A Kinetic Basis For T Cell Receptor Repertoire Selection during an Immune Response

AbstractThe basis for T cell antigen receptor (TCR) repertoire selection upon repeated antigenic challenge is unclear. We evaluated the avidity and dissociation kinetics of peptide/major histocompatibility complex (MHC) tetramer binding to antigen-specific T lymphocytes isolated following primary or secondary immunization. The data reveal a narrowing of the secondary repertoire relative to the primary repertoire, largely resulting from the loss of cells expressing TCRs with the fastest dissociation rates for peptide/MHC binding. In addition, T cells in the secondary response express TCRs of higher average affinity for peptide/MHC than cells in the primary response. These results provide a link between the kinetics and affinity of TCR-peptide/MHC interactions and TCR sequence selection during the course of an immune response

Evidence based survey of the distribution volume of ethanol:comparison of empirically determined values with anthropometric measures

The Widmark equation is commonly used when blood alcohol calculations are required in forensic and legal medicine, such as in road-traffic cases and alcohol-related deaths. An important biological variable in this connection is the volume of distribution (Vd) of ethanol, which is commonly referred to as the rho-factor. Although a person’s Vd can be determined empirically through controlled drinking experiments, this approach is not very practical in reality. For this reason, a number of anthropometric equations have been developed that utilize sex, age, height and weight to estimate the person’s total body water (TBW) and hence Vd of ethanol. To date, there aren’t any studies that compare Vd derived from anthropometric data with robust values measured empirically. From the literature we compiled information about the Vd of ethanol from drinking studies with 173 Caucasian males and 63 Caucasian females from Western Europe. These empirically derived values of Vd were then compared with estimates derived from various anthropometric equations. In males the Watson, Watson and Batt regression equation involving age, height and weight gave the most accurate results (bias was 0.00 L/Kg) and 95% confidence limits (CI) were ± 0.13 L/Kg. The equation derived by Forrest, which took into consideration a person’s body mass index (BMI), gave the best estimates of Vd for females; mean bias −0.01 L/Kg and 95% CI ± 0.15 L/Kg

SPIFI: a Direct-Detection Imaging Spectrometer for Submillimeter Wavelengths

The South Pole Imaging Fabry-Perot Interferometer (SPIFI) is the first instrument of its kind -a direct-detection imaging spectrometer for astronomy in the submillimeter band. SPIFI ’s focal plane is a square array of 25 silicon bolometers cooled to 60 mK; the spectrometer consists of two cryogenic scanning Fabry-Perot interferometers in series with a 60-mK bandpass filter. The instrument operates in the short submillimeter windows (350 and 450 μm) available from the ground, with spectral resolving power selectable between 500 and 10,000. At present, SPIFI’s sensitivity is within a factor of 1.5-3 of the photon background limit, comparable with the best heterodyne spectrometers. The instrument ’s large bandwidth and mapping capability provide substantial advantages for specific astrophysical projects, including deep extragalactic observations. We present the motivation for and design of SPIFI and its operational characteristics on the telescope

Spontaneous Stratification in Granular Mixtures

Granular materials size segregate when exposed to external periodic perturbations such as vibrations. Moreover, mixtures of grains of different sizes spontaneously segregate in the absence of external perturbations: when a mixture is simply poured onto a pile, the large grains are more likely to be found near the base, while the small grains are more likely to be near the top. Here, we report a spontaneous phenomenon arising when we pour a mixture between two vertical plates: the mixture spontaneously stratifies into alternating layers of small and large grains whenever the large grains are rougher than the small grains. In contrast, we find only spontaneous segregation when the large grains are more rounded than the small grains. The stratification is related to the occurrence of avalanches; during each avalanche the grains comprising the avalanche spontaneously stratify into a pair of layers through a "kink" mechanism, with the small grains forming a sublayer underneath the layer of large grains.Comment: 4 pages, 6 figures, http://polymer.bu.edu/~hmakse/Home.htm

A TMA De-Arraying Method for High Throughput Biomarker Discovery in Tissue Research

BACKGROUND: Tissue MicroArrays (TMAs) represent a potential high-throughput platform for the analysis and discovery of tissue biomarkers. As TMA slides are produced manually and subject to processing and sectioning artefacts, the layout of TMA cores on the final slide and subsequent digital scan (TMA digital slide) is often disturbed making it difficult to associate cores with their original position in the planned TMA map. Additionally, the individual cores can be greatly altered and contain numerous irregularities such as missing cores, grid rotation and stretching. These factors demand the development of a robust method for de-arraying TMAs which identifies each TMA core, and assigns them to their appropriate coordinates on the constructed TMA slide. METHODOLOGY: This study presents a robust TMA de-arraying method consisting of three functional phases: TMA core segmentation, gridding and mapping. The segmentation of TMA cores uses a set of morphological operations to identify each TMA core. Gridding then utilises a Delaunay Triangulation based method to find the row and column indices of each TMA core. Finally, mapping correlates each TMA core from a high resolution TMA whole slide image with its name within a TMAMap. CONCLUSION: This study describes a genuine robust TMA de-arraying algorithm for the rapid identification of TMA cores from digital slides. The result of this de-arraying algorithm allows the easy partition of each TMA core for further processing. Based on a test group of 19 TMA slides (3129 cores), 99.84% of cores were segmented successfully, 99.81% of cores were gridded correctly and 99.96% of cores were mapped with their correct names via TMAMaps. The gridding of TMA cores were also extensively tested using a set of 113 pseudo slide (13,536 cores) with a variety of irregular grid layouts including missing cores, rotation and stretching. 100% of the cores were gridded correctly

Upper mantle seismic anisotropy at a strike-slip boundary: South Island, New Zealand

New shear wave splitting measurements made from stations onshore and offshore the South Island of New Zealand show a zone of anisotropy 100–200 km wide. Measurements in central South Island and up to approximately 100 km offshore from the west coast yield orientations of the fast quasi-shear wave nearly parallel to relative plate motion, with increased obliquity to this orientation observed farther from shore. On the eastern side of the island, fast orientations rotate counterclockwise to become nearly perpendicular to the orientation of relative plate motion approximately 200 km off the east coast. Uniform delay times between the fast and slow quasi-shear waves of nearly 2.0 s onshore continue to stations approximately 100 km off the west coast, after which they decrease to ~1 s at 200 km. Stations more than ~300 km from the west coast show little to no splitting. East coast stations have delay times around 1 s. Simple strain fields calculated from a thin viscous sheet model (representing distributed lithospheric deformation) with strain rates decreasing exponentially to both the northwest and southeast with e-folding dimensions of 25–35 km (approximately 75% of the deformation within a zone 100–140 km wide) match orientations and amounts of observed splitting. A model of deformation localized in the lithosphere and then spreading out in the asthenosphere also yields predictions consistent with observed splitting if, at depths of 100–130 km below the lithosphere, typical grain sizes are ~ 6–7 mm.New Zealand. Ministry of Research, Science, and TechnologyNational Science Foundation (U.S.). Continental Dynamics Program (Grant EAR-0409564)National Science Foundation (U.S.). Continental Dynamics Program (Grant EAR-0409609)National Science Foundation (U.S.). Continental Dynamics Program (Grant EAR-0409835

Prospects for local co-governance

British local authorities and their partners are increasingly developing new ways of working together with local communities. The nature of this co-working, however, is complex, multi-faceted and little understood. This article argues for greater clarity of thinking on the topic, by analysing this co-working as a form of political co-governance, and drawing attention in particular to issues of scale and democracy. Using evidence from a study of 43 local authority areas, 16 authorities are identified where co-governance is practised, following three main types of approach: service-influencing, service-delivering and parish council developing. It is concluded that strengthening political co-governance is essential for a healthy democracy

The practical implications of using standardized estimation equations in calculating the prevalence of chronic kidney disease

BACKGROUND: Kidney Disease Outcomes Quality Initiative (KDOQI) chronic kidney disease (CKD) guidelines have focused on the utility of using the modified four-variable MDRD equation (now traceable by isotope dilution mass spectrometry IDMS) in calculating estimated glomerular filtration rates (eGFRs). This study assesses the practical implications of eGFR correction equations on the range of creatinine assays currently used in the UK and further investigates the effect of these equations on the calculated prevalence of CKD in one UK regionMETHODS: Using simulation, a range of creatinine data (30-300 micromol/l) was generated for male and female patients aged 20-100 years. The maximum differences between the IDMS and MDRD equations for all 14 UK laboratory techniques for serum creatinine measurement were explored with an average of individual eGFRs calculated according to MDRD and IDMS &lt; 60 ml/min/1.73 m(2) and 30 ml/min/1.73 m(2). Similar procedures were applied to 712,540 samples from patients &gt; or = 18 years (reflecting the five methods for serum creatinine measurement utilized in Northern Ireland) to explore, graphically, maximum differences in assays. CKD prevalence using both estimation equations was compared using an existing cohort of observed data.RESULTS: Simulated data indicates that the majority of laboratories in the UK have small differences between the IDMS and MDRD methods of eGFR measurement for stages 4 and 5 CKD (where the averaged maximum difference for all laboratory methods was 1.27 ml/min/1.73 m(2) for females and 1.59 ml/min/1.73 m(2) for males). MDRD deviated furthest from the IDMS results for the Endpoint Jaffe method: the maximum difference of 9.93 ml/min/1.73 m(2) for females and 5.42 ml/min/1.73 m(2) for males occurred at extreme ages and in those with eGFR &gt; 30 ml/min/1.73 m(2). Observed data for 93,870 patients yielded a first MDRD eGFR &lt; 60 ml/min/1.73 m(2) in 2001. 66,429 (71%) had a second test &gt; 3 months later of which 47,093 (71%) continued to have an eGFR &lt; 60 ml/min/1.73 m(2). Estimated crude prevalence was 3.97% for laboratory detected CKD in adults using the MDRD equation which fell to 3.69% when applying the IDMS equation. Over 95% of this difference in prevalence was explained by older females with stage 3 CKD (eGFR 30-59 ml/min/1.73 m(2)) close to the stage 2 CKD (eGFR 60-90 ml/min/1.73 m(2)) interface.CONCLUSIONS: Improved accuracy of eGFR is obtainable by using IDMS correction especially in the earlier stages of CKD 1-3. Our data indicates that this improved accuracy could lead to reduced prevalence estimates and potentially a decreased likelihood of onward referral to nephrology services particularly in older females.</p

Combinatorial realizations of crystals via torus actions on quiver varieties

Consider Kashiwara's crystal associated to a highest weight representation of a symmetric Kac-Moody algebra. There is a geometric realization of this object using Nakajima's quiver varieties, but in many particular cases it can also be realized by elementary combinatorial methods. Here we propose a framework for extracting combinatorial realizations from the geometric picture: We construct certain torus actions on the quiver varieties and use Morse theory to index the irreducible components by connected components of the subvariety of torus fixed points. We then discuss the case of affine sl(n). There the fixed point components are just points, and are naturally indexed by multi-partitions. There is some choice in our construction, leading to a family of combinatorial models for each highest weight crystal. Applying this construction to the crystal of the fundamental representation recovers a family of combinatorial realizations recently constructed by Fayers. This gives a more conceptual proof of Fayers' result as well as a generalization to higher level. We also discuss a relationship with Nakajima's monomial crystal.Comment: 23 pages, v2: added Section 8 on monomial crystals and some references; v3: many small correction