Role of the N-terminal region in G protein-coupled receptor functions : negative modulation revealed by 5-HT2B receptor polymorphisms

The putative role of the N-terminal region of rhodopsin-like 7 transmembrane biogenic amine receptors in agonist-induced signaling has not yet been clarified despite recent advances in 7 transmembrane receptor structural biology. Given the existence of N-terminal nonsynonymous polymorphisms (R6G;E42G) within the HTR2B gene in a drug-abusing population, we assessed whether these polymorphisms affect 5-hydroxytryptamine 2B (5-HT2B) receptor in vitro pharmacologic and coupling properties in transfected COS-7 cells. Modification of the 5-HT2B receptor N terminus by the R6G;E42G polymorphisms increases such agonist signaling pathways as inositol phosphate accumulation as assessed by either classic or operational models. The N-terminal R6G;E42G mutations of the 5-HT2B receptor also increase cell proliferation and slow its desensitization kinetics compared with the wild-type receptor, further supporting a role for the N terminus in transduction efficacy. Furthermore, by coexpressing a tethered wild-type 5-HT2B receptor N terminus with a 5-HT2B receptor bearing a N-terminal deletion, we were able to restore original coupling. This reversion to normal activity of a truncated 5-HT2B receptor by coexpression of the membrane-tethered wild-type 5-HT2B receptor N terminus was not observed using a membrane-tethered 5-HT2B receptor R6G;E42G N terminus. These data suggest that the N terminus exerts a negative control over basal as well as agonist-stimulated receptor activity that is lost in the R6G;E42G mutant. Our findings reveal a new and unanticipated role of the 5-HT2B receptor N terminus as a negative modulator, affecting both constitutive and agonist-stimulated activity. Moreover, our data caution against excluding the N terminus and extracellular loops in structural studies of this 7 transmembrane receptor family

Experimental evidence for competitive N–O and O–C bond homolysis in gasphase alkoxyamines

The extensive use of alkoxyamines in controlled radical polymerisation and polymer stabilisation is based on rapid cycling between the alkoxyamine (R1R2NO–R3) and a stable nitroxyl radical (R1R2NO•) via homolysis of the labile O–C bond. Competing homolysis of the alkoxyamine N–O bond has been predicted to occur for some substituents leading to production of aminyl and alkoxyl radicals. This intrinsic competition between the O–C and N–O bond homolysis processes has to this point been difficult to probe experimentally. Herein we examine the effect of local molecular structure on the competition between N–O and O–C bond cleavage in the gas phase by variable energy tandem mass spectrometry in a triple quadrupole mass spectrometer. A suite of cyclic alkoxyamines with remote carboxylic acid moieties (HOOC–R1R2NO–R3) were synthesised and subjected to negative ion electrospray ionisation to yield [M – H]− anions where the charge is remote from the alkoxyamine moiety. Collision-induced dissociation of these anions yield product ions resulting, almost exclusively, from homolysis of O–C and/or N–O bonds. The relative efficacy of N–O and O–C bond homolysis was examined for alkoxyamines incorporating different R3 substituents by varying the potential difference applied to the collision cell, and comparing dissociation thresholds of each product ion channel. For most R3 substituents, product ions from homolysis of the O–C bond are observed and product ions resulting from cleavage of the N–O bond are minor or absent. A limited number of examples were encountered however, where N–O homolysis is a competitive dissociation pathway because the O–C bond is stabilised by adjacent heteroatom(s) (e.g., R3 = CH2F). The dissociation threshold energies were compared for different alkoxyamine substituents (R3) and the relative ordering of these experimentally determined energies is shown to correlate with the bond dissociation free energies, calculated by ab initio methods. Understanding the structure-dependent relationship between these rival processes will assist in the design and selection of alkoxyamine motifs that selectively promote the desirable O–C homolysis pathway.

A comparison of lungworm faecal larval counts and trichostrongyloid faecal egg counts between Red Deer (Cervus elaphus) and Red DeerXWapiti F1 hybrids.

To determine if breed differences in susceptibility to trichostrongyloid and lungworm infection exist, two groups of weaner deer containing seven red deer and red deer X wapiti F1 hybrids were compared using faecal egg counts and faecal larval counts. All animals were run on the same pasture at the same time and treated with the same anthelmintics at the same time. Results indicated that there were significant differences between red deer and red deer X wapiti hybrids, with red deer having higher faecal lungworm counts and red deer X wapiti hybrids having significantly higher faecal egg counts. It is likely that these differences were due to breed. Differences in the efficacy of anthelmintic treatments were also noted between the two groups, with oral oxfendazole being less effective at reducing faecal lungworm counts in red deer X wapiti hybrids than red deer.

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10−14, odds ratio = 0.86, 95% confidence interval = 0.82–0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.

Rallying the troops or beating the horses? How project-related demands can lead to either high performance or abusive supervision

In today's high-pressure work environment, project managers are often forced to “do more with less.” We argue that this imperative can lead project managers to engage in either high-performance or abusive supervision behaviors. To understand this process, we develop a model and associated propositions linking a project manager's cognitive appraisal of project-related demands to high-performance work practices versus abusive supervision behaviors—both of which impact three project outcomes: stakeholder relationships, people-related project success factors, and employee well-being. We propose that the choice between high-performance work practices and abusive supervision behaviors is moderated by a project manager's personal resources (psychological capital, emotional intelligence, and dark triad personality).

Petrology and textural classification of the Jericho kimberlite, northern Slave Province, Nunavut, Canada

The paper presents data on petrology, bulk rock and mineral compositions, and textural classification of the Middle Jurassic Jericho kimberlite (Slave craton, Canada). The kimberlite was emplaced as three steep-sided pipes in granite that was overlain by limestones and minor soft sediments. The pipes are infilled with hypabyssal and pyroclastic kimberlites and connected to a satellite pipe by a dyke. The Jericho kimberlite is classified as a Group Ia, lacking groundmass tetraferriphlogopite and containing monticellite pseudomorphs. The kimberlite formed, during several consecutive emplacement events of compositionally different batches of kimberlite magma. Core-logging and thin-section observations identified at least two phases of hypabyssal kimberlites and three phases of pyroclastic kimberlites. Hypabyssal kimberlites intruded as a main dyke (HK1) and as late small-volume aphanitic and vesicular dykes. Massive pyroclastic kimberlite (MPK1) predominantly filled the northern and southern lobes of the pipe and formed from magma different from the HK1 magma. The MPK1 magma crystallized Ti-, Fe-, and Cr-rich phlogopite without rims of barian phlogopite, and clinopyroxene and spinel without atoll structures. MPK1 textures, superficially reminiscent of tuffisitic kimberlite, are caused by pervasive contamination by granite xenoliths. The next explosive events filled the central lobe with two varieties of pyroclastic kimberlite: (1) massive and (2) weakly bedded, normally graded pyroclastic kimberlite. The geology of the Jericho pipe differs from the geology of South African or the Prairie kimberlites, but may resemble Lac de Gras pipes, in which deeper erosion removed upper fades of resedimented kimberlites.

Relationships between biophysical and psychosocial outcomes following minor stroke

This descriptive correlational study examined relationships between mild stroke functional and psychosocial outcomes over the early post-discharge period among dyads of mild stroke patients (n=38) and their spousal caregivers (n=38). We measured patients' functional scores using the modified Rankin Scale; patients' and caregivers' quality of life (QoL) using Stroke Impact Scale and Short-Form 36 respectively, mood using the Beck Depression Inventory-II, and marital function scores using the Family Assessment Device. Spousal caregivers also completed the Bakas Caregiving Outcomes Scale as a measure of caregiver strain. The average age of stroke patients was 64 years and of spousal caregivers 58 years. All stroke patients were male; all spousal caregivers female. At three months post discharge, patient functional status scores had significantly improved from discharge (p=0.026) with a corresponding increase in QoL scores (p=0.012). Functional status was significantly correlated with patient perceptions of QoL at three months (r=.014, p=0.024) and spousal caregiver perceptions of physical domain QoL (r=.-.397, p=0.014). Spousal caregivers' mood at three months post discharge was strongly correlated with their perceptions of marital satisfaction (r=.578, p=0.000) and caregiver strain (r=-.620, p=0.000). In preparing patients for discharge following mild stroke, nurses must consider the psychological and social implications of the recovery process over time for both the patient with stroke and their spousal caregivers.

Experiences of male patients and wife-caregivers in the first year post-discharge following minor stroke: A descriptive qualitative study

Background Most patients with minor stroke are discharged directly home from acute care, under the assumption that little will be required in the way of adaptation and adjustment because informal caregivers will manage the stroke recovery process. We explored male patients with minor stroke and their wife-caregivers' perceptions of factors affecting quality of life and caregiver strain encountered during the first year post-discharge. Methods Data were obtained from responses to two open-ended questions, part of quality of life and caregiver strain scales administered to participants in a larger descriptive study. Conventional content analysis was used to assess narrative accounts of living with minor stroke provided by 26 male patients and their wife-caregivers over a period of 1-year post-discharge. Results Two major themes that emerged from these data were 'being vulnerable' and 'realization'. Subthemes that arose within the vulnerability theme included changes to patients' masculine image and wife-caregivers' assumption of a hyper-vigilance role. In terms of 'realization' patients and their wife-caregivers shared 'loss' as well as 'changing self and relationships'. Patients in this study focused primarily on their physical recovery and their perceptions of necessary changes. Wife-caregivers were actively involved in managing the day-to-day demands that stroke placed on individual, family and social roles. Conclusions We conclude that patients and wife-caregivers expend considerable time and energy reestablishing control of their lives following minor stroke in an attempt to incorporate changes to self and their relationship into the fabric of their lives.

Smell and taste dysfunction following minor stroke: A case report

Smell (olfactory) and taste (gustatory) are key senses in the regulation of nourishment and individual safety. Olfactory and gustatory dysfunctions have been infrequently reported together in patients following stroke (Landis et al., 2006; Leopold et al., 2006). This case report details two patients who experienced smell and taste dysfunction following minor stroke events. Symptoms reported included hyposmia (diminished sense of smell) and anosmia (complete loss of smell), and dysgeusia (distorted taste). Patients' sense of smell and taste were assessed in an ambulatory care stroke prevention clinic eight months following their strokes. Patient A presented with minor stroke due to a lesion in the anterior circulation, patient B with a lesion in the posterior circulation. Both patients reported intense olfactory and gustatory dysfunction immediately following their strokes. Examination revealed a general inability to detect subtle odours and the ability to identify only 'sweet' tastes for both patients. In addition, both patients reported heavily salting or sweetening their food to mask the distorted and unpleasant taste, which also impacted comorbid conditions such as hypertension and diabetes. Patients and their spouses reported a decrease in their appreciation of family-related activities due to the patients' olfactory and gustatory dysfunction. Patients reported weight loss, lack of energy and strength, likely due to poor nutrition. Olfactory and gustatory dysfunctions are potentially deleterious outcomes following minor stroke and should be assessed by health care professionals prior to patient discharge. Assistance may be required to promote the health and well-being of patients and their carers if smell and taste are impacted by the stroke event.

The trajectory of minor stroke recovery for men and their female spousal caregivers: Literature review

Title The trajectory of minor stroke recovery for men and their female spousal caregivers: literature review Aim This paper is a report of a narrative review to examine the current state of knowledge regarding the impact of minor stroke on male patients and their female spousal caregivers’ recovery trajectory and quality of life. Background Minor stroke survivors are often discharged early in the recovery process. The perception of the healthcare community that these patients and their female spousal caregivers will experience an uneventful recovery may lead to inadequate preparation for the postdischarge period. Methods A range of databases was searched to identify papers addressing ‘minor stroke’, ‘transitions’, ‘quality of life’, ‘chronic disease’, ‘caregivers’ and ‘spouse caregivers’, including AARP Ageline, AMED, CINAHL, Evidence Based Medicine Reviews, MEDLINE and PsychInfo. Papers published in English from 1990 to December 2006 were included. Thirty-four papers were in the final data set. Results Minor stroke survivors and their female spousal caregivers may experience major challenges in adaptations postdischarge. The trajectory of minor stroke recovery may necessitate a re-evaluation of life plans, rethinking of priorities and integration of resulting disabilities into current and emerging life situations for both stroke survivors and their female spousal caregivers. In many cases these adaptations are compounded by transitions associated with the normal ageing process. Conclusion While there is extensive literature on stroke recovery and the role of caregivers in general, there is little available describing the recovery of minor stroke survivors in relation to the normal ageing process. Further research is needed examining recovery from a transitional perspective, to support nurses and other health professionals discharge planning.

Commentary on the article by Swanenburg et al. ‘Validity and reliability of a German version of the Neck Disability Index (NDI-G)’

We commend Swanenburg et al. (2013) on translation, development, and clinimetric analysis of the NDI-G. However, the dual-factor structure with factor analysis and the high level of internal consistency (IC) highlighted in their discussion were not emphasized in the abstract or conclusion. These points may imply some inconsistencies with the final conclusions since determination of stable point estimates with the study's small sample are exceedingly difficult.

Genetic influences on brain asymmetry: A DTI study of 374 twins and siblings

Brain asymmetry, or the structural and functional specialization of each brain hemisphere, has fascinated neuroscientists for over a century. Even so, genetic and environmental factors that influence brain asymmetry are largely unknown. Diffusion tensor imaging (DTI) now allows asymmetry to be studied at a microscopic scale by examining differences in fiber characteristics across hemispheres rather than differences in structure shapes and volumes. Here we analyzed 4. Tesla DTI scans from 374 healthy adults, including 60 monozygotic twin pairs, 45 same-sex dizygotic pairs, and 164 mixed-sex DZ twins and their siblings; mean age: 24.4 years ± 1.9 SD). All DTI scans were nonlinearly aligned to a geometrically-symmetric, population-based image template. We computed voxel-wise maps of significant asymmetries (left/right differences) for common diffusion measures that reflect fiber integrity (fractional and geodesic anisotropy; FA, GA and mean diffusivity, MD). In quantitative genetic models computed from all same-sex twin pairs (N=210 subjects), genetic factors accounted for 33% of the variance in asymmetry for the inferior fronto-occipital fasciculus, 37% for the anterior thalamic radiation, and 20% for the forceps major and uncinate fasciculus (all L > R). Shared environmental factors accounted for around 15% of the variance in asymmetry for the cortico-spinal tract (R > L) and about 10% for the forceps minor (L > R). Sex differences in asymmetry (men > women) were significant, and were greatest in regions with prominent FA asymmetries. These maps identify heritable DTI-derived features, and may empower genome-wide searches for genetic polymorphisms that influence brain asymmetry.

Reducing structural variation to determine the genetics of white matter integrity across hemispheres - a dti study of 100 twins

Studies of cerebral asymmetry can open doors to understanding the functional specialization of each brain hemisphere, and how this is altered in disease. Here we examined hemispheric asymmetries in fiber architecture using diffusion tensor imaging (DTI) in 100 subjects, using high-dimensional fluid warping to disentangle shape differences from measures sensitive to myelination. Confounding effects of purely structural asymmetries were reduced by using co-registered structural images to fluidly warp 3D maps of fiber characteristics (fractional and geodesic anisotropy) to a structurally symmetric minimal deformation template (MDT). We performed a quantitative genetic analysis on 100 subjects to determine whether the sources of the remaining signal asymmetries were primarily genetic or environmental. A twin design was used to identify the heritable features of fiber asymmetry in various regions of interest, to further assist in the discovery of genes influencing brain micro-architecture and brain lateralization. Genetic influences and left/right asymmetries were detected in the fiber architecture of the frontal lobes, with minor differences depending on the choice of registration template.

A comparison of motivation to learn English between English major and non-English major students in a Vietnamese university

Despite the plethora of literature examining higher education students’ motivation to learn a second language, it is not known if students who choose to study English as their major differ from those who are required to study English as the minor component of their wider degree. Drawing on self-determination theory, this paper reports on the findings of a quantitative study designed to investigate the types of motivation demonstrated by English major (n=180) and non-English major students (n=242), and their levels of effort expended in learning English in a Vietnamese university. The findings revealed that both groups demonstrated high levels of motivation to learn English to prepare for their future profession. English major students felt more intrinsically motivated and less obligated to learn English. In addition, for both groups, intrinsically motivated students invested the highest levels of effort in learning English. This paper argues that it is imperative for lecturers to foster students’ intrinsic aspirations to learn English to improve the quality of the teaching and learning of English in Vietnamese higher education.

PTHR1 polymorphisms influence BMD variation through effects on the growing skeleton

We investigated whether polymorphisms in PTHR1 are associated with bone mineral density (BMD), to determine whether the association of this gene with BMD was due to effects on attainment of peak bone mass or effects on subsequent bone loss. The PTHR1 gene, including its 14 exons, their exon-intron boundaries, and 1,500 bp of its promoter region, was screened for polymorphisms by denaturing high-performance liquid chromatography (dHPLC) and sequencing in 36 osteoporotic cases. Eleven single-nucleotide polymorphisms (SNPs), one tetranucleotide repeat, and one tetranucleotide deletion were identified. A cohort of 634 families, including 1,236 men (39%) and 1,926 women (61%) ascertained with probands with low BMD (Z< -2.0) and the Children in Focus subset of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (785 unrelated individuals, mean age 118 months), were genotyped for the five most informative SNPs (minor allele frequency >5%) and the tetranucleotide repeat. In our osteoporosis families, association was noted between lumbar spine BMD and alleles of a known functional tetranucleotide repeat (U4) in the PTHR1 promoter region (P = 0.042) and between two and three marker haplotypes of PTHR1 polymorphisms with lumbar spine, femoral neck, and total hip BMD (P = 0.021-0.047). This association was restricted to the youngest tertile of the population (age 16-39 years, P = 0.013-0.048). A similar association was found for the ALSPAC cohort: two marker haplotypes of SNPs A48609T and C52813T were associated with height (P = 0.006) and total body less head BMD (P = 0.02), corrected for age and gender, confirming the family findings. These findings suggest a role for PTHR1 variation in determining peak BMD.