A crucial sequence for transglutaminase type 2 extracellular trafficking in renal tubular epithelial cells lies in its N-terminal {beta}-sandwich domain

Transglutaminase type 2 (TG2) catalyzes the formation of an -( -glutamyl)-lysine isopeptide bond between adjacent peptides or proteins including those of the extracellular matrix (ECM). Elevated extracellular TG2 leads to accelerated ECM deposition and reduced clearance that underlie tissue scarring and fibrosis. The extracellular trafficking of TG2 is crucial to its role in ECM homeostasis; however, the mechanism by which TG2 escapes the cell is unknown as it has no signal leader peptide and therefore cannot be transported classically. Understanding TG2 transport may highlight novel mechanisms to interfere with the extracellular function of TG2 as isoform-specific TG2 inhibitors remain elusive. Mammalian expression vectors were constructed containing domain deletions of TG2. These were transfected into three kidney tubular epithelial cell lines, and TG2 export was assessed to identify critical domains. Point mutation was then used to highlight specific sequences within the domain required for TG2 export. The removal of -sandwich domain prevented all TG2 export. Mutations of Asp94 and Asp97 within the N-terminal -sandwich domain were identified as crucial for TG2 externalization. These form part of a previously identified fibronectin binding domain (88WTATVVDQQDCTLSLQLTT106). However, siRNA knockdown of fibronectin failed to affect TG2 export. The sequence 88WTATVVDQQDCTLSLQLTT106 within the -sandwich domain of TG2 is critical to its export in tubular epithelial cell lines. The extracellular trafficking of TG2 is independent of fibronectin

'For this I was made': conflict and calling in the role of a woman priest

There has been an increasing focus on ‘work as calling’ in recent years, but relatively few empirical sociological accounts that shed light on the experience of performing calling work. Although callings have generally been referred to as positive and fulfilling to the individual and as beneficial to society, researchers have also suggested there is a ‘dark side’ to calling, and have drawn attention to the potential conflicts and tensions inherent in the pursuit of calling, especially for women. This article explores these themes through the first-hand experiences of one woman who felt called to work as a priest. Her narrative illustrates how callings draw the individual irresistibly towards a particular line of work. It also shows how calling work can be both satisfying individually and beneficial to the wider community but, at the same time, involves sacrifice, compromise and a willingness to defer personal rewards

Speech audiometry test with picture-related sentence lists in Modern Greek for partially hearing children

Objective: The aim of this study was to develop Greek Sentence Based Speech Audiometry Test in quiet test for Hearing Impaired (HI) children (G-SEBSAT). Methods: Seventy-six children were recruited following approval by the local ethics committee and after obtaining informed consent from their parents. The collection of vocabulary was based on showing pictures selected from popular reading materials in Greek to hearing impaired HI children. A grammatical content analysis was carried out to determine the average syntactic and morphological structures of the sentences used by the HI children. Ten picture related sentence lists were developed based on the vocabulary and the grammatical analysis, and recorded by a male native speaker of standard Modern Greek. These were presented to both normal hearing (NH) and HI children, and the average speech response threshold (SRT) as well as the slope of the SRT curve at the SRT level of 50% correct responses (S50) were recorded in both groups. Sentence lists were validated with respect to the variability of their difficulty within each group, as well the test-retest variability of the respective SRT scores. Results: The average speech response threshold (SRT) across all lists for HI children was 65.27 dB and the slope of the SRT curve at the SRT level of 50% correct responses was 3.11%/dB. The corresponding results across all lists for NH children were 17.66 dB and 9.7%/dB, respectively. The SRT of HI children were strongly positively correlated, in a statistically significant manner with the PTA in both the test and the retest sessions (test: r=0.750, P < 0.0005; retest: r=0.753, P < 0.0005). The Spearman correlation of the rankings of SRT values and the slope values was 0.998 and 0.997 respectively for the HI and 0.939 and 0.88, for the NH group, indicating very low variability across the test and retest sessions. In addition, the analysis of variance (ANOVA) of the average SRT in NH children and the SRT residuals in the HI group indicated that the different sentences were of the same difficulty within each group. ((F(9,81)=0.401, p=0.930 and (F(9,93)=2.241, p=0.025 respectively). Conclusions: A validated sentence based speech audiometry test was created in Greek for the first time. SRT and S50 values for both NH and HI children are comparable to similar tests developed in other languages

Computational complexity of the ground state energy density problem

We study the complexity of finding the ground state energy density of a local Hamiltonian on a lattice in the thermodynamic limit of infinite lattice size. We formulate this rigorously as a function problem, in which we request an estimate of the ground state energy density to some specified precision; and as an equivalent promise problem, GSED, in which we ask whether the ground state energy density is above or below specified thresholds. The ground state energy density problem is unusual, in that it concerns a single, fixed Hamiltonian in the thermodynamic limit, whose ground state energy density is just some fixed, real number. The only input to the computational problem is the precision to which to estimate this fixed real number, corresponding to the ground state energy density. Hardness of this problem for a complexity class therefore implies that the solutions to all problems in the class are encoded in this single number (analogous to Chaitin's constant in computability theory). This captures computationally the type of question most commonly encountered in condensed matter physics, which is typically concerned with the physical properties of a single Hamiltonian in the thermodynamic limit. We show that for classical, translationally invariant, nearest neighbour Hamiltonians on a 2D square lattice, PNEEXP†EXPGSED† EXPNEXP, and for quantum Hamiltonians PNEEXP†EXPGSED† EXPQMAEXP. With some technical caveats on the oracle definitions, the EXP in some of these results can be strengthened to PSPACE. We also give analogous complexity bounds for the function version of GSED

Uncomputability of phase diagrams

The phase diagram of a material is of central importance in describing the properties and behaviour of a condensed matter system. In this work, we prove that the task of determining the phase diagram of a many-body Hamiltonian is in general uncomputable, by explicitly constructing a continuous one-parameter family of Hamiltonians H(φ), where φ∈ R, for which this is the case. The H(φ) are translationally-invariant, with nearest-neighbour couplings on a 2D spin lattice. As well as implying uncomputablity of phase diagrams, our result also proves that undecidability can hold for a set of positive measure of a Hamiltonian’s parameter space, whereas previous results only implied undecidability on a zero measure set. This brings the spectral gap undecidability results a step closer to standard condensed matter problems, where one typically studies phase diagrams of many-body models as a function of one or more continuously varying real parameters, such as magnetic field strength or pressure

Uncomputably complex renormalisation group flows

Renormalisation group methods are among the most important techniques for analysing the physics of many-body systems: by iterating a renormalisation group map, which coarse-grains the description of a system and generates a flow in the parameter space, physical properties of interest can be extracted. However, recent work has shown that important physical features, such as the spectral gap and phase diagram, may be impossible to determine, even in principle. Following these insights, we construct a rigorous renormalisation group map for the original undecidable many-body system that appeared in the literature, which reveals a renormalisation group flow so complex that it cannot be predicted. We prove that each step of this map is computable, and that it converges to the correct fixed points, yet the resulting flow is uncomputable. This extreme form of unpredictability for renormalisation group flows had not been shown before and goes beyond the chaotic behaviour seen previously

Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT3 receptor antagonists

PURPOSE: The ferret cisplatin emesis model has been used for ~30 years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT(3) receptor antagonists to assess its translational validity. METHODS: A systematic review identified available evidence and was used to perform meta-analyses. RESULTS: Of 182 potentially relevant publications, 115 reported cisplatin-induced emesis in ferrets and 68 were included in the analysis. The majority (n = 53) used a 10 mg kg(−1) dose to induce acute emesis, which peaked after 2 h. More recent studies (n = 11) also used 5 mg kg(−1), which induced a biphasic response peaking at 12 h and 48 h. Overall, 5-HT(3) receptor antagonists reduced cisplatin (5 mg kg(−1)) emesis by 68% (45–91%) during the acute phase (day 1) and by 67% (48–86%) and 53% (38–68%, all P < 0.001), during the delayed phase (days 2, 3). In an analysis focused on the acute phase, the efficacy of ondansetron was dependent on the dosage and observation period but not on the dose of cisplatin. CONCLUSION: Our analysis enabled novel findings to be extracted from the literature including factors which may impact on the applicability of preclinical results to humans. It reveals that the efficacy of ondansetron is similar against low and high doses of cisplatin. Additionally, we showed that 5-HT(3) receptor antagonists have a similar efficacy during acute and delayed emesis, which provides a novel insight into the pharmacology of delayed emesis in the ferret

Chronic non-specific low back pain - sub-groups or a single mechanism?

Copyright 2008 Wand and O'Connell; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Low back pain is a substantial health problem and has subsequently attracted a considerable amount of research. Clinical trials evaluating the efficacy of a variety of interventions for chronic non-specific low back pain indicate limited effectiveness for most commonly applied interventions and approaches. Discussion: Many clinicians challenge the results of clinical trials as they feel that this lack of effectiveness is at odds with their clinical experience of managing patients with back pain. A common explanation for this discrepancy is the perceived heterogeneity of patients with chronic non-specific low back pain. It is felt that the effects of treatment may be diluted by the application of a single intervention to a complex, heterogeneous group with diverse treatment needs. This argument presupposes that current treatment is effective when applied to the correct patient. An alternative perspective is that the clinical trials are correct and current treatments have limited efficacy. Preoccupation with sub-grouping may stifle engagement with this view and it is important that the sub-grouping paradigm is closely examined. This paper argues that there are numerous problems with the sub-grouping approach and that it may not be an important reason for the disappointing results of clinical trials. We propose instead that current treatment may be ineffective because it has been misdirected. Recent evidence that demonstrates changes within the brain in chronic low back pain sufferers raises the possibility that persistent back pain may be a problem of cortical reorganisation and degeneration. This perspective offers interesting insights into the chronic low back pain experience and suggests alternative models of intervention. Summary: The disappointing results of clinical research are commonly explained by the failure of researchers to adequately attend to sub-grouping of the chronic non-specific low back pain population. Alternatively, current approaches may be ineffective and clinicians and researchers may need to radically rethink the nature of the problem and how it should best be managed

Asteroseismology

Asteroseismology is the determination of the interior structures of stars by using their oscillations as seismic waves. Simple explanations of the astrophysical background and some basic theoretical considerations needed in this rapidly evolving field are followed by introductions to the most important concepts and methods on the basis of example. Previous and potential applications of asteroseismology are reviewed and future trends are attempted to be foreseen.Comment: 38 pages, 13 figures, to appear in: "Planets, Stars and Stellar Systems", eds. T. D. Oswalt et al., Springer Verla