Impact of Rapamycin on Genome Organization

Rapamycin, a putative anti-aging drug, has been shown to extend the lifespan of several model organisms. Rapamycin’s core effect is to inhibit a major nutrient sensing pathway of the cell, mechanistic Target of Rapamycin Complex 1 (mTORC1). This inhibition was previously thought to induce similar beneficial effects that parallel caloric restriction – the restriction of calories in an organism without causing malnutrition. Previous work has shown that Rapamycin induces significant changes in gene expression of normal human dermal fibroblasts, as well as inducing repositioning of chromosome within the nuclear volume. However, questions remained on how other chromosomes repositioned and if changes were occurring at sub-chromosomal levels. By utilizing fluorescence in situ hybridization (FISH) and Chromosome Conformation Capture (3C), we analyzed genome organization under several different growth conditions including Rapamycin treatment. Despite significantly altering the transcript levels of several CXCL (chemokine C-X-C motif ligand) genes during treatment with Rapamycin, we observed only minimal movement of chromosome 4 which contains these genes. However, when we analyzed the sub-chromosomal organization of the locus containing these genes, we discovered altered topology in response to both Rapamycin treatment and reversible growth arrest through induction of quiescence. We also observed that interactions occurred between LIF (Leukemia inhibitory factor) and two putative enhancers. Furthermore, we investigated a locus containing several KRTAP (keratin associated proteins) on chromosome 17 and discovered they also altered local genome topology in response to our treatments

Search for the evidence of endocrine disruption in the aquatic environment: Lessons to be learned from joint biological and chemical monitoring in the European Project COMPREHEND

Between January 1999 and December 2001, the European Community project COMPREHEND was performed. The overall aim of COMPREHEND was to assess endocrine disruption in the aquatic environment in Europe, consequent to effluent discharge, with emphasis on estrogenic activity. COMPREHEND demonstrated the widespread occurrence of estrogenic effluents across Europe and presented evidence of impacts on a range of wild fish species. Using a variety of bioassays in combination with chemical analytical methods, estrogenic steroids of human origin from domestic wastewater effluents were identified as the most pervasive problem, although alkylphenols may be important estrogenic components of some industrial effluents. New tools have been developed for the identification of estrogenic effluents, and recommendations are made for the improvement of existing techniques. We have shown that individual fish within natural populations may be feminized to varying degrees, but it has not been possible to show, using traditional fish population parameters, that the survival of fish populations is threatened. However, laboratory-based fish life-cycle studies demonstrate the sensitivity of fish to estrogen (and androgen) exposure and how this might lead to complex (and potentially damaging) genetic changes at the population level. New approaches to this problem, utilizing recent advances made in the field of molecular and population genetics, are recommended. Finally, a study of estrogenic and androgenic activity of waste waters during the treatment process has shown that some of the existing wastewater treatment technologies have the potential to eliminate or minimize the hormonal activity of the final effluent

The development of path integration: combining estimations of distance and heading

Efficient daily navigation is underpinned by path integration, the mechanism by which we use self-movement information to update our position in space. This process is well-understood in adulthood, but there has been relatively little study of path integration in childhood, leading to an underrepresentation in accounts of navigational development. Previous research has shown that calculation of distance and heading both tend to be less accurate in children as they are in adults, although there have been no studies of the combined calculation of distance and heading that typifies naturalistic path integration. In the present study 5-year-olds and 7-year-olds took part in a triangle-completion task, where they were required to return to the startpoint of a multi-element path using only idiothetic information. Performance was compared to a sample of adult participants, who were found to be more accurate than children on measures of landing error, heading error, and distance error. 7-year-olds were significantly more accurate than 5-year-olds on measures of landing error and heading error, although the difference between groups was much smaller for distance error. All measures were reliably correlated with age, demonstrating a clear development of path integration abilities within the age range tested. Taken together, these data make a strong case for the inclusion of path integration within developmental models of spatial navigational processing

Interpreting the Global Enteric Multicenter Study (GEMS) Findings on Sanitation, Hygiene, and Diarrhea

Sanitation and hygiene are global concerns, as reflected in international development and human rights policy . The Sustainable Development Goals (SDGs) include target 6.2: to “achieve access to adequate and equitable sanitation and hygiene for all and end open defecation”. Globally, about 2.5 billion people do not use improved sanitation, of whom 1 billion defecate in the open. Fecal contamination of the environment and poor handwashing are responsible for an estimated 577,000 deaths annually. This is likely an underestimation: there is emerging evidence that poor sanitation and hygiene contribute to undernutrition and could be responsible for approximately half of all child stunting. Much of the health impact of inadequate sanitation and hygiene is attributed to diarrheal disease and its secondary effects. However, diarrhea is difficult to measure, and sanitation and hygiene are difficult to link to health outcomes

Atomoxetine for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children with ADHD and dyslexia

<p>Abstract</p> <p>Background</p> <p>The objective of this study was to assess the effects of atomoxetine on treating attention-deficit/hyperactivity disorder (ADHD), on reading performance, and on neurocognitive function in youth with ADHD and dyslexia (ADHD+D).</p> <p>Methods</p> <p>Patients with ADHD (n = 20) or ADHD+D (n = 36), aged 10-16 years, received open-label atomoxetine for 16 weeks. Data from the ADHD Rating Scale-IV (ADHDRS-IV), Kaufman Test of Educational Achievement (K-TEA), Working Memory Test Battery for Children (WMTB-C), and Life Participation Scale for ADHD-Child Version (LPS-C) were assessed.</p> <p>Results</p> <p>Atomoxetine demonstrated significant improvement for both groups on the ADHDRS-IV, LPS-C, and K-TEA reading comprehension standard and composite scores. K-TEA spelling subtest improvement was significant for the ADHD group, whereas the ADHD+D group showed significant reading decoding improvements. Substantial K-TEA reading and spelling subtest age equivalence gains (in months) were achieved for both groups. The WMTB-C central executive score change was significantly greater for the ADHD group. Conversely, the ADHD+D group showed significant phonological loop score enhancement by visit over the ADHD group. Atomoxetine was well tolerated, and commonly reported adverse events were similar to those previously reported.</p> <p>Conclusions</p> <p>Atomoxetine reduced ADHD symptoms and improved reading scores in both groups. Conversely, different patterns and magnitude of improvement in working memory component scores existed between ADHD and ADHD+D patients. Though limited by small sample size, group differences in relation to the comparable changes in improvement in ADHD symptoms could suggest that brain systems related to the therapeutic benefit of atomoxetine in reducing ADHD symptoms may be different in individuals with ADHD+D and ADHD without dyslexia.</p> <p>Trial Registration</p> <p>Clinical Trial Registry: ClinicalTrials.gov: NCT00191048</p

Direct Visualization of Dislocation Dynamics in Grain Boundary Scars

Mesoscale objects with unusual structural features may serve as the analogues of atoms in the design of larger-scale materials with novel optical, electronic or mechanical behaviour. In this paper we investigate the structural features and the equilibrium dynamics of micron-scale spherical crystals formed by polystyrene particles adsorbed on the surface of a spherical water droplet. The ground state of sufficiently large crystals possesses finite-length grain boundaries (scars). We determine the elastic response of the crystal by measuring single-particle diffusion and quantify the fluctuations of individual dislocations about their equilibrium positions within a scar determining the dislocation spring constants. We observe rapid dislocation glide with fluctuations over the barriers separating one local Peierls minimum from the next and rather weak binding of dislocations to their associated scars. The long-distance (renormalised) dislocation diffusion glide constant is extracted directly from the experimental data and is found to be moderately faster than single particle diffusion. We are also able to determine the parameters of the Peierls potential induced by the underlying crystalline lattice.Comment: 11 pages, 4 figures, pdf forma

Benefit of enactment over oral repetition of verbal instruction does not require additional working memory during encoding

For this research, we used a dual-task approach to investigate the involvement of working memory in following written instructions. In two experiments, participants read instructions to perform a series of actions on objects and then recalled the instructions either by spoken repetition or performance of the action sequence. Participants engaged in concurrent articulatory suppression, backward-counting, and spatial-tapping tasks during the presentation of the instructions, in order to disrupt the phonological-loop, central-executive, and visuospatial-sketchpad components of working memory, respectively. Recall accuracy was substantially disrupted by all three concurrent tasks, indicating that encoding and retaining verbal instructions depends on multiple components of working memory. The accuracy of recalling the instructions was greater when the actions were performed than when the instructions were repeated, and this advantage was unaffected by the concurrent tasks, suggesting that the benefit of enactment over oral repetition does not cost additional working memory resource

A RAC-GEF network critical for early intestinal tumourigenesis.

RAC1 activity is critical for intestinal homeostasis, and is required for hyperproliferation driven by loss of the tumour suppressor gene Apc in the murine intestine. To avoid the impact of direct targeting upon homeostasis, we reasoned that indirect targeting of RAC1 via RAC-GEFs might be effective. Transcriptional profiling of Apc deficient intestinal tissue identified Vav3 and Tiam1 as key targets. Deletion of these indicated that while TIAM1 deficiency could suppress Apc-driven hyperproliferation, it had no impact upon tumourigenesis, while VAV3 deficiency had no effect. Intriguingly, deletion of either gene resulted in upregulation of Vav2, with subsequent targeting of all three (Vav2-/- Vav3-/- Tiam1-/-), profoundly suppressing hyperproliferation, tumourigenesis and RAC1 activity, without impacting normal homeostasis. Critically, the observed RAC-GEF dependency was negated by oncogenic KRAS mutation. Together, these data demonstrate that while targeting RAC-GEF molecules may have therapeutic impact at early stages, this benefit may be lost in late stage disease

Neurophysiological evidence for rapid processing of verbal and gestural information in understanding communicative actions

During everyday social interaction, gestures are a fundamental part of human communication. The communicative pragmatic role of hand gestures and their interaction with spoken language has been documented at the earliest stage of language development, in which two types of indexical gestures are most prominent: the pointing gesture for directing attention to objects and the give-me gesture for making requests. Here we study, in adult human participants, the neurophysiological signatures of gestural-linguistic acts of communicating the pragmatic intentions of naming and requesting by simultaneously presenting written words and gestures. Already at ~150 ms, brain responses diverged between naming and request actions expressed by word-gesture combination, whereas the same gestures presented in isolation elicited their earliest neurophysiological dissociations significantly later (at ~210 ms). There was an early enhancement of request-evoked brain activity as compared with naming, which was due to sources in the frontocentral cortex, consistent with access to action knowledge in request understanding. In addition, an enhanced N400-like response indicated late semantic integration of gesture-language interaction. The present study demonstrates that word-gesture combinations used to express communicative pragmatic intentions speed up the brain correlates of comprehension processes – compared with gesture-only understanding – thereby calling into question current serial linguistic models viewing pragmatic function decoding at the end of a language comprehension cascade. Instead, information about the social-interactive role of communicative acts is processed instantaneously

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin