Role of the carboxyl terminal di-leucine in phosphorylation and internalization of C5a receptor

AbstractThe carboxyl tail of G protein-coupled receptors contains motifs that regulate receptor interactions with intracellular partners. Activation of the human neutrophil complement fragment C5a receptor (C5aR) is terminated by phosphorylation of the carboxyl tail followed by receptor internalization. In this study, we demonstrated that bulky hydrophobic residues in the membrane-proximal region of the C5aR carboxyl tail play an important role in proper structure and function of the receptor: Substitution of leucine 319 with alanine (L319A) resulted in receptor retention in the endoplasmic reticulum, whereas a L318A substitution allowed receptor transport to the cell surface, but showed slow internalization upon activation, presumably due to a defect in phosphorylation by both PKC and GRK. Normal agonist-induced activation of ERK1/2 and intracellular calcium release suggested that the L318A mutation did not affect receptor signaling. Binding of GRK2 and PKCβII to intracellular loop 3 of C5aR in vitro indicated that mutagenesis of L318 did not affect kinase binding. Limited proteolysis with trypsin revealed a conformational difference between wild type and mutant receptor. Our studies support a model in which the L318/L319 stabilizes an amphipathic helix (Q305–R320) in the membrane-proximal region of C5aR

On the number of signals in multivariate time series

We assume a second-order source separation model where the observed multivariate time series is a linear mixture of latent, temporally uncorrelated time series with some components pure white noise. To avoid the modelling of noise, we extract the non-noise latent components using some standard method, allowing the modelling of the extracted univariate time series individually. An important question is the determination of which of the latent components are of interest in modelling and which can be considered as noise. Bootstrap-based methods have recently been used in determining the latent dimension in various methods of unsupervised and supervised dimension reduction and we propose a set of similar estimation strategies for second-order stationary time series. Simulation studies and a sound wave example are used to show the method's effectiveness

Bilateral gluteal metastases from a misdiagnosed intrapelvic gastrointestinal stromal tumor

<p>Abstract</p> <p>Background</p> <p>The location of gastrointestinal stromal tumors (GIST) outside of the gastrointestinal system is a rare event.</p> <p>Case presentation</p> <p>A 56-year old woman presented with a GIST of the pelvis was misdiagnosed and treated as a uterine leiomyosarcoma. The diagnosis was made after the CD117 (KIT) positivity in the biopsy of the excised bowel mass four years from the first presentation. During this period she presented a bilateral muscle and subcutaneous metastasis in the gluteal area.</p> <p>Conclusion</p> <p>The correct diagnosis of the extra-gastrointestinal stromal tumor is a challenge even for experienced pathologists. CD117 (KIT) positivity is the most important immunohistochemical feature in the histological diagnosis. To our knowledge a metastatic EGIST (extra-gastrointestinal stromal tumor) to the skeletal muscle bilaterally has not been described previously in the English medical literature.</p

Using Open Data to Rapidly Benchmark Biomolecular Simulations : Phospholipid Conformational Dynamics

Molecular dynamics (MD) simulations are widely used to monitor time-resolved motions of biomacromolecules, although it often remains unknown how closely the conformational dynamics correspond to those occurring in real life. Here, we used a large set of open-access MD trajectories of phosphatidylcholine (PC) lipid bilayers to benchmark the conformational dynamics in several contemporary MD models (force fields) against nuclear magnetic resonance (NMR) data available in the literature: effective correlation times and spin-lattice relaxation rates. We found none of the tested MD models to fully reproduce the conformational dynamics. That said, the dynamics in CHARMM36 and Slipids are more realistic than in the Amber Lipid14, OPLS-based MacRog, and GROMOS-based Berger force fields, whose sampling of the glycerol backbone conformations is too slow. The performance of CHARMM36 persists when cholesterol is added to the bilayer, and when the hydration level is reduced. However, for conformational dynamics of the PC headgroup, both with and without cholesterol, Slipids provides the most realistic description because CHARMM36 overestimates the relative weight of similar to 1 ns processes in the headgroup dynamics. We stress that not a single new simulation was run for the present work. This demonstrates the worth of open-access MD trajectory databanks for the indispensable step of any serious MD study: benchmarking the available force fields. We believe this proof of principle will inspire other novel applications of MD trajectory databanks and thus aid in developing biomolecular MD simulations into a true computational microscope-not only for lipid membranes but for all biomacromolecular systems.Peer reviewe

Set covering with our eyes closed

Given a universe $U$ of $n$ elements and a weighted collection $\mathscr{S}$ of $m$ subsets of $U$, the universal set cover problem is to a priori map each element $u \in U$ to a set $S(u) \in \mathscr{S}$ containing $u$ such that any set $X{\subseteq U}$ is covered by S(X)=\cup_{u\in XS(u). The aim is to find a mapping such that the cost of $S(X)$ is as close as possible to the optimal set cover cost for $X$. (Such problems are also called oblivious or a priori optimization problems.) Unfortunately, for every universal mapping, the cost of $S(X)$ can be $\Omega(\sqrt{n})$ times larger than optimal if the set $X$ is adversarially chosen. In this paper we study the performance on average, when $X$ is a set of randomly chosen elements from the universe: we show how to efficiently find a universal map whose expected cost is $O(\log mn)$ times the expected optimal cost. In fact, we give a slightly improved analysis and show that this is the best possible. We generalize these ideas to weighted set cover and show similar guarantees to (nonmetric) facility location, where we have to balance the facility opening cost with the cost of connecting clients to the facilities. We show applications of our results to universal multicut and disc-covering problems and show how all these universal mappings give us algorithms for the stochastic online variants of the problems with the same competitive factors

Sopeutumisvalmennuksen työnjako

Sopeutumisvalmennus on osa kuntoutuksen kokonaisuutta. Sopeutumisvalmennusta on Suomessa tutkittu vain vähän ja siihen liittyvät tiedontarpeet ovat moninaiset. Toisaalta tarvitaan tietoa sopeutumisvalmennuksen toteutuksesta, sisällöistä ja siitä saatavasta hyödystä ja vaikuttavuudesta. Toisaalta tieto sopeutumisvalmennuksen järjestämisestä ja työnjaosta on tärkeää. Sopeutumisvalmennuksen järjestämisen yhtenä merkittävänä tavoitteena on välttää palvelujen päällekkäisyyksiä tai asiakkaiden väliinputoamista palvelujen välillä. Sujuvassa palvelukokonaisuudessa asiakkaiden tulisi saada tukea, ohjausta ja tietoa vaikeassa elämäntilanteessa selviytymiseen riippumatta asiakkaiden tilanteesta tai asuinalueesta. Tämän tutkimuksen tarkoituksena on ollut tuottaa tietoa, jonka avulla on mahdollista kehittää työnjakoa suomalaisen sopeutumisvalmennuksen järjestämisessä. Sopeutumisvalmennus on otettu huomioon osana muuta kuntoutustoimintaa ja käytännön tason asiat on nostettu kuntoutusjärjestelmän tasolle, siellä oleviksi ilmiöiksi. Tietoa koottiin sopeutumisvalmennuksen nykytilanteesta ja tulevaisuuden visioista. Tutkimus on keskittynyt neljään asiakasryhmään (diabetes, sydän- ja yleisimmät syöpäsairaudet sekä ja neuropsykiatriset häiriöt). Tutkimus on toteutettu kolmella alueella: Hämeenlinna, Oulu ja Vantaa. Tutkimus toteutettiin ajalla 1.11.2015–10.6.2016. Ensisijainen aineisto koostui alueellisten ja valtakunnallisten asiantuntijoiden yksilö-, pari- ja ryhmäteemahaastatteluista sekä avainasiantuntijoiden keskustelutilaisuudesta. Aineistoa täydennettiin eri toimijoiden paikallisten, alueellisten ja valtakunnallisten asiakirjojen, verkkosivujen ja esitteiden avulla. Lisäksi täydentävänä aineistona käytettiin Raha-automaattiyhdistykselle osoitettuja avustushakemuksia, tuloksellisuus- ja vaikutusselvityksiä sekä Lapin yliopistossa meneillään olevan tutkimushankkeen kyselyn tuloksia. Aineisto analysoitiin käyttäen laadullista sisällönerittelyä sekä aineistolähtöistä sisällönanalyysia. Tulosten mukaan sopeutumisvalmennus toteutuu tällä hetkellä vaihtelevasti eri asiakasryhmissä. Toimintatavoissa on eroja alue-, organisaatio ja asiantuntijakohtaisesti. Kentällä on monia toimijoita ja vastuut sekä työnjako ovat osittain epäselviä. Osittain toimijat täydentävät toisiaan. Sisällön suhteen haasteena on erityisesti käsitteen epäselvyys niin asiantuntijoille kuin myös asiakkaille. Kaikkiaan sopeutumisvalmennus mahdollistuu vaihtelevasti osana muuta hoito- ja kuntoutuspolkua. Tulevaisuudessa tulisi täsmentää vastuita ja selkeyttää työnjakoa. Kokonaisuutta tulee tarkastella asiakasprosessien näkökulmasta ja toimijoiden yhteistyötä tulee lisätä. Sopeutumisvalmennus on ymmärrettävä osaksi asiakkaan kokonaisprosessia. Kokonaisuus edellyttää toimintakulttuurin muutosta, mitä tulee tavoitella vähitellen

Disorders of sex development : timing of diagnosis and management in a single large tertiary center

Background: We describe the phenotypic spectrum and timing of diagnosis and management in a large series of patients with disorders of sexual development (DSD) treated in a single pediatric tertiary center. Methods: DSD patients who had visited our tertiary center during the survey period (between 2004 and 2014) were identified based on an ICD-10 inquiry, and their phenotypic and molecular genetic findings were recorded from patient charts. Results: Among the 550 DSD patients, 53.3% had 46,XY DSD; 37.1% had sex chromosome DSD and 9.6% had 46,XX DSD. The most common diagnoses were Turner syndrome (19.8%, diagnosed at the mean age of 4.7 +/- 5.5 years), Klinefelter syndrome (14.5%, 6.8 +/- 6.2 years) and bilateral cryptorchidism (23.1%). Very few patients with 46,XY DSD (7%) or 46,XX DSD (21%) had molecular genetic diagnosis. The yearly rate of DSD diagnoses remained stable over the survey period. After the release of the Nordic consensus on the management of undescended testes, the age at surgery for bilateral cryptorchidism declined significantly (P <0.001). Conclusions: Our results show that (i) Turner syndrome and Klinefelter syndrome, the most frequent single DSD diagnoses, are still diagnosed relatively late; (ii) a temporal shift was observed in the management of bilateral cryptorchidism, which may favorably influence patients' adulthood semen quality and (iii) next-generation sequencing methods are not fully employed in the diagnostics of DSD patients.Peer reviewe

Gastrointestinal stromal tumor of the anal canal: an unusual presentation

BACKGROUND: Gastrointestinal stromal tumors (GIST) of the stomach are the most frequent followed by those of the intestinal tract, while colon and rectum represent rare sites. GIST of the anal canal are extremely rare. They have been studied along with GIST of the rectum, as a single entity, and along with them they represent 5% of GIST. GIST arising from the anal canal account for only 2%–8% of the anorectal GIST. Thus anal GIST must be considered an exceptional case. CASE PRESENTATION: A 78-year-old man was referred to our Institution for an anal mass, in absence of any symptom. The patient was treated by local excision. An histological diagnosis of a low grade GIST was made. No further treatment was necessary. No local recurrence of distant metastases were found at follow-up. CONCLUSION: At the moment, only ten cases of c-kit positive anal GIST are reported in the literature. These few data are not sufficient to establish a widely accepted approach for this neoplasia. We recommend to perform an initial local excision, to define the risk of aggressive behavior and the resection margins and proceed to a more aggressive treatment, if the GIST belongs to high or very high risk group. The role of adjuvant therapy is still uncertain. Although inhibitors of tyrosine-kinase receptor needs further studies before their routine use, their role in case of distant or local recurrence has been accepted. Patients' close follow up is mandatory to disclose as soon as possible local recurrences or metastases

Semiclassical theory of spin-orbit interactions using spin coherent states

We formulate a semiclassical theory for systems with spin-orbit interactions. Using spin coherent states, we start from the path integral in an extended phase space, formulate the classical dynamics of the coupled orbital and spin degrees of freedom, and calculate the ingredients of Gutzwiller's trace formula for the density of states. For a two-dimensional quantum dot with a spin-orbit interaction of Rashba type, we obtain satisfactory agreement with fully quantum-mechanical calculations. The mode-conversion problem, which arose in an earlier semiclassical approach, has hereby been overcome.Comment: LaTeX (RevTeX), 4 pages, 2 figures, accepted for Physical Review Letters; final version (v2) for publication with minor editorial change