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Introduction: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development.
Methods: To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal.
Results: In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants.
Conclusion: Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF.
Background: A web-based malaria reporting information system (MRIS) has the potential to improve malaria reporting and management. The aim of this study was to evaluate the existing manual paper-based MRIS and to provide a way to overcome the obstacles by developing a web-based MRIS in Indonesia.
Methods: An exploratory study was conducted in 2012 in Lahat District, South Sumatra Province of Indonesia. We evaluated the current reporting system and identified the potential benefits of using a web-based MRIS by in-depth interviews on selected key informants. Feasibility study was then conducted to develop a prototype system. A web-based MRIS was developed, integrated and synchronized, with suitability ranging from Primary Healthcare Centres (PHCs) to the Lahat District Health Office.
Results: The paper-based reporting system was sub-optimal due to a lack of transportation, communication, and human capacity. We developed a web-based MRIS to replace the current one. Although the web-based system has the potential to improve the malaria reporting information system, there were some barriers to its implementation, including lack of skilled operators, computer availability and lack of internet access. Recommended ways to overcome the obstacles are by training operators, making the application in an offline mode and able to be operated by mobile phone text messaging for malaria reporting.
Conclusion: The web-based MRIS has the potential to be implemented as an enhanced malaria reporting information system and investment in the system to support timely management responses is essential for malaria elimination. The developed application can be cloned to other areas that have similar characteristics and MRIS with a built-in web base to aid its application in the 5G future.
This Policy White Paper assesses several main elements of ECB’s upcoming review of its monetary policy strategy, announced in January 2020. Four aspects of the review are discussed in detail: i) ECB’s definition of price stability and the arguments for and against inflation targeting; ii) the scope of ECB’s objectives, considering financial stability, employment and the sustainability of the environment; iii) an update of ECB’s economic and monetary analyses to assess the risks to price stability; iv) the ECB’s communication practice. Furthermore, an overview of the ECB’s monetary policy strategy and its last evaluation in 2003 is given.
Mit dem Ziel, Erkenntnisse zum individuellen Mobilitätsverhalten im Zusammenhang mit der Gestaltung des umgebenden Verkehrssystems zu gewinnen, wurde im Rahmen des vom Land Hessen geförderten LOEWE-Schwerpunkts „Infrastruktur – Design – Gesellschaft“ im März und April 2019 eine schriftliche Haushaltsbefragung in einem innerstädtischen Gebiet der Großstadt Offenbach am Main durchgeführt (n=701). Der vorliegende Bericht beschreibt die methodische Vorgehensweise bei der Umsetzung und Datenerfassung dieser Erhebung. Dabei wird auf die vorbereitenden Maßnahmen mit Hinblick auf die Erstellung des Fragebogens und weiterer Befragungsmaterialen sowie die Durchführung des Pretests und der eigentlichen Hauptbefragung eingegangen. Um die Bereitschaft einer Teilnahme zu erhöhen, wurden die Haushalte mittels Vorankündigungsschreiben, Pressemitteilung und Erinnerungsrundgang mehrfach kontaktiert. Außerdem wurde ein Teil der Rücksendeumschläge mit Sonderbriefmarken versehen. Abschließend befasst sich der Bericht mit dem Erhebungsrücklauf, der Dateneingabe und -aufbereitung sowie dem ermittelten Antwortverhalten und der Repräsentativität der Stichprobe.
NKG2D is a potent activating immunoreceptor expressed on nearly all cytotoxic lymphocytes promoting their cytotoxicity against self-cells expressing NKG2D ligands (NKG2DLs). NKG2DLs are MHC class I-like glycoproteins that usually are not expressed on “healthy” cells. Rather, their surface expression is induced by various forms of cellular stress, viral infection, or malignant transformation. Hence, cell surface NKG2DLs mark “dangerous” cells for elimination by cytotoxic lymphocytes and therefore can be considered as “kill-me” signals. In addition, NKG2DLs are up-regulated on activated leukocytes, which facilitates containment of immune responses. While the NKG2D receptor is conserved among mammals, NKG2DL genes have rapidly diversified during mammalian speciation, likely due to strong selective pressures exerted by species-specific pathogens. Consequently, NKG2DL genes are not conserved in man and mice, although their NKG2D-binding domains maintained structural homology. Human NKG2DLs comprise two members of the MIC (MICA/MICB) and six members of the ULBP family of glycoproteins (ULBP1–6) with MICA representing the best-studied human NKG2DLs by far. Many of these studies implicate a role of MICA in various malignant, infectious, or autoimmune diseases. However, conclusions from these studies often were limited in default of supporting in vivo experiments. Here, we report a MICA transgenic (MICAgen) mouse model that replicates central features of human MICA expression and function and, therefore, constitutes a novel tool to critically assess and extend conclusions from previous in vitro studies on MICA. Similarly to humans, MICA transcripts are broadly present in organs of MICAgen mice, while MICA glycoproteins are barely detectable. Upon activation, hematopoietic cells up-regulate and proteolytically shed surface MICA. Shed soluble MICA (sMICA) is also present in plasma of MICAgen mice but affects neither surface NKG2D expression of circulating NK cells nor their functional recognition of MICA-expressing tumor cells. Accordingly, MICAgen mice also show a delayed growth of MICA-expressing B16F10 tumors, not accompanied by an emergence of MICA-specific antibodies. Such immunotolerance for the xenoantigen MICA ideally suits MICAgen mice for anti-MICA-based immunotherapies. Altogether, MICAgen mice represent a valuable model to study regulation, function, disease relevance, and therapeutic targeting of MICA in vivo.
Risk evaluations for agricultural chemicals are necessary to preserve healthy populations of honey bee colonies. Field studies on whole colonies are limited in behavioural research, while results from lab studies allow only restricted conclusions on whole colony impacts. Methods for automated long-term investigations of behaviours within comb cells, such as brood care, were hitherto missing. In the present study, we demonstrate an innovative video method that enables within-cell analysis in honey bee (Apis mellifera) observation hives to detect chronic sublethal neonicotinoid effects of clothianidin (1 and 10 ppb) and thiacloprid (200 ppb) on worker behaviour and development. In May and June, colonies which were fed 10 ppb clothianidin and 200 ppb thiacloprid in syrup over three weeks showed reduced feeding visits and duration throughout various larval development days (LDDs). On LDD 6 (capping day) total feeding duration did not differ between treatments. Behavioural adaptation was exhibited by nurses in the treatment groups in response to retarded larval development by increasing the overall feeding timespan. Using our machine learning algorithm, we demonstrate a novel method for detecting behaviours in an intact hive that can be applied in a versatile manner to conduct impact analyses of chemicals, pests and other stressors.