Identifizierung neuer Kandidatengene in Patienten mit autosomal-rezessiver mentaler Retardierung

Die mentale Retardierung, gekennzeichnet durch eine in der Entwicklungsperiode auftretende Einschränkung der geistigen Fähigkeiten, präsentiert sich als eine bezüglich des Phänotyps und der Ursachen sehr heterogene Krankheit. In den letzten Jahren konnte die Erforschung der genetischen Ursachen mentaler Retardierung große Fortschritte verzeichnen, dennoch bleiben viele Fälle mentaler Retardierung ungeklärt. In dieser Arbeit sollten bisher ungeklärte Fälle von mentaler Retardierung aufgeklärt und dabei neue Kandidatengene für mentale Retardierung identifiziert und bestätigt werden. In einem Untersuchungskollektiv aus 26 konsanguinen, jordanischen Familien wurde für jeweils einen Betroffenen aus den Familien eine Exomsequenzierung mittels NGS vorgenommen. In jedem sequenzierten Exom wurde nach möglicherweise krankheitsverursachenden CNVs gesucht. Die Exome von fünf Familien wurden auf monogene Ursachen der mentalen Retardierung untersucht. Hierzu wurde eine Priorisierung der gefundenen Varianten nach bestimmten Kriterien vorgenommen und die Segregation der aussichtsreichsten Kandidatenvarianten in den Familien mittels Sanger-Sequenzierung überprüft. Gegebenenfalls wurden weitere funktionelle Analysen angestellt, um die Pathogenität der Kandidatenmutationen zu untersuchen. Auf diese Weise konnte in einer Familie mit epileptischer Enzephalopathie mit schwerer mentaler Retardierung und Verkalkungen in den Basalganglien eine homozygote frameshift-Mutation in DENND5A identifiziert werden. DENND5A ist als GTP-Austauschfaktor für Proteine der rab-Familie am Vesikeltransport am Golgi-Apparat beteiligt. Die Rekrutierung zweier weiterer betroffener Geschwister aus einer anderen Familie mit ähnlichem Phänotyp und homozygoter frameshift-Mutation in DENND5A und funktionelle Untersuchung von DENND5A durch unseren Kooperationspartner konnten die Einordnung von DENND5A als neues Gen für mentale Retardierung bestätigen. In zwei weiteren Familien konnten Mutationen in bereits bekannten Genen für mentale Retardierung (DNAJC6, NT5C2) nachgewiesen werden. Der Phänotyp der Betroffenen entspricht und erweitert die bereits in der Literatur für Mutationen in diesen Genen beschriebene Krankheitsbilder. In einer weiteren Familie wurden compound-heterozygote Mutationen in PTPRD identifiziert. PTPRD codiert für den Protein-Tyrosin-Phosphatase-Rezeptor PTPRδ, der an der Entwicklung des Nervensystems und insbesondere der Synaptogenese beteiligt ist. Die Pathogenität der Varianten in PTPRD müssten noch weiter untersucht werden, um PTPRD als Gen für mentale Retardierung zu bestätigen. Schließlich konnte für eine Familie ein CNV als Ursache für die mentale Retardierung bestätigt werden. Hierbei handelte es sich um eine 2,86 Mb große Deletion in einer bereits für das 4q21 Mikrodeletions Syndrom bekannten Region. Der Phänotyp der Betroffenen in Verbindung mit den von der Deletion erfassten Genen liefert einen neuen Beitrag zu der bisher angenommenen Genotyp-Phänotyp-Korrelation bei dem 4q21 Mikrodeletions Syndrom. Insgesamt konnten somit in vier Familien die genetische Ursache der mentalen Retardierung aufgeklärt und dabei ein neues Gen für mentale Retardierung identifiziert und bestätigt werden

The Use of Optical Coherence Tomography in Dental Diagnostics: a State-of-the-Art Review

Optical coherence tomography provides sections of tissues in a noncontact and noninvasive manner. The device measures the time delay and intensity of the light scattered or reflected from biological tissues, which results in tomographic imaging of their internal structure. This is achieved by scanning tissues at a resolution ranging from 1 to 15 μm. OCT enables real-time in situ imaging of tissues without the need for biopsy, histological procedures, or the use of X-rays, so it can be used in many fields of medicine. Its properties are not only particularly used in ophthalmology, in the diagnosis of all layers of the retina, but also increasingly in cardiology, gastroenterology, pulmonology, oncology, and dermatology. The basic properties of OCT, that is, noninvasiveness and low wattage of the used light, have also been appreciated in analytical technology by conservators, who use it to identify the quality and age of paintings, ceramics, or glass. Recently, the OCT technique of visualization is being tested in different fields of dentistry, which is depicted in the article

Evaluation of changes in enamel thickness after orthodontic treatment depending on the force applied to remove orthodontic brackets: OCT analysis and universal testing machine

Background. Adhesive materials used in orthodontics have contributed to the broadening of treatment options with fixed braces. The adhesive materials physically and chemically bond to the enamel surface and orthodontic bracket base, which, apart from offering advantages, also entails the risk of enamel damage when removing these materials from the tissue surface after the treatment is complete. Objectives. The objective of this study was to assess how the bond strength of adhesive materials affects enamel thickness after removing brackets and whether the type of bonding system affects the amount of adhesive strength of the discussed materials. Material and methods. The tests were carried out on 2 groups of 40 bovine teeth in each group. In the 1st group, the classical orthophosphoric acid and the Transbond Plus self-etching primer (SEP) were used. In the 2nd group, the Transbond XT SEP was applied. In both groups, Transbond XT Light Cure Adhesive was used. The same metal orthodontic brackets were attached to the enamel surface. Optical Coherence Tomography (OCT) scans were made before and after removing brackets, which enabled tissue thickness measurements. The bond strength was evaluated using a universal testing machine. Parametric tests were performed on all obtained variables. Student’s t-tests for independent samples and analysis of correlation with Pearson’s r were carried out. Results. The bond strength between the orthodontic bracket and enamel is statistically significantly different in the 1st group and the 2nd group, and is higher in the 2nd group. Conclusions. There are no significant differences in enamel thickness depending on the bonding system type and there is no correlation between the enamel thickness and the bond strength of orthodontic brackets to the enamel

The Use of Optical Coherence Tomography in Dental Diagnostics: A State-of-the-Art Review

Optical coherence tomography provides sections of tissues in a noncontact and noninvasive manner. The device measures the time delay and intensity of the light scattered or reflected from biological tissues, which results in tomographic imaging of their internal structure. This is achieved by scanning tissues at a resolution ranging from 1 to 15 μm. OCT enables real-time in situ imaging of tissues without the need for biopsy, histological procedures, or the use of X-rays, so it can be used in many fields of medicine. Its properties are not only particularly used in ophthalmology, in the diagnosis of all layers of the retina, but also increasingly in cardiology, gastroenterology, pulmonology, oncology, and dermatology. The basic properties of OCT, that is, noninvasiveness and low wattage of the used light, have also been appreciated in analytical technology by conservators, who use it to identify the quality and age of paintings, ceramics, or glass. Recently, the OCT technique of visualization is being tested in different fields of dentistry, which is depicted in the article

Context-dependent changes in maritime traffic activity during the first year of the COVID-19 pandemic

This article is a contribution of the COVID-19 Bio-Logging Initiative, which is funded in part by the Gordon and Betty Moore Foundation (GBMF9881) and the National Geographic Society (NGS-82515R-20) (both grants to C.R.), and endorsed by the United Nations Decade of Ocean Science for Sustainable Development. Specifically, A.L.’s, R.P.’s and B.R.’s postdoctoral positions were funded by the Gordon and Betty Moore Foundation (GBMF9881), and J.S.’s contributions were funded by the National Geographic Society (NGS-82515R-20). D.W.S. was supported by a Marine Biological Association Senior Research Fellowship with additional support from the Natural Environment Research Council (Discovery Science NE/R00997/X/1) and the European Research Council (Advanced Grant 883583 OCEAN DEOXYFISH).Rapid implementation of human mobility restrictions during the COVID-19 pandemic dramatically reduced maritime activity in early 2020. But where and when activity rebounded, or remained low, during the full extent of 2020 restrictions remains unclear. Using global high-resolution datasets, we reveal a surprising degree of complexity in maritime activity patterns during 2020, yielding a more nuanced picture of how restrictions affected activity. Overall, shipping activity in Exclusive Economic Zones decreased (1.35 %), as expected, however high-seas activity increased (0.28 %). While these annual changes appear modest, there were striking spatially and temporally asynchronous variations in different vessel types’ activity in the second half of 2020, ranging from an > 80 % sustained reduction in passenger vessel activity to a 150 % increase in fishing activity. Results suggest systems-level responses were highly context-dependent, pinpointing areas that experienced significant reductions and spikes in activity, and providing hitherto missing details of COVID-19 impacts on economic and environmental sustainability.Publisher PDFPeer reviewe

SO(10) Cosmic Strings and SU(3) Color Cheshire Charge

Certain cosmic strings that occur in GUT models such as $SO(10)$ can carry a magnetic flux which acts nontrivially on objects carrying $SU(3)_{color}$ quantum numbers. We show that such strings are non-Abelian Alice strings carrying nonlocalizable colored ``Cheshire" charge. We examine claims made in the literature that $SO(10)$ strings can have a long-range, topological Aharonov-Bohm interaction that turns quarks into leptons, and observe that such a process is impossible. We also discuss flux-flux scattering using a multi-sheeted formalism.Comment: 37 Pages, 8 Figures (available upon request) phyzzx, iassns-hep-93-6, itp-sb-93-6

Hepatic p53 is regulated by transcription factor FOXO1 and acutely controls glycogen homeostasis

The tumor suppressor p53 is involved in the adaptation of hepatic metabolism to nutrient availability. Acute deletion of p53 in the mouse liver affects hepatic glucose and triglyceride metabolism. However, long-term adaptations upon the loss of hepatic p53 and its transcriptional regulators are unknown. Here we show that short-term, but not chronic, liver-specific deletion of p53 in mice reduces liver glycogen levels, and we implicate the transcription factor forkhead box O1 protein (FOXO1) in the regulation of p53 and its target genes. We demonstrate that acute p53 deletion prevents glycogen accumulation upon refeeding, whereas a chronic loss of p53 associates with a compensational activation of the glycogen synthesis pathway. Moreover, we identify fasting-activated FOXO1 as a repressor of p53 transcription in hepatocytes. We show that this repression is relieved by inactivation of FOXO1 by insulin, which likely mediates the upregulation of p53 expression upon refeeding. Strikingly, we find that high-fat diet-induced insulin resistance with persistent FOXO1 activation not only blunted the regulation of p53 but also the induction of p53 target genes like p21 during fasting, indicating overlapping effects of both FOXO1 and p53 on target gene expression in a context-dependent manner. Thus, we conclude that p53 acutely controls glycogen storage in the liver and is linked to insulin signaling via FOXO1, which has important implications for our understanding of the hepatic adaptation to nutrient availability

MOSAiC Extended Acknowledgement

For years, the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI), together with the international MOSAiC partners, had been planning and developing the scientific, logistical and financial concept for the implementation of the MOSAiC expedition. The planning and organization of this endeavor was an enormous e˙ort, involving more than 80 institutions from 20 countries. The number of groups and individuals that significantly contributed to the success of the drift observatory goes far beyond the scope of usual polar expeditions

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Overview of the MOSAiC expedition: Physical oceanography

Arctic Ocean properties and processes are highly relevant to the regional and global coupled climate system, yet still scarcely observed, especially in winter. Team OCEAN conducted a full year of physical oceanography observations as part of the Multidisciplinary drifting Observatory for the Study of the Arctic Climate (MOSAiC), a drift with the Arctic sea ice from October 2019 to September 2020. An international team designed and implemented the program to characterize the Arctic Ocean system in unprecedented detail, from the seafloor to the air-sea ice-ocean interface, from sub-mesoscales to pan-Arctic. The oceanographic measurements were coordinated with the other teams to explore the ocean physics and linkages to the climate and ecosystem. This paper introduces the major components of the physical oceanography program and complements the other team overviews of the MOSAiC observational program. Team OCEAN’s sampling strategy was designed around hydrographic ship-, ice- and autonomous platform-based measurements to improve the understanding of regional circulation and mixing processes. Measurements were carried out both routinely, with a regular schedule, and in response to storms or opening leads. Here we present alongdrift time series of hydrographic properties, allowing insights into the seasonal and regional evolution of the water column from winter in the Laptev Sea to early summer in Fram Strait: freshening of the surface, deepening of the mixed layer, increase in temperature and salinity of the Atlantic Water. We also highlight the presence of Canada Basin deep water intrusions and a surface meltwater layer in leads. MOSAiC most likely was the most comprehensive program ever conducted over the ice-covered Arctic Ocean. While data analysis and interpretation are ongoing, the acquired datasets will support a wide range of physical oceanography and multi-disciplinary research. They will provide a significant foundation for assessing and advancing modeling capabilities in the Arctic Ocean