RAD54 family translocases counter genotoxic effects of RAD51 in human tumor cells.

The RAD54 family DNA translocases have several biochemical activities. One activity, demonstrated previously for the budding yeast translocases, is ATPase-dependent disruption of RAD51-dsDNA binding. This activity is thought to promote dissociation of RAD51 from heteroduplex DNA following strand exchange during homologous recombination. In addition, previous experiments in budding yeast have shown that the same activity of Rad54 removes Rad51 from undamaged sites on chromosomes; mutants lacking Rad54 accumulate nonrepair-associated complexes that can block growth and lead to chromosome loss. Here, we show that human RAD54 also promotes the dissociation of RAD51 from dsDNA and not ssDNA. We also show that translocase depletion in tumor cell lines leads to the accumulation of RAD51 on chromosomes, forming complexes that are not associated with markers of DNA damage. We further show that combined depletion of RAD54L and RAD54B and/or artificial induction of RAD51 overexpression blocks replication and promotes chromosome segregation defects. These results support a model in which RAD54L and RAD54B counteract genome-destabilizing effects of direct binding of RAD51 to dsDNA in human tumor cells. Thus, in addition to having genome-stabilizing DNA repair activity, human RAD51 has genome-destabilizing activity when expressed at high levels, as is the case in many human tumors

Prevalence of mental health disorders in inflammatory bowel disease: an Australian outpatient cohort

BACKGROUND: This study aimed to characterize prevalence of anxiety and depressive conditions and uptake of mental health services in an Australian inflammatory bowel disease (IBD) outpatient setting. METHODS: Eighty-one IBD patients (39 males, mean age 35 years) attending a tertiary hospital IBD outpatient clinic participated in this study. Disease severity was evaluated according to the Manitoba Index. Diagnosis of an anxiety or depressive condition was based upon the Mini-International Neuropsychiatric Interview and the Hospital Anxiety and Depression Scale. RESULTS: Based on Hospital Anxiety and Depression Scale subscale scores >8 and meeting Mini-International Neuropsychiatric Interview criteria, 16 (19.8%) participants had at least one anxiety condition, while nine (11.1%) had a depressive disorder present. Active IBD status was associated with higher prevalence rates across all anxiety and depressive conditions. Generalized anxiety was the most common (12 participants, 14.8%) anxiety condition, and major depressive disorder (recurrent) was the most common depressive condition reported (five participants, 6.2%). Seventeen participants (21%) reported currently seeking help for mental health issues while 12.4% were identified has having at least one psychological condition but not seeking treatment. CONCLUSION: We conclude that rates of anxiety and depression are high in this cohort, and that IBD-focused psychological services should be a key component of any holistic IBD service, especially for those identified as having active IBD

Synthesis and Characterization of Copolyimides Containing Fluorine and Silicon Surface Modifying Agents

Understanding the effects that monomer chemistries have on material properties allows for fine tuning of polymer synthesis for current and future applications. In order to develop polymeric based coatings that have minimal surface adhesion characteristics when exposed to a variety of contaminants, a more thorough understanding of fundamental structure-property relationships is needed. In the aeronautics field, one concept to improve fuel efficiency of future aircraft is to modify the wing design to enable laminar flow. There is a concern that contaminants such as insect residue and other debris will adhere to airflow surfaces and have sufficient height to disrupt laminar flow thereby increasing drag with concomitant loss of fuel efficiency. One potential solution would be a polymer surface or coating that prevents or minimizes adhesion of such contaminants. As part of a structure-property relationship study involving modification of surface properties, a series of copolyimides containing both fluorine and silicon surface modifying agents (SMAs) were prepared and characterized. Based on knowledge of structure-property relationships with polyimides containing either type of SMA, it was hypothesized that the combination of two different surface-modifying agents may lead to unique surface properties as the two SMAs competed for surface area at the polymer-air interface. Copolyimides for this study were prepared through a multi-step synthesis using an aromatic dianhydride with equimolar amounts of diamino functionalities comprised of an aromatic diamine along with two SMAs. Films were cast from copoly(amide acid) solutions that were subsequently thermally imidized under a nitrogen atmosphere. Polyimide films and coatings were characterized using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), ultravioletvisible spectroscopy (UV-Vis), contact angle goniometry (CAG), scanning electron microscopy (SEM), and energy-dispersive X-ray spectroscopy (EDS) to determine chemical, thermal, and surface properties. Select samples were subject to high velocity insect impacts in a small scale wind tunnel and the resulting residues were characterized for height and surface area and compared to those of a control surface

Nano-Particle Enhanced Polymer Materials for Space Flight Applications

Recent advances in materials technology both in polymer chemistry and nano-materials warrant development of enhanced structures for space flight applications. This work aims to develop spacecraft structures based on polymer matrix composites (PMCs) that utilize these advancements.. Multi-wall carbon nano-tubes (MWCNTs) are expected to increase mechanical performance, lower coefficient of thermal expansion (CTE), increase electrical conductivity (mitigate electrostatic charge), increase thermal conductivity, and reduce moisture absorption of the resultant space structures. In this work, blends of MWCNTs with PETI-330 were prepared and characterized. The nano-reinforced resins were then resin transfer molded (RTM) into composite panels using M55J carbon fabric and compared to baseline panels fabricated from a cyanate ester (RS-3) or a polyimide (PETI-330) resin containing no MWCNTs. In addition, methods of pre-loading the fabric with the MWCNTs were also investigated. The effects of the MWCNTs on the resin processing properties and on the composite end-use properties were also determined

Genomic instability in human cancer: molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition

Genomic instability can initiate cancer, augment progression, and influence the overall prognosis of the affected patient. Genomic instability arises from many different pathways, such as telomere damage, centrosome amplification, epigenetic modifications, and DNA damage from endogenous and exogenous sources, and can be perpetuating, or limiting, through the induction of mutations or aneuploidy, both enabling and catastrophic. Many cancer treatments induce DNA damage to impair cell division on a global scale but it is accepted that personalized treatments, those that are tailored to the particular patient and type of cancer, must also be developed. In this review, we detail the mechanisms from which genomic instability arises and can lead to cancer, as well as treatments and measures that prevent genomic instability or take advantage of the cellular defects caused by genomic instability. In particular, we identify and discuss five priority targets against genomic instability: (1) prevention of DNA damage; (2) enhancement of DNA repair; (3) targeting deficient DNA repair; (4) impairing centrosome clustering; and, (5) inhibition of telomerase activity. Moreover, we highlight vitamin D and B, selenium, carotenoids, PARP inhibitors, resveratrol, and isothiocyanates as priority approaches against genomic instability. The prioritized target sites and approaches were cross validated to identify potential synergistic effects on a number of important areas of cancer biology

In vivo alpha-V beta-3 integrin expression in human aortic atherosclerosis.

OBJECTIVES: Intraplaque angiogenesis and inflammation are key promoters of atherosclerosis and are mediated by the alpha-V beta-3 (αvβ3) integrin pathway. We investigated the applicability of the αvβ3-integrin receptor-selective positron emission tomography (PET) radiotracer 18F-fluciclatide in assessing human aortic atherosclerosis. METHODS: Vascular 18F-fluciclatide binding was evaluated using ex vivo analysis of carotid endarterectomy samples with autoradiography and immunohistochemistry, and in vivo kinetic modelling following radiotracer administration. Forty-six subjects with a spectrum of atherosclerotic disease categorised as stable (n=27) or unstable (n=19; recent myocardial infarction) underwent PET and CT imaging of the thorax after administration of 229 (IQR 217-237) MBq 18F-fluciclatide. Thoracic aortic 18F-fluciclatide uptake was quantified on fused PET-CT images and corrected for blood-pool activity using the maximum tissue-to-background ratio (TBRmax). Aortic atherosclerotic burden was quantified by CT wall thickness, plaque volume and calcium scoring. RESULTS: 18F-Fluciclatide uptake co-localised with regions of increased αvβ3 integrin expression, and markers of inflammation and angiogenesis. 18F-Fluciclatide vascular uptake was confirmed in vivo using kinetic modelling, and on static imaging correlated with measures of aortic atherosclerotic burden: wall thickness (r=0.57, p=0.001), total plaque volume (r=0.56, p=0.001) and aortic CT calcium score (r=0.37, p=0.01). Patients with recent myocardial infarction had greater aortic 18F-fluciclatide uptake than those with stable disease (TBRmax 1.29 vs 1.21, p=0.02). CONCLUSIONS: In vivo expression of αvβ3 integrin in human aortic atheroma is associated with plaque burden and is increased in patients with recent myocardial infarction. Quantification of αvβ3 integrin expression with 18F-fluciclatide PET has potential to assess plaque vulnerability and disease activity in atherosclerosis

Copolyimides Containing Surface Modifying Groups: Competition Between Silicone and Flourine-Containing Blocks

No abstract availabl

Distributive justice with and without culture

Academic treatments of distributive justice normally adopt a static approach centred on resource allocation among a set of individual agents. The resulting models, expressed in mathematical language, make no allowance for culture, as they never engage with the society’s way of life or the moulding of individuals within society. This paper compares the static approach to distributive justice with a cultural one, arguing that a case for redistribution should rest upon its cultural effects in assisting well-being and social cohesion. Unless we recognise culture, we can have little understanding of why inequalities matter, where they come from, and how they might be reduced. Redistribution may be motivated by universal value judgements taken from external sources, but it also entails internal cultural changes that refashion social relations through cumulative causation. In practical terms, it has to penetrate beyond reallocating resource endowments to bring revised attitudes in a society less tolerant of unequal outcomes. Egalitarian reforms will flourish only if they generate and reflect an egalitarian culture

ESX1-dependent fractalkine mediates chemotaxis and Mycobacterium tuberculosis infection in humans

SummaryMycobacterium tuberculosis-induced cellular aggregation is essential for granuloma formation and may assist establishment and early spread of M. tuberculosis infection. The M. tuberculosis ESX1 mutant, which has a non-functional type VII secretion system, induced significantly less production of the host macrophage-derived chemokine fractalkine (CX3CL1). Upon infection of human macrophages ESX1-dependent fractalkine production mediated selective recruitment of CD11b+ monocytic cells and increased infection of neighbouring cells consistent with early local spread of infection. Fractalkine levels were raised in vivo at tuberculous disease sites in humans and were significantly associated with increased CD11b+ monocytic cellular recruitment and extent of granulomatous disease. These findings suggest a novel fractalkine-dependent ESX1-mediated mechanism in early tuberculous disease pathogenesis in humans. Modulation of M. tuberculosis-mediated fractalkine induction may represent a potential treatment option in the future, perhaps allowing us to switch off a key mechanism required by the pathogen to spread between cells