Small-Sample Analysis and Inference of Networked Dependency Structures from Complex Genomic Data

Die vorliegende Arbeit beschäftigt sich mit der statistischen Modellierung und Inferenz genetischer Netzwerke. Assoziationsstrukturen und wechselseitige Einflüsse sind ein wichtiges Thema in der Systembiologie. Genexpressionsdaten weisen eine hohe Dimensionalität auf, die geringen Stichprobenumfängen gegenübersteht ("small n, large p"). Die Analyse von Interaktionsstrukturen mit Hilfe graphischer Modelle ist demnach ein schlecht gestelltes (inverses) Problem, dessen Lösung Methoden zur Regularisierung erfordert. Ich schlage neuartige Schätzfunktionen für Kovarianzstrukturen und (partielle) Korrelationen vor. Diese basieren entweder auf Resampling-Verfahren oder auf Shrinkage zur Varianzreduktion. In der letzteren Methode wird die optimale Shrinkage Intensität analytisch berechnet. Im Vergleich zur klassischen Stichprobenkovarianzmatrix besitzt speziell diese Schätzfunktion wünschenswerte Eigenschaften im Sinne von gesteigerter Effizienz und von kleinerem mittleren quadratischen Fehler. Außerdem ergeben sich stets positiv definite und gut konditionierte Parameterschätzungen. Zur Bestimmung der Netzwerktopologie wird auf das Konzept graphischer Gaußscher Modelle zurückgegriffen, mit deren Hilfe sich sowohl marginale als auch bedingte Unabhängigkeiten darstellen lassen. Es wird eine Methode zur Modellselektion vorgestellt, die auf einer multiplen Testprozedur mit Kontrolle der False Discovery Rate beruht. Dabei wird die zugrunde liegende Nullverteilung adaptiv geschätzt. Das vorgeschlagene Framework ist rechentechnisch effizient und schneidet im Vergleich mit konkurrierenden Verfahren sowohl in Simulationen als auch in der Anwendung auf molekulare Daten sehr gut ab

Perceived cycling safety during Corona times - Results of a longitudinal study in Germany

With the beginning of the COVID-19 outbreak and the restrictions put in place to prevent an uncontrolled spread of the virus, the circumstances for daily activities changed. A remarkable shift in the modal split distribution was observed. Cycling was seen as a reliable and resilient option in pandemic times as it allowed social distancing and poses a low risk of contagion. There are detailed studies on the effect of the pandemic on cycling traffic all over the globe which used different data sources, like app data. counters or surveys [1] [2]. Apart from the citizens' behavioral responses to the corona pandemic, the municipalities also put up interventions that were meant to support a shift to cycling-based movements in cities. The question to discuss is what changes will be permanent and which changed circumstances, e.g. increased subjective safety, lead to a long-term change of mobility patterns. The changes in mobility during the COVID-19 pandemic bad different impacts on road traffic collisions and road deaths in different countries. While there was a reduction of both indicators in 32 out of 36 countries in April 2020 compared to April 2019, there was an increase in the other four countries [3]. Others also found a reduction of traffic fatalities in 23 out of 24 countries in 2020 compared to a baseline of the previous years (2017-2019), the only exception being Switzerland [4]. The subjective well-being has also changed differently for the different transport modes throughout the pandemic. For example, in April 2020, 9% of respondents said they would feel more comfortable or much more comfortable if they used or would use a bicycle compared to pre-pandemic times; in summer and autumn 2020, this figure was 11 %, in spring 2021, it was 13%. In autumn 2021, 15% of respondents said they would feel more comfortable or much more comfortable if they used or would use a bicycle than before the spread of the coronavirus [ 5]. [From: Introduction

Ureterolitíase bilateral em um gato de sete meses de idade

Feline ureteral obstruction can have several causes; however, ureterolithiasis has been increasing in occurrence. The restriction of urinary flow induced by the obstruction has harmful consequences to the body and can lead to acute renal failure. Calcium oxalate ureterolithiasis is reported in older cats, aged mean 12 years old. A case of bilateral ureteral obstruction in a 7-month-old mixed breed cat is described in this report. Imaging tests such as abdominal ultrasonography, radiography and excretory urography were performed to determine the diagnosis. The surgical procedure of bilateral ureterotomy was then performed, which allowed the improvement of the urinary flow of both kidneys and the resolution of clinical signs caused by uremia. The quantitative analysis of both uroliths revealed the composition of 100% monohydrate calcium oxalate. Calcium oxalate stones can also cause ureteral obstruction in young cats; although, are less common in this age. When conservative treatment fails, surgical intervention becomes necessary for the rapid return of renal function. To author’s knowledge this is the first report of a ureterolithiasis caused by calcium oxalate in a young cat.A obstrução ureteral em gatos pode ter diversas causas, entretanto, a ureterolitíase vem apresentando um aumento na sua ocorrência. A restrição do fluxo urinário induzida pela obstrução traz consequências graves ao organismo, podendo levar a insuficiência renal aguda. A ureterolitíase por cálculos de oxalato de cálcio é relatada em gatos mais velhos, com média de idade de 12 anos. Um caso de obstrução ureteral bilateral em um gato, SRD, com sete meses de idade é descrito nesse relato. Exames de imagem, como ultrassonografia e radiografia abdominais e urografia excretora, foram realizados para confirmar o diagnóstico. O procedimento cirúrgico de ureterotomia bilateral foi então realizado, permitindo a melhora do fluxo urinário de ambos os rins e dos sinais clínicos de uremia. A análise quantitativa de ambos os urólitos revelou a composição de 100% oxalato de cálcio monohidratado. Cálculos de oxalato de cálcio são um diagnóstico diferencial para obstrução ureteral também em gatos jovens, apesar de serem menos comuns. Quando há falha no tratamento conservador, a intervenção cirúrgica torna-se necessária para o rápido restabelecimento e preservação da função renal. No conhecimento dos autores, esse é o primeiro relato de ureterolitíase causada por oxalato de cálcio em um gato jovem

Conceptual Aspects of Large Meta-Analyses with Publicly Available Microarray Data: A Case Study in Oncology

Large public repositories of microarray experiments offer an abundance of biological data. It is of interest to use and to combine the available material to create new biological information and to develop a broader view on biological phenomena

Holistic wild bee management in urban spaces

Projects promoting bees in urban areas are initiated in cities around the world but evidence-based conservation concepts at a city-wide scale are scarce. We developed a holistic approach for assessment of bee and flowering plant diversity in a medium-sized city. In addition to standard mapping approaches in bee hotspots, we initiated citizen science projects for participative urban bee research to be able to collect comprehensive bee data across the entire city. We identified 22 hotspots of bee diversity, analyzed connectivity between those hotspots and evaluated the impact of flower patches planted in collaboration with the municipal gardens department as stepping stones for oligolectic bee species throughout the city. Participation by urban citizens in bee identification trainings was high (c. 630 persons) but their subsequent contribution through observation reports was relatively low (1,165 records by 140 observers). However, we identified a total of 139 bee taxa, seven of them only discovered by citizen scientists. Total species richness was higher in extensively managed orchards than in semi-natural and wasteland areas. Half of the stepping stone flower patches were occupied by the target oligolectic bee species in the year of planting. After 3 years, all but two species could be confirmed. We suggest a 5-step concept for bee management in cities: (1) identification of bee hotspots combined with standardized surveys, especially of rare species; (2) training of citizen scientists at two different levels for comprehensive surveys in all parts of the city: (a) half-day introductions to wild bee diversity, ecology and conservation in order to create more awareness and (b) 2-weeks workshops for in-depth training of a small number of dedicated citizen scientists; (3) extensive management of existing habitats and special conservation programs for very rare species; (4) creation of high-value habitats which take into account the varied resource needs of bees within flight ranges of only a few hundred meters; (5) creation of stepping stone habitats as floral and nesting resources, integrating educative and participative aspects

Prospective evaluation of quality of life effects in patients undergoing palliative radiotherapy for brain metastases

Background: Recently published results of quality of life (QoL) studies indicated different outcomes of palliative radiotherapy for brain metastases. This prospective multi-center QoL study of patients with brain metastases was designed to investigate which QoL domains improve or worsen after palliative radiotherapy and which might provide prognostic information. Methods: From 01/2007-01/2009, n=151 patients with previously untreated brain metastases were recruited at 14 centers in Germany and Austria. Most patients (82 %) received whole-brain radiotherapy. QoL was measured with the EORTC-QLQ-C15-PAL and brain module BN20 before the start of radiotherapy and after 3 months. Results: At 3 months, 88/142 (62 %) survived. Nine patients were not able to be followed up. 62 patients (70.5 % of 3-month survivors) completed the second set of questionnaires. Three months after the start of radiotherapy QoL deteriorated significantly in the areas of global QoL, physical function, fatigue, nausea, pain, appetite loss, hair loss, drowsiness, motor dysfunction, communication deficit and weakness of legs. Although the use of corticosteroid at 3 months could be reduced compared to pre-treatment (63 % vs. 37 %), the score for headaches remained stable. Initial QoL at the start of treatment was better in those alive than in those deceased at 3 months, significantly for physical function, motor dysfunction and the symptom scales fatigue, pain, appetite loss and weakness of legs. In a multivariate model, lower Karnofsky performance score, higher age and higher pain ratings before radiotherapy were prognostic of 3-month survival. Conclusions: Moderate deterioration in several QoL domains was predominantly observed three months after start of palliative radiotherapy for brain metastases. Future studies will need to address the individual subjective benefit or burden from such treatment. Baseline QoL scores before palliative radiotherapy for brain metastases may contain prognostic information

АСР температуры и расхода гелеобразного топлива в системе топливоподачи испытательного стенда

Объектом автоматизации является система топливоподачи испытательного стенда. Цель работы – проектирование автоматической системы регулирования температуры и расхода гелеобразного топлива в системе топливоподачи испытательного стенда. В процессе выполнения работы проводились экспериментальные исследования, анализ объекта автоматизации, составление структурной схемы автоматической системы регулирования температуры и расхода гелеобразного топлива в системе топливоподачи испытательного стенда, проектирование функциональной схемы, монтажной и принципиальной электрической схем, а также разработка чертежа общего вида щита автоматизации, выбор технических средств и приборов автоматизации с последующим составлением заказной спецификации, разработка мнемосхемы проекта.The object of automation is the fuel supply system of the test stand. The purpose of the work is to design an automatic system for controlling the temperature and the flow rate of gel-like fuel in the fuel dispensing system of the test bench. In the course of the work carried out, experimental studies, analysis of the automation facility, drafting structural diagram of the automatic temperature and flow gel-like fuel management system in the test bench system were carried out, Design of the functional circuit, mounting diagram and principle electrical circuits, as well as drawing of the general kind of automation shield, selection of technical means and automation devices with subsequent elaboration of the custom specification, development of the design mnemonic diagram

Ablation of Dicer from murine Schwann cells increases their proliferation while blocking myelination

The myelin sheaths that surround the thick axons of the peripheral nervous system are produced by the highly specialized Schwann cells. Differentiation of Schwann cells and myelination occur in discrete steps. Each of these requires coordinated expression of specific proteins in a precise sequence, yet the regulatory mechanisms controlling protein expression during these events are incompletely understood. Here we report that Schwann cell-specific ablation of the enzyme Dicer1, which is required for the production of small non-coding regulatory microRNAs, fully arrests Schwann cell differentiation, resulting in early postnatal lethality. Dicer(-/-) Schwann cells had lost their ability to myelinate, yet were still capable of sorting axons. Both cell death and, paradoxically, proliferation of immature Schwann cells was markedly enhanced, suggesting that their terminal differentiation is triggered by growth-arresting regulatory microRNAs. Using microRNA microarrays, we identified 16 microRNAs that are upregulated upon myelination and whose expression is controlled by Dicer in Schwann cells. This set of microRNAs appears to drive Schwann cell differentiation and myelination of peripheral nerves, thereby fulfilling a crucial function for survival of the organism

The 20S Proteasome Splicing Activity Discovered by SpliceMet

The identification of proteasome-generated spliced peptides (PSP) revealed a new unpredicted activity of the major cellular protease. However, so far characterization of PSP was entirely dependent on the availability of patient-derived cytotoxic CD8+ T lymphocytes (CTL) thus preventing a systematic investigation of proteasome-catalyzed peptide splicing (PCPS). For an unrestricted PSP identification we here developed SpliceMet, combining the computer-based algorithm ProteaJ with in vitro proteasomal degradation assays and mass spectrometry. By applying SpliceMet for the analysis of proteasomal processing products of four different substrate polypeptides, derived from human tumor as well as viral antigens, we identified fifteen new spliced peptides generated by PCPS either by cis or from two separate substrate molecules, i.e., by trans splicing. Our data suggest that 20S proteasomes represent a molecular machine that, due to its catalytic and structural properties, facilitates the generation of spliced peptides, thereby providing a pool of qualitatively new peptides from which functionally relevant products may be selected

Full-Length L1CAM and Not Its Δ2Δ27 Splice Variant Promotes Metastasis through Induction of Gelatinase Expression

Tumour-specific splicing is known to contribute to cancer progression. In the case of the L1 cell adhesion molecule (L1CAM), which is expressed in many human tumours and often linked to bad prognosis, alternative splicing results in a full-length form (FL-L1CAM) and a splice variant lacking exons 2 and 27 (SV-L1CAM). It has not been elucidated so far whether SV-L1CAM, classically considered as tumour-associated, or whether FL-L1CAM is the metastasis-promoting isoform. Here, we show that both variants were expressed in human ovarian carcinoma and that exposure of tumour cells to pro-metastatic factors led to an exclusive increase of FL-L1CAM expression. Selective overexpression of one isoform in different tumour cells revealed that only FL-L1CAM promoted experimental lung and/or liver metastasis in mice. In addition, metastasis formation upon up-regulation of FL-L1CAM correlated with increased invasive potential and elevated Matrix metalloproteinase (MMP)-2 and -9 expression and activity in vitro as well as enhanced gelatinolytic activity in vivo. In conclusion, we identified FL-L1CAM as the metastasis-promoting isoform, thereby exemplifying that high expression of a so-called tumour-associated variant, here SV-L1CAM, is not per se equivalent to a decisive role of this isoform in tumour progression