Having a workforce that is willing to respond is a critical component of mitigating the effects of any disaster, and our study results are a clear call for action. While work is being done by disaster planners to improve “readiness” or “ability” to respond during disasters, such as encouraging personal preparedness planning, more needs to be done to address beliefs and attitudes that may hinder “willingness” to respond. It is thus critically important for us to understand why some healthcare workers are unwilling to perform their duties during a radiological emergency in order to implement changes in disaster training, education and messaging. Survey responses suggest that more attention is needed to address healthcare workers’ basic knowledge level with regard to radiation events. In fact, 58% of respondents disagreed with the statement “I am knowledgeable about the potential medical impacts of a dirty bomb emergency.” Two thirds of the staff surveyed did not feel educated enough to address public questions, and less than one third of the staff knew their role-specific responsibilities. Indeed, in a recent study of 668 emergency nurses in New York, the existing knowledge in regards to radiological emergencies was determined to be poor. In that study, knowledge level and clinical ability had a positive association with nurses’ level of willingness to respond to a radiological terrorism event. Quantitative results from our hospital-based study also echo a qualitative study that assessed the views and perspectives of emergency department clinicians in regard to radiologic terrorism. Researchers found through a series of ten focus groups that study participants clearly and consistently felt that their facilities were not adequately prepared for such an event, due to inadequacy of response protocols, potential for staffing shortages, and concerns about contamination and self-protection. When considering the fear of potential staffing shortages indeed, in our study, staff who felt that their peers are unlikely to respond to duty, were 17 times more likely to refrain from reporting to duty themselves in our study. This finding lends us a potentially powerful tool to impact willingness to respond, by targeted education campaigns to change subjective norms regarding response to such an emergency. One construct that was strongly and independently associated with WTR was belief that the workplace will be safe. kinase inhibitors Perception of personal safety was identified as a primary determinant of willingness to respond in a radiological disaster in other previous work as well. This concern about personal protection is not unique among responders to the potential scenario of radiological terrorism events; in one study the question of “Will the hospital protect me?” was the most important factor in determining the workers willingness to respond. First responders must be educated as to the minimal risk of contamination from radiologic materials in such an attack if universal precautions are used, as well as in specific strategies of mitigating and minimizing personal risk in such events. Thus, it is not surprising that requiring the staff to report will not be enough to address the worker shortage.

Additionally, we demonstrate that CCI also causes acute Ab accumulation in young APP/PS1 mice, which harbor a different PS1 mutation from 3xTg-AD mice, and acutely accelerates tau pathology in TauP301L transgenic mice. Overall, our CCI model represents a useful tool for LY294002 future investigation into the link between TBI and AD. The current study shows that CCI TBI can cause rapid Ab accumulation in injured axons of young 3xTg-AD mice. This intra-axonal Ab was detectable at 1 hour post injury, and continued to rise monotonically through 24 hours. Several brain regions of injured 3xTg-AD mice also exhibited increased tau immunoreactivity, but the time course was different across regions. In particular, puntate tau staining the ipsilateral fimbria and perinuclear tau staining in the amygdala had a biphasic response with peaks at 1 hour and 24 hours post TBI. Instead, the numbers of tau-positive processes in the contralateral CA1 started to increase at 12 h post injury. However, total tau immunoreactivity in the ipsilateral CA1 of 3xTg-AD mice was not significantly affected by TBI. Neuronal damage to this region may have caused release of tau into the extracellular space, where it could not be detected by immunohistochemistry. Importantly, the finding of post-traumatic Ab accumulation in 3xTg-AD mice was recapitulated in a different transgenic mouse model of Alzheimer’s disease, APP/PS1. Similarly,accelerated tau pathology in 3xTgAD mice was also observed in transgenic mice carrying only TauP301L mutation at 24 hours following TBI. We have previously presented evidence that CCI can independently alter Ab and tau abnormalities in 3xTg-AD mice. Specifically, systemic inhibition of c-secretase activity, an enzyme required for Ab generation from its precursor, APP, successfully blocked post-traumatic Ab accumulation in injured mice. However, tau pathology was unaffected following blockade of Ab generation and accumulation. In the present study, we found distinct anatomical and temporal patterns of Ab and total tau abnormalities throughout 24 hours post TBI in 3xTg-AD mice. Furthermore, we found abnormal total and phospho-tau accumulation in injured axons, and increased somatic tau staining in single-transgenic TauP301L mice subjected to TBI. Although the temporal distribution of phospho-tau following acute TBI in 3xTgAD mice remains to be investigated, findings in this study add additional support to the hypothesis that Ab and tau pathologies are independent in the setting of TBI. As such, future studies will be required to investigate the mechanisms underlying TBIinduced tau hyperphosphorylation. APP, the precursor protein of Ab, has been found to accumulate in injured axons within 30 minutes following central nervous system injury. Axonal APP accumulation has in turn been hypothesized to serve as substrate for intra-axonal Ab generation. Thus, our finding that intra-axonal Ab was detected starting at 1 hour post TBI in 3xTg-AD mice is in line with the reported time for the earliest APP accumulation following brain trauma. PS1 mutations are thought to drive intracellular Ab generation.

The etiology of ovarian cancer remains largely unknown, although hormonal factors, inflammation, and wound healing are thought to play important roles. Ovarian cancer is a multifactorial disease and genetic susceptibility has been suggested in previous studies. For example, mutations in BRCA1, BRCA2, MLH1, and MSH2 were found to account for approximately 50% of familial ovarian cancers. However, there are compelling evidence suggesting that common genetic variants contribute to ovarian cancer susceptibility. Recently, genome-wide association studies have identified several common susceptibility alleles in four loci showing strong associations, but as most SNPs identified in GWAs, the associations are usually low in magnitude with most of the ORs less than 1.3. Due to the heterogeneous and multigenic nature of ovarian cancer, it is unlikely that any single SNP will be sufficient to confer disease risk. A comprehensive pathway-based analysis that focuses on evaluating the cumulative effects of a panel of SNPs would be more powerful to pinpoint the susceptibility genes and polymorphisms. The transforming growth factor-b pathway, including TGF-bs, bone morphogenetic proteins, activins, and related proteins, is involved in a diverse array of cellular processes, including cell proliferation, morphogenesis, migration, extracellular matrix production, and apoptosis. Alteration of TGF-b superfamily signaling has been implicated in various human ICG-001 pathologies, including cancer, developmental disorders, cardiovascular and autoimmune diseases. Experimental data have shown that more than 75% of human ovarian cancers exhibit resistance to TGF-b signaling, suggesting that diminished TGF-b responsiveness is a key event in this disease. In normal ovarian surface epithelial cells, autocrine growth inhibition is maintained by TGF-b, but tumor cells escape the antiproliferative effects of TGF-b by acquiring mutations in the components of the signaling pathways or by selectively disrupting TGF-b. Mutations and deletions of Smad genes in the TGF-b signaling pathway often lead to unstable protein products that are rapidly degraded after ubiquitination and shift the equilibrium of the signaling cascade resulting in tumorigenesis. Studies have reported the presence of some common genetic variations in the TGF-b signaling pathway to be related to ovarian carcinogenesis, such as TGFB1: rs56361919 in 23% of ovarian cancer cases. In addition, mutations and/or alterations in the expression of TGF-b receptors and loss of SMAD4 are frequently detected in human ovarian tumors. Given the critical role of the TGF-b pathway in maintaining proper cellular function and the disruption of this pathway in ovarian cancer, it is possible that common genetic variations in this pathway may affect the risk of ovarian cancer. To our knowledge, no molecular epidemiologic studies have been performed to comprehensively evaluate genetic variants in this pathway with ovarian cancer risk. In this study, we aimed to test the hypothesis that common germline genetic variants in the TGF-b pathway are associated with ovarian cancer risk.

Reviews of highthroughput sequencing technologies and assembly tools can be found elsewhere. In addition to short read assemblers, there are specialized tools for assembling longer pyrosequencing reads, such as CABOG. Even the current assemblies of important model organisms are subject to continuing finishing processes; for example, recent improvements in the mouse genome assembly added 267 Mb of previously missing or misassembled sequence. Efforts to finish shotgun-based vertebrate genome assemblies are further complicated by a high amount of species-specific variability regarding mis-assembly and gap characteristics, making it challenging to apply standardized finishing strategies. Some promising approaches for tackling the problem of high-throughput sequence assembly by using a closely related reference genome have been proposed, including gene-boosted assembly and assisted assembly. Further complicating the picture are the error profiles of the various new sequencing technologies and associated platforms. These profiles have not been adequately characterized in the literature, and they appear to be changing with every iteration of a given platform. To the best of our knowledge, there has been only anecdotal evidence on the impact of the resulting error rates on the available assembly tools. The work described below has been motivated by our participation in the USDA/MARS/IBM consortium whose goal is to sequence and analyze the genome of Theobroma cacao with an estimated length of approximately 400 M bases. One of the questions that arose in the context of the project is whether the capabilities of today’s high-throughput sequencing platforms are such that a de novo assembly of T. cacao from short reads is feasible. Short read lengths present formidable challenges for de novo genome assembly because several valid alignments can exist for a given set of very short sequences. In principle, one of those possibilities corresponds to the target genome sequence. The number of alignment possibilities depends on the length of overlap that is required to align the ends of two sequences. There are also limits to the quality of the assembly results that can be achieved: it is not possible to determine the exact size of tandem repeats that are longer than the read length. Also distinguishing between two near-exact copies of the same repeat in different parts of the genome may not be possible, since short reads do not necessarily provide enough sequence context to determine the relative position of the read in the genome. Adding information from paired reads with large insert sizes can potentially assist in determining the correct origin of repeat copies and can also help in scaffolding contigs into longer stretches of ordered sequence. Highly fragmented assemblies with repeat expansions and collapses, and falsely joined sequences can be characteristic of short read assembly results on repeat-rich genomes. Wortmannin clinical trial Clearly, these complications continue to persist even in the presence of high sequencing coverage. As outlined above, there are several challenges and sources of error associated with genome.

Administered N-acetylcysteine reduces the viscosity and purulence of phlegm in COPD patients. CuZn superoxide dismutase is known to be a strong antioxidant, and Tg mice overproducing human CuZn superoxide dismutase do not develop pulmonary inflammation in models of pulmonary emphysema induced by cigarette smoke or elastase. In addition, the antioxidant thioredoxin 1 inhibits elastase-induced emphysema in mice. In the present study, we showed that expression of antioxidant genes such as GST, SOD1, and SOD3 was decreased in the lungs of IL-18 Tg mice. These results suggest that decreased antioxidant activities in the lungs may contribute to pulmonary inflammation and emphysema in the COPD mouse model. Expression of cathepsin S is induced by IFN-c in several cell types, including smooth muscle cells. Increased levels of cathepsin L have been observed in BALF of patients with emphysema, and alveolar macrophages from COPD patient Tubacin 537049-40-4 secrete more cysteine protease than macrophages from smokers without disease, or those from non-smokers. Overexpression of IFN-c in the lungs induces emphysema in mice with increased expression of cathepsins B, D, H, L and S. In the present study, we found that cathepsins S, D, B, Z, L and C were strongly expressed in the lungs of IL-18 Tg mice, and that this was associated with severe emphysematous changes. These results suggest that in Tg mice, overexpression of IL-18 may increase the levels of cathepsins, which may in turn induce the development of emphysematous changes in the lungs. In the present study we found that the levels of mRNA and/or protein for the chitinase-related genes Chi3l1, Chi3l3, and AMCase were strongly increased in the lungs of IL-18 Tg mice, relative to Tg negative littermate mice, suggesting that IL-18 induces the expression of chitinase-related genes in vivo. Previous studies have demonstrated that IL-13 directly induces the expression of Chi3l1 in vivo and Chi3l1 induction by cigarette smoke was found to be partly dependent on the IL-18 pathway. In contrast, IL-18 induction was not significantly modulated in the absence of the Chi3l1 gene, suggesting that Chi3l1 operates downstream of IL-18. A previous study reported that AMCase was greatly induced in lung-specific IL-13 transgenic mice over-expressing mouse IL-13 proteins in the lungs. In contrast, AMCase was not up-regulated relative to WT mice in the IL-13 mouse asthma model. These results suggest that Chi3l3 and AMCase are IL-13-driven chitinase-like proteins. We have reported that IL-18 induces both Th1 and Th2 cytokines, including IL-13 and IFN-c in vivo and in vitro. Moreover, disruption of the IL-13 gene but not the IFN-c gene prevented emphysema and pulmonary inflammation in SPC-IL-18 Tg mice. Therefore, we hypothesized that the expression of Chi3l1 induced by IL-18 is at least partly dependent on the IL-13 pathway in vivo. We established IL-13 SPC-IL-18 Tg mice by backcrossing B6 SPC-IL-18 Tg mice with B6 IL-13 mice. However, IL-13 gene deletion did not significantly reduce the protein level of Chi3l1 in the lungs of IL-18 transgenic mice, suggesting that IL-18 drives the expression of Chi3l1 independently of the IL-13 pathway.