Mitochondrialer Import und Protein-Protein-Interaktionsnetzwerk varianter Glutaryl-CoA-Dehydrogenase

Zirka 99 % des mitochondrialen Proteoms sind nukleär kodiert. Mitochondriale Matrixproteine werden als Präkursor-Proteine im Cytosol synthetisiert und post-translational in das Mitochondrium importiert, um dort nach Abspaltung eines Signalpeptids in reife und funktionelle Proteine prozessiert zu werden. Die cytosolischen molekularen Chaperone Hsc70 und Hsp90 binden kotranslational das Präkursor-Protein. Damit werden die Aufrechterhaltung eines ungefalteten Zustandes und die Übergabe an mitochondriale Importrezeptoren zur korrekten mitochondrialen Translokation gewährleistet. Dennoch ist das Zusammenspiel von cytosolischen Proteinen, mitochondrialen Importrezeptoren und Präkursor-Proteinen nicht hinreichend untersucht. Die meisten monogenetischen mitochondrialen Erkrankungen basieren auf Mutationen in der nukleären DNA. Mutationsbedingte Veränderungen der Primärsequenz von cytosolischen Proteinen führen häufig zu Veränderungen ihrer Tertiär- und Quartärstruktur und in der Folge zu Störungen des Protein-Protein-Interaktionsnetzwerks der betroffenen Proteine. In der vorliegenden Arbeit wurde die Hypothese aufgestellt, dass Missense-Mutationen in mitochondrialen Präkursor-Proteinen zu Veränderungen des cytosolischem Protein-Protein-Interaktionsnetzwerks führen, insbesondere zu Störungen der Interaktion mit Proteinen des Proteinhomöostasenetzwerks, die einen reduzierten mitochondrialen Import zur Folge haben. Im Rahmen dieser Arbeit wurde der Einfluss genetischer Variation auf den Import nukleär kodierter mitochondrialer Proteine charakterisiert. Es konnten cytosolische Mechanismen der Krankheitsentstehung am Beispiel des Glutaryl-CoA-Dehydrogenase-Mangels, basierend auf Mutationen im Gen der Glutaryl-CoA-Dehydrogenase (GCDH), aufgedeckt werden. Mutationen im maturen Anteil des Proteins können zu einem Importdefekt in das Mitochondrium führen. Es konnte gezeigt werden, dass der mature Anteil der GCDH, auch ohne Vorliegen einer mitochondrialen Signalsequenz am N-Terminus, eine Bindung an die Mitochondrienoberfläche vermitteln kann. Mittels massenspektrometrischer sowie lumineszenz- und fluoreszenzspektroskopischer Methoden konnte ein cytosolisches Interaktionsnetzwerk mitochondrialer Präkursor-Proteine identifiziert werden. Quantitative Interaktionsanalysen zeigten eine reduzierte oder aufgehobene Bindung varianter Präkursor-Proteine an die cytosolischen molekularen Chaperonen Hsc70 und Hsp90 sowie den löslichen mitochondrialen Importrezeptor Tom34. Die Stärke der Bindungen an Hsc70 war negativ korreliert mit dem Ausmaß des Importdefektes. Es wird gefolgert, dass neben einem loss of function ein loss of import für variante nukleär kodierte mitochondriale Proteine als krankheitsauslösender Mechanismus relevant sein kann. Die Erkenntnisse rücken cytosolische molekulare Chaperone und deren Einfluss auf den mitochondrialen Import in den Fokus der Evaluierung neuer Therapiestrategien, beispielsweise durch den Einsatz von proteostasis regulators, die durch Regulation von mit GCDH interagierenden Proteinen des Proteinhomöostasenetzwerks wirken, oder (de-) stabilisierenden Substanzen, die die energetische Balance des mitochondrialen Präkursor-Proteins zugunsten eines effektiveren Importes modulieren. Die Charakterisierung des mitochondrialen Importes varianter nukleär kodierter Proteine sowie ihres cytosolischen Interaktionsnetzwerks könnten als Parameter des molekularen Phänotyps zu einem besseren Verständnis von Genotyp-Phänotyp-Korrelationen und des klinischen Verlaufs betroffener Patienten mit genetischen mitochondrialen Erkrankungen beitragen

The Simultaneous Detection and Classification of Mass and Calcification Leading to Breast Cancer in Mammograms

In this paper, we present a novel method for detecting and classifying breast cancer calcification and masses in a single step. The detection and classification steps of calcifications and masses identifiable with a mammogram image are typically performed independently even though their simultaneous solution may lead to a more efficient approach. Our novel method utilizes a Convolutional Neural Network (CNN) to classify the calcifications and masses of different cropped images of a mammogram. We utilize a sliding window detector to break apart full mammogram images into sub-images, and identify and classify the observable objects in the sub-images. We receive multiple probabilities for each sub-image for the different possible classifications. We rank the sub-images, displaying the coordinates of the highest ranked sub-images for each classification. The results of this process are that we detect 46% of cancer within the mammograms and properly classify 64% of the calcifications and masses identified

Phishing Detection Using Natural Language Processing and Machine Learning

Phishing emails are a primary mode of entry for attackers into an organization. A successful phishing attempt leads to unauthorized access to sensitive information and systems. However, automatically identifying phishing emails is often difficult since many phishing emails have composite features such as body text and metadata that are nearly indistinguishable from valid emails. This paper presents a novel machine learning-based framework, the DARTH framework, that characterizes and combines multiple models, with one model for each composite feature, that enables the accurate identification of phishing emails. The framework analyses each composite feature independently utilizing a multi-faceted approach using Natural Language Processing (NLP) and neural network-based techniques and combines the results of these analyses to classify the emails as malicious or legitimate. Utilizing the framework on more than 150,000 emails and training data from multiple sources, including the authors’ emails and phishtank.com, resulted in the precision (correct identification of malicious observations to the total prediction of malicious observations) of 99.97% with an f-score of 99.98% and accurately identifying phishing emails 99.98% of the time. Utilizing multiple machine learning techniques combined in an ensemble approach across a range of composite features yields highly accurate identification of phishing emails

LAS:eR – Einblicke in das Pilotsystem

Im Rahmen des DFG-Projekts ERMS – Electronic Resource Management System entwickelt die LAS:eR-Projektgruppe ein herstellerunabhängiges ERMS auf Open Source Basis zur Organisation und Verwaltung von elektronischen Ressourcen unter Verwendung der Global Open Knowledge Base (GOKb) als offener Knowledge Base und Nutzung standardisierter Schnittstellen zum Datenaustausch mit Drittsystemen. Mit dem im Mai 2018 gestarteten Pilotbetrieb ist es ausgewählten Einrichtungen bereits möglich, lokale Lizenzen mit LAS:eR zu verwalten und durch ihre Rückmeldungen aktiv die laufende Entwicklung der Vollversion zu beeinflussen, die als bundesweite Dienstleistung des hbz im Herbst 2019 mit weitergehenden Funktionalitäten für das Management von Konsortiallizenzen und einem nach Nutzergruppen differenzierten Geschäftsmodell zur Verfügung stehen wird

An Energy-Efficient ECC Processor of UHF RFID Tag for Banknote Anti-Counterfeiting

In this paper, we present the design and analysis of an energy-efficient 163-b elliptic curve cryptographic (ECC) processor suitable for passive ultrahigh frequency (UHF) radio frequency identification (RFID) tags that are usable for banknote authentication and anti-counterfeiting. Even partial public key cryptographic functionality has long been thought to consume too much power and to be too slow to be usable in passive UHF RFID systems. Utilizing a low-power design strategy with optimized register file management and an architecture based on the López-Dahab Algorithm, we designed a low-power ECC processor that is used with a modified ECC-DH authentication protocol. The ECC-DH authentication protocol is compatible with the ISO/IEC 18000-63 (“Gen2”) passive UHF RFID protocol. The ECC processor requires 12 145 gate equivalents. The ECC processor consumes 5.04 nJ/b at a frequency of 960 kHz when implemented in a 0.13-μm standard CMOS process. The tag identity authentication function requires 30 600 cycles to complete all scalar multiplication operations. This size, speed, and power of the ECC processor makes it practical to use within a passive UHF RFID tag and achieve up to 1500 banknote authentications per minute, which is sufficient for use in the fastest banknote counting machines

A Do-It-All-Cipher for RFID: Design Requirements (Extended Abstract)

Recent years have seen significant progress in the development of lightweight symmetric cryptoprimitives. The main concern of the designers of these primitives has been to minimize the number of gate equivalents (GEs) of the hardware implementation. However, there are numerous additional requirements that are present in real-life RFID systems. We give an overview of requirements emerging or already present in the widely deployed EPCGlobal Gen2 and ISO / IEC 18000-63 passive UHF RFID air interface standards. Lightweight stateful authenticated encryption algorithms seem to offer the most complete set of features for this purpose. In this work we give a Gen2-focused ”lessons learned” overview of the challenges and related developments in RFID cryptography and propose what we see as appropriate design criteria for a cipher (dubbed “Do-It-All-Cipher” or DIAC) for the Internet of Things. We also comment on the applicability of NSA’s new SIMON and SPECK proposals for this purpose

Harvest site influences the growth properties of adipose derived stem cells

The therapeutic potential of adult stem cells may become a relevant option in clinical care in the future. In hand and plastic surgery, cell therapy might be used to enhance nerve regeneration and help surgeons and clinicians to repair debilitating nerve injuries. Adipose-derived stem cells (ASCs) are found in abundant quantities and can be harvested with a low morbidity. In order to define the optimal fat harvest location and detect any potential differences in ASC proliferation properties, we compared biopsies from different anatomical sites (inguinal, flank, pericardiac, omentum, neck) in Sprague-Dawley rats. ASCs were expanded from each biopsy and a proliferation assay using different mitogenic factors, basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) was performed. Our results show that when compared with the pericardiac region, cells isolated from the inguinal, flank, omental and neck regions grow significantly better in growth medium alone. bFGF significantly enhanced the growth rate of ASCs isolated from all regions except the omentum. PDGF had minimal effect on ASC proliferation rate but increases the growth of ASCs from the neck region. Analysis of all the data suggests that ASCs from the neck region may be the ideal stem cell sources for tissue engineering approaches for the regeneration of nervous tissu

Islands of spatially discordant APD alternans underlie arrhythmogenesis by promoting electrotonic dyssynchrony in models of fibrotic rat ventricular myocardium

Fibrosis and altered gap junctional coupling are key features of ventricular remodelling and are associated with abnormal electrical impulse generation and propagation. Such abnormalities predispose to reentrant electrical activity in the heart. In the absence of tissue heterogeneity, high-frequency impulse generation can also induce dynamic electrical instabilities leading to reentrant arrhythmias. However, because of the complexity and stochastic nature of such arrhythmias, the combined effects of tissue heterogeneity and dynamical instabilities in these arrhythmias have not been explored in detail. Here, arrhythmogenesis was studied using in vitro and in silico monolayer models of neonatal rat ventricular tissue with 30% randomly distributed cardiac myofibroblasts and systematically lowered intercellular coupling achieved in vitro through graded knockdown of connexin43 expression. Arrhythmia incidence and complexity increased with decreasing intercellular coupling efficiency. This coincided with the onset of a specialized type of spatially discordant action potential duration alternans characterized by island-like areas of opposite alternans phase, which positively correlated with the degree of connexinx43 knockdown and arrhythmia complexity. At higher myofibroblast densities, more of these islands were formed and reentrant arrhythmias were more easily induced. This is the first study exploring the combinatorial effects of myocardial fibrosis and dynamic electrical instabilities on reentrant arrhythmia initiation and complexity

Examining the Relationship between Urogenital Schistosomiasis and HIV Infection

Urogenital schistosomiasis is a parasitic infection caused by a worm, Schistosoma haematobium, which lives in the bloodstream of infected individuals. It affects at least 112 million people, mostly in sub-Saharan Africa, and has been suggested to be a risk factor for becoming infected with HIV. We reviewed publications in order to examine whether it seems likely that this parasitic infection could be a risk factor for HIV. Evidence from many types of studies supports the hypothesis that urogenital schistosomiasis does increase a person's risk of becoming infected with HIV. Studies also suggest that individuals who have both urogenital schistosomiasis and HIV have a more aggressive HIV infection and can more easily transmit HIV to their sexual partners. Praziquantel is an oral, nontoxic, inexpensive medication that is safe in pregnancy and is recommended for treatment of schistosomiasis. In areas where both infections co-exist, regular administration of praziquantel both to young girls and to sexually-active women may be an important approach to reducing HIV transmission. Our findings support the importance of making praziquantel more available to people who live in areas of the world where both urogenital schistosomiasis and HIV infection are widespread

Percolation and Magnetization in the Continuous Spin Ising Model

In the strong coupling limit the partition function of SU(2) gauge theory can be reduced to that of the continuous spin Ising model with nearest neighbour pair-interactions. The random cluster representation of the continuous spin Ising model in two dimensions is derived through a Fortuin-Kasteleyn transformation, and the properties of the corresponding cluster distribution are analyzed. It is shown that for this model, the magnetic transition is equivalent to the percolation transition of Fortuin-Kasteleyn clusters, using local bond weights. These results are also illustrated by means of numerical simulations