22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion disorder, estimated to result mainly from de novo non-homologous meiotic recombination events occurring in approximately 1 in every 1,000 fetuses. The first description in the English language of the constellation of findings now known to be due to this chromosomal difference was made in the 1960s in children with DiGeorge syndrome, who presented with the clinical triad of immunodeficiency, hypoparathyroidism and congenital heart disease. The syndrome is now known to have a heterogeneous presentation that includes multiple additional congenital anomalies and later-onset conditions, such as palatal, gastrointestinal and renal abnormalities, autoimmune disease, variable cognitive delays, behavioural phenotypes and psychiatric illness - all far extending the original description of DiGeorge syndrome. Management requires a multidisciplinary approach involving paediatrics, general medicine, surgery, psychiatry, psychology, interventional therapies (physical, occupational, speech, language and behavioural) and genetic counselling. Although common, lack of recognition of the condition and/or lack of familiarity with genetic testing methods, together with the wide variability of clinical presentation, delays diagnosis. Early diagnosis, preferably prenatally or neonatally, could improve outcomes, thus stressing the importance of universal screening. Equally important, 22q11.2DS has become a model for understanding rare and frequent congenital anomalies, medical conditions, psychiatric and developmental disorders, and may provide a platform to better understand these disorders while affording opportunities for translational strategies across the lifespan for both patients with 22q11.2DS and those with these associated features in the general population

Statistics of non-linear stochastic dynamical systems under L\'evy noises by a convolution quadrature approach

This paper describes a novel numerical approach to find the statistics of the non-stationary response of scalar non-linear systems excited by L\'evy white noises. The proposed numerical procedure relies on the introduction of an integral transform of Wiener-Hopf type into the equation governing the characteristic function. Once this equation is rewritten as partial integro-differential equation, it is then solved by applying the method of convolution quadrature originally proposed by Lubich, here extended to deal with this particular integral transform. The proposed approach is relevant for two reasons: 1) Statistics of systems with several different drift terms can be handled in an efficient way, independently from the kind of white noise; 2) The particular form of Wiener-Hopf integral transform and its numerical evaluation, both introduced in this study, are generalizations of fractional integro-differential operators of potential type and Gr\"unwald-Letnikov fractional derivatives, respectively.Comment: 20 pages, 5 figure

Ten Simple Rules for Getting Help from Online Scientific Communities

The increasing complexity of research requires scientists to work at the intersection of multiple fields and to face problems for which their formal education has not prepared them. For example, biologists with no or little background in programming are now often using complex scripts to handle the results from their experiments; vice versa, programmers wishing to enter the world of bioinformatics must know about biochemistry, genetics, and other fields. In this context, communication tools such as mailing lists, web forums, and online communities acquire increasing importance. These tools permit scientists to quickly contact people skilled in a specialized field. A question posed properly to the right online scientific community can help in solving difficult problems, often faster than screening literature or writing to publication authors. The growth of active online scientific communities, such as those listed in Table S1, demonstrates how these tools are becoming an important source of support for an increasing number of researchers. Nevertheless, making proper use of these resources is not easy. Adhering to the social norms of World Wide Web communication—loosely termed “netiquette”—is both important and non-trivial. In this article, we take inspiration from our experience on Internet-shared scientific knowledge, and from similar documents such as “Asking the Questions the Smart Way” and “Getting Answers”, to provide guidelines and suggestions on how to use online communities to solve scientific problems

Comparing climate sensitivity, past and present

Climate sensitivity represents the global mean temperature change caused by changes in the radiative balance of climate; it is studied for both present/future (actuo) and past (paleo) climate variations, with the former based on instrumental records and/or various types of model simulations. Paleo-estimates are often considered informative for assessments of actuo-climate change caused by anthropogenic greenhouse forcing, but this utility remains debated because of concerns about the impacts of uncertainties, assumptions, and incomplete knowledge about controlling mechanisms in the dynamic climate system, with its multiple interacting feedbacks and their potential dependence on the climate background state. This is exacerbated by the need to assess actuo- and paleoclimate sensitivity over different timescales, with different drivers, and with different (data and/or model) limitations. Here, we visualize these impacts with idealized representations that graphically illustrate the nature of time-dependent actuo- and paleoclimate sensitivity estimates, evaluating the strengths, weaknesses, agreements, and differences of the two approaches. We also highlight priorities for future research to improve the use of paleo-estimates in evaluations of current climate change.E.J.R. and G.M. acknowledge support from the Australian Research Council via Australian Laureate Fellowship FL120100050. A.S.v.d.H. acknowledges support from the Netherlands Earth System Science Centre, financially supported by the Ministry of Education, Culture, and Science. P.K. is funded by Polar Regions and Coasts in the Changing Earth System II (PACES II), the Helmholtz research program to which the Alfred Wegener Institute contributes

Conservation policies informed by food system feedbacks can avoid unintended consequences

Understanding the feedbacks between food systems and conservation policies can help avoid unintended environmental consequences. Using a survey-based choice experiment and economic modelling, we quantify the potential impact of tourists’ responses to a shift in offshore fish supply after the designation of a large-scale marine protected area in Palau. We find that this conservation policy may increase offshore fish prices and tourists’ consumption of reef fish, thereby further endangering local reef ecosystems. However, if tourists are offered a sustainable offshore choice, their demand for fish could be kept at current levels, and environmental impacts from increased reef fish consumption would be avoided

Carbon stable isotope analysis of cereal remains as a way to reconstruct water availability: preliminary results

Reconstructing past water availability, both as rainfall and irrigation, is important to answer questions about the way society reacts to climate and its changes and the role of irrigation in the development of social complexity. Carbon stable isotope analysis of archaeobotanical remains is a potentially valuable method for reconstructing water availability. To further define the relationship between water availability and plant carbon isotope composition and to set up baseline values for the Southern Levant, grains of experimentally grown barley and sorghum were studied. The cereal crops were grown at three stations under five different irrigation regimes in Jordan. Results indicate that a positive but weak relationship exists between irrigation regime and total water input of barley grains, but no relationship was found for sorghum. The relationship for barley is site-specific and inter-annual variation was present at Deir ‘Alla, but not at Ramtha and Khirbet as-Samra

Field Blue Stragglers and Related Mass Transfer Issues

This chapter contains my impressions and perspectives about the current state of knowledge about field blue stragglers (FBS) stars, drawn from an extensive literature that I searched. I conclude my review of issues that attend FBS and mass transfer, by a brief enumeration of a few mildly disquieting observational facts.Comment: Chapter 4, in Ecology of Blue Straggler Stars, H.M.J. Boffin, G. Carraro & G. Beccari (Eds), Astrophysics and Space Science Library, Springe

ADAM22/LGI1 complex as a new actionable target for breast cancer brain metastasis

Background: Metastatic breast cancer is a major cause of cancer-related deaths in woman. Brain metastasis is a common and devastating site of relapse for several breast cancer molecular subtypes, including oestrogen receptor-positive disease, with life expectancy of less than a year. While efforts have been devoted to developing therapeutics for extra-cranial metastasis, drug penetration of blood–brain barrier (BBB) remains a major clinical challenge. Defining molecular alterations in breast cancer brain metastasis enables the identification of novel actionable targets.Methods: Global transcriptomic analysis of matched primary and metastatic patient tumours (n = 35 patients, 70 tumour samples) identified a putative new actionable target for advanced breast cancer which was further validated in vivo and in breast cancer patient tumour tissue (n = 843 patients). A peptide mimetic of the target's natural ligand was designed in silico and its efficacy assessed in in vitro, ex vivo and in vivo models of breast cancer metastasis.Results: Bioinformatic analysis of over-represented pathways in metastatic breast cancer identified ADAM22 as a top ranked member of the ECM-related druggable genome specific to brain metastases. ADAM22 was validated as an actionable target in in vitro, ex vivo and in patient tumour tissue (n = 843 patients). A peptide mimetic of the ADAM22 ligand LGI1, LGI1MIM, was designed in silico. The efficacy of LGI1MIM and its ability to penetrate the BBB were assessed in vitro, ex vivo and in brain metastasis BBB 3D biometric biohybrid models, respectively. Treatment with LGI1MIM in vivo inhibited disease progression, in particular the development of brain metastasis.Conclusion: ADAM22 expression in advanced breast cancer supports development of breast cancer brain metastasis. Targeting ADAM22 with a peptide mimetic LGI1MIM represents a new therapeutic option to treat metastatic brain disease

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts