Patterns and flow in frictional fluid dynamics

Pattern-forming processes in simple fluids and suspensions have been studied extensively, and the basic displacement structures, similar to viscous fingers and fractals in capillary dominated flows, have been identified. However, the fundamental displacement morphologies in frictional fluids and granular mixtures have not been mapped out. Here we consider Coulomb friction and compressibility in the fluid dynamics, and discover surprising responses including highly intermittent flow and a transition to quasi-continuodynamics. Moreover, by varying the injection rate over several orders of magnitude, we characterize new dynamic modes ranging from stick-slip bubbles at low rate to destabilized viscous fingers at high rate. We classify the fluid dynamics into frictional and viscous regimes, and present a unified description of emerging morphologies in granular mixtures in the form of extended phase diagrams

The responses of cancer cells to PLK1 inhibitors reveal a novel protective role for p53 in maintaining centrosome separation

Polo-like kinase-1 (PLK1) plays a major role in driving mitotic events, including centrosome disjunction and separation, and is frequently over-expressed in human cancers. PLK1 inhibition is a promising therapeutic strategy and works by arresting cells in mitosis due to monopolar spindles. The p53 tumour suppressor protein is a short-lived transcription factor that can inhibit the growth, or stimulate the death, of developing cancer cells. Curiously, although p53 normally acts in an anti-cancer capacity, it can offer significant protection against inhibitors of PLK1, but the events underpinning this effect are not known. Here, we show that functional p53 reduces the sensitivity to PLK1 inhibitors by permitting centrosome separation to occur, allowing cells to traverse mitosis and re-enter cycle with a normal complement of 2N chromosomes. Protection entails the activation of p53 through the DNA damage-response enzymes, ATM and ATR, and requires the phosphorylation of p53 at the key regulatory site, Ser15. These data highlight a previously unrecognised link between p53, PLK1 and centrosome separation that has therapeutic implications for the use of PLK1 inhibitors in the clinic

The impact of disease progression on perceived health status and quality of life of long-term cancer survivors

Introduction The number of cancer survivors experiencing disease progression (DP) is increasing with the number of cancer survivors. However, little is known whether DP affects health-related quality of life (HRQL) of long-term cancer survivors. We aimed therefore to compare the health status (HS) and HRQL of DP and disease-free (DF) survivors up to 15 years after initial diagnosis. Methods 232 cancer survivors with DP identified through the Eindhoven Cancer Registry were matched with 232 DF survivors of similar demographic and clinical characteristics. Patients completed generic HS (SF-36) and cancer-specific HRQL (QOL-CS) questionnaires 5-15 years after diagnosis. Results Compared with DF survivors, DP survivors exhibited significantly lower scores on all SF-36 and QOL-CS (except spiritual well-being) dimensions. DF survivors had better scores than the normative population on all SF-36 dimensions. Among survivors with DP, those with short survival (<5 years) had significantly poorer HS scores on all dimensions except bodily pain compared with the normative population. Comparatively, the long survival (≥5 years) DP group had better HRQL than the short DP group but poorer HRQL than the normative population. In multivariate analyses, DP and DF survival time were independently associated with aspects of HS and HRQL in cancer survivors. Discussions/Conclusions DP cancer survivors have poorer long-term HS and HRQL compared with DF survivors. However, there is suggestion that HS and HRQL does improve over time following DP. Implication for Cancer Survivors Although DP survivors report poorer long-term HRQL compared with DF cancer survivors, results suggest that time can attenuate the distress of DP on HRQL. Psycho-educational programs could help to increase patients' sense of empowerment and personal control should DP occur

Physician practices related to use of BMI-for-age and counseling for childhood obesity prevention: A cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Screening for obesity and providing appropriate obesity-related counseling in the clinical setting are important strategies to prevent and control childhood obesity. The purpose of this study is to document pediatricians (PEDs) and general practitioners (GPs) with pediatric patients use of BMI-for-age to screen for obesity, confidence in explaining BMI, access to referral clinics, and characteristics associated with screening and counseling to children and their caregivers.</p> <p>Methods</p> <p>The authors used 2008 DocStyles survey data to examine these practices at every well child visit for children aged two years and older. Counseling topics included: physical activity, TV viewing time, energy dense foods, fruits and vegetables, and sugar-sweetened beverages. Chi-square tests were used to examine differences in proportions and logistic regression to identify characteristics associated with screening and counseling.</p> <p>Results</p> <p>The final analytic sample included 250 PEDs and 621 GPs. Prevalence of using BMI-for-age to screen for obesity at every well child visit was higher for PEDs than GPs (50% vs. 22%, χ2 = 67.0, p ≤ 0.01); more PEDs reported being very/somewhat confident in explaining BMI (94% vs. GPs, 87%, p < 0.01); more PEDs reported access to a pediatric obesity specialty clinic for referral (PEDs = 65% vs. GPs = 42%, χ2 = 37.5, p ≤ 0.0001).</p> <p>In general, PEDs reported higher counseling prevalence than GPs. There were significant differences in the following topics: TV viewing (PEDs, 79% vs. GPs, 61%, χ2 = 19.1, p ≤ 0.0001); fruit and vegetable consumption (PEDs, 87% vs. GPs, 78%, χ2 = 6.4, p ≤ 0.01). The only characteristics associated with use of BMI for GPs were being female (OR = 2.3, 95% CI = 1.5-3.5) and serving mostly non-white patients (OR = 1.8, 95% CI = 1.1-2.9); there were no significant associations for PEDs.</p> <p>Conclusions</p> <p>The findings for use of BMI-for-age, counseling habits, and access to a pediatric obesity specialty clinic leave room for improvement. More research is needed to better understand why BMI-for-age is not being used to screen at every well child visit, which may increase the likelihood overweight and obese patients receive counseling and referrals for additional services. The authors also suggest more communication between PEDs and GPs through professional organizations to increase awareness of existing resources, and to enhance access and referral to pediatric obesity specialty clinics.</p

The evolution and appearance of c3 duplications in fish originate an exclusive teleost c3 gene form with anti- inflammatory activity

12 páginas, 6 figuras, 3 tablas.-- This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedThe complement system acts as a first line of defense and promotes organism homeostasis by modulating the fates of diverse physiological processes. Multiple copies of component genes have been previously identified in fish, suggesting a key role for this system in aquatic organisms. Herein, we confirm the presence of three different previously reported complement c3 genes (c3.1, c3.2, c3.3) and identify five additional c3 genes (c3.4, c3.5, c3.6, c3.7, c3.8) in the zebrafish genome. Additionally, we evaluate the mRNA expression levels of the different c3 genes during ontogeny and in different tissues under steady-state and inflammatory conditions. Furthermore, while reconciling the phylogenetic tree with the fish species tree, we uncovered an event of c3 duplication common to all teleost fishes that gave rise to an exclusive c3 paralog (c3.7 and c3.8). These paralogs showed a distinct ability to regulate neutrophil migration in response to injury compared with the other c3 genes and may play a role in maintaining the balance between inflammatory and homeostatic processes in zebrafishThis work has been funded by the project CSD2007-00002 “Aquagenomics” from the Spanish Ministerio de Ciencia e Innovación, the ITN 289209 “FISHFORPHARMA” (EU) and project 201230E057 from the Agencia Estatal Consejo Superior de Investigaciones Científicas (CSIC).Peer reviewe

Biological effects of naturally occurring and man-made fibres: in vitro cytotoxicity and mutagenesis in mammalian cells

Cytotoxicity and mutagenicity of tremolite, erionite and the man-made ceramic (RCF-1) fibre were studied using the human– hamster hybrid A L cells. Results from these fibres were compared with those of UICC Rhodesian chrysotile fibres. The A L cell mutation assay, based on the S1 gene marker located on human chromosome 11, the only human chromosome contained in the hybrid cell, has been shown to be more sensitive than conventional assays in detecting deletion mutations. Tremolite, erionite and RCF-1 fibres were significantly less cytotoxic to A L cells than chrysotile. Mutagenesis studies at the HPRT locus revealed no significant mutant yield with any of these fibres. In contrast, both erionite and tremolite induced dose-dependent S1− mutations in fibre-exposed cells, with the former inducing a significantly higher mutant yield than the latter fibre type. On the other hand, RCF-1 fibres were largely non-mutagenic. At equitoxic doses (cell survival at ∼ 0.7), erionite was found to be the most potent mutagen among the three fibres tested and at a level comparable to that of chrysotile fibres. These results indicate that RCF-1 fibres are non-genotoxic under the conditions used in the studies and suggest that the high mesothelioma incidence previously observed in hamster may either be a result of selective sensitivity of hamster pleura to fibre-induced chronic irritation or as a result of prolonged fibre treatment. Furthermore, the relatively high mutagenic potential for erionite is consistent with its documented carcinogenicity. © 1999 Cancer Research Campaig

Mitochondrial 2,4-dienoyl-CoA Reductase Deficiency in Mice Results in Severe Hypoglycemia with Stress Intolerance and Unimpaired Ketogenesis

The mitochondrial β-oxidation system is one of the central metabolic pathways of energy metabolism in mammals. Enzyme defects in this pathway cause fatty acid oxidation disorders. To elucidate the role of 2,4-dienoyl-CoA reductase (DECR) as an auxiliary enzyme in the mitochondrial β-oxidation of unsaturated fatty acids, we created a DECR–deficient mouse line. In Decr−/− mice, the mitochondrial β-oxidation of unsaturated fatty acids with double bonds is expected to halt at the level of trans-2, cis/trans-4-dienoyl-CoA intermediates. In line with this expectation, fasted Decr−/− mice displayed increased serum acylcarnitines, especially decadienoylcarnitine, a product of the incomplete oxidation of linoleic acid (C18:2), urinary excretion of unsaturated dicarboxylic acids, and hepatic steatosis, wherein unsaturated fatty acids accumulate in liver triacylglycerols. Metabolically challenged Decr−/− mice turned on ketogenesis, but unexpectedly developed hypoglycemia. Induced expression of peroxisomal β-oxidation and microsomal ω-oxidation enzymes reflect the increased lipid load, whereas reduced mRNA levels of PGC-1α and CREB, as well as enzymes in the gluconeogenetic pathway, can contribute to stress-induced hypoglycemia. Furthermore, the thermogenic response was perturbed, as demonstrated by intolerance to acute cold exposure. This study highlights the necessity of DECR and the breakdown of unsaturated fatty acids in the transition of intermediary metabolism from the fed to the fasted state

Cohort differences in disease and disability in the young-old: findings from the MRC Cognitive Function and Ageing Study (MRC-CFAS)

© 2007 Jagger et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Investigating Bacterial Sources of Toxicity as an Environmental Contributor to Dopaminergic Neurodegeneration

Parkinson disease (PD) involves progressive neurodegeneration, including loss of dopamine (DA) neurons from the substantia nigra. Select genes associated with rare familial forms of PD function in cellular pathways, such as the ubiquitin-proteasome system (UPS), involved in protein degradation. The misfolding and accumulation of proteins, such as α-synuclein, into inclusions termed Lewy Bodies represents a clinical hallmark of PD. Given the predominance of sporadic PD among patient populations, environmental toxins may induce the disease, although their nature is largely unknown. Thus, an unmet challenge surrounds the discovery of causal or contributory neurotoxic factors that could account for the prevalence of sporadic PD. Bacteria within the order Actinomycetales are renowned for their robust production of secondary metabolites and might represent unidentified sources of environmental exposures. Among these, the aerobic genera, Streptomyces, produce natural proteasome inhibitors that block protein degradation and may potentially damage DA neurons. Here we demonstrate that a metabolite produced by a common soil bacterium, S. venezuelae, caused DA neurodegeneration in the nematode, Caenorhabditis elegans, which increased as animals aged. This metabolite, which disrupts UPS function, caused gradual degeneration of all neuronal classes examined, however DA neurons were particularly vulnerable to exposure. The presence of DA exacerbated toxicity because neurodegeneration was attenuated in mutant nematodes depleted for tyrosine hydroxylase (TH), the rate-limiting enzyme in DA production. Strikingly, this factor caused dose-dependent death of human SH-SY5Y neuroblastoma cells, a dopaminergic line. Efforts to purify the toxic activity revealed that it is a highly stable, lipophilic, and chemically unique small molecule. Evidence of a robust neurotoxic factor that selectively impacts neuronal survival in a progressive yet moderate manner is consistent with the etiology of age-associated neurodegenerative diseases. Collectively, these data suggest the potential for exposures to the metabolites of specific common soil bacteria to possibly represent a contributory environmental component to PD