Corticotropinoma as a Component of Carney Complex.

Known germline gene abnormalities cause one-fifth of the pituitary adenomas in children and adolescents, but, in contrast with other pituitary tumor types, the genetic causes of corticotropinomas are largely unknown. In this study, we report a case of Cushing disease (CD) due to a loss-of-function mutation in PRKAR1A, providing evidence for association of this gene with a corticotropinoma. A 15-year-old male presenting with hypercortisolemia was diagnosed with CD. Remission was achieved after surgical resection of a corticotropin (ACTH)-producing pituitary microadenoma, but recurrence 3 years later prompted reoperation and radiotherapy. Five years after the original diagnosis, the patient developed ACTH-independent Cushing syndrome, and a diagnosis of primary pigmented nodular adrenocortical disease was confirmed. A PRKAR1A mutation (c.671delG, p.G225Afs*16) was detected in a germline DNA sample from the patient, which displayed loss of heterozygosity in the corticotropinoma. No other germline or somatic mutations of interest were found. As corticotropinomas are not a known component of Carney complex (CNC), we performed loss of heterozygosity and messenger RNA stability studies in the patient's tissues, and analyzed the effect of Prkar1a silencing on AtT-20/D16v-F2 mouse corticotropinoma cells. No PRKAR1A defects were found among 97 other pediatric CD patients studied. Our clinical case and experimental data support a role for PRKAR1A in the pathogenesis of a corticotroph cell tumor. This is a molecularly confirmed report of a corticotropinoma presenting in association with CNC. We conclude that germline PRKAR1A mutations are a novel, albeit apparently infrequent, cause of CD

Canonical Melnikov theory for diffeomorphisms

We study perturbations of diffeomorphisms that have a saddle connection between a pair of normally hyperbolic invariant manifolds. We develop a first-order deformation calculus for invariant manifolds and show that a generalized Melnikov function or Melnikov displacement can be written in a canonical way. This function is defined to be a section of the normal bundle of the saddle connection. We show how our definition reproduces the classical methods of Poincar\'{e} and Melnikov and specializes to methods previously used for exact symplectic and volume-preserving maps. We use the method to detect the transverse intersection of stable and unstable manifolds and relate this intersection to the set of zeros of the Melnikov displacement.Comment: laTeX, 31 pages, 3 figure

Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing's disease.

The CABLES1 cell cycle regulator participates in the adrenal-pituitary negative feedback, and its expression is reduced in corticotropinomas, pituitary tumors with a largely unexplained genetic basis. We investigated the presence of CABLES1 mutations/copy number variations (CNVs) and their associated clinical, histopathological and molecular features in patients with Cushing's disease (CD). Samples from 146 pediatric (118 germline DNA only/28 germline and tumor DNA) and 35 adult (tumor DNA) CD patients were screened for CABLES1 mutations. CNVs were assessed in 116 pediatric CD patients (87 germline DNA only/29 germline and tumor DNA). Four potentially pathogenic missense variants in CABLES1 were identified, two in young adults (c.532G > A, p.E178K and c.718C > T, p.L240F) and two in children (c.935G > A, p.G312D and c.1388A > G, and p.D463G) with CD; no CNVs were found. The four variants affected residues within or close to the predicted cyclin-dependent kinase-3 (CDK3)-binding region of the CABLES1 protein and impaired its ability to block cell growth in a mouse corticotropinoma cell line (AtT20/D16v-F2). The four patients had macroadenomas. We provide evidence for a role of CABLES1 as a novel pituitary tumor-predisposing gene. Its function might link two of the main molecular mechanisms altered in corticotropinomas: the cyclin-dependent kinase/cyclin group of cell cycle regulators and the epidermal growth factor receptor signaling pathway. Further studies are needed to assess the prevalence of CABLES1 mutations among patients with other types of pituitary adenomas and to elucidate the pituitary-specific functions of this gene

The Maximal Denumerant of a Numerical Semigroup

Given a numerical semigroup S = and n in S, we consider the factorization n = c_0 a_0 + c_1 a_1 + ... + c_t a_t where c_i >= 0. Such a factorization is maximal if c_0 + c_1 + ... + c_t is a maximum over all such factorizations of n. We provide an algorithm for computing the maximum number of maximal factorizations possible for an element in S, which is called the maximal denumerant of S. We also consider various cases that have connections to the Cohen-Macualay and Gorenstein properties of associated graded rings for which this algorithm simplifies.Comment: 13 Page

Bridging the Binding Sites : Dualsteric Ligands for the Cannabinoid 2 Receptor (CB2R)

Acknowledgements This project was financially supported by the German Research Foundation (Deutsche Forschungsgemeinschaft under DFG DE1546/10-1). Gratitude is expressed to the International Doctorate Program “Receptor Dynamics” of the Elite Network of Bavaria (ENB) for financial support of A.T. and S.A.M.S. (grant No. K-BM-2013-247). Y.A.R. was granted a scholarship by the German Academic Exchange Service (Deutscher Akademischer Austauschdienst, DAAD) program “Research stays for university academics and scientists.” D.A.R.-S. was awarded a Ph.D. scholarship by the DAAD. J.N.H. was financially supported by NHS Grampian. Furthermore, the authors thank Professor Dr. Kristina Lorenz (Institute of Pharmacology and Toxicology, University of Würzburg) for enabling them to conduct in vitro experiments in her laboratory. Open access funding enabled and organized by Projekt DEAL.Peer reviewedPublisher PD

Brownian bridges to submanifolds

We introduce and study Brownian bridges to submanifolds. Our method involves proving a general formula for the integral over a submanifold of the minimal heat kernel on a complete Riemannian manifold. We use the formula to derive lower bounds, an asymptotic relation and derivative estimates. We also see a connection to hypersurface local time. This work is motivated by the desire to extend the analysis of path and loop spaces to measures on paths which terminate on a submanifold

Barium abundance in red giants of NGC 6752. Non-local thermodynamic equilibrium and three-dimensional effects

(Abridged) Aims: We study the effects related to departures from non-local thermodynamic equilibrium (NLTE) and homogeneity in the atmospheres of red giant stars in Galactic globular cluster NGC 6752, to assess their influence on the formation of Ba II lines. Methods: One-dimensional (1D) local thermodynamic equilibrium (LTE) and 1D NLTE barium abundances were derived using classical 1D ATLAS stellar model atmospheres. The three-dimensional (3D) LTE abundances were obtained for 8 red giants on the lower RGB, by adjusting their 1D LTE abundances using 3D-1D abundance corrections, i.e., the differences between the abundances obtained from the same spectral line using the 3D hydrodynamical (CO5BOLD) and classical 1D (LHD) stellar model atmospheres. Results: The mean 1D barium-to-iron abundance ratios derived for 20 giants are _{1D NLTE} = 0.05 \pm0.06 (stat.) \pm0.08 (sys.). The 3D-1D abundance correction obtained for 8 giants is small (~+0.05 dex), thus leads to only minor adjustment when applied to the mean 1D NLTE barium-to-iron abundance ratio for the 20 giants, _{3D+NLTE} = 0.10 \pm0.06(stat.) \pm0.10(sys.). The intrinsic abundance spread between the individual cluster stars is small and can be explained in terms of uncertainties in the abundance determinations. Conclusions: Deviations from LTE play an important role in the formation of barium lines in the atmospheres of red giants studied here. The role of 3D hydrodynamical effects should not be dismissed either, even if the obtained 3D-1D abundance corrections are small. This result is a consequence of subtle fine-tuning of individual contributions from horizontal temperature fluctuations and differences between the average temperature profiles in the 3D and 1D model atmospheres: owing to the comparable size and opposite sign, their contributions nearly cancel each other.Comment: Minor typos corrected. Accepted for publication in A&A (9 pages, 3 figures, 6 tables

EFECTO DE TRATAMIENTOS PRE-GERMINATIVOS EN LA CALIDAD DE PLÁNTULAS GUAPINOL (HYMENAEA COURBARIL)

This research has evaluated the effect of five pre-germination treatments on the quality and structure of plant locust (Hymenaea courbaril) due to the high variability in the germination and emergency tillage. Five treatments were evaluated by measuring the rate of Germanization and emergency speed; quality parameters (height and diameter) together with biomass (fresh and dry weight) of seedlings, bringing the Dickson quality index were estimated. Each treatment group contained 50 replicates for 250 plants in the experiment. The data were processed with statistical SPSS V.22.0: variance, standard deviation, variance analysis, obtaining statistical tests of binary correlations, repeated measures analysis and analysis of variance (ANOVA), intra and inter groups, 95% (P-valor 0.05) of confidence. The results show differences between treatments three (hydration) and four (mechanical scarification) regarding treatment one (thermal) and two (chemical) where no statistically significant difference. Treatment five (witness) has less statistical difference with all other evaluated. These same data for determining a positive effect between application of pre germination treatments and increased seedling quality of 93.0%, this translates to a greater chance of survival of the plant to be transplanted in the field. It is tested combination treatments one and three.Esta investigación ha evaluado el efecto que tiene cinco tratamientos pre-germinativos en la calidad y estructura de las planta de guapinol (Hymenaea courbaril) debido a la elevada variabilidad en la germinación y emergencia con la siembra directa. Se evaluaron cinco tratamientos, midiendo el índice de germanización y velocidad de emergencia, parámetros de calidad (altura y diámetro) junto con la de biomasa (peso fresco y seco) de las plántulas, con lo que se estimó el índice de calidad de Dickson. Cada uno de los tratamientos consto de 50 repeticiones para un total de 250 plántulas dentro del experimento. Los datos se procesaron SPSS V.22.0 con los estadísticos: varianza, desviación estándar, análisis de varianza, obteniendo las pruebas estadísticas de correlaciones binarias, análisis de medidas repetidas y análisis de varianza (ANOVA), intra e inter grupos, a un 95% (P-valor 0.05) de confianza. Los resultados muestran diferencia entre los tratamientos tres (hidratación) y cuatro (escarificación mecánica) respecto al tratamiento uno (térmico) y dos (químico) donde no hay diferencia estadísticamente significativa. El tratamiento cinco (testigo) presenta diferencia estadística menor con todos los demás evaluados. Estos mismos datos permiten determinar un efecto positivo entre la aplicación de tratamientos pre-germinativos y el aumento de la calidad de la plántula de un 93.0%, esto se traduce a mayores posibilidades de sobrevivencia de la planta al ser trasplantada en campo. Debe probarse la combinación de los tratamientos uno y tres

Midazolam nasal spray to treat intermittent, stereotypic episodes of frequent seizure activity: pharmacology and clinical role, a comprehensive review.

An intranasal formulation of midazolam, Nayzilam, has been FDA-approved to treat intermittent, stereotypic episodes of frequent seizure activity. Nayzilam is easy to administer and can quickly treat seizures that occur outside of the hospital. The intra-nasal route of administration allows non-medical personal to administer the drug which makes it more accessible and user-friendly in the event of a seizure. Many studies have indicated quick cessation of seizures with Nayzilam compared to rectal diazepam, which has been the standard of care treatment. Nayzilam has been proven to be safe and effective for acute seizures in children, deeming it a revolutionary alternative in times where intravenous administration is not possible