Metastability of native proteins and the phenomenon of amyloid formation

An experimental determination of the thermodynamic stabilities of a series of amyloid fibrils reveals that this structural form is likely to be the most stable one that protein molecules can adopt even under physiological conditions. This result challenges the conventional assumption that functional forms of proteins correspond to the global minima in their free energy surfaces and suggests that living systems are conformationally as well as chemically metastable. © 2011 American Chemical Society

Dynamical chiral symmetry breaking and confinement with an infrared-vanishing gluon propagator?

We study a model Dyson-Schwinger equation for the quark propagator closed using an {\it Ansatz} for the gluon propagator of the form \mbox{$D(q) \sim q^2/[(q^2)^2 + b^4]$} and two {\it Ans\"{a}tze} for the quark-gluon vertex: the minimal Ball-Chiu and the modified form suggested by Curtis and Pennington. Using the quark condensate as an order parameter, we find that there is a critical value of $b=b_c$ such that the model does not support dynamical chiral symmetry breaking for $b>b_c$. We discuss and apply a confinement test which suggests that, for all values of $b$, the quark propagator in the model {\bf is not} confining. Together these results suggest that this Ansatz for the gluon propagator is inadequate as a model since it does not yield the expected behaviour of QCD.Comment: 21 Pages including 4 PostScript figures uuencoded at the end of the file. Replacement: slight changes of wording and emphasis. ADP-93-215/T133, ANL-PHY-7599-TH-93, FSU-SCRI-93-108, REVTEX 3.

Haptoglobin Phenotype, Preeclampsia Risk and the Efficacy of Vitamin C and E Supplementation to Prevent Preeclampsia in a Racially Diverse Population

Haptoglobin's (Hp) antioxidant and pro-angiogenic properties differ between the 1-1, 2-1, and 2-2 phenotypes. Hp phenotype affects cardiovascular disease risk and treatment response to antioxidant vitamins in some non-pregnant populations. We previously demonstrated that preeclampsia risk was doubled in white Hp 2-1 women, compared to Hp 1-1 women. Our objectives were to determine whether we could reproduce this finding in a larger cohort, and to determine whether Hp phenotype influences lack of efficacy of antioxidant vitamins in preventing preeclampsia and serious complications of pregnancy-associated hypertension (PAH). This is a secondary analysis of a randomized controlled trial in which 10,154 low-risk women received daily vitamin C and E, or placebo, from 9-16 weeks gestation until delivery. Hp phenotype was determined in the study prediction cohort (n = 2,393) and a case-control cohort (703 cases, 1,406 controls). The primary outcome was severe PAH, or mild or severe PAH with elevated liver enzymes, elevated serum creatinine, thrombocytopenia, eclampsia, fetal growth restriction, medically indicated preterm birth or perinatal death. Preeclampsia was a secondary outcome. Odds ratios were estimated by logistic regression. Sampling weights were used to reduce bias from an overrepresentation of women with preeclampsia or the primary outcome. There was no relationship between Hp phenotype and the primary outcome or preeclampsia in Hispanic, white/other or black women. Vitamin supplementation did not reduce the risk of the primary outcome or preeclampsia in women of any phenotype. Supplementation increased preeclampsia risk (odds ratio 3.30; 95% confidence interval 1.61-6.82, p<0.01) in Hispanic Hp 2-2 women. Hp phenotype does not influence preeclampsia risk, or identify a subset of women who may benefit from vitamin C and E supplementation to prevent preeclampsia

The QUaD Galactic Plane Survey. I. Maps and Analysis of Diffuse Emission

We present a survey of ~800 deg$^{2}$ of the galactic plane observed with the QUaD telescope. The primary products of the survey are maps of Stokes I, Q, and U parameters at 100 and 150 GHz, with spatial resolution of 5' and 3'.5, respectively. Two regions are covered, spanning approximately 245°-295° and 315°-5° in the galactic longitude l and –4° < b < +4° in the galactic latitude b. At 0°.02 square pixel size, the median sensitivity is 74 and 107 kJy sr$^{–1}$ at 100 GHz and 150 GHz respectively in I, and 98 and 120 kJy sr$^{–1}$ for Q and U. In total intensity, we find an average spectral index of α = 2.35 ± 0.01(stat) ± 0.02(sys) for |b| ≤ 1°, indicative of emission components other than thermal dust. A comparison to published dust, synchrotron, and free-free models implies an excess of emission in the 100 GHz QUaD band, while better agreement is found at 150 GHz. A smaller excess is observed when comparing QUaD 100 GHz data to the WMAP five-year W band; in this case, the excess is likely due to the wider bandwidth of QUaD. Combining the QUaD and WMAP data, a two-component spectral fit to the inner galactic plane (|b| ≤ 1°) yields mean spectral indices of α s = –0.32 ± 0.03 and α$_{d}$ = 2.84 ± 0.03; the former is interpreted as a combination of the spectral indices of synchrotron, free-free, and dust, while the second is largely attributed to the thermal dust continuum. In the same galactic latitude range, the polarization data show a high degree of alignment perpendicular to the expected galactic magnetic field direction, and exhibit mean polarization fraction 1.38 ± 0.08(stat) ± 0.1(sys)% at 100 GHz and 1.70 ± 0.06(stat) ± 0.1(sys)% at 150 GHz. We find agreement in polarization fraction between QUaD 100 GHz and the WMAP W band, the latter giving 1.1% ± 0.4%.Astronom

Parameter Estimation From Improved Measurements of the Cosmic Microwave Background From QUaD

We evaluate the contribution of cosmic microwave background (CMB) polarization spectra to cosmological parameter constraints. We produce cosmological parameters using high-quality CMB polarization data from the ground-based QUaD experiment and demonstrate for the majority of parameters that there is significant improvement on the constraints obtained from satellite CMB polarization data. We split a multi-experiment CMB data set into temperature and polarization subsets and show that the best-fit confidence regions for the ΛCDM six-parameter cosmological model are consistent with each other, and that polarization data reduces the confidence regions on all parameters. We provide the best limits on parameters from QUaD EE/BB polarization data and we find best-fit parameters from the multi-experiment CMB data set using the optimal pivot scale of k$_{p}$ = 0.013 Mpc$^{–1}$ to be {h$^{2}$Ω$_{c}$, h$^{2}$Ω$_{b}$, H$_{0}$, A$_{s}$, n$_{s}$, τ} = {0.113, 0.0224, 70.6, 2.29 × 10$^{-9}$, 0.960, 0.086}.Astronom

Does the mind map learning strategy facilitate information retrieval and critical thinking in medical students?

<p>Abstract</p> <p>Background</p> <p>A learning strategy underutilized in medical education is mind mapping. Mind maps are multi-sensory tools that may help medical students organize, integrate, and retain information. Recent work suggests that using mind mapping as a note-taking strategy facilitates critical thinking. The purpose of this study was to investigate whether a relationship existed between mind mapping and critical thinking, as measured by the Health Sciences Reasoning Test (HSRT), and whether a relationship existed between mind mapping and recall of domain-based information.</p> <p>Methods</p> <p>In this quasi-experimental study, 131 first-year medical students were randomly assigned to a standard note-taking (SNT) group or mind map (MM) group during orientation. Subjects were given a demographic survey and pre-HSRT. They were then given an unfamiliar text passage, a pre-quiz based upon the passage, and a 30-minute break, during which time subjects in the MM group were given a presentation on mind mapping. After the break, subjects were given the same passage and wrote notes based on their group (SNT or MM) assignment. A post-quiz based upon the passage was administered, followed by a post-HSRT. Differences in mean pre- and post-quiz scores between groups were analyzed using independent samples <it>t</it>-tests, whereas differences in mean pre- and post-HSRT total scores and subscores between groups were analyzed using ANOVA. Mind map depth was assessed using the Mind Map Assessment Rubric (MMAR).</p> <p>Results</p> <p>There were no significant differences in mean scores on both the pre- and post-quizzes between note-taking groups. And, no significant differences were found between pre- and post-HSRT mean total scores and subscores.</p> <p>Conclusions</p> <p>Although mind mapping was not found to increase short-term recall of domain-based information or critical thinking compared to SNT, a brief introduction to mind mapping allowed novice MM subjects to perform similarly to SNT subjects. This demonstrates that medical students using mind maps can successfully retrieve information in the short term, and does not put them at a disadvantage compared to SNT students. Future studies should explore longitudinal effects of mind-map proficiency training on both short- and long-term information retrieval and critical thinking.</p

A Commensal Helicobacter sp. of the Rodent Intestinal Flora Activates TLR2 and NOD1 Responses in Epithelial Cells

Helicobacter spp. represent a proportionately small but significant component of the normal intestinal microflora of animal hosts. Several of these intestinal Helicobacter spp. are known to induce colitis in mouse models, yet the mechanisms by which these bacteria induce intestinal inflammation are poorly understood. To address this question, we performed in vitro co-culture experiments with mouse and human epithelial cell lines stimulated with a selection of Helicobacter spp., including known pathogenic species as well as ones for which the pathogenic potential is less clear. Strikingly, a member of the normal microflora of rodents, Helicobacter muridarum, was found to be a particularly strong inducer of CXC chemokine (Cxcl1/KC, Cxcl2/MIP-2) responses in a murine intestinal epithelial cell line. Time-course studies revealed a biphasic pattern of chemokine responses in these cells, with H. muridarum lipopolysaccharide (LPS) mediating early (24–48 h) responses and live bacteria seeming to provoke later (48–72 h) responses. H. muridarum LPS per se was shown to induce CXC chemokine production in HEK293 cells stably expressing Toll-like receptor 2 (TLR2), but not in those expressing TLR4. In contrast, live H. muridarum bacteria were able to induce NF-κB reporter activity and CXC chemokine responses in TLR2–deficient HEK293 and in AGS epithelial cells. These responses were attenuated by transient transfection with a dominant negative construct to NOD1, and by stable expression of NOD1 siRNA, respectively. Thus, the data suggest that both TLR2 and NOD1 may be involved in innate immune sensing of H. muridarum by epithelial cells. This work identifies H. muridarum as a commensal bacterium with pathogenic potential and underscores the potential roles of ill-defined members of the normal flora in the initiation of inflammation in animal hosts. We suggest that H. muridarum may act as a confounding factor in colitis model studies in rodents

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection

How Past and Present Influence the Foraging of Clonal Plants?

Clonal plants spreading horizontally and forming a network structure of ramets exhibit complex growth patterns to maximize resource uptake from the environment. They respond to spatial heterogeneity by changing their internode length or branching frequency. Ramets definitively root in the soil but stay interconnected for a varying period of time thus allowing an exchange of spatial and temporal information. We quantified the foraging response of clonal plants depending on the local soil quality sampled by the rooting ramet (i.e. the present information) and the resource variability sampled by the older ramets (i.e. the past information). We demonstrated that two related species, Potentilla reptans and P. anserina, responded similarly to the local quality of their environment by decreasing their internode length in response to nutrient-rich soil. Only P. reptans responded to resource variability by decreasing its internode length. In both species, the experience acquired by older ramets influenced the plastic response of new rooted ramets: the internode length between ramets depended not only on the soil quality locally sampled but also on the soil quality previously sampled by older ramets. We quantified the effect of the information perceived at different time and space on the foraging behavior of clonal plants by showing a non-linear response of the ramet rooting in the soil of a given quality. These data suggest that the decision to grow a stolon or to root a ramet at a given distance from the older ramet results from the integration of the past and present information about the richness and the variability of the environment

Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials