DNA damage alters nuclear mechanics through chromatin reorganization

AbstractDNA double-strand breaks drive genomic instability. However, it remains unknown how these processes may affect the biomechanical properties of the nucleus and what role nuclear mechanics play in DNA damage and repair efficiency. Here, we have used Atomic Force Microscopy to investigate nuclear mechanical changes, arising from externally induced DNA damage. We found that nuclear stiffness is significantly reduced after cisplatin treatment, as a consequence of DNA damage signalling. This softening was linked to global chromatin decondensation, which improves molecular diffusion within the organelle. We propose that this can increase recruitment for repair factors. Interestingly, we also found that reduction of nuclear tension, through cytoskeletal relaxation, has a protective role to the cell and reduces accumulation of DNA damage. Overall, these changes protect against further genomic instability and promote DNA repair. We propose that these processes may underpin the development of drug resistance

A role for the cell-wall protein silacidin in cell size of the diatom Thalassiosira pseudonana

Diatoms contribute 20% of global primary production and form the basis of many marine food webs. Although their species diversity correlates with broad diversity in cell size, there is also an intraspecific cell-size plasticity due to sexual reproduction and varying environmental conditions. However, despite the ecological significance of the diatom cell size for food-web structure and global biogeochemical cycles, our knowledge about genes underpinning the size of diatom cells remains elusive. Here, a combination of reverse genetics, experimental evolution and comparative RNA8 sequencing analyses enabled us to identify a previously unknown genetic control of cell size in the diatom Thalassiosira pseudonana. In particular, the targeted deregulation of the expression of the cell-wall protein silacidin caused a significant increase in valve diameter. Remarkably, the natural downregulation of the silacidin gene transcript due to experimental evolution under low temperature also correlated with cell-size increase. Our data give first evidence for a genetically controlled regulation of cell size in Thalassiosira pseudonana and possibly other centric diatoms as they also encode the silacidin gene in their genomes

Interventions targeting social isolation in older people: a systematic review

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.BACKGROUND: Targeting social isolation in older people is a growing public health concern. The proportion of older people in society has increased in recent decades, and it is estimated that approximately 25% of the population will be aged 60 or above within the next 20 to 40 years. Social isolation is prevalent amongst older people and evidence indicates the detrimental effect that it can have on health and wellbeing. The aim of this review was to assess the effectiveness of interventions designed to alleviate social isolation and loneliness in older people. METHODS: Relevant electronic databases (MEDLINE, EMBASE, ASSIA, IBSS, PsycINFO, PubMed, DARE, Social Care Online, the Cochrane Library and CINAHL) were systematically searched using an extensive search strategy, for randomised controlled trials and quasi-experimental studies published in English before May 2009. Additional articles were identified through citation tracking. Studies were included if they related to older people, if the intervention aimed to alleviate social isolation and loneliness, if intervention participants were compared against inactive controls and, if treatment effects were reported. Two independent reviewers extracted data using a standardised form. Narrative synthesis and vote-counting methods were used to summarise and interpret study data. RESULTS: Thirty two studies were included in the review. There was evidence of substantial heterogeneity in the interventions delivered and the overall quality of included studies indicated a medium to high risk of bias. Across the three domains of social, mental and physical health, 79% of group-based interventions and 55% of one-to-one interventions reported at least one improved participant outcome. Over 80% of participatory interventions produced beneficial effects across the same domains, compared with 44% of those categorised as non-participatory. Of interventions categorised as having a theoretical basis, 87% reported beneficial effects across the three domains compared with 59% of interventions with no evident theoretical foundation. Regarding intervention type, 86% of those providing activities and 80% of those providing support resulted in improved participant outcomes, compared with 60% of home visiting and 25% of internet training interventions. Fifty eight percent of interventions that explicitly targeted socially isolated or lonely older people reported positive outcomes, compared with 80% of studies with no explicit targeting. CONCLUSIONS: More, well-conducted studies of the effectiveness of social interventions for alleviating social isolation are needed to improve the evidence base. However, it appeared that common characteristics of effective interventions were those developed within the context of a theoretical basis, and those offering social activity and/or support within a group format. Interventions in which older people are active participants also appeared more likely to be effective. Future interventions incorporating all of these characteristics may therefore be more successful in targeting social isolation in older people.National Institute for Health Researc

PREDIVAC: CD4+T-cell epitope prediction for vaccine design that covers 95% of HLA class II DR protein diversity

Background: CD4+ T-cell epitopes play a crucial role in eliciting vigorous protective immune responses during peptide (epitope)-based vaccination. The prediction of these epitopes focuses on the peptide binding process by MHC class II proteins. The ability to account for MHC class II polymorphism is critical for epitope-based vaccine design tools, as different allelic variants can have different peptide repertoires. In addition, the specificity of CD4+ T-cells is often directed to a very limited set of immunodominant peptides in pathogen proteins. The ability to predict what epitopes are most likely to dominate an immune response remains a challenge

Pathogen Proteins Eliciting Antibodies Do Not Share Epitopes with Host Proteins: A Bioinformatics Approach

The best way to prevent diseases caused by pathogens is by the use of vaccines. The advent of genomics enables genome-wide searches of new vaccine candidates, called reverse vaccinology. The most common strategy to apply reverse vaccinology is by designing subunit recombinant vaccines, which usually generate an humoral immune response due to B-cell epitopes in proteins. A major problem for this strategy is the identification of protective immunogenic proteins from the surfome of the pathogen. Epitope mimicry may lead to auto-immune phenomena related to several human diseases. A sequence-based computational analysis has been carried out applying the BLASTP algorithm. Therefore, two huge databases have been created, one with the most complete and current linear B-cell epitopes, and the other one with the surface-protein sequences of the main human respiratory bacterial pathogens. We found that none of the 7353 linear B-cell epitopes analysed shares any sequence identity region with human proteins capable of generating antibodies, and that only 1% of the 2175 exposed proteins analysed contain a stretch of shared sequence with the human proteome. These findings suggest the existence of a mechanism to avoid autoimmunity. We also propose a strategy for corroborating or warning about the viability of a protein linear B-cell epitope as a putative vaccine candidate in a reverse vaccinology study; so, epitopes without any sequence identity with human proteins should be very good vaccine candidates, and the other way around

Evolutionary genomics of a cold-adapted diatom: Fragilariopsis cylindrus

The Southern Ocean houses a diverse and productive community of organisms1, 2. Unicellular eukaryotic diatoms are the main primary producers in this environment, where photosynthesis is limited by low concentrations of dissolved iron and large seasonal fluctuations in light, temperature and the extent of sea ice3, 4, 5, 6, 7. How diatoms have adapted to this extreme environment is largely unknown. Here we present insights into the genome evolution of a cold-adapted diatom from the Southern Ocean, Fragilariopsis cylindrus8, 9, based on a comparison with temperate diatoms. We find that approximately 24.7 per cent of the diploid F. cylindrus genome consists of genetic loci with alleles that are highly divergent (15.1 megabases of the total genome size of 61.1 megabases). These divergent alleles were differentially expressed across environmental conditions, including darkness, low iron, freezing, elevated temperature and increased CO2. Alleles with the largest ratio of non-synonymous to synonymous nucleotide substitutions also show the most pronounced condition-dependent expression, suggesting a correlation between diversifying selection and allelic differentiation. Divergent alleles may be involved in adaptation to environmental fluctuations in the Southern Ocean

Factors contributing to posttraumatic growth and its buffering effect in adult chidren of cancer patients undergoing treatment

This study examined relationships among demographic, clinical, and psychosocial variables in adult children of cancer patients. Two hundred and fourteen participants completed measures of posttraumatic growth (PTG), distress, posttraumatic stress disorder (PTSD) symptoms, social support, and family functioning. Significant gender differences in all PTG dimensions were found, as well as associations among PTG, gender, parental dependency, distress, PTSD, and family functioning. Social support was not a mediator in the relationship between gender and PTG. Gender, education, disease duration, dependency, distress, and family flexibility predicted PTG. Finally, PTG had amoderating effect in the relationship between distress and PTSD/social support. These results may guide psychosocial interventions in this population.Fundação para a Ciência e Tecnologia (FCT

Enhancing the effectiveness of interdisciplinary mental health treatment teams

Mental health administrators often lack guidelines for promoting and evaluating the effectiveness of interdisciplinary clinical treatment teams. This article describes the use of a model of group effectiveness that elucidates several aspects of team effectiveness. Also discussed are how administrators can support such teams by reviewing their initial set-up, how the organization influences the team's productivity and longevity, and how team members can better understand one another's personal and professional frames of reference to improve mutual collaboration.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44090/1/10488_2005_Article_BF02106536.pd