Exploring potential energy surfaces in ground- and excited states

Chemical reactivity of atoms, molecules and ions is governed by their underlying potential energy surface. Calculating the whole potential energy surface within reasonable bounds, is impossible for all but the smallest molecules. Usually, only parts of the full potential energy surface can be studied, namely stationary points and the minimum energy paths connecting them. By comparing energies of stationary points and their separating barriers, conclusions regarding possible reactions mechanism, or their infeasibility, can be drawn. Taking excited states into account leads to further complications, as now multiple potential energy surfaces have to be considered and root flips between different excited states may occur, requiring effective state-tracking. Part II of this thesis describes the required methods to locate stationary points and minimum energy paths on potential energy surfaces, by using surface-walking, chain-of-states optimization and intrinsic reaction coordinate integration. Several approaches to state-tracking are presented in chapter 4. Results of this thesis are presented in Part III, containing two contributions to the field of photochemistry: chapter 12 provides a possible excited-state reaction mechanism for a biaryl cross-coupling reaction and offers a plausible explanation for its high regioselectivity. The second contribution is the development pysisyphus (chapter 13), an external optimizer implemented in python, aware of excited states and thus the core of this thesis. By implementing the state-tracking algorithms outlined in chapter 4 it allows effective and efficient optimizations of stationary points in ground- and excited-states. The performance of pysisyphus is verified for several established benchmark sets. Results for several excited-state optimizations are presented in section 13.3, where pysisyphus shows good performance for the optimization of sizeable transition-metal complexes

Survey and Systematization of Secure Device Pairing

Secure Device Pairing (SDP) schemes have been developed to facilitate secure communications among smart devices, both personal mobile devices and Internet of Things (IoT) devices. Comparison and assessment of SDP schemes is troublesome, because each scheme makes different assumptions about out-of-band channels and adversary models, and are driven by their particular use-cases. A conceptual model that facilitates meaningful comparison among SDP schemes is missing. We provide such a model. In this article, we survey and analyze a wide range of SDP schemes that are described in the literature, including a number that have been adopted as standards. A system model and consistent terminology for SDP schemes are built on the foundation of this survey, which are then used to classify existing SDP schemes into a taxonomy that, for the first time, enables their meaningful comparison and analysis.The existing SDP schemes are analyzed using this model, revealing common systemic security weaknesses among the surveyed SDP schemes that should become priority areas for future SDP research, such as improving the integration of privacy requirements into the design of SDP schemes. Our results allow SDP scheme designers to create schemes that are more easily comparable with one another, and to assist the prevention of persisting the weaknesses common to the current generation of SDP schemes.Comment: 34 pages, 5 figures, 3 tables, accepted at IEEE Communications Surveys & Tutorials 2017 (Volume: PP, Issue: 99

Automated Cryptanalysis of Bloom Filter Encryptions of Health Records

Privacy-preserving record linkage with Bloom filters has become increasingly popular in medical applications, since Bloom filters allow for probabilistic linkage of sensitive personal data. However, since evidence indicates that Bloom filters lack sufficiently high security where strong security guarantees are required, several suggestions for their improvement have been made in literature. One of those improvements proposes the storage of several identifiers in one single Bloom filter. In this paper we present an automated cryptanalysis of this Bloom filter variant. The three steps of this procedure constitute our main contributions: (1) a new method for the detection of Bloom filter encrytions of bigrams (so-called atoms), (2) the use of an optimization algorithm for the assignment of atoms to bigrams, (3) the reconstruction of the original attribute values by linkage against bigram sets obtained from lists of frequent attribute values in the underlying population. To sum up, our attack provides the first convincing attack on Bloom filter encryptions of records built from more than one identifier.Comment: Contribution to the 8th International Conference on Health Informatics, Lisbon 201

Optimierung synthetischer Inhibitoren des Gerinnungsfaktors Xa vom 4-Amidinobenzylamid-Typ

Die Entwicklung von wirksamen und sicheren Antikoagulantien, die ergänzend und anstelle der bisherigen Standardtherapeutika zur Behandlung thromboembolischer Erkrankungen eingesetzt werden können, ist weltweit ein aktuelles Forschungsziel vieler Firmen und Gruppen. Dabei ist, neben Thrombin, auch der Gerinnungsfaktor Xa (FXa) ein wichtiges Zielenzym, das entscheidend an der Regulierung der Blutgerinnung beteiligt ist. In den letzten Jahren sind viele synthetische niedermolekulare FXa-Inhibitoren entwickelt worden und einige oral wirksame Verbindungen befinden sich zur Zeit in der klinischen Entwicklung. Bislang ist jedoch kein oral bioverfügbarer Hemmstoff des FXa als Arzneimittel zugelassen. Im Rahmen dieser Arbeit sollten die Grundstrukturen bereits bekannter Inhibitoren optimiert werden, um eine Verbesserung der Affinität, verbunden mit einer verzögerten Eliminierung aus der Zirkulation im Tiermodell an der Ratte zu erreichen. Idealerweise sollten die Verbindungen auch oral aufgenommen werden. Durch gezielte Substitution der P3-Aminosäure ist es gelungen, mehrere wirksame und selektive Substrat-analoge FXa-Hemmstoffe mit D-Homophenylalanin und anderen aromatischen Homoaminosäuren, wie z.B. D-Homotyrosin und verschiedenen D,L-Homopyridylalaninen, in P3-Position zu entwickeln. Dagegen konnte nur in wenigen Fällen ein verzögertes Eliminationsverhalten der Inhibitoren erreicht werden. Das Modeling der Verbindung 802 im Komplex mit FXa hat gezeigt, dass im Vergleich zu den D-Phenylalanin-Derivaten der aromatische Ring des P3-D-Homophenylalanins aufgrund der zusätzlichen Methylengruppe in der Seitenkette optimal in der Aryl-Bindungstasche lokalisiert ist. Die durchgeführten Variationen an P4- und P2-Resten in Kombination mit D-Homophenylalanin, D-Homotyrosin und verschiedenen D,L-Homopyridylalaninen haben zu Inhibitoren mit sehr unterschiedlichen Hemmkonstanten geführt. Eine Substitution des P4-Rings mit Carboxymethyl- oder Nitrogruppen sowie Pyridylringen bewirkte in den meisten Fällen einen Affinitätsverlust, lediglich der Einbau einer Aminogruppe in para-Position am P4-Ring führte zu einer leichten Verstärkung der FXa-Hemmwirkung. Allerdings wurden bei Untersuchung des P4-Amino-substituierten Inhibitors 760 im Ames-Test mutagene und zytotoxische Effekte beobachtet, die möglicherweise auf die anilinische Aminofunktion zurückzuführen sind. Deshalb wurde bei der weiteren Optimierung der Inhibitoren auf den Einbau des 4-Aminobenzylsulfonylrestes in P4-Position verzichtet. Daneben zeigte sich bezüglich Affinität und Selektivität eine deutliche Präferenz des FXa für Gly als P2-Rest; der Einbau anderer Aminosäuren führte zu weniger wirksamen Inhibitoren mit geringerer Selektivität. Um die schnelle Eliminierung der Hemmstoffe im Tierversuch zu reduzieren, wurde der Stickstoff der P4- und P3-Pyridylringe zu den entsprechenden N-Oxiden oxidiert. Diese Modifizierungen bewirkten am P4-Ring in allen Fällen einen starken Affinitätsverlust. Im Gegensatz dazu führte der Einbau des D,L-2-Homopyridylalanin-N-Oxids in P3-Position zu einem Inhibitor (1215) mit starker FXa-Hemmwirkung, exzellenter Selektivität und einer deutlich verzögerten Eliminationsgeschwindigkeit an der Ratte nach i.v.-Gabe. Da aus früheren Synthesen bekannt war, dass FXa in P3-Position Aminosäuren in der D-Konfiguration bevorzugt, wurde eine Racemattrennung der D,L-Homopyridylalanine durchgeführt. Gegenüber den racemischen Inhibitoren sind deren D-Derivate - wie erwartet - inhibitorisch etwa doppelt so aktiv. Der Hemmstoff 1332 mit D-2-Homopyridylalanin-N-Oxid ist mit einem Ki-Wert von 0,32 nM der wirksamste aller bis dahin untersuchten FXa-Inhibitoren dieses Strukturtyps. Obwohl die Verbindung 1332 im Vergleich zum racemischen Inhibitor 1215 schneller eliminiert wird, zeigt sich in allen anderen Untersuchungen eine erhöhte Wirksamkeit im Vergleich zum Racemat. Neben den verbesserten Ki-Werten ist der Hemmstoff 1332 auch in vitro im Gerinnungstest (aPTT und PT) etwa doppelt so aktiv; der ED50-Wert der antithrombotischen Wirksamkeit in vivo wurde ebenfalls deutlich verbessert. Aufgrund der positiv geladenen Benzamidingruppe in P1-Position besitzen die Hemmstoffe keine orale Bioverfügbarkeit. Um die orale Aufnahme des Inhibitors 1332 zu erhöhen, wurde dessen Hydroxyamidino-Prodrug 1331 synthetisiert. Während der Resorptionsversuche mit dem Prodrug 1331 an der Ratte traten ungewöhnlich starke Schwankungen in den für Inhibitor 1332 gemessenen Blutspiegeln auf. In einigen Fällen sind die erhaltenen Plasmaspiegel nach oraler bzw. duodenaler Applikation jedoch mit denen des Thrombinhemmstoffs Ximelagatran vergleichbar, der zu etwa 20 % oral bioverfügbar ist

Cálculo da eficiência da simetria usando a relação de simetria da marcha, aplicando deformação dinâmica normalizada ao longo do tempo

In this paper we propose a new method for symmetry calculation in wearable devices. The problem in this domain is that only discrete features such as stride length, stride duration, or duration of gait phases are used for the symmetry calculation. However, this can lead to failures, since the use of features can result in partial loss of information from the time series. From this we present a possibility to calculate the symmetry by using Dynamic Time Warping (DTW). DTW uses the complete time series for the analysis and is therefore independent of certain features.En este artículo proponemos un nuevo método para el cálculo de la simetría para la resistencia sensible a la fuerza (FSR) en dispositivos portátiles. El problema en este dominio es que solo se utilizan características discretas como la longitud de la zancada, la duración de la zancada o la duración de las fases de la marcha para el cálculo de la simetría. Sin embargo, esto puede conducir a fallas, ya que el uso de funciones puede resultar en una pérdida parcial de información de la serie temporal. A partir de esto, presentamos la posibilidad de calcular la simetría utilizando el método de Dynamic Time Warping (DTW). El DTW utiliza la serie de tiempo completa para el análisis y, por lo tanto, es independiente de ciertas características.Neste artigo propomos um novo método para cálculo de simetria para resistência sensível à força (FSR) em dispositivos portáteis. O problema neste domínio é que apenas são utilizadas características discretas, como comprimento da passada, duração da passada ou duração da fase da marcha para o cálculo de simetria. No entanto, isso pode levar a falhas, pois o uso de funções pode resultar em perda parcial de informações da série temporal. A partir disso, apresentamos a possibilidade de calcular a simetria utilizando o método Dynamic Time Warping (DTW). O DTW usa toda a série temporal para a análise e, portanto, é independente de determinados recursos

Growth of sulfate-reducing bacteria in the high concentrations of iron ions

Sulphate-reducing bacteria (SRB) are anaerobic microorganisms that use sulphate as a terminal electron acceptor in, for example, the degradation of organic compounds. They are ubiquitous in anoxic habitats, where they have an important role in both the sulphur and carbon cycles. SRB can cause a serious problem for industries, such as the offshore oil industry, because of the production of sulphide, which is highly reactive, corrosive and toxic. However, these organisms can also be beneficial by removing sulphate and heavy metals from waste streams. Although SRB have been studied for more than a century, it is only with the recent emergence of new molecular biological and genomic techniques that we have begun to obtain detailed information on their way of life

Performance and Security Enhancements in Practical Millimeter-Wave Communication Systems

Millimeter-wave (mm-wave) communication systems achieve extremely high data rates and provide interference-free transmissions. to overcome high attenuations, they employ directional antennas that focus their energy in the intended direction. Transmissions can be steered such that signals only propagate within a specific area-of-interest. Although these advantages are well-known, they are not yet available in practical networks. IEEE 802.11ad, the recent standard for communications in the unlicensed 60 GHz band, exploits a subset of the directional propagation effects only. Despite the large available spectrum, it does not outperform other developments in the prevalent sub-6 GHz bands. This underutilization of directional communications causes unnecessary performance limitations and leaves a false sense of security. For example, standard compliant beam training is very time consuming. It uses suboptimal beam patterns, and is unprotected against malicious behaviors. Furthermore, no suitable research platform exists to validate protocols in realistic environments. To address these challenges, we develop a holistic evaluation framework and enhance the performance and security in practical mm-wave communication systems. Besides signal propagation analyses and environment simulations, our framework enables practical testbed experiments with off-the-shelf devices. We provide full access to a tri-band router’s operating system, modify the beam training operation in the Wi-Fi firmware, and create arbitrary beam patterns with the integrated antenna array. This novel approach allows us to implement custom algorithms such as a compressive sector selection that reduces the beam training overhead by a factor of 2.3. By aligning the receive beam, our adaptive beam switching algorithm mitigates interference from lateral directions and achieves throughput gains of up to 60%. With adaptive beam optimization, we estimate the current channel conditions and generate directional beams that implicitly exploit potential reflections in the environment. These beams increase the received signal strength by about 4.4 dB. While intercepting a directional link is assumed to be challenging, our experimental studies show that reflections on small-scale objects are sufficient to enable eavesdropping from afar. Additionally, we practically demonstrate that injecting forged feedback in the beam training enables Man-in-the Middle attacks. With only 7.3% overhead, our authentication scheme protects against this beam stealing and enforces responses to be only accepted from legitimate devices. By making beam training more efficient, effective, and reliable, our contributions finally enable practical applications of highly directional transmissions

Cryptanalysis of Basic Bloom Filters Used for Privacy Preserving Record Linkage

Bloom filter encoded identifiers are increasingly used for privacy preserving record linkage applications, because they allow for errors in encrypted identifiers. However, little research on the security of Bloom filters has been published so far. In this paper, we formalize a successful attack on Bloom filters composed of bigrams. It has previously been assumed in the literature that an attacker knows the global data set from which a sample is drawn. In contrast, we suppose that an attacker does not know this global data set. Instead, we assume the adversary knows a publicly available list of the most frequent attributes. The attack is based on subtle filtering and elementary statistical analysis of encrypted bigrams. The attack described in this paper can be used for the deciphering of a whole database instead of only a small subset of the most frequent names, as in previous research. We illustrate our proposed method with an attack on a database of encrypted surnames. Finally, we describe modifications of the Bloom filters for preventing similar attacks

3-Amidinophenylalanine-Derived Matriptase Inhibitors can Modulate Hepcidin Production in vitro

Matriptase-2 (MT-2) is a type II transmembrane serine protease and predominantly attached to the surface of hepatocytes. MT-2 decreases the production of hepcidin, a key regulator of iron homeostasis. In this study, the effects of four 3-amidinophenylalanine-derived combined matriptase-1/matriptase-2 (MT-1/2) inhibitors (MI-432, MI-441, MI-460, and MI-461) on hepcidin production were investigated in hepatocyte mono- and hepatocyte-Kupffer cell co-cultures. In MI-461-treated cell cultures, the extracellular hydrogen peroxide contents and the interleukin-6 and -8 (IL-6 and IL-8) levels were determined and compared to controls. Hepcidin overproduction was observed in hepatocytes upon treatment with MI-432, MI-441 and MI-461 at 50 mu M. In contrast, extracellular hydrogen peroxide levels were not elevated significantly after matriptase inhibition with MI-461. Furthermore, MI-461 did not induce increases in IL-6 and IL-8 levels in these hepatic models. A model of the binding mode of inhibitor MI-461 in complex with MT-2 revealed numerous polar contacts contributing to the nanomolar potency of this compound. Based on the in vitro data on hepcidin regulation, treatment with MI-461 might be valuable in pathological states of iron metabolism without causing excessive oxidative stress

Quantifying Protein-Ligand Binding Constants using Electrospray Ionization Mass Spectrometry: A Systematic Binding Affinity Study of a Series of Hydrophobically Modified Trypsin Inhibitors

NanoESI-MS is used for determining binding strengths of trypsin in complex with two different series of five congeneric inhibitors, whose binding affinity in solution depends on the size of the P3 substituent. The ligands of the first series contain a 4-amidinobenzylamide as P1 residue, and form a tight complex with trypsin. The inhibitors of the second series have a 2-aminomethyl-5-chloro-benzylamide as P1 group, and represent a model system for weak binders. The five different inhibitors of each group are based on the same scaffold and differ only in the length of the hydrophobic side chain of their P3 residue, which modulates the interactions in the S3/4 binding pocket of trypsin. The dissociation constants (KD) for high affinity ligands investigated by nanoESI-MS ranges from 15nM to 450nM and decreases with larger hydrophobic P3 side chains. Collision-induced dissociation (CID) experiments of five trypsin and benzamidine-based complexes show a correlation between trends in KD and gas-phase stability. For the second inhibitor series we could show that the effect of imidazole, a small stabilizing additive, can avoid the dissociation of the complex ions and as a result increases the relative abundance of weakly bound complexes. Here the KD values ranging from 2.9 to 17.6μM, some 1-2 orders of magnitude lower than the first series. For both ligand series, the dissociation constants (KD) measured via nanoESI-MS were compared with kinetic inhibition constants (Ki) in solutio