On constructions preserving the asymptotic topology of metric spaces

We prove that graph products constructed over infinite graphs with bounded clique number preserve finite asymptotic dimension. We also study the extent to which Dranishnikov's property C, and Dranishnikov and Zarichnyi's straight finite decomposition complexity are preserved by constructions such as unions, free products, and group extensions.Comment: 13 pages, accepted for publication in NC Journal of Mathematics and Statistic

A forward genetic screen with a thalamocortical axon reporter mouse yields novel neurodevelopment mutants and a distinct emx2 mutant phenotype

<p>Abstract</p> <p>Background</p> <p>The dorsal thalamus acts as a gateway and modulator for information going to and from the cerebral cortex. This activity requires the formation of reciprocal topographic axon connections between thalamus and cortex. The axons grow along a complex multistep pathway, making sharp turns, crossing expression boundaries, and encountering intermediate targets. However, the cellular and molecular components mediating these steps remain poorly understood.</p> <p>Results</p> <p>To further elucidate the development of the thalamocortical system, we first created a thalamocortical axon reporter line to use as a genetic tool for sensitive analysis of mutant mouse phenotypes. The TCA-<it>tau-lacZ </it>reporter mouse shows specific, robust, and reproducible labeling of thalamocortical axons (TCAs), but not the overlapping corticothalamic axons, during development. Moreover, it readily reveals TCA pathfinding abnormalities in known cortical mutants such as <it>reeler</it>. Next, we performed an unbiased screen for genes involved in thalamocortical development using random mutagenesis with the TCA reporter. Six independent mutant lines show aberrant TCA phenotypes at different steps of the pathway. These include ventral misrouting, overfasciculation, stalling at the corticostriatal boundary, and invasion of ectopic cortical cell clusters. An outcross breeding strategy coupled with a genomic panel of single nucleotide polymorphisms facilitated genetic mapping with small numbers of mutant mice. We mapped a ventral misrouting mutant to the <it>Emx2 </it>gene, and discovered that some TCAs extend to the olfactory bulbs in this mutant. Mapping data suggest that other lines carry mutations in genes not previously known for roles in thalamocortical development.</p> <p>Conclusions</p> <p>These data demonstrate the feasibility of a forward genetic approach to understanding mammalian brain morphogenesis and wiring. A robust axonal reporter enabled sensitive analysis of a specific axon tract inside the mouse brain, identifying mutant phenotypes at multiple steps of the pathway, and revealing a new aspect of the <it>Emx2 </it>mutant. The phenotypes highlight vulnerable choice points and latent tendencies of TCAs, and will lead to a refined understanding of the elements and interactions required to form the thalamocortical system.</p> <p>See Commentary: <url>http://www.biomedcentral.com/1741-7007/9/1</url></p

The effectiveness of high intensity intermittent training on metabolic, reproductive and mental health in women with polycystic ovary syndrome: study protocol for the iHIT- randomised controlled trial

Abstract Background Polycystic ovary syndrome (PCOS) is a reproductive-metabolic condition. Insulin resistance is a hallmark of PCOS and is related to increased hyperandrogenism that drives inherent metabolic, reproductive and psychological features of the syndrome. Insulin resistance in women with PCOS is managed by weight loss, lifestyle interventions (i.e. exercise, diet) and insulin-sensitising medications. This manuscript describes the protocol of our study evaluating the effectiveness of high intensity intermittent training (HIIT) or moderate intensity exercise on cardiometabolic, reproductive and mental health in overweight women with PCOS. Methods/design We will employ a three arm, parallel-group, randomised controlled trial recruiting 60 women diagnosed with PCOS, aged between 18 and 45 years and with a body mass index (BMI) greater than 25 kg/m2. Following screening and baseline testing, women will be randomised by simple randomisation procedure using computer generated sequence allocation to undergo one of two 12-week supervised interventions: either HIIT or moderate intensity exercise (standard supervised exercise), or to standard care [Con] (unsupervised lifestyle advice) at a 1:1:1 allocation ratio. The primary outcome for this trial is to measure the improvements in metabolic health; specifically changes in insulin sensitivity in response to different exercise intensities. Baseline and post-intervention testing include anthropometric measurements, cardiorespiratory fitness testing, reproductive hormone profiles (anti-müllerian hormone and steroid profiles), metabolic health, health-related quality of life and mental health questionnaires and objective and subjective lifestyle monitoring. Reporting of the study will follow the CONSORT statement. Discussion This trial aims to demonstrate the comparative efficacy and maintenance of different exercise intensities to advance the understanding of PCOS management and provide insight into the optimal exercise intensity for improved cardiometabolic outcomes. Secondary outcomes will include the impact of different exercise protocols on reproductive hormone profiles, mental health and health-related quality of life. Trial registration Australian New Zealand Clinical Trials Registry, ACTRN12615000242527. Registered on 17 March 2015

Comparison of Outcomes of antibiotic Drugs and Appendectomy (CODA) trial: a protocol for the pragmatic randomised study of appendicitis treatment.

INTRODUCTION: Several European studies suggest that some patients with appendicitis can be treated safely with antibiotics. A portion of patients eventually undergo appendectomy within a year, with 10%-15% failing to respond in the initial period and a similar additional proportion with suspected recurrent episodes requiring appendectomy. Nearly all patients with appendicitis in the USA are still treated with surgery. A rigorous comparative effectiveness trial in the USA that is sufficiently large and pragmatic to incorporate usual variations in care and measures the patient experience is needed to determine whether antibiotics are as good as appendectomy. OBJECTIVES: The Comparing Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial for acute appendicitis aims to determine whether the antibiotic treatment strategy is non-inferior to appendectomy. METHODS/ANALYSIS: CODA is a randomised, pragmatic non-inferiority trial that aims to recruit 1552 English-speaking and Spanish-speaking adults with imaging-confirmed appendicitis. Participants are randomised to appendectomy or 10 days of antibiotics (including an option for complete outpatient therapy). A total of 500 patients who decline randomisation but consent to follow-up will be included in a parallel observational cohort. The primary analytic outcome is quality of life (measured by the EuroQol five dimension index) at 4 weeks. Clinical adverse events, rate of eventual appendectomy, decisional regret, return to work/school, work productivity and healthcare utilisation will be compared. Planned exploratory analyses will identify subpopulations that may have a differential risk of eventual appendectomy in the antibiotic treatment arm. ETHICS AND DISSEMINATION: This trial was approved by the University of Washington\u27s Human Subjects Division. Results from this trial will be presented in international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02800785

Role of Hypothalamic Melanocortin System in Adaptation of Food Intake to Food Protein Increase in Mice

The hypothalamic melanocortin system—the melanocortin receptor of type 4 (MC4R) and its ligands: α-melanin-stimulating hormone (α-MSH, agonist, inducing hypophagia), and agouti-related protein (AgRP, antagonist, inducing hyperphagia)—is considered to play a central role in the control of food intake. We tested its implication in the mediation of the hunger-curbing effects of protein-enriched diets (PED) in mice. Whereas there was a 20% decrease in food intake in mice fed on the PED, compared to mice fed on an isocaloric starch-enriched diet, there was a paradoxical decrease in expression of the hypothalamic proopiomelanocortin gene, precursor of α-MSH, and increase in expression of the gene encoding AgRP. The hypophagia effect of PED took place in mice with invalidation of either MC4R or POMC, and was even strengthened in mice with ablation of the AgRP-expressing neurons. These data strongly suggest that the hypothalamic melanocortin system does not mediate the hunger-curbing effects induced by changes in the macronutrient composition of food. Rather, the role of this system might be to defend the body against the variations in food intake generated by the nutritional environment

Mutations causing medullary cystic kidney disease type 1 (MCKD1) lie in a large VNTR in MUC1 missed by massively parallel sequencing

While genetic lesions responsible for some Mendelian disorders can be rapidly discovered through massively parallel sequencing (MPS) of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple Mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing, and de novo assembly, we found that each of six MCKD1 families harbors an equivalent, but apparently independently arising, mutation in sequence dramatically underrepresented in MPS data: the insertion of a single C in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (~1.5-5 kb), GC-rich (>80%), coding VNTR in the mucin 1 gene. The results provide a cautionary tale about the challenges in identifying genes responsible for Mendelian, let alone more complex, disorders through MPS

Mutations causing medullary cystic kidney disease type 1 (MCKD1) lie in a large VNTR in MUC1 missed by massively parallel sequencing

While genetic lesions responsible for some Mendelian disorders can be rapidly discovered through massively parallel sequencing (MPS) of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple Mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing, and de novo assembly, we found that each of six MCKD1 families harbors an equivalent, but apparently independently arising, mutation in sequence dramatically underrepresented in MPS data: the insertion of a single C in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (~1.5-5 kb), GC-rich (>80%), coding VNTR in the mucin 1 gene. The results provide a cautionary tale about the challenges in identifying genes responsible for Mendelian, let alone more complex, disorders through MPS

Episodic Memory and Appetite Regulation in Humans

Psychological and neurobiological evidence implicates hippocampal-dependent memory processes in the control of hunger and food intake. In humans, these have been revealed in the hyperphagia that is associated with amnesia. However, it remains unclear whether 'memory for recent eating' plays a significant role in neurologically intact humans. In this study we isolated the extent to which memory for a recently consumed meal influences hunger and fullness over a three-hour period. Before lunch, half of our volunteers were shown 300 ml of soup and half were shown 500 ml. Orthogonal to this, half consumed 300 ml and half consumed 500 ml. This process yielded four separate groups (25 volunteers in each). Independent manipulation of the 'actual' and 'perceived' soup portion was achieved using a computer-controlled peristaltic pump. This was designed to either refill or draw soup from a soup bowl in a covert manner. Immediately after lunch, self-reported hunger was influenced by the actual and not the perceived amount of soup consumed. However, two and three hours after meal termination this pattern was reversed - hunger was predicted by the perceived amount and not the actual amount. Participants who thought they had consumed the larger 500-ml portion reported significantly less hunger. This was also associated with an increase in the 'expected satiation' of the soup 24-hours later. For the first time, this manipulation exposes the independent and important contribution of memory processes to satiety. Opportunities exist to capitalise on this finding to reduce energy intake in humans

Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing

Although genetic lesions responsible for some mendelian disorders can be rapidly discovered through massively parallel sequencing of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing and de novo assembly did we find that each of six families with MCKD1 harbors an equivalent but apparently independently arising mutation in sequence markedly under-represented in massively parallel sequencing data: the insertion of a single cytosine in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (~1.5–5 kb), GC-rich (>80%) coding variable-number tandem repeat (VNTR) sequence in the MUC1 gene encoding mucin 1. These results provide a cautionary tale about the challenges in identifying the genes responsible for mendelian, let alone more complex, disorders through massively parallel sequencing.National Institutes of Health (U.S.) (Intramural Research Program)National Human Genome Research Institute (U.S.)Charles University (program UNCE 204011)Charles University (program PRVOUK-P24/LF1/3)Czech Republic. Ministry of Education, Youth, and Sports (grant NT13116-4/2012)Czech Republic. Ministry of Health (grant NT13116-4/2012)Czech Republic. Ministry of Health (grant LH12015)National Institutes of Health (U.S.) (Harvard Digestive Diseases Center, grant DK34854

Genome-wide Association Analysis Identifies 14 New Risk Loci for Schizophrenia

Schizophrenia is a heritable disorder with substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases, 6,243 controls) followed by meta-analysis with prior schizophrenia GWAS (8,832 cases, 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls, and 581 trios). In total, 22 regions met genome-wide significance (14 novel and one previously implicated in bipolar disorder). The results strongly implicate calcium signaling in the etiology of schizophrenia, and include genome-wide significant results for CACNA1C and CACNB2 whose protein products interact. We estimate that ∼8,300 independent and predominantly common SNPs contribute to risk for schizophrenia and that these collectively account for most of its heritability. Common genetic variation plays an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this devastating disorder