Structural and functional properties of human alpha-thrombin, phosphopyridoxylated alpha-thrombin, and gamma T-thrombin. Identification of lysyl residues in alpha-thrombin that are critical for heparin and fibrin (ogen) interactions.

alpha-Thrombin derivatives obtained either by site-specific modification at lysyl residues (phosphopyridoxylated) or by limited trypsinolysis (gamma T-thrombin) were compared to correlate structural modifications with the functional reactivity toward fibrin(ogen) and heparin. alpha-Thrombin phosphopyridoxylated in the absence of heparin (unprotected) showed approximately 2 mol of label incorporated/mol of thrombin, but only 1 mol of label incorporated/mol of proteinase when modified in the presence of added heparin (protected). In contrast to native alpha-thrombin, both phosphopyridoxylated alpha-thrombin derivatives failed to interact with a fibrin monomer-agarose column and had reduced fibrinogen clotting activity, which is very similar to gamma T-thrombin. Heparin accelerated the rate of antithrombin III inhibition of alpha-thrombin, heparin-protected modified-alpha-thrombin, and gamma T-thrombin in a manner consistent with a template mechanism but was without effect on unprotected modified alpha-thrombin. In a heparin-catalyzed antithrombin III inhibition assay of alpha-thrombin, we found that D-Phe-Pro-Arg chloromethyl ketone-active site-inactivated gamma T-thrombin competed for heparin binding. It has been shown that limited proteolysis/autolysis of the B-chain of alpha-thrombin in the area around Arg-B73 (in beta T/beta- and gamma T/gamma-thrombin), but not that around Lys-B154 (in gamma T/gamma-thrombin), diminishes specific interactions with fibrinogen (Hofsteenge, J., Braun, P. J., and Stone , S. R. (1988) Biochemistry 27, 2144-2151). In unprotected modified alpha-thrombin, lysyl residues B21, B65, B174, and B252 were phosphopyridoxylated. In heparin-protected modified alpha-thrombin, only lysyl residues B21 and B65 were phosphopyridoxylated. These observations suggest that lysyl residues 21/65 of the B-chain of alpha-thrombin are involved in fibrin(ogen) interactions, and lysyl residues 174/252 of the B-chain are important in heparin interactions

Displaced vertices from pseudo-Dirac dark matter

Displaced vertices are relatively unusual signatures for dark matter searches at the LHC. We revisit the model of pseudo-Dirac dark matter (pDDM), which can accommodate the correct relic density, evade direct detection constraints, and generically provide observable collider signatures in the form of displaced vertices. We use this model as a benchmark to illustrate the general techniques involved in the analysis, the complementarity between monojet and displaced vertex searches, and provide a comprehensive study of the current bounds and prospective reach

Mid-mantle deformation inferred from seismic anisotropy

With time, convective processes in the Earth's mantle will tend to align crystals, grains and inclusions. This mantle fabric is detectable seismologically, as it produces an anisotropy in material properties—in particular, a directional dependence in seismic-wave velocity. This alignment is enhanced at the boundaries of the mantle where there are rapid changes in the direction and magnitude of mantle flow, and therefore most observations of anisotropy are confined to the uppermost mantle or lithosphere and the lowermost-mantle analogue of the lithosphere, the D" region. Here we present evidence from shear-wave splitting measurements for mid-mantle anisotropy in the vicinity of the 660-km discontinuity, the boundary between the upper and lower mantle. Deep-focus earthquakes in the Tonga–Kermadec and New Hebrides subduction zones recorded at Australian seismograph stations record some of the largest values of shear-wave splitting hitherto reported. The results suggest that, at least locally, there may exist a mid-mantle boundary layer, which could indicate the impediment of flow between the upper and lower mantle in this region

The present-day number of tectonic plates

The number of tectonic plates on Earth described in the literature has expanded greatly since the start of the plate tectonic era, when only about a dozen plates were considered in global models of present-day plate motions. With new techniques of more accurate earthquake epicenter locations, modern ways of measuring ocean bathymetry using swath mapping, and the use of space based geodetic techniques, there has been a huge growth in the number of plates thought to exist. The study by Bird (2003) proposed 52 plates, many of which were delineated on the basis of earthquake locations. Because of the pattern of areas of these plates, he suggested that there should be more small plates than he could identify. In this paper, I gather together publications that have proposed a total of 107 new plates, giving 159 plates in all. The largest plate (Pacific) is about 20 % of the Earth's area or 104 Mm (super 2) , and the smallest of which (Plate number 5 from Hammond et al. 2011) is only 273 km (super 2) in area. Sorting the plates by size allows us to investigate how size varies as a function of order. There are several changes of slope in the plots of plate number organized by size against plate size order which are discussed. The sizes of the largest seven plates is constrained by the area of the Earth. A middle set of 73 plates down to an area of 97,563 km (super 2) (the Danakil plate at number 80, is the plate of median size) follows a fairly regular pattern of plate size as a function of plate number. For smaller plates, there is a break in the slope of the plate size/plate number plot and the next 32 plates follow a pattern of plate size proposed by the models of Koehn et al. (2008) down to an area of 11,638 km (super 2) (West Mojave plate # 112). Smaller plates do not follow any regular pattern of area as a function of plate number, probably because we have not sampled enough of these very small plates to reveal any clear pattern. Copyright 2016 The Author(s) and Harrison

Secluded Dark Matter Coupled to a Hidden CFT

Models of secluded dark matter offer a variant on the standard WIMP picture and can modify our expectations for hidden sector phenomenology and detection. In this work we extend a minimal model of secluded dark matter, comprised of a U(1)'-charged dark matter candidate, to include a confining hidden-sector CFT. This provides a technically natural explanation for the hierarchically small mediator-scale, with hidden-sector confinement generating m_{gamma'}>0. Furthermore, the thermal history of the universe can differ markedly from the WIMP picture due to (i) new annihilation channels, (ii) a (potentially) large number of hidden-sector degrees of freedom, and (iii) a hidden-sector phase transition at temperatures T << M_{dm} after freeze out. The mediator allows both the dark matter and the Standard Model to communicate with the CFT, thus modifying the low-energy phenomenology and cosmic-ray signals from the secluded sector.Comment: ~50p, 8 figs; v2 JHEP versio

Systematically missing confounders in individual participant data meta-analysis of observational cohort studies.

One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154,012 participants in 31 cohort

Efficacy and safety of recruitment maneuvers in acute respiratory distress syndrome

Recruitment maneuvers (RM) consist of a ventilatory strategy that increases the transpulmonary pressure transiently to reopen the recruitable lung units in acute respiratory distress syndrome (ARDS). The rationales to use RM in ARDS are that there is a massive loss of aerated lung and that once the end-inspiratory pressure surpasses the regional critical opening pressure of the lung units, those units are likely to reopen. There are different methods to perform RM when using the conventional ICU ventilator. The three RM methods that are mostly used and investigated are sighs, sustained inflation, and extended sigh. There is no standardization of any of the above RM. Meta-analysis recommended not to use RM in routine in stable ARDS patients but to run them in case of life-threatening hypoxemia. There are some concerns regarding the safety of RM in terms of hemodynamics preservation and lung injury as well. The rapid rising in pressure can be a factor that explains the potential harmful effects of the RM. In this review, we describe the balance between the beneficial effects and the harmful consequences of RM. Recent animal studies are discussed

FTIR-based spectroscopic analysis in the identification of clinically aggressive prostate cancer

Fourier transform infrared (FTIR) spectroscopy is a vibrational spectroscopic technique that uses infrared radiation to vibrate molecular bonds within the sample that absorbs it. As different samples contain different molecular bonds or different configurations of molecular bonds, FTIR allows us to obtain chemical information on molecules within the sample. Fourier transform infrared microspectroscopy in conjunction with a principal component-discriminant function analysis (PC-DFA) algorithm was applied to the grading of prostate cancer (CaP) tissue specimens. The PC-DFA algorithm is used alongside the established diagnostic measures of Gleason grading and the tumour/node/metastasis system. Principal component-discriminant function analysis improved the sensitivity and specificity of a three-band Gleason score criterion diagnosis previously reported by attaining an overall sensitivity of 92.3% and specificity of 99.4%. For the first time, we present the use of a two-band criterion showing an association of FTIR-based spectral characteristics with clinically aggressive behaviour in CaP manifest as local and/or distal spread. This paper shows the potential for the use of spectroscopic analysis for the evaluation of the biopotential of CaP in an accurate and reproducible manner

How a Diverse Research Ecosystem Has Generated New Rehabilitation Technologies: Review of NIDILRR’s Rehabilitation Engineering Research Centers

Over 50 million United States citizens (1 in 6 people in the US) have a developmental, acquired, or degenerative disability. The average US citizen can expect to live 20% of his or her life with a disability. Rehabilitation technologies play a major role in improving the quality of life for people with a disability, yet widespread and highly challenging needs remain. Within the US, a major effort aimed at the creation and evaluation of rehabilitation technology has been the Rehabilitation Engineering Research Centers (RERCs) sponsored by the National Institute on Disability, Independent Living, and Rehabilitation Research. As envisioned at their conception by a panel of the National Academy of Science in 1970, these centers were intended to take a “total approach to rehabilitation”, combining medicine, engineering, and related science, to improve the quality of life of individuals with a disability. Here, we review the scope, achievements, and ongoing projects of an unbiased sample of 19 currently active or recently terminated RERCs. Specifically, for each center, we briefly explain the needs it targets, summarize key historical advances, identify emerging innovations, and consider future directions. Our assessment from this review is that the RERC program indeed involves a multidisciplinary approach, with 36 professional fields involved, although 70% of research and development staff are in engineering fields, 23% in clinical fields, and only 7% in basic science fields; significantly, 11% of the professional staff have a disability related to their research. We observe that the RERC program has substantially diversified the scope of its work since the 1970’s, addressing more types of disabilities using more technologies, and, in particular, often now focusing on information technologies. RERC work also now often views users as integrated into an interdependent society through technologies that both people with and without disabilities co-use (such as the internet, wireless communication, and architecture). In addition, RERC research has evolved to view users as able at improving outcomes through learning, exercise, and plasticity (rather than being static), which can be optimally timed. We provide examples of rehabilitation technology innovation produced by the RERCs that illustrate this increasingly diversifying scope and evolving perspective. We conclude by discussing growth opportunities and possible future directions of the RERC program