AIPvariant causing familial prolactinoma

Pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene are increasingly recognised as a cause of familial isolated pituitary adenoma. AIP-associated tumours are most commonly growth hormone (GH) producing. In our cohort of 175 AIP mutation positive patients representing 93 kindreds, 139 (79%) have GH excess, 19 have prolactinoma (17 familial and 2 sporadic cases) and out of the 17 clinically non-functioning tumours 4 were subsequently operated and found to be GH or GH & prolactin immunopositive adenoma. Here we report a family with an AIP variant, in which multiple family members are affected by prolactinoma, but none with GH excess. To our knowledge this is the first reported family with an AIP pathogenic variant to be affected solely by prolactinoma. These data suggest that prolactinoma families represent a small subset of AIP mutation positive kindreds, and similar to young-onset sporadic prolactinomas, AIP screening would be indicated

What do the JAMA editors say when they discuss manuscripts that they are considering for publication? Developing a schema for classifying the content of editorial discussion

<p>Abstract</p> <p>Background</p> <p>In an effort to identify previously unrecognized aspects of editorial decision-making, we explored the words and phrases that one group of editors used during their meetings.</p> <p>Methods</p> <p>We performed an observational study of discussions at manuscript meetings at <it>JAMA</it>, a major US general medical journal. One of us (KD) attended 12 editorial meetings in 2003 as a visitor and took notes recording phrases from discussion surrounding 102 manuscripts. In addition, editors attending the meetings completed a form for each manuscript considered, listing the reasons they were inclined to proceed to the next step in publication and reasons they were not (DR attended 4/12 meetings). We entered the spoken and written phrases into NVivo 2.0. We then developed a schema for classifying the editors' phrases, using an iterative approach.</p> <p>Results</p> <p>Our classification schema has three main themes: science, journalism, and writing. We considered 2,463 phrases, of which 87 related mainly to the manuscript topic and were not classified (total 2,376 classified). Phrases related to science predominated (1,274 or 54%). The editors, most of whom were physicians, also placed major weight on goals important to JAMA's mission (journalism goals) such as importance to medicine, strategic emphasis for the journal, interest to the readership, and results (729 or 31% of phrases). About 16% (n = 373) of the phrases used related to writing issues, such as clarity and responses to the referees' comments.</p> <p>Conclusion</p> <p>Classification of editorial discourse provides insight into editorial decision making and concepts that need exploration in future studies.</p

Scattering Amplitudes and BCFW Recursion in Twistor Space

Twistor ideas have led to a number of recent advances in our understanding of scattering amplitudes. Much of this work has been indirect, determining the twistor space support of scattering amplitudes by examining the amplitudes in momentum space. In this paper, we construct the actual twistor scattering amplitudes themselves. We show that the recursion relations of Britto, Cachazo, Feng and Witten have a natural twistor formulation that, together with the three-point seed amplitudes, allows us to recursively construct general tree amplitudes in twistor space. We obtain explicit formulae for $n$-particle MHV and NMHV super-amplitudes, their CPT conjugates (whose representations are distinct in our chiral framework), and the eight particle N^2MHV super-amplitude. We also give simple closed form formulae for the N=8 supergravity recursion and the MHV and conjugate MHV amplitudes. This gives a formulation of scattering amplitudes in maximally supersymmetric theories in which superconformal symmetry and its breaking is manifest. For N^kMHV, the amplitudes are given by 2n-4 integrals in the form of Hilbert transforms of a product of $n-k-2$ purely geometric, superconformally invariant twistor delta functions, dressed by certain sign operators. These sign operators subtly violate conformal invariance, even for tree-level amplitudes in N=4 super Yang-Mills, and we trace their origin to a topological property of split signature space-time. We develop the twistor transform to relate our work to the ambidextrous twistor diagram approach of Hodges and of Arkani-Hamed, Cachazo, Cheung and Kaplan.Comment: v2: minor corrections + extra refs. v3: further minor corrections, extra discussion of signature issues + more ref

Glucose-6-phosphate dehydrogenase contributes to the regulation of glucose uptake in skeletal muscle

The development of skeletal muscle insulin resistance is an early physiological defect, yet the intracellular mechanisms accounting for this metabolic defect remained unresolved. Here, we have examined the role of glucose-6-phosphate dehydrogenase (G6PDH) activity in the pathogenesis of insulin resistance in skeletal muscle. Methods Multiple mouse disease states exhibiting insulin resistance and glucose intolerance, as well as obese humans defined as insulin-sensitive, insulin-resistant, or pre-diabetic, were examined. Results We identified increased glucose-6-phosphate dehydrogenase (G6PDH) activity as a common intracellular adaptation that occurs in parallel with the induction of insulin resistance in skeletal muscle and is present across animal and human disease states with an underlying pathology of insulin resistance and glucose intolerance. We observed an inverse association between G6PDH activity and nitric oxide synthase (NOS) activity and show that increasing NOS activity via the skeletal muscle specific neuronal (n)NOS&mu; partially suppresses G6PDH activity in skeletal muscle cells. Furthermore, attenuation of G6PDH activity in skeletal muscle cells via (a) increased nNOS&mu;/NOS activity, (b) pharmacological G6PDH inhibition, or (c) genetic G6PDH inhibition increases insulin-independent glucose uptake. Conclusions We have identified a novel, previously unrecognized role for G6PDH in the regulation of skeletal muscle glucose metabolism. <br /

Phylogeography of Japanese encephalitis virus:genotype is associated with climate

The circulation of vector-borne zoonotic viruses is largely determined by the overlap in the geographical distributions of virus-competent vectors and reservoir hosts. What is less clear are the factors influencing the distribution of virus-specific lineages. Japanese encephalitis virus (JEV) is the most important etiologic agent of epidemic encephalitis worldwide, and is primarily maintained between vertebrate reservoir hosts (avian and swine) and culicine mosquitoes. There are five genotypes of JEV: GI-V. In recent years, GI has displaced GIII as the dominant JEV genotype and GV has re-emerged after almost 60 years of undetected virus circulation. JEV is found throughout most of Asia, extending from maritime Siberia in the north to Australia in the south, and as far as Pakistan to the west and Saipan to the east. Transmission of JEV in temperate zones is epidemic with the majority of cases occurring in summer months, while transmission in tropical zones is endemic and occurs year-round at lower rates. To test the hypothesis that viruses circulating in these two geographical zones are genetically distinct, we applied Bayesian phylogeographic, categorical data analysis and phylogeny-trait association test techniques to the largest JEV dataset compiled to date, representing the envelope (E) gene of 487 isolates collected from 12 countries over 75 years. We demonstrated that GIII and the recently emerged GI-b are temperate genotypes likely maintained year-round in northern latitudes, while GI-a and GII are tropical genotypes likely maintained primarily through mosquito-avian and mosquito-swine transmission cycles. This study represents a new paradigm directly linking viral molecular evolution and climate

Population Genetics of Franciscana Dolphins (Pontoporia blainvillei): Introducing a New Population from the Southern Edge of Their Distribution

Due to anthropogenic factors, the franciscana dolphin, Pontoporia blainvillei, is the most threatened small cetacean on the Atlantic coast of South America. Four Franciscana Management Areas have been proposed: Espiritu Santo to Rio de Janeiro (FMA I), São Paulo to Santa Catarina (FMA II), Rio Grande do Sul to Uruguay (FMA III), and Argentina (FMA IV). Further genetic studies distinguished additional populations within these FMAs. We analyzed the population structure, phylogeography, and demographic history in the southernmost portion of the species range. From the analysis of mitochondrial DNA control region sequences, 5 novel haplotypes were found, totalizing 60 haplotypes for the entire distribution range. The haplotype network did not show an apparent phylogeographical signal for the southern FMAs. Two populations were identified: Monte Hermoso (MH) and Necochea (NC)+Claromecó (CL)+Río Negro (RN). The low levels of genetic variability, the relative constant size over time, and the low levels of gene flow may indicate that MH has been colonized by a few maternal lineages and became isolated from geographically close populations. The apparent increase in NC+CL+RN size would be consistent with the higher genetic variability found, since genetic diversity is generally higher in older and expanding populations. Additionally, RN may have experienced a recent split from CL and NC; current high levels of gene flow may be occurring between the latter ones. FMA IV would comprise four franciscana dolphin populations: Samborombón West+Samborombón South, Cabo San Antonio+Buenos Aires East, NC+CL+Buenos Aires Southwest+RN and MH. Results achieved in this study need to be taken into account in order to ensure the long-term survival of the species.Fil: Gariboldi, María Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; ArgentinaFil: Tunez, Juan Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Luján; ArgentinaFil: Dejean, Cristina Beatriz. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; Argentina. Universidad de Buenos Aires. Facultad de Filosofía y Letras. Instituto de Ciencias Antropológicas. Sección Antropología Biológica; ArgentinaFil: Failla, Mauricio. Fundación Cethus; ArgentinaFil: Vitullo, Alfredo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; ArgentinaFil: Negri, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales ; ArgentinaFil: Cappozzo, Humberto Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales ; Argentin

The cost of changing physical activity behaviour: Evidence from a "physical activity pathway" in the primary care setting

Copyright @ 2011 Boehler et al.BACKGROUND: The ‘Physical Activity Care Pathway’ (a Pilot for the ‘Let’s Get Moving’ policy) is a systematic approach to integrating physical activity promotion into the primary care setting. It combines several methods reported to support behavioural change, including brief interventions, motivational interviewing, goal setting, providing written resources, and follow-up support. This paper compares costs falling on the UK National Health Service (NHS) of implementing the care pathway using two different recruitment strategies and provides initial insights into the cost of changing physical activity behaviour. METHODS: A combination of a time driven variant of activity based costing, audit data through EMIS and a survey of practice managers provided patient-level cost data for 411 screened individuals. Self reported physical activity data of 70 people completing the care pathway at three month was compared with baseline using a regression based ‘difference in differences’ approach. Deterministic and probabilistic sensitivity analyses in combination with hypothesis testing were used to judge how robust findings are to key assumptions and to assess the uncertainty around estimates of the cost of changing physical activity behaviour. RESULTS: It cost £53 (SD 7.8) per patient completing the PACP in opportunistic centres and £191 (SD 39) at disease register sites. The completer rate was higher in disease register centres (27.3% vs. 16.2%) and the difference in differences in time spent on physical activity was 81.32 (SE 17.16) minutes/week in patients completing the PACP; so that the incremental cost of converting one sedentary adult to an ‘active state’ of 150 minutes of moderate intensity physical activity per week amounts to £ 886.50 in disease register practices, compared to opportunistic screening. CONCLUSIONS: Disease register screening is more costly than opportunistic patient recruitment. However, additional costs come with a higher completion rate and better outcomes in terms of behavioural change in patients completing the care pathway. Further research is needed to rigorously evaluate intervention efficiency and to assess the link between behavioural change and changes in quality adjusted life years (QALYs).This article is available through the Brunel Open Access Publishing Fund

Localisation of RNAs into the germ plasm of vitellogenic xenopus oocytes

We have studied the localisation of mRNAs in full-grown Xenopus laevis oocytes by injecting fluorescent RNAs, followed by confocal microscopy of the oocyte cortex. Concentrating on RNA encoding the Xenopus Nanos homologue, nanos1 (formerly Xcat2), we find that it consistently localised into aggregated germ plasm ribonucleoprotein (RNP) particles, independently of cytoskeletal integrity. This implies that a diffusion/entrapment-mediated mechanism is active, as previously reported for previtellogenic oocytes. Sometimes this was accompanied by localisation into scattered particles of the “late”, Vg1/VegT pathway; occasionally only late pathway localisation was seen. The Xpat RNA behaved in an identical fashion and for neither RNA was the localisation changed by any culture conditions tested. The identity of the labelled RNP aggregates as definitive germ plasm was confirmed by their inclusion of abundant mitochondria and co-localisation with the germ plasm protein Hermes. Further, the nanos1/Hermes RNP particles are interspersed with those containing the germ plasm protein Xpat. These aggregates may be followed into the germ plasm of unfertilized eggs, but with a notable reduction in its quantity, both in terms of injected molecules and endogenous structures. Our results conflict with previous reports that there is no RNA localisation in large oocytes, and that during mid-oogenesis even germ plasm RNAs localise exclusively by the late pathway. We find that in mid oogenesis nanos1 RNA also localises to germ plasm but also by the late pathway. Late pathway RNAs, Vg1 and VegT, also may localise into germ plasm. Our results support the view that mechanistically the two modes of localisation are extremely similar, and that in an injection experiment RNAs might utilise either pathway, the distinction in fates being very subtle and subject to variation. We discuss these results in relation to their biological significance and the results of others

Phylogenetic relationships of cone snails endemic to Cabo Verde based on mitochondrial genomes

Background: Due to their great species and ecological diversity as well as their capacity to produce hundreds of different toxins, cone snails are of interest to evolutionary biologists, pharmacologists and amateur naturalists alike. Taxonomic identification of cone snails still relies mostly on the shape, color, and banding patterns of the shell. However, these phenotypic traits are prone to homoplasy. Therefore, the consistent use of genetic data for species delimitation and phylogenetic inference in this apparently hyperdiverse group is largely wanting. Here, we reconstruct the phylogeny of the cones endemic to Cabo Verde archipelago, a well-known radiation of the group, using mitochondrial (mt) genomes. Results: The reconstructed phylogeny grouped the analyzed species into two main clades, one including Kalloconus from West Africa sister to Trovaoconus from Cabo Verde and the other with a paraphyletic Lautoconus due to the sister group relationship of Africonus from Cabo Verde and Lautoconus ventricosus from Mediterranean Sea and neighboring Atlantic Ocean to the exclusion of Lautoconus endemic to Senegal (plus Lautoconus guanche from Mauritania, Morocco, and Canary Islands). Within Trovaoconus, up to three main lineages could be distinguished. The clade of Africonus included four main lineages (named I to IV), each further subdivided into two monophyletic groups. The reconstructed phylogeny allowed inferring the evolution of the radula in the studied lineages as well as biogeographic patterns. The number of cone species endemic to Cabo Verde was revised under the light of sequence divergence data and the inferred phylogenetic relationships. Conclusions: The sequence divergence between continental members of the genus Kalloconus and island endemics ascribed to the genus Trovaoconus is low, prompting for synonymization of the latter. The genus Lautoconus is paraphyletic. Lautoconus ventricosus is the closest living sister group of genus Africonus. Diversification of Africonus was in allopatry due to the direct development nature of their larvae and mainly triggered by eustatic sea level changes during the Miocene-Pliocene. Our study confirms the diversity of cone endemic to Cabo Verde but significantly reduces the number of valid species. Applying a sequence divergence threshold, the number of valid species within the sampled Africonus is reduced to half.Spanish Ministry of Science and Innovation [CGL2013-45211-C2-2-P, CGL2016-75255-C2-1-P, BES-2011-051469, BES-2014-069575, Doctorado Nacional-567]info:eu-repo/semantics/publishedVersio

Different diversity-dependent declines in speciation rate unbalances species richness in terrestrial slugs

Two genera of terrestrial slugs (Arion and Geomalacus) display a striking disproportion in species richness in the Iberian Peninsula. While there are 17 Iberian endemic species in Arion, morphological criteria only recognize four species within Geomalacus. Sequence data were used to test whether these differences could result from: (1) cryptic diversity within Geomalacus; (2) an earlier origin for Arion (older clades are expected to accumulate more species); (3) distinct patterns of diversification rates (higher initial speciation rates in Arion), and (4) some combination of the above factors (e.g., an older clade with higher speciation rates). Species delimitation tests based on mitochondrial and nuclear data revealed eight cryptic lineages within Geomalacus that lessened the asymmetry; nevertheless, the disparity required further investigation. No meaningful differences in crown group ages of each recovered clade were found. Regardless the different premises of the two equally plausible diversification models (similar initial speciation rates vs. higher initial speciation rates in Geomalacus), both coincide on diversity-dependent diversification for the two groups but weaker rate declines in Arion best explains the observed asymmetry in species richness. Also, the broader environmental tolerance combined with a faster dispersal and wider distribution may have represented an evolutionary advantage for Arion.FCT (Fundacao para a Ciencia e Tecnologia, Portugal) [SFRH/BPD/109685/2015]; FSE (Fundo Social Europeu). [SFRH/BD/30024/2006]; FCT strategic plan [UID/Multi/04326/2013]info:eu-repo/semantics/publishedVersio