with the use of non-prescription remedies (p < 0.05). Multiple logistic regression analysis controlling for covariates confirmed the location of ART clinic as the only predictor of the use of non-prescription remedies. Compared to clients at the large urban teaching hospital (Korle-Bu Fevers Unit ART center), those at the district level (Atua ART center) were ninefold more likely to use non-prescription remedies [adjusted odds ratio (AOR) = 8.84; 95% confidence interval (CI) 2.83-33.72]. Those from a district level mission hospital (St. Martin's ART center) were threefold as likely to use these remedies (AOR = 2.610; 95% CI 1.074-9.120). The use of non-prescription remedies by PLHIV on ART is common in southern Ghana. Usage is mostly self-initiated because of perceived efficacy of remedy, and was more common among clients attending rural ART clinics.


Conservation strategies for orangutans: reintroduction versus habitat preservation and the benefits of sustainably logged forest.
The Sumatran orangutan is currently listed by the IUCN as critically endangered and the Bornean species as endangered. Unless effective conservation measures are enacted quickly, most orangutan populations without adequate protection face a dire future. Two main strategies are being pursued to conserve orangutans: (i) rehabilitation and reintroduction of ex-captive or displaced individuals; and (ii) protection of their forest habitat to abate threats like deforestation and hunting. These strategies are often mirrored in similar programs to save other valued and endangered mega-fauna. Through GIS analysis, collating data from across the literature, and combining this information within a modelling and decision analysis framework, we analysed which strategy or combination of strategies is the most cost-effective at maintaining wild orangutan populations, and under what conditions. We discovered that neither strategy was optimal under all circumstances but was dependent on the relative cost per orangutan, the timescale of management concern, and the rate of deforestation. Reintroduction, which costs twelve times as much per animal as compared to protection of forest, was only a cost-effective strategy at very short timescales. For time scales longer than 10-20 years, forest protection is the more cost-efficient strategy for maintaining wild orangutan populations. Our analyses showed that a third, rarely utilised strategy is intermediate: introducing sustainable logging practices and protection from hunting in timber production forest. Maximum long-term cost-efficiency is achieved by working in conservation forest. However, habitat protection involves addressing complex conservation issues and conflicting needs at the landscape level. We find a potential resolution in that well-managed production forests could achieve intermediate conservation outcomes. This has broad implications for sustaining biodiversity more generally within an economically productive landscape. Insights from this analysis should provide a better framework to prioritize financial investments, and facilitate improved integration between the organizations that implement these strategies.


Antispasmodic effects of valeriana compounds: an in-vivo and in-vitro study on the guinea-pig ileum.
The valepotriates isovaltrate and valtrate, and the essential oil compound valeranone caused a suppression of rhythmic contractions in a closed part of the guinea-pig ileum in-vivo. The same compounds and didrovaltrate relaxed potassium stimulated contractures and inhibited BaCl2 contractions in guinea-pig ileum preparations in-vitro. Guinea-pig stomach fundic strips stimulated by carbachol were also relaxed by these substances. Potassium stimulated smooth muscle cells were also relaxed by the valeriana compounds (10(-5)-10(-4) M) even, when autonomic receptors were blocked by appropriate antagonists. In lower concentrations (10(-6)-10(-5) M), the compounds did not affect the dose-response curves of carbachol and isoprenaline. In some experiments valeranone at 4.10(-6) M produced an increased isoprenaline relaxation of the guinea-pig ileum. Valeranone and didrovaltrate were about equipotent to papaverine in inhibiting BaCl2 contractions. It is concluded that the valeriana compounds probably relax stimulated smooth muscle cells by acting as musculotropic agents and not by interacting with receptors of the autonomic nervous system.


Rapid Macrosatellite Evolution Promotes X-Linked Hybrid Male Sterility in a Feline Interspecies Cross.
The sterility or inviability of hybrid offspring produced from an interspecific mating result from incompatibilities between parental genotypes that are thought to result from divergence of loci involved in epistatic interactions. However, attributes contributing to the rapid evolution of these regions also complicates their assembly, thus discovery of candidate hybrid sterility loci is difficult and has been restricted to a small number of model systems. Here we reported rapid interspecific divergence at the DXZ4 macrosatellite locus in an interspecific cross between two closely related mammalian species: the domestic cat (Felis silvestris catus) and the Jungle cat (Felis chaus). DXZ4 is an interesting candidate due to its structural complexity, copy number variability, and described role in the critical yet complex biological process of X-chromosome inactivation. However, the full structure of DXZ4 was absent or incomplete in nearly every available mammalian genome assembly given its repetitive complexity. We compared highly continuous genomes for three cat species, each containing a complete DXZ4 locus, and discovered that the felid DXZ4 locus differs substantially from the human ortholog, and that it varies in copy number between cat species. Additionally, we reported expression, methylation, and structural conformation profiles of DXZ4 and the X chromosome during stages of spermatogenesis that have been previously associated with hybrid male sterility. Collectively, these findings suggest a new role for DXZ4 in male meiosis and a mechanism for feline interspecific incompatibility through rapid satellite divergence.


The Atg1-Tor pathway regulates yolk catabolism in Drosophila embryos.
Yolk provides an important source of nutrients during the early development of oviparous organisms. It is composed mainly of vitellogenin proteins packed into membrane-bound compartments called yolk platelets. Catabolism of yolk is initiated by acidification of the yolk platelet, leading to the activation of Cathepsin-like proteinases, but it is unknown how this process is triggered. Yolk catabolism initiates at cellularization in Drosophila melanogaster embryos. Using maternal shRNA technology we found that yolk catabolism depends on the Tor pathway and on the autophagy-initiating kinase Atg1. Whereas Atg1 was required for a burst of spatially regulated autophagy during late cellularization, autophagy was not required for initiating yolk catabolism. We propose that the conserved Tor metabolic sensing pathway regulates yolk catabolism, similar to Tor-dependent metabolic regulation on the lysosome.


Leadership in primary health care: an international perspective.
A primary health care approach is essential to contemporary nursing roles such as practice nursing. This paper examines the evolution of primary health care as a global strategy for responding to the social determinants of health. Primary health care roles require knowledge of, and a focus on social determinants of health, particularly the societal factors that allow and perpetuate inequities and disadvantage. They also require a depth and breadth of leadership skills that are responsive to health needs, appropriate in the social and regulatory context, and visionary in balancing both workforce and client needs. The key to succeeding in working with communities and groups under a primary health care umbrella is to balance the big picture of comprehensive primary health care with operational strategies for selective primary health care. The other essential element involves using leadership skills to promote inclusiveness, empowerment and health literacy, and ultimately, better health.


Modeling the evolution of regulatory elements by simultaneous detection and alignment with phylogenetic pair HMMs.
The computational detection of regulatory elements in DNA is a difficult but important problem impacting our progress in understanding the complex nature of eukaryotic gene regulation. Attempts to utilize cross-species conservation for this task have been hampered both by evolutionary changes of functional sites and poor performance of general-purpose alignment programs when applied to non-coding sequence. We describe a new and flexible framework for modeling binding site evolution in multiple related genomes, based on phylogenetic pair hidden Markov models which explicitly model the gain and loss of binding sites along a phylogeny. We demonstrate the value of this framework for both the alignment of regulatory regions and the inference of precise binding-site locations within those regions. As the underlying formalism is a stochastic, generative model, it can also be used to simulate the evolution of regulatory elements. Our implementation is scalable in terms of numbers of species and sequence lengths and can produce alignments and binding-site predictions with accuracy rivaling or exceeding current systems that specialize in only alignment or only binding-site prediction. We demonstrate the validity and power of various model components on extensive simulations of realistic sequence data and apply a specific model to study Drosophila enhancers in as many as ten related genomes and in the presence of gain and loss of binding sites. Different models and modeling assumptions can be easily specified, thus providing an invaluable tool for the exploration of biological hypotheses that can drive improvements in our understanding of the mechanisms and evolution of gene regulation.


The Use of a Smart Bolus Calculator Informed by Real-time Insulin Sensitivity Assessments Reduces Postprandial Hypoglycemia Following an Aerobic Exercise Session in Individuals With Type 1 Diabetes.
Insulin dosing in type 1 diabetes (T1D) is oftentimes complicated by fluctuating insulin requirements driven by metabolic and psychobehavioral factors impacting individuals' insulin sensitivity (IS). In this context, smart bolus calculators that automatically tailor prandial insulin dosing to the metabolic state of a person can improve glucose management in T1D. Fifteen adults with T1D using continuous glucose monitors (CGMs) and insulin pumps completed two 24-h admissions in a hotel setting. During the admissions, participants engaged in an early afternoon 45-min aerobic exercise session, after which they received a standardized dinner meal. The dinner bolus was computed using a standard bolus calculator or smart bolus calculator informed by real-time IS estimates. Glucose control was assessed in the 4 h following dinner using CGMs and was compared between the two admissions. The IS-informed bolus calculator allowed for a reduction in postprandial hypoglycemia as quantified by the low blood glucose index (2.02 vs. 3.31, P = 0.006) and percent time <70 mg/dL (8.48% vs. 15.18%, P = 0.049), without increasing hyperglycemia (high blood glucose index: 3.13 vs. 2.09, P = 0.075; percent time >180 mg/dL: 13.24% vs. 10.42%, P = 0.5; percent time >250 mg/dL: 2.08% vs. 1.19%, P = 0.317). In addition, the number of hypoglycemia rescue treatments was reduced from 12 to 7 with the use of the system. The study shows that the proposed IS-informed bolus calculator is safe and feasible in adults with T1D, appropriately reducing postprandial hypoglycemia following an exercise-induced IS increase.