waveTM: wavelet-based transmembrane segment prediction

waveTM is a web tool for the prediction of transmembrane segments in alpha-helical membrane proteins. Prediction is performed by a dynamic programming algorithm on wavelet-denoised 'hydropathy' signals. Users submit a protein sequence and receive interactively the results. Topology prediction can also be obtained in conjunction with the algorithm OrienTM. A web server that implements the waveTM algorithm is freely available at http://bioinformatics.biol.uoa.gr/waveTM.     

Genetic structure in the European endemic seabird,Phalacrocorax aristotelis,shaped by a complex interaction of historical and contemporary,physical and nonphysical drivers

Geographically separated populations tend to be less connected by gene flow, as a result of physical or nonphysical barriers preventing dispersal, and this can lead to genetic structure. In this context, highly mobile organisms such as seabirds are interesting because the small effect of physical barriers means nonphysical ones may be relatively more important. Here, we use microsatellite and mitochondrial data to explore the genetic structure and phylogeography of Atlantic and Mediterranean populations of a European endemic seabird, the European shag, Phalacrocorax aristotelis, and identify the primary drivers of their diversification. Analyses of mitochondrial markers revealed three phylogenetic lineages grouping the North Atlantic, Spanish/Corsican and eastern Mediterranean populations, apparently arising from fragmentation during the Pleistocene followed by range expansion. These traces of historical fragmentation were also evident in the genetic structure estimated by microsatellite markers, despite significant contemporary gene flow among adjacent populations. Stronger genetic structure, probably promoted by landscape, philopatry and local adaptation, was found among distant populations and those separated by physical and ecological barriers. This study highlights the enduring effect of Pleistocene climatic changes on shag populations, especially within the Mediterranean Basin, and suggests a role for cryptic northern refugia, as well as known southern refugia, on the genetic structure of European seabirds. Finally, it outlines how contemporary ecological barriers and behavioural traits may maintain population divergence, despite long‐distance dispersal triggered by extreme environmental conditions (e.g. population crashes).     

Oral disease experience of older adults seeking oral health services

doi:10.1111/j.1741‐2358.2009.00311.x
Oral disease experience of older adults seeking oral health services Objective: The objective of this investigation was to describe the dental disease (dental caries and alveolar bone loss) experience in a sample of community‐dwelling older adults who regularly utilize dental services in New York City. Background: Public financing for dental care directed at older adults in the United States is minimal. Improved preventive methods, primarily the use of fluorides, have resulted in declines in tooth loss, and concomitant increase in risk for dental diseases among older adults. While the oral disease burden in institutionalized elderly and those unable to access services is well‐documented, the dental care needs of older adults who access dental services are not well documented. Materials and Methods: Radiographic and record review were used to determine prevalence of dental caries, alveolar bone loss, frequency of service utilization, and medical status in this cross‐sectional investigation of a sample of older adults (N = 200) using dental services at Columbia University College of Dental Medicine. Results: Only 9% of the sample was completely edentulous, the mean DMFT was 19.9 and mean alveolar bone loss was 3.6 mm. Missing and Decayed Teeth accounted for 57.8% and 6.5% of the total caries burden respectively. Missing Teeth and alveolar bone loss increased with increasing age, but there was no increase in Decayed Teeth. Conclusions: While access to and utilization of dental services may result in improved tooth retention, older adults who use dental services continue to have dental care needs, especially periodontal care needs.     

Dephosphorylation of HuR Protein during Alphavirus Infection Is Associated with HuR Relocalization to the Cytoplasm

We have demonstrated previously that the cellular HuR protein binds U-rich elements in the 3′ untranslated region (UTR) of Sindbis virus RNA and relocalizes from the nucleus to the cytoplasm upon Sindbis virus infection in 293T cells. In this study, we show that two alphaviruses, Ross River virus and Chikungunya virus, lack the conserved high-affinity U-rich HuR binding element in their 3′ UTRs but still maintain the ability to interact with HuR with nanomolar affinities through alternative binding elements. The relocalization of HuR protein occurs during Sindbis infection of multiple mammalian cell types as well as during infections with three other alphaviruses. Interestingly, the relocalization of HuR is not a general cellular reaction to viral infection, as HuR protein remained largely nuclear during infections with dengue and measles virus. Relocalization of HuR in a Sindbis infection required viral gene expression, was independent of the presence of a high-affinity U-rich HuR binding site in the 3′ UTR of the virus, and was associated with an alteration in the phosphorylation state of HuR. Sindbis virus-induced HuR relocalization was mechanistically distinct from the movement of HuR observed during a cellular stress response, as there was no accumulation of caspase-mediated HuR cleavage products. Collectively, these data indicate that virus-induced HuR relocalization to the cytoplasm is specific to alphavirus infections and is associated with distinct posttranslational modifications of this RNA-binding protein.     

bHLH-O proteins are crucial for Drosophila neuroblast self-renewal and mediate Notch-induced overproliferation

Drosophila larval neurogenesis is an excellent system for studying the balance between self-renewal and differentiation of a somatic stem cell (neuroblast). Neuroblasts (NBs) give rise to differentiated neurons and glia via intermediate precursors called GMCs or INPs. We show that E(spl)mγ, E(spl)mβ, E(spl)m8 and Deadpan (Dpn), members of the basic helix-loop-helix-Orange protein family, are expressed in NBs but not in differentiated cells. Double mutation for the E(spl) complex and dpn severely affects the ability of NBs to self-renew, causing premature termination of proliferation. Single mutations produce only minor defects, which points to functional redundancy between E(spl) proteins and Dpn. Expression of E(spl)mγ and m8, but not of dpn, depends on Notch signalling from the GMC/INP daughter to the NB. When Notch is abnormally activated in NB progeny cells, overproliferation defects are seen. We show that this depends on the abnormal induction of E(spl) genes. In fact E(spl) overexpression can partly mimic Notch-induced overproliferation. Therefore, E(spl) and Dpn act together to maintain the NB in a self-renewing state, a process in which they are assisted by Notch, which sustains expression of the E(spl) subset.     

Hexadecenoic Fatty Acid Isomers in Human Blood Lipids and Their Relevance for the Interpretation of Lipidomic Profiles

Monounsaturated fatty acids (MUFA) are emerging health biomarkers, and in particular the ratio between palmitoleic acid (9cis-16:1) and palmitic acid (16:0) affords the delta-9 desaturase index that is increased in obesity. Recently, other positional and geometrical MUFA isomers belonging to the hexadecenoic family (C16 MUFA) were found in circulating lipids, such as sapienic acid (6cis-16:1), palmitelaidic acid (9trans-16:1) and 6trans-16:1. In this work we report: i) the identification of sapienic acid as component of human erythrocyte membrane phospholipids with significant increase in morbidly obese patients (n = 50) compared with age-matched lean controls (n = 50); and ii) the first comparison of erythrocyte membrane phospholipids (PL) and plasma cholesteryl esters (CE) in morbidly obese patients highlighting that some of their fatty acid levels have opposite trends: increases of both palmitic and sapienic acids with the decrease of linoleic acid (9cis,12cis-18:2, omega-6) in red blood cell (RBC) membrane PL were reversed in plasma CE, whereas the increase of palmitoleic acid was similar in both lipid species. Consequentially, desaturase enzymatic indexes gave different results, depending on the lipid class used for the fatty acid content. The fatty acid profile of morbidly obese subjects also showed significant increases of stearic acid (C18:0) and C20 omega-6, as well as decreases of oleic acid (9cis-18:1) and docosahexaenoic acid (C22:6 omega-3) as compared with lean healthy controls. Trans monounsaturated and polyunsaturated fatty acids were also measured and found significantly increased in both lipid classes of morbidly obese subjects. These results highlight the C16 MUFA isomers as emerging metabolic marker provided that the assignment of the double bond position and geometry is correctly performed, thus identifying the corresponding lipidomic pathway. Since RBC membrane PL and plasma CE have different fatty acid trends, caution must also be used in the choice of lipid species for the interpretation of lipidomic profiles.     

Impact of heart rate variability,a marker for cardiac health,on lupus disease activity

BackgroundDecreased heart rate variability (HRV) is associated with adverse outcomes in cardiovascular diseases and has been observed in patients with systemic lupus erythematosus (SLE). We examined the relationship of HRV with SLE disease activity and selected cytokine pathways.MethodsFifty-three patients from the Oklahoma Lupus Cohort were evaluated at two visits each. Clinical assessments included the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), British Isles Lupus Assessment Group (BILAG) index, physician global assessment (PGA), and Safety of Estrogens in Lupus Erythematosus National Assessment-SLEDAI Flare Index. HRV was assessed with a 5-minute electrocardiogram, and the following HRV parameters were calculated: square root of the mean of the squares of differences between adjacent NN intervals (RMSSD), percentage of pairs of adjacent NN intervals differing by more than 50 milliseconds (pNN50), high-frequency power (HF power), and low frequency to high frequency (LF/HF) ratio, which reflects sympathetic/vagal balance. Plasma cytokine levels were measured with a multiplex, bead-based immunoassay. Serum B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) were measured with an enzyme-linked immunosorbent assay. Linear regression analysis was applied.ResultsBaseline HRV (pNN50, HF power, LF/HF ratio) was inversely related to disease activity (BILAG, PGA) and flare. Changes in RMSSD between visits were inversely related to changes in SLEDAI (p = 0.007). Age, caffeine, tobacco and medication use had no impact on HRV. Plasma soluble tumor necrosis factor receptor II (sTNFRII) and monokine induced by interferon gamma (MIG) were inversely related with all baseline measures of HRV (p = 0.039 to <0.001). Plasma stem cell factor (SCF), interleukin (IL)-1 receptor antagonist (IL-1RA), and IL-15 showed similar inverse relationships with baseline HRV, and weaker trends were observed for interferon (IFN)-α, interferon gamma-induced protein (IP)-10, and serum BLyS. Changes in the LF/HF ratio between visits were also associated with changes in sTNFRII (p = 0.021), MIG (p = 0.003), IFN-α (p = 0.012), SCF (p = 0.001), IL-1RA (p = 0.023), and IL-15 (p = 0.010). On the basis of multivariate linear regression, MIG was an independent predictor of baseline HRV after adjusting for plasma IL-1RA, SCF, IFN-α, IP-10, and serum BLyS. In a similar model, the sTNFRII impact remained significant after adjusting for the same variables.ConclusionsImpaired HRV, particularly the LF/HF ratio, is associated with lupus disease activity and several cytokines related to IFN type II and TNF pathways. The strongest association was with MIG and sTNFRII, expanding previous immune connections of vagal signaling.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-016-1087-x) contains supplementary material, which is available to authorized users.     

Impaired fertility and spermiogenetic disorders with loss of cell adhesion in male mice expressing an interfering Rap1 mutant

The guanosine trisphosphatase Rap1 serves as a critical player in signal transduction, somatic cell proliferation and differentiation, and cell-cell adhesion by acting through distinct mechanisms. During mouse spermiogenesis, Rap1 is activated and forms a signaling complex with its effector, the serine-threonine kinase B-Raf. To investigate the functional role of Rap1 in male germ cell differentiation, we generated transgenic mice expressing an inactive Rap1 mutant selectively in differentiating spermatids. This expression resulted in a derailment of spermiogenesis due to an anomalous release of immature round spermatids from the seminiferous epithelium within the tubule lumen and in low sperm counts. These spermiogenetic disorders correlated with impaired fertility, with the transgenic males being severely subfertile. Because mutant testis exhibited perturbations in ectoplasmic specializations (ESs), a Sertoli-germ cell-specific adherens junction, we searched for expression of vascular endothelial cadherin (VE-cadherin), an adhesion molecule regulated by Rap1, in spermatogenic cells of wild-type and mutant mice. We found that germ cells express VE-cadherin with a timing strictly related to apical ES formation and function; immature, VE-cadherin-positive spermatids were, however, prematurely released in the transgenic testis. In conclusion, interfering with Rap1 function during spermiogenesis leads to reduced fertility by impairment of germ-Sertoli cell contacts; our transgenic mouse provides an in vivo model to study the regulation of ES dynamics.     

The Role of CaV2.1 Channel Facilitation in Synaptic Facilitation

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