US IOOS coastal and ocean modeling testbed: Inter-model evaluation of tides, waves, and hurricane surge in the Gulf of Mexico

A Gulf of Mexico performance evaluation and comparison of coastal circulation and wave models was executed through harmonic analyses of tidal simulations, hindcasts of Hurricane Ike (2008) and Rita (2005), and a benchmarking study. Three unstructured coastal circulation models (ADCIRC, FVCOM, and SELFE) validated with similar skill on a new common Gulf scale mesh (ULLR) with identical frictional parameterization and forcing for the tidal validation and hurricane hindcasts. Coupled circulation and wave models, SWAN+ADCIRC and WWMII+SELFE, along with FVCOM loosely coupled with SWAN, also validated with similar skill. NOAA\u27s official operational forecast storm surge model (SLOSH) was implemented on local and Gulf scale meshes with the same wind stress and pressure forcing used by the unstructured models for hindcasts of Ike and Rita. SLOSH\u27s local meshes failed to capture regional processes such as Ike\u27s forerunner and the results from the Gulf scale mesh further suggest shortcomings may be due to a combination of poor mesh resolution, missing internal physics such as tides and nonlinear advection, and SLOSH\u27s internal frictional parameterization. In addition, these models were benchmarked to assess and compare execution speed and scalability for a prototypical operational simulation. It was apparent that a higher number of computational cores are needed for the unstructured models to meet similar operational implementation requirements to SLOSH, and that some of them could benefit from improved parallelization and faster execution speed

Identification of novel subgroup a variants with enhanced receptor binding and replicative capacity in primary isolates of anaemogenic strains of feline leukaemia virus

<b>BACKGROUND:</b> The development of anaemia in feline leukaemia virus (FeLV)-infected cats is associated with the emergence of a novel viral subgroup, FeLV-C. FeLV-C arises from the subgroup that is transmitted, FeLV-A, through alterations in the amino acid sequence of the receptor binding domain (RBD) of the envelope glycoprotein that result in a shift in the receptor usage and the cell tropism of the virus. The factors that influence the transition from subgroup A to subgroup C remain unclear, one possibility is that a selective pressure in the host drives the acquisition of mutations in the RBD, creating A/C intermediates with enhanced abilities to interact with the FeLV-C receptor, FLVCR. In order to understand further the emergence of FeLV-C in the infected cat, we examined primary isolates of FeLV-C for evidence of FeLV-A variants that bore mutations consistent with a gradual evolution from FeLV-A to FeLV-C.<p></p> <b>RESULTS:</b> Within each isolate of FeLV-C, we identified variants that were ostensibly subgroup A by nucleic acid sequence comparisons, but which bore mutations in the RBD. One such mutation, N91D, was present in multiple isolates and when engineered into a molecular clone of the prototypic FeLV-A (Glasgow-1), enhanced replication was noted in feline cells. Expression of the N91D Env on murine leukaemia virus (MLV) pseudotypes enhanced viral entry mediated by the FeLV-A receptor THTR1 while soluble FeLV-A Env bearing the N91D mutation bound more efficiently to mouse or guinea pig cells bearing the FeLV-A and -C receptors. Long-term in vitro culture of variants bearing the N91D substitution in the presence of anti-FeLV gp70 antibodies did not result in the emergence of FeLV-C variants, suggesting that additional selective pressures in the infected cat may drive the subsequent evolution from subgroup A to subgroup C.<p></p> <b>CONCLUSIONS:</b> Our data support a model in which variants of FeLV-A, bearing subtle differences in the RBD of Env, may be predisposed towards enhanced replication in vivo and subsequent conversion to FeLV-C. The selection pressures in vivo that drive the emergence of FeLV-C in a proportion of infected cats remain to be established

High-quality habitat and facilitation ameliorate competitive effects of prior residents on new settlers

Many species disperse during their lifetime. Two factors that can affect the performance of individuals following dispersal are the presence of conspecifics and intrinsic habitat quality at the settlement site. Detecting the influence of these factors can be difficult for at least two reasons: (1) the outcomes of interactions with conspecifics are often variable including both competition and facilitation, and (2) selection of high quality habitats often leads to positive covariance between habitat quality and density. In this study, I investigate positive and negative effects of resident blue streak cleaner wrasse (Labroides dimidiatus) on the growth and survival of recently settled conspecifics while accounting for habitat quality. Juvenile L. dimidiatus settle near adult conspecifics, but likely have to compete with resident adults for access to food. However, field experiments indicate that settlers have access to more resources at occupied sites, and as a result, grow faster despite evidence for competition with residents. This result is a direct consequence of two factors: (1) resident conspecifics facilitate settlers by attracting client fish, and (2) resident conspecifics are strongly associated with high quality habitat. These results highlight the need to simultaneously consider habitat quality and competitive and facilitative interactions between conspecifics when making inferences about ecological processes from spatial patterns of individual performance

Length of patient-physician relationship and patients' satisfaction and preventive service use in the rural south: a cross-sectional telephone study

BACKGROUND: Physicians and patients highly value continuity in health care. Continuity can be measured in several ways but few studies have examined the specific association between the duration of the patient-doctor relationship and patient outcomes. This study (1) examines characteristics of rural adults who have had longer relationships with their physicians and (2) assesses if the length of relationship is associated with patients' satisfaction and likelihood of receiving recommended preventive services. METHODS: Cross-sectional telephone survey of health care access indicators of adults in selected non-metropolitan counties of eight U.S. predominantly southern states. Analyses were restricted to adults who see a particular physician for their care and weighted for demographics and county sampling probabilities. RESULTS: Of 3176 eligible respondents, 10.8% saw the same physician for the past 12 months, 11.8% for the previous 13–24 months, 20.7% for the past 25–60 months and 56.7% for more than 60 months. Compared to persons with one year or less continuity with the same physician, respondents with over five years continuity more often were Caucasian, insured, a high school graduate, and more often reported good to excellent health and an income above $25,000. Compared to those with more than five years of continuity, participants with either less than one year or one to two years of continuity with the same physician were more often not satisfied with their overall health care (OR 2.34; OR 1.78), participants with less than one year continuity were more often not satisfied with the concern shown them by their physician (O.R. 1.90) and having their health questions answered, and those with one to two years continuity were more often not satisfied with the quality of their care (OR 2.37). No significant associations were found between physician continuity and use rates of any of the queried preventive services. CONCLUSION: Over half of this rural population has seen the same physician for more than five years. Longer continuity of care was associated with greater patient satisfaction and confidence in one's physician, but not with a greater likelihood of receiving recommended preventive services

SMAD4 - Molecular gladiator of the TGF-β signaling is trampled upon by mutational insufficiency in colorectal carcinoma of Kashmiri population: an analysis with relation to KRAS proto-oncogene

<p>Abstract</p> <p>Background</p> <p>The development and progression of colorectal cancer has been extensively studied and the genes responsible have been well characterized. However the correlation between the <it>SMAD4 </it>gene mutations with <it>KRAS </it>mutant status has not been explored by many studies so far. Here, in this study we aimed to investigate the role of <it>SMAD4 </it>gene aberrations in the pathogenesis of CRC in Kashmir valley and to correlate it with various clinicopathological variables and <it>KRAS </it>mutant genotype.</p> <p>Methods</p> <p>We examined the paired tumor and normal tissue specimens of 86 CRC patients for the occurrence of aberrations in MCR region of <it>SMAD4 </it>and exon 1 of <it>KRAS </it>by PCR-SSCP and/or PCR-Direct sequencing.</p> <p>Results</p> <p>The overall mutation rate of mutation cluster region (MCR) region of <it>SMAD4 </it>gene among 86 patients was 18.6% (16 of 86). 68.75% (11/16) of the <it>SMAD4 </it>gene mutants were found to have mutations in <it>KRAS </it>gene as well. The association between the <it>KRAS </it>mutant genotype with <it>SMAD4 </it>mutants was found to be significant (P =< 0.05). Further more, we found a significant association of tumor location, tumor grade, node status, occupational exposure to pesticides and bleeding PR/Constipation with the mutation status of the <it>SMAD4 </it>gene (P =< 0.05).</p> <p>Conclusion</p> <p>Our study suggests that <it>SMAD4 </it>gene aberrations are the common event in CRC development but play a differential role in the progression of CRC in higher tumor grade (C+D) and its association with the <it>KRAS </it>mutant status suggest that these two molecules together are responsible for the progression of the tumor to higher/advanced stage.</p

The immune system and the impact of zinc during aging

The trace element zinc is essential for the immune system, and zinc deficiency affects multiple aspects of innate and adaptive immunity. There are remarkable parallels in the immunological changes during aging and zinc deficiency, including a reduction in the activity of the thymus and thymic hormones, a shift of the T helper cell balance toward T helper type 2 cells, decreased response to vaccination, and impaired functions of innate immune cells. Many studies confirm a decline of zinc levels with age. Most of these studies do not classify the majority of elderly as zinc deficient, but even marginal zinc deprivation can affect immune function. Consequently, oral zinc supplementation demonstrates the potential to improve immunity and efficiently downregulates chronic inflammatory responses in the elderly. These data indicate that a wide prevalence of marginal zinc deficiency in elderly people may contribute to immunosenescence

Differentiated neuroprogenitor cells incubated with human or canine adenovirus, or lentiviral vectors have distinct transcriptome profiles

Several studies have demonstrated the potential for vector-mediated gene transfer to the brain. Helper-dependent (HD) human (HAd) and canine (CAV-2) adenovirus, and VSV-G-pseudotyped self-inactivating HIV-1 vectors (LV) effectively transduce human brain cells and their toxicity has been partly analysed. However, their effect on the brain homeostasis is far from fully defined, especially because of the complexity of the central nervous system (CNS). With the goal of dissecting the toxicogenomic signatures of the three vectors for human neurons, we transduced a bona fide human neuronal system with HD-HAd, HD-CAV-2 and LV. We analysed the transcriptional response of more than 47,000 transcripts using gene chips. Chip data showed that HD-CAV-2 and LV vectors activated the innate arm of the immune response, including Toll-like receptors and hyaluronan circuits. LV vector also induced an IFN response. Moreover, HD-CAV-2 and LV vectors affected DNA damage pathways - but in opposite directions - suggesting a differential response of the p53 and ATM pathways to the vector genomes. As a general response to the vectors, human neurons activated pro-survival genes and neuron morphogenesis, presumably with the goal of re-establishing homeostasis. These data are complementary to in vivo studies on brain vector toxicity and allow a better understanding of the impact of viral vectors on human neurons, and mechanistic approaches to improve the therapeutic impact of brain-directed gene transfer

Curcumin-induced HDAC inhibition and attenuation of medulloblastoma growth in vitro and in vivo

<p>Abstract</p> <p>Background</p> <p>Medulloblastoma is the most common brain tumor in children, and its prognosis is worse than for many other common pediatric cancers. Survivors undergoing treatment suffer from serious therapy-related side effects. Thus, it is imperative to identify safer, effective treatments for medulloblastoma. In this study we evaluated the anti-cancer potential of curcumin in medulloblastoma by testing its ability to induce apoptosis and inhibit tumor growth <it>in vitro </it>and <it>in vivo </it>using established medulloblastoma models.</p> <p>Methods</p> <p>Using cultured medulloblastoma cells, tumor xenografts, and the Smo/Smo transgenic medulloblastoma mouse model, the antitumor effects of curcumin were tested <it>in vitro </it>and <it>in vivo</it>.</p> <p>Results</p> <p>Curcumin induced apoptosis and cell cycle arrest at the G2/M phase in medulloblastoma cells. These effects were accompanied by reduced histone deacetylase (HDAC) 4 expression and activity and increased tubulin acetylation, ultimately leading to mitotic catastrophe. In <it>in vivo </it>medulloblastoma xenografts, curcumin reduced tumor growth and significantly increased survival in the Smo/Smo transgenic medulloblastoma mouse model.</p> <p>Conclusions</p> <p>The <it>in vitro </it>and <it>in vivo </it>data suggest that curcumin has the potential to be developed as a therapeutic agent for medulloblastoma.</p

The imperative for controlled mechanical stresses in unraveling cellular mechanisms of mechanotransduction

BACKGROUND: In vitro mechanotransduction studies are designed to elucidate cell behavior in response to a well-defined mechanical signal that is imparted to cultured cells, e.g. through fluid flow. Typically, flow rates are calculated based on a parallel plate flow assumption, to achieve a targeted cellular shear stress. This study evaluates the performance of specific flow/perfusion chambers in imparting the targeted stress at the cellular level. METHODS: To evaluate how well actual flow chambers meet their target stresses (set for 1 and 10 dyn/cm(2 )for this study) at a cellular level, computational models were developed to calculate flow velocity components and imparted shear stresses for a given pressure gradient. Computational predictions were validated with micro-particle image velocimetry (μPIV) experiments. RESULTS: Based on these computational and experimental studies, as few as 66% of cells seeded along the midplane of commonly implemented flow/perfusion chambers are subjected to stresses within ±10% of the target stress. In addition, flow velocities and shear stresses imparted through fluid drag vary as a function of location within each chamber. Hence, not only a limited number of cells are exposed to target stress levels within each chamber, but also neighboring cells may experience different flow regimes. Finally, flow regimes are highly dependent on flow chamber geometry, resulting in significant variation in magnitudes and spatial distributions of stress between chambers. CONCLUSION: The results of this study challenge the basic premise of in vitro mechanotransduction studies, i.e. that a controlled flow regime is applied to impart a defined mechanical stimulus to cells. These results also underscore the fact that data from studies in which different chambers are utilized can not be compared, even if the target stress regimes are comparable

MAL2 and tumor protein D52 (TPD52) are frequently overexpressed in ovarian carcinoma, but differentially associated with histological subtype and patient outcome

Background: The four-transmembrane MAL2 protein is frequently overexpressed in breast carcinoma, and MAL2 overexpression is associated with gain of the corresponding locus at chromosome 8q24.12. Independent expression microarray studies predict MAL2 overexpression in ovarian carcinoma, but these had remained unconfirmed. MAL2 binds tumor protein D52 (TPD52), which is frequently overexpressed in ovarian carcinoma, but the clinical significance of MAL2 and TPD52 overexpression was unknown. Methods: Immunohistochemical analyses of MAL2 and TPD52 expression were performed using tissue microarray sections including benign, borderline and malignant epithelial ovarian tumours. Inmmunohistochemical staining intensity and distribution was assessed both visually and digitally. Results: MAL2 and TPD52 were significantly overexpressed in high-grade serous carcinomas compared with serous borderline tumours. MAL2 expression was highest in serous carcinomas relative to other histological subtypes, whereas TPD52 expression was highest in clear cell carcinomas. MAL2 expression was not related to patient survival, however high-level TPD52 staining was significantly associated with improved overall survival in patients with stage III serous ovarian carcinoma (log-rank test, p < 0.001; n = 124) and was an independent predictor of survival in the overall carcinoma cohort (hazard ratio (HR), 0.498; 95% confidence interval (CI), 0.34-0.728; p < 0.001; n = 221), and in serous carcinomas (HR, 0.440; 95% CI, 0.294-0.658; p < 0.001; n = 182). Conclusions: MAL2 is frequently overexpressed in ovarian carcinoma, and TPD52 overexpression is a favourable independent prognostic marker of potential value in the management of ovarian carcinoma patients.11 page(s