Structure-mechanics relationships of collagen fibrils in the Osteogenesis Imperfecta Mouse model

The collagen molecule, which is the building block of collagen fibrils, is a triple helix of two α1(I) chains and one α2(I) chain. However, in the severe mouse model of osteogenesis imperfecta (OIM), deletion of the COL1A2 gene results in the substitution of the α2(I) chain by one α1(I) chain. As this substitution severely impairs the structure and mechanics of collagen-rich tissues at the tissue and organ level, the main aim of this study was to investigate how the structure and mechanics are altered in OIM collagen fibrils. Comparing results from atomic force microscopy imaging and cantilever-based nanoindentation on collagen fibrils from OIM and wild-type (WT) animals, we found a 33% lower indentation modulus in OIM when air-dried (bound water present) and an almost fivefold higher indentation modulus in OIM collagen fibrils when fully hydrated (bound and unbound water present) in phosphate-buffered saline solution (PBS) compared with WT collagen fibrils. These mechanical changes were accompanied by an impaired swelling upon hydration within PBS. Our experimental and atomistic simulation results show how the structure and mechanics are altered at the individual collagen fibril level as a result of collagen gene mutation in OIM. We envisage that the combination of experimental and modelling approaches could allow mechanical phenotyping at the collagen fibril level of virtually any alteration of collagen structure or chemistry.United States. Dept. of Defense. Presidential Early Career Award for Scientists and EngineersNational Science Foundation (U.S.) (CAREER Award

Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders.

Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically

The holographic principle

There is strong evidence that the area of any surface limits the information content of adjacent spacetime regions, at 10^(69) bits per square meter. We review the developments that have led to the recognition of this entropy bound, placing special emphasis on the quantum properties of black holes. The construction of light-sheets, which associate relevant spacetime regions to any given surface, is discussed in detail. We explain how the bound is tested and demonstrate its validity in a wide range of examples. A universal relation between geometry and information is thus uncovered. It has yet to be explained. The holographic principle asserts that its origin must lie in the number of fundamental degrees of freedom involved in a unified description of spacetime and matter. It must be manifest in an underlying quantum theory of gravity. We survey some successes and challenges in implementing the holographic principle.Comment: 52 pages, 10 figures, invited review for Rev. Mod. Phys; v2: reference adde

Preliminary Limits on the WIMP-Nucleon Cross Section from the Cryogenic Dark Matter Search (CDMS)

We are conducting an experiment to search for WIMPs, or weakly-interacting massive particles, in the galactic halo using terrestrial detectors. This generic class of hypothetical particles, whose properties are similar to those predicted by extensions of the standard model of particle physics, could comprise the cold component of non-baryonic dark matter. We describe our experiment, which is based on cooled germanium and silicon detectors in a shielded low-background cryostat. The detectors achieve a high degree of background rejection through the simultaneous measurement of the energy in phonons and ionization. Using exposures on the order of one kilogram-day from initial runs of our experiment, we have achieved (preliminary) upper limits on the WIMP-nucleon cross section that are comparable to much longer runs of other experiments.Comment: 5 LaTex pages, 5 eps figs, epsf.sty, espcrc2dsa2.sty. Proceedings of TAUP97, Gran Sasso, Italy, 7-11 Sep 1997, Nucl. Phys. Suppl., A. Bottino, A. di Credico and P. Monacelli (eds.). See also http://cfpa.berkeley.ed

Optimising use of electronic health records to describe the presentation of rheumatoid arthritis in primary care: a strategy for developing code lists

Background Research using electronic health records (EHRs) relies heavily on coded clinical data. Due to variation in coding practices, it can be difficult to aggregate the codes for a condition in order to define cases. This paper describes a methodology to develop ‘indicator markers’ found in patients with early rheumatoid arthritis (RA); these are a broader range of codes which may allow a probabilistic case definition to use in cases where no diagnostic code is yet recorded. Methods We examined EHRs of 5,843 patients in the General Practice Research Database, aged ≥30y, with a first coded diagnosis of RA between 2005 and 2008. Lists of indicator markers for RA were developed initially by panels of clinicians drawing up code-lists and then modified based on scrutiny of available data. The prevalence of indicator markers, and their temporal relationship to RA codes, was examined in patients from 3y before to 14d after recorded RA diagnosis. Findings Indicator markers were common throughout EHRs of RA patients, with 83.5% having 2 or more markers. 34% of patients received a disease-specific prescription before RA was coded; 42% had a referral to rheumatology, and 63% had a test for rheumatoid factor. 65% had at least one joint symptom or sign recorded and in 44% this was at least 6-months before recorded RA diagnosis. Conclusion Indicator markers of RA may be valuable for case definition in cases which do not yet have a diagnostic code. The clinical diagnosis of RA is likely to occur some months before it is coded, shown by markers frequently occurring ≥6 months before recorded diagnosis. It is difficult to differentiate delay in diagnosis from delay in recording. Information concealed in free text may be required for the accurate identification of patients and to assess the quality of care in general practice

Lovelock gravity from entropic force

In this paper, we first generalize the formulation of entropic gravity to (n+1)-dimensional spacetime. Then, we propose an entropic origin for Gauss-Bonnet gravity and more general Lovelock gravity in arbitrary dimensions. As a result, we are able to derive Newton's law of gravitation as well as the corresponding Friedmann equations in these gravity theories. This procedure naturally leads to a derivation of the higher dimensional gravitational coupling constant of Friedmann/Einstein equation which is in complete agreement with the results obtained by comparing the weak field limit of Einstein equation with Poisson equation in higher dimensions. Our study shows that the approach presented here is powerful enough to derive the gravitational field equations in any gravity theory. PACS: 04.20.Cv, 04.50.-h, 04.70.Dy.Comment: 10 pages, new versio

Anomalous tqγtq\gamma coupling effects in exclusive radiative B-meson decays

The top-quark FCNC processes will be searched for at the CERN LHC, which are correlated with the B-meson decays. In this paper, we study the effects of top-quark anomalous interactions $tq\gamma$ in the exclusive radiative $B\to K^*\gamma$ and $B\to\rho\gamma$ decays. With the current experimental data of the branching ratios, the direct CP and the isospin asymmetries, bounds on the coupling $\kappa_{tcR}^{\gamma}$ from $B\to K^*\gamma$ and $\kappa_{tuR}^{\gamma}$ from $B\to \rho\gamma$ decays are derived, respectively. The bound on $|\kappa_{tcR}^{\gamma}|$ from ${\mathcal B}(B\to K^{*}\gamma)$ is generally compatible with that from ${\mathcal B}(B\to X_{s}\gamma)$. However, the isospin asymmetry $\Delta(K^{*}\gamma)$ further restrict the phase of $\kappa_{tcR}^{\gamma}$, and the combined bound results in the upper limit, $\mathcal B(t\to c\gamma)<0.21$, which is lower than the CDF result. For real $\kappa_{tcR}^{\gamma}$, the upper bound on $\mathcal B(t\to c\gamma)$ is about of the same order as the $5\sigma$ discovery potential of ATLAS with an integrated luminosity of $10 {\rm fb}^{-1}$. For $B\to\rho\gamma$ decays, the NP contribution is enhanced by a large CKM factor $|V_{ud}/V_{td}|$, and the constraint on $tu\gamma$ coupling is rather restrictive, $\mathcal B(t\to u\gamma)<1.44\times 10^{-5}$. With refined measurements to be available at the LHCb and the future super-B factories, we can get close correlations between $B\to V \gamma$ and the rare $t\to q\gamma$ decays, which will be studied directly at the LHC ATLAS and CMS.Comment: 25 pages, 15 figures, pdflate

Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling

Although concern remains about the athero-thrombotic risk posed by cyclo-oxygenase (COX)-2-selective inhibitors, recent data implicates rofecoxib, while celecoxib appears equivalent to NSAIDs naproxen and ibuprofen. We investigated the hypothesis that celecoxib activates AMP kinase (AMPK) signalling to enhance vascular endothelial protection. In human arterial and venous endothelial cells (EC), and in contrast to ibuprofen and naproxen, celecoxib induced the protective protein heme oxygenase-1 (HO-1). Celecoxib derivative 2,5-dimethyl-celecoxib (DMC) which lacks COX-2 inhibition also upregulated HO-1, implicating a COX-2-independent mechanism. Celecoxib activated AMPKα(Thr172) and CREB-1(Ser133) phosphorylation leading to Nrf2 nuclear translocation. Importantly, these responses were not reproduced by ibuprofen or naproxen, while AMPKα silencing abrogated celecoxib-mediated CREB and Nrf2 activation. Moreover, celecoxib induced H-ferritin via the same pathway, and increased HO-1 and H-ferritin in the aortic endothelium of mice fed celecoxib (1000 ppm) or control chow. Functionally, celecoxib inhibited TNF-α-induced NF-κB p65(Ser536) phosphorylation by activating AMPK. This attenuated VCAM-1 upregulation via induction of HO-1, a response reproduced by DMC but not ibuprofen or naproxen. Similarly, celecoxib prevented IL-1β-mediated induction of IL-6. Celecoxib enhances vascular protection via AMPK-CREB-Nrf2 signalling, a mechanism which may mitigate cardiovascular risk in patients prescribed celecoxib. Understanding NSAID heterogeneity and COX-2-independent signalling will ultimately lead to safer anti-inflammatory drugs

Carbon stable isotope analysis of cereal remains as a way to reconstruct water availability: preliminary results

Reconstructing past water availability, both as rainfall and irrigation, is important to answer questions about the way society reacts to climate and its changes and the role of irrigation in the development of social complexity. Carbon stable isotope analysis of archaeobotanical remains is a potentially valuable method for reconstructing water availability. To further define the relationship between water availability and plant carbon isotope composition and to set up baseline values for the Southern Levant, grains of experimentally grown barley and sorghum were studied. The cereal crops were grown at three stations under five different irrigation regimes in Jordan. Results indicate that a positive but weak relationship exists between irrigation regime and total water input of barley grains, but no relationship was found for sorghum. The relationship for barley is site-specific and inter-annual variation was present at Deir ‘Alla, but not at Ramtha and Khirbet as-Samra