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

Mild cold effects on hunger, food intake, satiety and skin temperature in humans.

BACKGROUND: Mild cold exposure increases energy expenditure and can influence energy balance, but at the same time it does not increase appetite and energy intake. OBJECTIVE: To quantify dermal insulative cold response, we assessed thermal comfort and skin temperatures changes by infrared thermography. METHODS: We exposed healthy volunteers to either a single episode of environmental mild cold or thermoneutrality. We measured hunger sensation and actual free food intake. After a thermoneutral overnight stay, five males and five females were exposed to either 18°C (mild cold) or 24°C (thermoneutrality) for 2.5 h. Metabolic rate, vital signs, skin temperature, blood biochemistry, cold and hunger scores were measured at baseline and for every 30 min during the temperature intervention. This was followed by an ad libitum meal to obtain the actual desired energy intake after cold exposure. RESULTS: We could replicate the cold-induced increase in REE. But no differences were detected in hunger, food intake, or satiety after mild cold exposure compared with thermoneutrality. After long-term cold exposure, high cold sensation scores were reported, which were negatively correlated with thermogenesis. Skin temperature in the sternal area was tightly correlated with the increase in energy expenditure. CONCLUSIONS: It is concluded that short-term mild cold exposure increases energy expenditure without changes in food intake. Mild cold exposure resulted in significant thermal discomfort, which was negatively correlated with the increase in energy expenditure. Moreover, there is a great between-subject variability in cold response. These data provide further insights on cold exposure as an anti-obesity measure.The study was funded by NIHR, BRC Seed Fund, individual grants: ML and MS: Marie Curie Fellowship, CYT: Welcome Trust Fellowship, SV: MRC, BHF and BBSRC, AVP: BBSRC.This is the final version of the article. It first appeared from Bioscientifica via https://doi.org/ 10.1530/EC-16-000

The age of anxiety? It depends where you look: changes in STAI trait anxiety, 1970–2010

Purpose Population-level surveys suggest that anxiety has been increasing in several nations, including the USA and UK. We sought to verify the apparent anxiety increases by looking for systematic changes in mean anxiety questionnaire scores from research publications. Methods We analyzed all available mean State–Trait Anxiety Inventory scores published between 1970 and 2010. We collected 1703 samples, representing more than 205,000 participants from 57 nations. Results Results showed a significant anxiety increase worldwide, but the pattern was less clear in many individual nations. Our analyses suggest that any increase in anxiety in the USA and Canada may be limited to students, anxiety has decreased in the UK, and has remained stable in Australia. Conclusions Although anxiety may have increased worldwide, it might not be increasing as dramatically as previously thought, except in specific populations, such as North American students. Our results seem to contradict survey results from the USA and UK in particular. We do not claim that our results are more reliable than those of large population surveys. However, we do suggest that mental health surveys and other governmental sources of disorder prevalence data may be partially biased by changing attitudes toward mental health: if respondents are more aware and less ashamed of their anxiety, they are more likely to report it to survey takers. Analyses such as ours provide a useful means of double-checking apparent trends in large population surveys

RF IC performance optimization by synthesizing optimum inductors

Even with optimal system design and careful choice of topology for a particular RF application, large amounts of energy are often wasted due to low-quality passives, especially inductors. Inductors have traditionally been difficult to integrate due to their inherent low quality factors and modelling complexity. Furthermore, although many different inductor configurations are available for an RF designer to explore, support for integrated inductors in electronic design automation tools and process design kits has been very limited in the past. In this chapter, a recent advance in technology-aware integrated inductor design is presented, where drawbacks of the integrated inductor design are addressed by introducing an equation-based inductor synthesis algorithm. The intelligent computation technique aims to allow RF designers to optimize integrated inductors, given the inductor center frequency dictated by the device application, and geometry constraints. This does not only lay down a foundation for system-level RF circuit performance optimization, but, because inductors are often the largest parts of an RF system, it also allows for optimal usage of chip real estate

Novel role for the innate immune receptor toll-like receptor 4 (TLR4) in the regulation of the wnt signaling pathway and photoreceptor apoptosis

Recent evidence has implicated innate immunity in regulating neuronal survival in the brain during stroke and other neurodegenerations. Photoreceptors are specialized light-detecting neurons in the retina that are essential for vision. In this study, we investigated the role of the innate immunity receptor TLR4 in photoreceptors. TLR4 activation by lipopolysaccharide (LPS) significantly reduced the survival of cultured mouse photoreceptors exposed to oxidative stress. With respect to mechanism, TLR4 suppressed Wnt signaling, decreased phosphorylation and activation of the Wnt receptor LRP6, and blocked the protective effect of the Wnt3a ligand. Paradoxically, TLR4 activation prior to oxidative injury protected photoreceptors, in a phenomenon known as preconditioning. Expression of TNFα and its receptors TNFR1 and TNFR2 decreased during preconditioning, and preconditioning was mimicked by TNFα antagonists, but was independent of Wnt signaling. Therefore, TLR4 is a novel regulator of photoreceptor survival that acts through the Wnt and TNFα pathways. © 2012 Yi et al

Measurement of the running of the QED coupling in small-angle Bhabha scattering at LEP

Using the OPAL detector at LEP, the running of the effective QED coupling alpha(t) is measured for space-like momentum transfer from the angular distribution of small-angle Bhabha scattering. In an almost ideal QED framework, with very favourable experimental conditions, we obtain: Delta alpha(-6.07GeV^2) - Delta alpha(-1.81GeV^2) = (440 pm 58 pm 43 pm 30) X 10^-5, where the first error is statistical, the second is the experimental systematic and the third is the theoretical uncertainty. This agrees with current evaluations of alpha(t).The null hypothesis that alpha remains constant within the above interval of -t is excluded with a significance above 5sigma. Similarly, our results are inconsistent at the level of 3sigma with the hypothesis that only leptonic loops contribute to the running. This is currently the most significant direct measurment where the running alpha(t) is probed differentially within the measured t range.Comment: 43 pages, 12 figures, Submitted to Euro. Phys. J.

Persistent orocutaneous and anal fistulae induced by nicorandil: a case report

<p>Abstract</p> <p>Introduction</p> <p>Although nicorandil is prescribed widely, awareness of its potential to cause serious complications to the gastrointestinal tract mucosa is limited. Whilst nicorandil-induced oral and anal ulceration is well documented in the literature, nicorandil-induced fistulation is not. This is the first report in the literature of a single patient demonstrating simultaneous orocutaneous and anal fistulae during nicorandil therapy. Two separate cases of orocutaneous and anal fistulae associated nicorandil usage have previously been documented in specialist journals.</p> <p>Case presentation</p> <p>A 71-year-old Caucasian man presented with a 3-year history of concurrent orocutaneous and anal fistulae. He had been exposed to 30 mg twice-daily nicorandil therapy for 4 years. Both fistulae responded poorly to intensive and prolonged conventional treatment but healed promptly on reduction and eventual withdrawal of nicorandil therapy.</p> <p>Conclusion</p> <p>Management of resistant cases of orocutaneous and anal fistulae in patients on high-dose nicorandil therapy may be impossible without reduction or even withdrawal of nicorandil.</p

Symptom recognition and health care seeking among immigrants and native Swedish patients with heart failure

<p>Abstract</p> <p>Background</p> <p>It is not known what patient perceptions or beliefs lead to beneficial decisions or response patterns in symptom interpretation among heart failure (HF) patients, especially immigrants. The aim of this study was to explore and compare symptom recognition and health care seeking patterns among immigrants and native Swedes with HF.</p> <p>Methods</p> <p>The study used a qualitative design. Semi-structured interviews were conducted with 42 patients with HF, of whom 21 were consecutively selected immigrants and 21 were randomly selected Swedish patients. The interviews were analysed using content analysis.</p> <p>Results</p> <p>A majority of the immigrant patients sought health care for symptoms and signs, such as breathing difficulties, fatigue and swelling. Twice as many immigrants as Swedes were unaware of "what the illness experience entailed" and which symptoms indicated worsening of HF.</p> <p>Conclusion</p> <p>The symptoms that patients sought care for, were similar among immigrants and Swedes. However, when interpreting symptoms more immigrants were unaware of the connection between the symptoms/signs and their HF condition. More tailored educational interventions might improve recognition of worsening symptoms in immigrant patients with chronic heart failure.</p

A Measurement of Rb using a Double Tagging Method

The fraction of Z to bbbar events in hadronic Z decays has been measured by the OPAL experiment using the data collected at LEP between 1992 and 1995. The Z to bbbar decays were tagged using displaced secondary vertices, and high momentum electrons and muons. Systematic uncertainties were reduced by measuring the b-tagging efficiency using a double tagging technique. Efficiency correlations between opposite hemispheres of an event are small, and are well understood through comparisons between real and simulated data samples. A value of Rb = 0.2178 +- 0.0011 +- 0.0013 was obtained, where the first error is statistical and the second systematic. The uncertainty on Rc, the fraction of Z to ccbar events in hadronic Z decays, is not included in the errors. The dependence on Rc is Delta(Rb)/Rb = -0.056*Delta(Rc)/Rc where Delta(Rc) is the deviation of Rc from the value 0.172 predicted by the Standard Model. The result for Rb agrees with the value of 0.2155 +- 0.0003 predicted by the Standard Model.Comment: 42 pages, LaTeX, 14 eps figures included, submitted to European Physical Journal

WNT signalling in prostate cancer

Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours-particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT-β-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer