Krein systems

In the present paper we extend results of M.G. Krein associated to the spectral problem for Krein systems to systems with matrix valued accelerants with a possible jump discontinuity at the origin. Explicit formulas for the accelerant are given in terms of the matrizant of the system in question. Recent developments in the theory of continuous analogs of the resultant operator play an essential role

On Global Conservation Laws at Null Infinity

The ``standard'' expressions for total energy, linear momentum and also angular momentum of asymptotically flat Bondi metrics at null infinity are also obtained from differential conservation laws on asymptotically flat backgrounds, derived from a quadratic Lagrangian density by methods currently used in classical field theory. It is thus a matter of taste and commodity to use or not to use a reference spacetime in defining these globally conserved quantities. Backgrounds lead to N\oe ther conserved currents; the use of backgrounds is in line with classical views on conservation laws. Moreover, the conserved quantities are in principle explicitly related to the sources of gravity through Einstein's equations, while standard definitions are not. The relations depend, however, on a rule for mapping spacetimes on backgrounds

Metabolic effects of diets differing in glycaemic index depend on age and endogenous GIP

Aims/hypothesis High- vs low-glycaemic index (GI) diets unfavourably affect body fat mass and metabolic markers in rodents. Different effects of these diets could be age-dependent, as well as mediated, in part, by carbohydrate-induced stimulation of glucose-dependent insulinotrophic polypeptide (GIP) signalling. Methods Young-adult (16 weeks) and aged (44 weeks) male wild-type (C57BL/6J) and GIP-receptor knockout (Gipr −/− ) mice were exposed to otherwise identical high-carbohydrate diets differing only in GI (20–26 weeks of intervention, n = 8–10 per group). Diet-induced changes in body fat distribution, liver fat, locomotor activity, markers of insulin sensitivity and substrate oxidation were investigated, as well as changes in the gene expression of anorexigenic and orexigenic hypothalamic factors related to food intake. Results Body weight significantly increased in young-adult high- vs low-GI fed mice (two-way ANOVA, p < 0.001), regardless of the Gipr genotype. The high-GI diet in young-adult mice also led to significantly increased fat mass and changes in metabolic markers that indicate reduced insulin sensitivity. Even though body fat mass also slightly increased in high- vs low-GI fed aged wild-type mice (p < 0.05), there were no significant changes in body weight and estimated insulin sensitivity in these animals. However, aged Gipr −/− vs wild-type mice on high-GI diet showed significantly lower cumulative net energy intake, increased locomotor activity and improved markers of insulin sensitivity. Conclusions/interpretation The metabolic benefits of a low-GI diet appear to be more pronounced in younger animals, regardless of the Gipr genotype. Inactivation of GIP signalling in aged animals on a high-GI diet, however, could be beneficial

Kank Is an EB1 Interacting Protein that Localises to Muscle-Tendon Attachment Sites in Drosophila

Little is known about how microtubules are regulated in different cell types during development. EB1 plays a central role in the regulation of microtubule plus ends. It directly binds to microtubule plus ends and recruits proteins which regulate microtubule dynamics and behaviour. We report the identification of Kank, the sole Drosophila orthologue of human Kank proteins, as an EB1 interactor that predominantly localises to embryonic attachment sites between muscle and tendon cells. Human Kank1 was identified as a tumour suppressor and has documented roles in actin regulation and cell polarity in cultured mammalian cells. We found that Drosophila Kank binds EB1 directly and this interaction is essential for Kank localisation to microtubule plus ends in cultured cells. Kank protein is expressed throughout fly development and increases during embryogenesis. In late embryos, it accumulates to sites of attachment between muscle and epidermal cells. A kank deletion mutant was generated. We found that the mutant is viable and fertile without noticeable defects. Further analysis showed that Kank is dispensable for muscle function in larvae. This is in sharp contrast to C. elegans in which the Kank orthologue VAB-19 is required for development by stabilising attachment structures between muscle and epidermal cells

The quality and diagnostic value of open narratives in verbal autopsy: a mixed-methods analysis of partnered interviews from Malawi

Background Verbal autopsy (VA), the process of interviewing a deceased’s family or caregiver about signs and symptoms leading up to death, employs tools that ask a series of closed questions and can include an open narrative where respondents give an unprompted account of events preceding death. The extent to which an individual interviewer, who generally does not interpret the data, affects the quality of this data, and therefore the assigned cause of death, is poorly documented. We aimed to examine inter-interviewer reliability of open narrative and closed question data gathered during VA interviews. Methods During the introduction of VA data collection, as part of a larger study in Mchinji district, Malawi, we conducted partner interviews whereby two interviewers independently recorded open narrative and closed questions during the same interview. Closed questions were collected using a smartphone application (mobile-InterVA) and open narratives using pen and paper. We used mixed methods of analysis to evaluate the differences between recorded responses to open narratives and closed questions, causes of death assigned, and additional information gathered by open narrative. Results Eighteen partner interviews were conducted, with complete data for 11 pairs. Comparing closed questions between interviewers, the median number of differences was 1 (IQR: 0.5–3.5) of an average 65 answered; mean inter-interviewer concordance was 92 % (IQR: 92–99 %). Discrepancies in open narratives were summarized in five categories: demographics, history and care-seeking, diagnoses and symptoms, treatment and cultural. Most discrepancies were seen in the reporting of diagnoses and symptoms (e.g., malaria diagnosis); only one pair demonstrated no clear differences. The average number of clinical symptoms reported was 9 in open narratives and 20 in the closed questions. Open narratives contained additional information on health seeking and social issues surrounding deaths, which closed questions did not gather. Conclusions The information gleaned during open narratives was subject to inter-interviewer variability and contained a limited number of symptom indicators, suggesting that their use for assigning cause of death is questionable. However, they contained rich information on care-seeking, healthcare provision and social factors in the lead-up to death, which may be a valuable source of information for promoting accountable health services

The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic, Affecting Reward as Well as Movement

Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis

Sequence analysis of 5' regulatory regions of the Machado-Joseph Disease gene (ATXN3)

Machado–Joseph disease (MJD) is a late-onset autosomal dominant neurodegenerative disorder, which is caused by a coding (CAG)n expansion in the ATXN3 gene (14q32.1). The number of CAG repeats in the expanded alleles accounts only for 50 to 75 % of onset variance, the remaining variation being dependent on other factors. Differential allelic expression of ATXN3 could contribute to the explanation of different ages at onset in patients displaying similar CAG repeat sizes. Variation in 5′ regulatory regions of the ATXN3 gene may have the potential to influence expression levels and, ultimately, modulate the MJD phenotype. The main goal of this work was to analyze the extent of sequence variation upstream of the ATXN3 start codon. A fragment containing the core promoter and the 5′ untranslated region (UTR) was sequenced and analyzed in 186 patients and 59 controls (490 chromosomes). In the core promoter, no polymorphisms were observed. In the 5′ UTR, only one SNP (rs3814834) was found, but no improvements on the explanation of onset variance were observed, when adding its allelic state in a linear model. Accordingly, in silico analysis predicted that this SNP lays in a nonconserved position for CMYB binding. Therefore, no functional effect could be predicted for this variant.Institute of Biotechnology and Biomedicine of the Azores - “High Prevalence Diseases in the Azores Islands” M2.1.2/I/026/2008,Fundação para a Ciência e a Tecnologia (FCT) - “Transcriptional variation of the ATXN3 gene as modulator of the clinical heterogeneity in Machado–Joseph disease (MJD)Secretaria Regional da Ciência, Tecnologia e Equipamentos - M3.1.3/F/004/2009CNP

Young hands, old books: : Drawings by children in a fourteenth-century manuscript, LJS MS. 361

This article scrutinises three marginal drawings in LJS 361, Kislak Center for Special Collections, Rare Books and Manuscripts, University of Pennsylvania Libraries. It first considers the provenance of the manuscript, questioning how it got into the hands of children. Then, it combines developmental psychology with close examination of the material evidence to develop a list of criteria to attribute the drawings to children. There is consideration of the features that help us estimate the age of the artists, and which indicate that one drawing was a collaborative effort between two children. A potential relationship is identified between the doodles and the subject matter of the text, prompting questions about pre-modern child education and literacy. Finally, the article considers the implications of this finding in both codicology and social history since these marginal illustrations demonstrate that children were active in the material life of medieval books

Impact of the AHI1 Gene on the Vulnerability to Schizophrenia: A Case-Control Association Study

BackgroundThe Abelson helper integration-1 (AHI1) gene is required for both cerebellar and cortical development in humans. While the accelerated evolution of AHI1 in the human lineage indicates a role in cognitive (dys)function, a linkage scan in large pedigrees identified AHI1 as a positional candidate for schizophrenia. To further investigate the contribution of AHI1 to the susceptibility of schizophrenia, we evaluated the effect of AHI1 variation on the vulnerability to psychosis in two samples from Spain and Germany.Methodology/Principal Findings29 single-nucleotide polymorphisms (SNPs) located in a genomic region including the AHI1 gene were genotyped in two samples from Spain (280 patients with psychotic disorders; 348 controls) and Germany (247 patients with schizophrenic disorders; 360 controls). Allelic, genotypic and haplotype frequencies were compared between cases and controls in both samples separately, as well as in the combined sample. The effect of genotype on several psychopathological measures (BPRS, KGV, PANSS) assessed in a Spanish subsample was also evaluated. We found several significant associations in the Spanish sample. Particularly, rs7750586 and rs911507, both located upstream of the AHI1 coding region, were found to be associated with schizophrenia in the analysis of genotypic (p = 0.0033, and 0.031, respectively) and allelic frequencies (p = 0.001 in both cases). Moreover, several other risk and protective haplotypes were detected (0.006<p<0.036). Joint analysis also supported the association of rs7750586 and rs911507 with the risk for schizophrenia. The analysis of clinical measures also revealed an effect on symptom severity (minimum P value = 0.0037).Conclusions/SignificanceOur data support, in agreement with previous reports, an effect of AHI1 variation on the susceptibility to schizophrenia in central and southern European populations