Receptor protein tyrosine phosphatases are novel components of the polycystin complex

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutation of PKD1 and PKD2 that encode polycystin-1 and polycystin-2. Polycystin-1 is tyrosine phosphorylated and modulates multiple signaling pathways including AP-1, and the identity of the phosphatases regulating polycystin-1 are previously uncharacterized. Here we identify members of the LAR protein tyrosine phosphatase (RPTP) superfamily as members of the polycystin-1complex mediated through extra- and intracellular interactions. The first extracellular PKD1 domain of polycystin-1 interacts with the first Ig domain of RPTPσ, while the polycystin-1 C-terminus of polycystin-1 interacts with the regulatory D2 phosphatase domain of RPTPγ. Additional homo- and heterotypic interactions between RPTPs recruit RPTPδ. The multimeric polycystin protein complex is found localised in cilia. RPTPσ and RPTPδ are also part of a polycystin-1/E-cadherin complex known to be important for early events in adherens junction stabilisation. The interaction between polycystin-1 and RPTPγ is disrupted in ADPKD cells, while RPTPσ and RPTPδ remain closely associated with E-cadherin, largely in an intracellular location. The polycystin-1 C-terminus is an in vitro substrate of RPTPγ, which dephosphorylates the c-Src phosphorylated Y4237 residue and activates AP1-mediated transcription. The data identify RPTPs as novel interacting partners of the polycystins both in cilia and at adhesion complexes and demonstrate RPTPγ phosphatase activity is central to the molecular mechanisms governing polycystin-dependent signaling. This article is part of a Special Issue entitled: Polycystic Kidney Disease

Operational forecasting of daily summer maximum and minimum temperatures in the Valencia Region

Extreme-temperature events have a great impact on human society. Thus, knowledge of summer temperatures can be very useful both for the general public and for organizations whose workers operate in the open. An accurate forecasting of summer maximum and minimum temperatures could help to predict heatwave conditions and permit the implementation of strategies aimed at minimizing the negative effects that high temperatures have on human health. The objective of this work is to evaluate the skill of the regional atmospheric and modelling system (RAMS) model in determining daily summer maximum and minimum temperatures in the Valencia Region. For this, we have used the real-time configuration of this model currently running at the Centro de Estudios Ambientales de Mediterráneo Foundation. This operational system is run twice a day, and both runs have a 3-day forecast range. To carry out the verification of the model in this work, the information generated by the system has been broken into individual simulation days for a specific daily run of the model. Moreover, we have analysed the summer forecast period from 1 June to 31 August for 2007, 2008, 2009 and 2010. The results indicate good agreement between observed and simulated maximum temperatures, with RMSE in general near 2 °C both for coastal and inland stations. For this parameter, the model shows a negative bias around −1.5 °C in the coast, while the opposite trend is observed inland. In addition, RAMS also shows good results in forecasting minimum temperatures for coastal locations, with bias lower than 1 °C and RMSE below 2 °C. However, the model presents some difficulties for this parameter inland, where bias higher than 3 °C and RMSE of about 4 °C have been found. Besides, there is little difference in both temperatures forecasted within the two daily RAMS cycles and that RAMS is very stable in maintaining the forecast performance at least for three forecast days

Menstruation angina: a case report

<p>Abstract</p> <p>Introduction</p> <p>Menstruation is commonly associated with migraine and irritable bowel but is rarely correlated with angina or myocardial ischaemia. Only a small number of cases have been reported suggesting a link between menstruation and myocardial ischaemic events.</p> <p>Case presentation</p> <p>A case of menstruation angina is reported in order to raise awareness of this association. A 47-year-old South Asian woman presented with recurrent chest pains in a monthly fashion coinciding with her menstruations. Each presentation was associated with troponin elevation. Angioplasty failed to resolve her symptoms but she eventually responded to hormonal therapy.</p> <p>Conclusions</p> <p>The possibility of menstruation angina should always be taken into account in any female patients from puberty to menopause presenting with recurrent chest pains. This can allow an earlier introduction of hormonal therapy to arrest further myocardial damage.</p

Association between retinal vein occlusion, axial length and vitreous chamber depth measured by optical low coherence reflectometry.

BACKGROUND: Results of ocular biometric measurements in retinal vein occlusion (RVO) eyes are still inconclusive and controversial. The aim of this study was to evaluate the association between ocular axial length (AL), vitreous chamber depth (VCD) and both central (CRVO) and branch retinal vein occlusions (BRVO) using optical low coherence reflectometry (OLCR). METHODS: Both eyes of 37 patients with unilateral CRVO (mean age: 66 +/- 14 years, male:female - 21:16) and 46 patients with unilateral BRVO (mean age: 63 +/- 12 years, male:female - 24:22) were enrolled in this study. The control group consisted of randomly selected single eyes of 67 age and gender matched volunteers without the presence or history of RVO (mean age: 64 +/- 14 years, male:female - 34:33). Optical biometry was performed by OLCR biometer (LenStar LS 900). Average keratometry readings, central corneal thickness (CCT), anterior chamber depth (ACD), lens thickness (LT), AL and VCD of eyes with RVO were compared with those of fellow eyes using paired t-tests and with those of control eyes using independent t-tests. RESULTS: Mean CCT, ACD and LT, average keratometry readings of affected RVO eyes, unaffected fellow eyes and control eyes was not statistically different in either groups. In eyes with CRVO mean AL and VCD of affected eyes were significantly shorter than those of control eyes (p < 0.001, p < 0.05), mean difference in AL and VCD between the affected and control eyes was 0.56 +/- 0.15 mm and 0.45 +/- 0.19 mm, respectively. In eyes with BRVO, mean AL of the affected eyes was significantly shorter with a mean difference of 0.57 +/- 0.15 mm (p < 0.001) and the VCD was significantly shorter with a mean difference of 0.61 +/- 0.15 mm (p < 0.001) comparing with the control eyes. CONCLUSION: Shorter AL and VCD might be a potential anatomical predisposing factor for development either of CRVO or BRVO

An assessment of functioning and non-functioning distractors in multiple-choice questions: a descriptive analysis

<p>Abstract</p> <p>Background</p> <p>Four- or five-option multiple choice questions (MCQs) are the standard in health-science disciplines, both on certification-level examinations and on in-house developed tests. Previous research has shown, however, that few MCQs have three or four functioning distractors. The purpose of this study was to investigate non-functioning distractors in teacher-developed tests in one nursing program in an English-language university in Hong Kong.</p> <p>Methods</p> <p>Using item-analysis data, we assessed the proportion of non-functioning distractors on a sample of seven test papers administered to undergraduate nursing students. A total of 514 items were reviewed, including 2056 options (1542 distractors and 514 correct responses). Non-functioning options were defined as ones that were chosen by fewer than 5% of examinees and those with a positive option discrimination statistic.</p> <p>Results</p> <p>The proportion of items containing 0, 1, 2, and 3 functioning distractors was 12.3%, 34.8%, 39.1%, and 13.8% respectively. Overall, items contained an average of 1.54 (SD = 0.88) functioning distractors. Only 52.2% (n = 805) of all distractors were functioning effectively and 10.2% (n = 158) had a choice frequency of 0. Items with more functioning distractors were more difficult and more discriminating.</p> <p>Conclusion</p> <p>The low frequency of items with three functioning distractors in the four-option items in this study suggests that teachers have difficulty developing plausible distractors for most MCQs. Test items should consist of as many options as is feasible given the item content and the number of plausible distractors; in most cases this would be three. Item analysis results can be used to identify and remove non-functioning distractors from MCQs that have been used in previous tests.</p

Iodine Atoms: A New Molecular Feature for the Design of Potent Transthyretin Fibrillogenesis Inhibitors

The thyroid hormone and retinol transporter protein known as transthyretin (TTR) is in the origin of one of the 20 or so known amyloid diseases. TTR self assembles as a homotetramer leaving a central hydrophobic channel with two symmetrical binding sites. The aggregation pathway of TTR into amiloid fibrils is not yet well characterized but in vitro binding of thyroid hormones and other small organic molecules to TTR binding channel results in tetramer stabilization which prevents amyloid formation in an extent which is proportional to the binding constant. Up to now, TTR aggregation inhibitors have been designed looking at various structural features of this binding channel others than its ability to host iodine atoms. In the present work, greatly improved inhibitors have been designed and tested by taking into account that thyroid hormones are unique in human biochemistry owing to the presence of multiple iodine atoms in their molecules which are probed to interact with specific halogen binding domains sitting at the TTR binding channel. The new TTR fibrillogenesis inhibitors are based on the diflunisal core structure because diflunisal is a registered salicylate drug with NSAID activity now undergoing clinical trials for TTR amyloid diseases. Biochemical and biophysical evidence confirms that iodine atoms can be an important design feature in the search for candidate drugs for TTR related amyloidosis

The relationship between a child's postural stability and manual dexterity

The neural systems responsible for postural control are separate from the neural substrates that underpin control of the hand. Nonetheless, postural control and eye-hand coordination are linked functionally. For example, a stable platform is required for precise manual control tasks (e.g. handwriting) and thus such skills often cannot develop until the child is able to sit or stand upright. This raises the question of the strength of the empirical relationship between measures of postural stability and manual motor control. We recorded objective computerised measures of postural stability in stance and manual control in sitting in a sample of school children (n = 278) aged 3–11 years in order to explore the extent to which measures of manual skill could be predicted by measures of postural stability. A strong correlation was found across the whole sample between separate measures of postural stability and manual control taken on different days. Following correction for age, a significant but modest correlation was found. Regression analysis with age correction revealed that postural stability accounted for between 1 and 10 % of the variance in manual performance, dependent on the specific manual task. These data reflect an interdependent functional relationship between manual control and postural stability development. Nevertheless, the relatively small proportion of the explained variance is consistent with the anatomically distinct neural architecture that exists for ‘gross’ and ‘fine’ motor control. These data justify the approach of motor batteries that provide separate assessments of postural stability and manual dexterity and have implications for therapeutic intervention in developmental disorders

Stratification of co-evolving genomic groups using ranked phylogenetic profiles

<p>Abstract</p> <p>Background</p> <p>Previous methods of detecting the taxonomic origins of arbitrary sequence collections, with a significant impact to genome analysis and in particular metagenomics, have primarily focused on compositional features of genomes. The evolutionary patterns of phylogenetic distribution of genes or proteins, represented by phylogenetic profiles, provide an alternative approach for the detection of taxonomic origins, but typically suffer from low accuracy. Herein, we present <it>rank-BLAST</it>, a novel approach for the assignment of protein sequences into genomic groups of the same taxonomic origin, based on the ranking order of phylogenetic profiles of target genes or proteins across the reference database.</p> <p>Results</p> <p>The rank-BLAST approach is validated by computing the phylogenetic profiles of all sequences for five distinct microbial species of varying degrees of phylogenetic proximity, against a reference database of 243 fully sequenced genomes. The approach - a combination of sequence searches, statistical estimation and clustering - analyses the degree of sequence divergence between sets of protein sequences and allows the classification of protein sequences according to the species of origin with high accuracy, allowing taxonomic classification of 64% of the proteins studied. In most cases, a main cluster is detected, representing the corresponding species. Secondary, functionally distinct and species-specific clusters exhibit different patterns of phylogenetic distribution, thus flagging gene groups of interest. Detailed analyses of such cases are provided as examples.</p> <p>Conclusion</p> <p>Our results indicate that the rank-BLAST approach can capture the taxonomic origins of sequence collections in an accurate and efficient manner. The approach can be useful both for the analysis of genome evolution and the detection of species groups in metagenomics samples.</p

Wnt signaling and orthopedics, an overview

Wnt signaling is a ubiquitous system for intercellular communication, with multiple functions during development and in homeostasis of the body. It comprises several ligands, receptors, and inhibitors. Some molecules, such as sclerostin, appear to have bone-specific functions, and can be targeted by potential drugs. Now, ongoing clinical trials are testing these drugs as treatments for osteoporosis. Animal studies have also suggested that these drugs can accelerate fracture healing and implant fixation. This brief overview focuses on currently available information on the effects of manipulations of Wnt signaling on bone healing