Crystal structure of human erythrocyte carbonic anhydrase B. Three-dimensional structure at a nominal 2.2-Å resolution

The three-dimensional structure of carbonic anhydrase B (EC 4,2,1,1; carbonate hydro-lyase) from human erythrocytes has been determined to high resolution. Parallel and antiparallel pleated sheet makes up the predominant secondary structure of the enzyme. The tertiary structure is unique for its folding and is very similar to the structure is unique for its folding and is very similar to the structure of the isoenzyme, human erythrocyte carbonic anhydrase C. The essential metal ion, zinc, is firmly bound to the enzyme through three histidyl ligands and located at the bottom of a 12-Å deep conical cavity. The zinc ligands are involved in a number of hydrogen bond formations with residues in the immediate vicinity of the active site cavity. Some of the similarities and differences in the sidechain orientation and active site topography of the two isoenzymes are also discussed

Reduced basis isogeometric mortar approximations for eigenvalue problems in vibroacoustics

We simulate the vibration of a violin bridge in a multi-query context using reduced basis techniques. The mathematical model is based on an eigenvalue problem for the orthotropic linear elasticity equation. In addition to the nine material parameters, a geometrical thickness parameter is considered. This parameter enters as a 10th material parameter into the system by a mapping onto a parameter independent reference domain. The detailed simulation is carried out by isogeometric mortar methods. Weakly coupled patch-wise tensorial structured isogeometric elements are of special interest for complex geometries with piecewise smooth but curvilinear boundaries. To obtain locality in the detailed system, we use the saddle point approach and do not apply static condensation techniques. However within the reduced basis context, it is natural to eliminate the Lagrange multiplier and formulate a reduced eigenvalue problem for a symmetric positive definite matrix. The selection of the snapshots is controlled by a multi-query greedy strategy taking into account an error indicator allowing for multiple eigenvalues

A spectral element reduced basis method in parametric CFD

We consider the Navier-Stokes equations in a channel with varying Reynolds numbers. The model is discretized with high-order spectral element ansatz functions, resulting in 14,259 degrees of freedom. The steady-state snapshot solutions define a reduced order space, which allows to accurately evaluate the steady-state solutions for varying Reynolds number with a reduced order model within a fixed-point iteration. In particular, we compare different aspects of implementing the reduced order model with respect to the use of a spectral element discretization. It is shown, how a multilevel static condensation (Karniadakis and Sherwin, Spectral/hp element methods for computational fluid dynamics, 2nd edn. Oxford University Press, Oxford, 2005) in the pressure and velocity boundary degrees of freedom can be combined with a reduced order modelling approach to enhance computational times in parametric many-query scenarios

ISML: an interface specification meta-language

In this paper we present an abstract metaphor model situated within a model-based user interface framework. The inclusion of metaphors in graphical user interfaces is a well established, but mostly craft-based strategy to design. A substantial body of notations and tools can be found within the model-based user interface design literature, however an explicit treatment of metaphor and its mappings to other design views has yet to be addressed. We introduce the Interface Specification Meta-Language (ISML) framework and demonstrate its use in comparing the semantic and syntactic features of an interactive system. Challenges facing this research are outlined and further work proposed

emm typing and validation of provisional M types for group A streptococci.

This report discusses the following issues related to typing of group A streptococci (GAS): The development and use of the 5' emm variable region sequencing (emm typing) in relation to the existing serologic typing system; the designation of emm types in relation to M types; a system for validation of new emm types; criteria for validation of provisional M types to new M-types; a list of reference type cultures for each of the M-type or emm-type strains of GAS; the results of the first culture exchange program for a quality control testing system among the national and World Health Organization collaborating centers for streptococci; and dissemination of new approaches to typing of GAS to the international streptococcal community

Prothrombin time is predictive of low plasma prothrombin concentration and clinical outcome in patients with trauma hemorrhage: analyses of prospective observational cohort studies

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Analyses of data previously generated through ACIT and DIA-TRE-TIC studies was funded by AstraZeneca R&D Gothenburg, Sweden

Analogue peptides for the immunotherapy of human acute myeloid leukemia

Accepted manuscript. The final publication is available at: http://link.springer.com/article/10.1007%2Fs00262-015-1762-9The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies

Prognostic and Mechanistic Potential of Progesterone Sulfates in Intrahepatic Cholestasis of Pregnancy and Pruritus Gravidarum

A challenge in obstetrics is to distinguish pathological symptoms from those associated with normal changes of pregnancy, typified by the need to differentiate whether gestational pruritus of the skin is an early symptom of intrahepatic cholestasis of pregnancy (ICP) or due to benign pruritus gravidarum. ICP is characterized by raised serum bile acids and complicated by spontaneous preterm labor and stillbirth. A biomarker for ICP would be invaluable for early diagnosis and treatment and to enable its differentiation from other maternal diseases. Three progesterone sulfate compounds, whose concentrations have not previously been studied, were newly synthesized and assayed in the serum of three groups of ICP patients and found to be significantly higher in ICP at 9-15 weeks of gestation and prior to symptom onset (group 1 cases/samples: ICP n = 35/80, uncomplicated pregnancy = 29/100), demonstrating that all three progesterone sulfates are prognostic for ICP. Concentrations of progesterone sulfates were associated with itch severity and, in combination with autotaxin, distinguished pregnant women with itch that would subsequently develop ICP from pruritus gravidarum (group 2: ICP n = 41, pruritus gravidarum n = 14). In a third group of first-trimester samples all progesterone sulfates were significantly elevated in serum from low-risk asymptomatic women who subsequently developed ICP (ICP/uncomplicated pregnancy n = 54/51). Finally, we show mechanistically that progesterone sulfates mediate itch by evoking a Tgr5-dependent scratch response in mice. Conclusion: Our discovery that sulfated progesterone metabolites are a prognostic indicator for ICP will help predict onset of ICP and distinguish it from benign pruritus gravidarum, enabling targeted obstetric care to a high-risk population. Delineation of a progesterone sulfate-TGR5 pruritus axis identifies a therapeutic target for itch management in ICP

Living with persistent pain: experiences of older people receiving home care.

Background. Although the topic of pain among older people has received increasing interest, little is still known about how pain is experienced or handled by those who no longer manage independently but depend on professionals for help with daily living. Developing pain management for older people requires such knowledge. Aim. To explore sense of self, sense of pain, daily living with pain, sense of others and ways of handling pain in older people with persistent pain. Methods. Interviews with 90 older people receiving home care from nursing auxiliaries in their own homes or in sheltered accommodation were collected from January to June 2000. A typology of older people in persistent pain was developed. Activities for handling pain were examined using content analysis. Findings. Respondents' experiences of themselves and their pain varied. Two groups of older people, considered as 'competent and proud' and 'confident and serene', expressed satisfaction in spite of pain, while the groups 'misunderstood and disappointed' and 'resigned and sad' expressed dissatisfaction. The most common strategies used were medication, rest, mobility, distracting activities and talking about pain. Respondents chose strategies by balancing the advantages of the activities against the disadvantages these brought for their daily living. Conclusion. This study indicates that characteristics of the older people, such as their way of experiencing themselves, how pain affects their daily life and how they perceive effects and side-effects of pain management are areas that need to be identified when staff assess pain and plan pain management. Caring for older people in pain could be improved by listening to and believing their complaints, evaluating effects and side-effects from medications and nonpharmacological pain management and by emphasising the importance of common everyday activities such as mobility and distraction to relieve pain

Community-Based Outbreaks in Vulnerable Populations of Invasive Infections Caused by Streptococcus pneumoniae Serotypes 5 and 8 in Calgary, Canada

BACKGROUND: Outbreaks of invasive pneumococcal disease (IPD) typically occur within institutions. Beginning in 2005, we detected an increase in serotype (ST) 5 and ST8 IPD cases, predominantly in homeless persons living in an open community. METHODOLOGY/PRINCIPAL FINDINGS: CASPER (Calgary Area S. pneumoniae Epidemiology Research) surveillance study of all IPD (sterile site isolates) in our region (pop ~1,100,000). Interviews and chart reviews of all cases and all isolates phenotypically analyzed and selected isolated tested by multi-locus sequence typing (MLST). CONCLUSIONS/SIGNIFICANCE: During 2005-2007, 162 cases of ST5 IPD and 45 cases of ST8 IPD were identified. The isolates demonstrated phenotypic and genotypic clonality. The ST5 isolates were sequence type (ST) 289 and demonstrated intermediate susceptibility to TMP-SMX. The ST8 isolates were predominantly ST1268, with a susceptible antimicrobial susceptibility profile. Individuals with ST5 IPD were more likely to be middle aged (OR 2.6), homeless (OR 4.4), using illicit drugs(OR 4.8), and asthmatic(OR 2.6). Those with ST8 were more likely to be male (OR 4.4), homeless (OR 2.6), aboriginal (OR7.3), and a current smoker (OR 2.5). Overlapping outbreaks of ST5 and ST8 IPD occurred in an open community in Calgary, Canada and homelessness was a predominant risk factor. Homelessness represents a unique community in which pneumococcal outbreaks can occur