I Love A Little Cottage

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Characterization of the interaction between HMGB1 and H3-a possible means of positioning HMGB1 in chromatin.

High mobility group protein B1 (HMGB1) binds to the internucleosomal linker DNA in chromatin and abuts the nucleosome. Bending and untwisting of the linker DNA results in transmission of strain to the nucleosome core, disrupting histone/DNA contacts. An interaction between H3 and HMGB1 has been reported. Here we confirm and characterize the interaction of HMGB1 with H3, which lies close to the DNA entry/exit points around the nucleosome dyad, and may be responsible for positioning of HMGB1 on the linker DNA. We show that the interaction is between the N-terminal unstructured tail of H3 and the C-terminal unstructured acidic tail of HMGB1, which are presumably displaced from DNA and the HMG boxes, respectively, in the HMGB1-nucleosome complex. We have characterized the interaction by nuclear magnetic resonance spectroscopy and show that it is extensive for both peptides, and appears not to result in the acquisition of significant secondary structure by either partner

Exploring Factors Influencing Outcomes of a Five-Week Youth Expedition in The Himalayas Using The Sail Training Programme Self-Assessment Toolkit

Much evidence to link youth expeditions and gap years with a range of outcome benefits for participants exists, but to date, there have been relatively few insights into what exactly brings about these reported outcomes. A modified version of the Sail Training Voyage Toolkit (2011) was used to evaluate outcomes of a five-week British Exploring Society youth expedition in the Himalayas. Data generated from 22 participants completing the modified Sail Training Voyage Feedback Form at the end of their expedition were complemented by data from 16 interviews conducted during weeks one, three and five of the expedition. Key factors identified by the participants which had influenced their learning were: (1) Other Young Explorers, (2) being involved in making decisions and having choices, (3) having time to learn at their own pace; time to get comfortable with people; being able to talk with other people (to make connections); (4) group leaders, and (5) wild camping. Data from 16 interviews supported these outcomes, while the physical challenges (of climbing peaks) and cultural interaction with local people were highly valued aspects of the expedition. Participants were more aware of risks and more confident about safety issues and taking risks after the expedition. These important outcomes may be transferred to future expeditions, higher education or employment. Personal development and training organisations should consider these findings

Characterization of chromoshadow domain-mediated binding of heterochromatin protein 1α (HP1α) to histone H3.

The chromoshadow domain (CSD) of heterochromatin protein 1 (HP1) was recently shown to contribute to chromatin binding and transcriptional regulation through interaction with histone H3. Here, we demonstrate the structural basis of this interaction for the CSD of HP1α. This mode of H3 binding is dependent on dimerization of the CSD and recognition of a PxVxL-like motif, as for other CSD partners. NMR chemical shift mapping showed that the H3 residues that mediate the CSD interaction occur in and adjacent to the αN helix just within the nucleosome core. Access to the binding region would require some degree of unwrapping of the DNA near the nucleosomal DNA entry/exit site

Structural insights into the mechanism of negative regulation of single-box high mobility group proteins by the acidic tail domain.

The Drosophila and plant (maize) functional counterparts of the abundant vertebrate chromosomal protein HMGB1 (HMG-D and ZmHMGB1, respectively) differ from HMGB1 in having a single HMG box, as well as basic and acidic flanking regions that vary greatly in length and charge. We show that despite these variations, HMG-D and ZmHMGB1 exist in dynamic assemblies in which the basic HMG boxes and linkers associate with their intrinsically disordered, predominantly acidic, tails in a manner analogous to that observed previously for HMGB1. The DNA-binding surfaces of the boxes and linkers are occluded in "auto-inhibited" forms of the protein, which are in equilibrium with transient, more open structures that are "binding-competent." This strongly suggests that the mechanism of auto-inhibition may be a general one. HMG-D and ZmHMGB1 differ from HMGB1 in having phosphorylation sites in their tail and linker regions. In both cases, in vitro phosphorylation of serine residues within the acidic tail stabilizes the assembled form, suggesting another level of regulation for interaction with DNA, chromatin, and other proteins that is not possible for the uniformly acidic (hence unphosphorylatable) tail of HMGB1.This work was supported by the Biotechnology and Biological Sciences Research Council through the award of Grant BB/D002257/1 (to J. O. T.) and a grant from the Deutsche Forschungsgemeinschaft (DFG) (to K. D. G.).This is the final published version. It first appeared at http://www.jbc.org/content/289/43/29817.long

Unusual past dry and wet rainy seasons over Southern Africa and South America from a climate perspective

Southern Africa and Southern South America have experienced recent extremes in dry and wet rainy seasons which have caused severe socio-economic damages. Selected past extreme events are here studied, to estimate how human activity has changed the risk of the occurrence of such events, by applying an event attribution approach (Stott et al., 2004)comprising global climate models of Coupled Model Intercomparison Project 5 (CMIP5). Our assessment shows that models' representation of mean precipitation variability over Southern South America is not adequate to make a robust attribution statement about seasonal rainfall extremes in this region. Over Southern Africa, we show that unusually dry austral summers as occurred during 2002/2003 have become more likely, whereas unusually wet austral summers like that of 1999/2000 have become less likely due to anthropogenic climate change. There is some tentative evidence that the risk of extreme high 5-day precipitation totals (as observed in 1999/2000) have increased in the region. These results are consistent with CMIP5 models projecting a general drying trend over SAF during December–January–February (DJF) but also an increase in atmospheric moisture availability to feed heavy rainfall events when they do occur. Bootstrapping the confidence intervals of the fraction of attributable risk has demonstrated estimates of attributable risk are very uncertain, if the events are very rare. The study highlights some of the challenges in making an event attribution study for precipitation using seasonal precipitation and extreme 5-day precipitation totals and considering natural drivers such as ENSO in coupled ocean–atmosphere models

A Systematic Review of Digital Storytelling as Psychotherapy for People with Mental Health Needs

Storytelling is used in many cultures as an important way to communicate historical messages of lived experiences intergenerationally. Past studies indicated that storytelling is an effective tool in education and mental health, but evidence of the therapeutic use of digital storytelling is scarce. This review therefore explored available literature evidence of the use of digital storytelling media as mental health therapy to identify knowledge gaps for a further Secret Story Network role-playing game intervention study. Based on some key search terms and a set of inclusion and exclusion criteria, 14 full-text articles were systematically selected through searches of mainly EBSCOhost that connected seven databases, including AMED, BNI, CINAHL, EMBASE, EMCARE, Medline, and APA PsycInfo. The studies reviewed suggested a tactical focus on adolescents and adults older than 18 years and more females than men. Ten digital storytelling media interventions were found in 11 sources, but only two studies on older adults with dementia had a therapeutic intervention framework. Qualitative and mixed-methods reported in nine sources were shown to be the common study methodologies. The evidence extracted also revealed six criteria for classifying storytelling types, and the purposes, effects, benefits, and uses of digital storytelling indicated a general assumption that digital storytelling interventions have therapeutic, educational, social, and psychological effects. However, evidence suggests that while digital storytelling may significantly reduce symptoms of depression (p < .05), its effects on other mental health symptoms are inconclusive. Thus, further research into the psychotherapeutic effect of digital storytelling is necessary. Five implications for future research are discussed

Close companions to Brightest Cluster Galaxies: Support for minor mergers and downsizing

We identify close companions of Brightest Cluster Galaxies (BCGs) for the purpose of quantifying the rate at which these galaxies grow via mergers. By exploiting deep photometric data from the CFHTLS, we probe the number of companions per BCG (Nc) with luminosity ratios down to those corresponding to potential minor mergers of 20:1. We also measure the average luminosity in companions per galaxy (Lc). We find that Nc and Lc rise steeply with luminosity ratio for both the BCGs, and a control sample of other bright, red, cluster galaxies. The trend for BCGs rises more steeply, resulting in a larger number of close companions. For companions within 50kpc of a BCG, Nc= 1.38+/-0.14 and Lc=(2.14+/-0.31)x10^(10)L_sun and for companions within 50kpc of a luminosity matched control sample of non-BCGs, Nc=0.87+/-0.08 and Lc=(1.48+/-0.20)x10^(10)L_sun. This suggests that the BCGs are likely to undergo more mergers compared to otherwise comparable luminous galaxies. Additionally, compared to a local sample of luminous red galaxies, the more distant sample presented in this study (with redshifts between 0.15-0.39,) shows a higher Nc, suggesting the younger and smaller BCGs are still undergoing hierarchical formation. Using the Millennium Simulations we model and estimate the level of contamination due to unrelated cluster galaxies. The contamination by interloping galaxies is 50% within projected separations of 50kpc, but within 30kpc, 60% of identified companions are real physical companions. We conclude that the luminosity of bound merger candidates down to luminosity ratios of 20:1 could be adding as much as 10% to the mass of a typical BCG over 0.5Gyr at redshifts of z~0.3.Comment: 10 pages, 7 figures. Accepted and to be published in MNRA

Deformability of Tumor Cells versus Blood Cells

The potential for circulating tumor cells (CTCs) to elucidate the process of cancer metastasis and inform clinical decision-making has made their isolation of great importance. However, CTCs are rare in the blood, and universal properties with which to identify them remain elusive. As technological advancements have made single-cell deformability measurements increasingly routine, the assessment of physical distinctions between tumor cells and blood cells may provide insight into the feasibility of deformability-based methods for identifying CTCs in patient blood. To this end, we present an initial study assessing deformability differences between tumor cells and blood cells, indicated by the length of time required for them to pass through a microfluidic constriction. Here, we demonstrate that deformability changes in tumor cells that have undergone phenotypic shifts are small compared to differences between tumor cell lines and blood cells. Additionally, in a syngeneic mouse tumor model, cells that are able to exit a tumor and enter circulation are not required to be more deformable than the cells that were first injected into the mouse. However, a limited study of metastatic prostate cancer patients provides evidence that some CTCs may be more mechanically similar to blood cells than to typical tumor cell lines.Janssen Pharmaceutical Ltd.National Cancer Institute (U.S.). Physical Sciences Oncology Center (U54CA143874)MIT-Harvard Center of Cancer Nanotechnology Excellence (Grant 26697290-47281-A)Stand Up To CancerNational Institutes of Health (U.S.). P41 Biotechnology Resource CenterNational Cancer Institute (U.S.) (Koch Institute Support Grant P30-CA14051

‘The oxygen of shared experience’: exploring social support processes within peer support groups for carers of people with non-memory-led and inherited dementias

Objectives: To explore support processes and behaviours taking place during online peer support groups for family carers of people living with rare, non-memory-led and inherited dementias (PLWRD). Methods: Twenty-five family carers of PLWRD participated in a series of ongoing online peer supportgroups on the theme of ‘Independence and Identity’. Transcripts from 16 sessions were analysed using qualitative directed content analysis with a coding framework informed by Cutrona & Suhr’s (2004) Social Support Behaviour Code (SSBC). Results: Most of the social support behaviours outlined in the SSBC were identified within the sessions, along with two novel social support categories – ‘Experiential Support’ and ‘Community Support’ – and novel support behaviours including ‘Advocacy and Collective Action’ and ‘Uses Humour’. The SSBC code ‘Relationship’ appeared to be of central importance. Conclusions: This study sheds light on the unique challenges of the caring context for those affected by non-memory-led and inherited dementias and the significant contributions carers can offer to, and receive from, peers in similar situations. It highlights the importance of services which recognise the value of the informational and emotional expertise of carers of PLWRD and encourages the continued development and delivery of tailored support for these populations