Obesity-associated GNAS mutations and the melanocortin pathway.

This is the final version. Available from Massachusetts Medical Society via the DOI in this record. BACKGROUND: GNAS encodes the Gαs (stimulatory G-protein alpha subunit) protein, which mediates G protein-coupled receptor (GPCR) signaling. GNAS mutations cause developmental delay, short stature, and skeletal abnormalities in a syndrome called Albright's hereditary osteodystrophy. Because of imprinting, mutations on the maternal allele also cause obesity and hormone resistance (pseudohypoparathyroidism). METHODS: We performed exome sequencing and targeted resequencing in 2548 children who presented with severe obesity, and we unexpectedly identified 22 GNAS mutation carriers. We investigated whether the effect of GNAS mutations on melanocortin 4 receptor (MC4R) signaling explains the obesity and whether the variable clinical spectrum in patients might be explained by the results of molecular assays. RESULTS: Almost all GNAS mutations impaired MC4R signaling. A total of 6 of 11 patients who were 12 to 18 years of age had reduced growth. In these patients, mutations disrupted growth hormone-releasing hormone receptor signaling, but growth was unaffected in carriers of mutations that did not affect this signaling pathway (mean standard-deviation score for height, -0.90 vs. 0.75, respectively; P = 0.02). Only 1 of 10 patients who reached final height before or during the study had short stature. GNAS mutations that impaired thyrotropin receptor signaling were associated with developmental delay and with higher thyrotropin levels (mean [±SD], 8.4±4.7 mIU per liter) than those in 340 severely obese children who did not have GNAS mutations (3.9±2.6 mIU per liter; P = 0.004). CONCLUSIONS: Because pathogenic mutations may manifest with obesity alone, screening of children with severe obesity for GNAS deficiency may allow early diagnosis, improving clinical outcomes, and melanocortin agonists may aid in weight loss. GNAS mutations that are identified by means of unbiased genetic testing differentially affect GPCR signaling pathways that contribute to clinical heterogeneity. Monogenic diseases are clinically more variable than their classic descriptions suggest. (Funded by Wellcome and others.).Wellcome TrustWellcome TrustResearch EnglandNational Institute for Health Researc

Measurement of global polarization of {\Lambda} hyperons in few-GeV heavy-ion collisions

The global polarization of {\Lambda} hyperons along the total orbital angular momentum of a relativistic heavy-ion collision is presented based on the high statistics data samples collected in Au+Au collisions at \sqrt{s_{NN}} = 2.4 GeV and Ag+Ag at 2.55 GeV with the High-Acceptance Di-Electron Spectrometer (HADES) at GSI, Darmstadt. This is the first measurement below the strangeness production threshold in nucleon-nucleon collisions. Results are reported as a function of the collision centrality as well as a function of the hyperon transverse momentum (p_T) and rapidity (y_{CM}) for the range of centrality 0--40%. We observe a strong centrality dependence of the polarization with an increasing signal towards peripheral collisions. For mid-central (20--40%) collisions the polarization magnitudes are (%) = 6.0 \pm 1.3 (stat.) \pm 2.0 (syst.) for Au+Au and (%) = 4.6 \pm 0.4 (stat.) \pm 0.5 (syst.) for Ag+Ag, which are the largest values observed so far. This observation thus provides a continuation of the increasing trend previously observed by STAR and contrasts expectations from recent theoretical calculations predicting a maximum in the region of collision energies about 3 GeV. The observed polarization is of a similar magnitude as predicted by 3D fluid dynamics and the UrQMD plus thermal vorticity model and significantly above results from the AMPT model.Comment: 8 pages, 4 figure

The trace fossil Lepidenteron lewesiensis: a taphonomic window on diversity of Late Cretaceous fishes

The trace fossil Lepidenteron lewesiensis (Mantell 1822) provides an exceptional taphonomic window to diversity of fishes as shown for the Upper Cretaceous of Poland, in the Middle Turonian–Lower Maastrichtian deposits of the Opole Trough, Miechów Trough, Mazury-Podlasie Homocline, and SE part of the Border Synclinorium. Lepidenteron lewesiensis is an unbranched burrow lined with small fish scales and bones, without a constructed wall. It contains scales, vertebrae, and bones of the head belonging to ten taxa of teleostean fishes: two undetermined teleosteans, six undetermined Clupeocephala, one Dercetidae, and one undetermined euteleostean. The preservation of fish remains suggests that fishes were pulled down into the burrow by an animal, probably by eunicid polychaetes.Das Spurenfossil Lepidenteron lewesiensis (Mantell 1822) ermöglicht einen biostratinomischen Einblick in die Diversität von Fischen, wie Fossilmaterial aus der Oberkreide von Polen zeigt. Es stammt aus dem Mittelturonium bis Untermaastrichtium des südöstlichen Abschnittes der Grenz-Synklinale, dem Opolen-Trog, dem Miechów-Trog und der Masuren-Podlachien-Homoklinale. L. lewesiensis ist ein unverzweigter Grabgang ohne ausgekleidete Wände, dessen Ränder von kleinen Fischschuppen und—knochen gebildet werden. Diese setzen sich aus Schuppen, Wirbel und Schädelknochen von zehn Teleostei-Taxa zusammen und zwar aus zwei unbestimmte Teleosteer, sechs unbestimmten Clupeocephala, einem Dercetidae und einem unbestimmten Euteleostei. Die Erhaltung der Fischüberreste deutet darauf hin, dass die Fische von einem Tier, wahrscheinlich einem Polychaeten der Familie Eunicidae, in den Bau gezogen wurden.We are very grateful to Dr. Lionel Cavin (Geneva) and the anonymous reviewer for constructive comments on an earlier version of the manuscript. Additional support was provided by the Jagiellonian University (DS funds), National Science Center (Grant Number: PRO-2011/01/N/ST10/07717), and the Laboratory of Geology (University of Lodz) BSt Grant No. 560/844. We are grateful to Dr. Johann Egger (Wien) and Kilian Eichenseer M.Sc. (Erlangen) for help with translating the abstract into German. We are grateful to Dr. Ursula Göhlich (Wien) for access to the Dercetis specimen

The project of the Geopark "Wisłok Valley - The Polish Texas”

The Polish Geological Institute - National Research Institute is implementing a number of projects of new geoparks in Poland. One of them is the Geopark "Wislok Valley - The Polish Texas", which is located in the Polish Outer Carpathians (SE part). Oil resources, nappe tectonics and other geological components of the Outer Carpathians constitute important elements of the geodiversity of this region. The area is located in the Beskid Niski Mts. in the Jaslo-Sanok Basin and Strzyżów, Dynów, Jaslo and Bukowskie Foothills, between Strzyżów and Barwinek, and encloses an area of about 1000 km2. It covers 19 municipalities in six districts of the Podkarpackie Voivodeship: Krosno (city county and county), Jaslo, Brzozów, Strzyżów, Sanok. For the project of the geopark's geotouristic map, geosites and geological-educational paths will be created. The geopark website and different advertising brochures will promote geoturism. The final product will be targeted at regional and local public administration bodies

Tectonic zones of southwestern Podhale

Various structural observations were collected in southwestern Podhale Trough during investigations for Detailed map of Tatra Mts., scale 1 : 10 000. Fault surfaces, strikes and dips of beds and fold axes were measured in the field. Statistical analysis of results allow to recognize 5 groups of dislocations with variable types of movement, directions and age: 1) slickensides onW-E striking, almost horizontal bedding surfaces show reverse motion towards S, 2) steeply-dipping (80–90(centigrade)) faults, striking parallel to bedding and also showing reverse motion towards S, 3) vertical transcurrent faults associated with main tectonic zones, striking almost N-S, 4) normal faults striking ca 38(centigrade) (NE-SW) and 135(centigrade) (NW-SE). Attitudes of beds different from regional trend were separated. Deviations are caused by flexural bending along tectonic zones. Anomalous attitudes of beds coincide with directions of dislocations recognized in the field. A map of lineaments in the study area is also presented. Analysis of landforms on Digital Terrain Model (DTM) led to recognition of series of lineaments related to either tectonic structures or lithology. Main transverse tectonic zones were identified on the map of lineaments: Chochołowski Potok-Czarny Dunajec, Kooecieliski Potok, Mała Łąka; as well as some minor faults and zones where particular directions of faults predominate. Statistic analysis of directions of tectolineaments allows to recognize 4 main directions: 1) about 90°, associated to thrusts and folds (parallel to strikes of beds), 2) N-S and slightly oblique directions associated to transcurrent zones, 3) approximately 40(centigrade) and 4) 140(centigrade) directions associated to normal faults. Results obtained using these 3 methods (analysis of field data, analysis of DTM, analysis of attitudes of beds different from regional trend) are consistent with each other

Oligocene bivalve faunas from the Silesian Nappe, Polish Outer Carpathians: Evidence for the early history of the Paratethys

The study is focused on the taxonomic inventory of an intriguing bivalve fauna from the Lower Oligocene Menilite Beds (Dynów Marls) within the Silesian Nappe, Polish Outer Carpathians. Sixteen bivalve species have been identified within the material collected in two small quarries in Jabłonica Polska near Krosno. Stratigraphic and geographic distributions of all recognized species are considered. This assemblage, the first of this kind in Poland and one of three recognized in the Outer Carpathians, shows clear affinities to coeval typical Solenovian faunas from Ukraine to Kazakhstan, with particular comparison made to bivalve faunas from the Menilite Formation (Subchert Member) within the Boryslav-Pokuttya Nappe, Ukrainian Outer Carpathians. Moreover, this study presents an overview of the main aspects and definitions of the date of the Paratethys origin. The main criterion used to define the time of the Paratethys birth is the distinct faunal turnover from the moderately diverse boreal or Tethyan bivalve faunas populating particular basins of the Northern Peri-Tethys in the earliest Oligocene to the uniform, highly endemic fauna inhabiting the newly formed semi-closed basin. This vast inland sea, named Paratethys, was populated by representatives of eight euryhaline bivalve families. They are characterized by extinct Paratethyan genera, such as Bessia Kojumdgieva et Sapungieva, Merklinicardium Popov, Korobkoviella Merklin, Urbnisia Goncharova, Ergenica G. Popov and Janschinella Merklin

The business case for sustainable commercial buildings

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НОВЕ МІСЦЕЗНАХОДЖЕННЯ ДВОСТУЛКОВИХ МОЛЮСКІВ ЗОВНІШНИХ КАРПАТ ПОЛЬЩІ

The peculiar Oligocene bivalve fauna typical of the Solenovian stage of the Paratethys has been found in the Outer Carpathians, Poland. It includes nine species, six of which are characteristic Paratethyan endemics known from the Solenovian Sea (second part of the Rupelian) with brackishwater conditions.Своеобразный комплекс двустворчатых моллюсков, характерных для соленовского уровня опреснения бассейна Паратетис, впервые найден во Внешних Карпатах Польши. Он содержит девять видов, из которых шесть являются специфичными солоноватоводными эндемиками Паратетиса, известными для соленовского времени опреснения бассейна позднего рюпеля.Своєрідний комплекс двостулкових молюсків, характерних для солонівського рівня опріснення басейну Паратетіс, вперше знайдено в Зовнішніх Карпатах Польщі. Він містить дев’ять видів, з яких шість є специфічними солонуватоводними ендеміками Паратетісу, відомими для солонівського часу опріснення басейну пізнього рюпелю