Metastability-Containing Circuits

In digital circuits, metastability can cause deteriorated signals that neither are logical 0 or logical 1, breaking the abstraction of Boolean logic. Unfortunately, any way of reading a signal from an unsynchronized clock domain or performing an analog-to-digital conversion incurs the risk of a metastable upset; no digital circuit can deterministically avoid, resolve, or detect metastability (Marino, 1981). Synchronizers, the only traditional countermeasure, exponentially decrease the odds of maintained metastability over time. Trading synchronization delay for an increased probability to resolve metastability to logical 0 or 1, they do not guarantee success. We propose a fundamentally different approach: It is possible to contain metastability by fine-grained logical masking so that it cannot infect the entire circuit. This technique guarantees a limited degree of metastability in---and uncertainty about---the output. At the heart of our approach lies a time- and value-discrete model for metastability in synchronous clocked digital circuits. Metastability is propagated in a worst-case fashion, allowing to derive deterministic guarantees, without and unlike synchronizers. The proposed model permits positive results and passes the test of reproducing Marino's impossibility results. We fully classify which functions can be computed by circuits with standard registers. Regarding masking registers, we show that they become computationally strictly more powerful with each clock cycle, resulting in a non-trivial hierarchy of computable functions

Complexity of the General Chromatic Art Gallery Problem

In the original Art Gallery Problem (AGP), one seeks the minimum number of guards required to cover a polygon $P$. We consider the Chromatic AGP (CAGP), where the guards are colored. As long as $P$ is completely covered, the number of guards does not matter, but guards with overlapping visibility regions must have different colors. This problem has applications in landmark-based mobile robot navigation: Guards are landmarks, which have to be distinguishable (hence the colors), and are used to encode motion primitives, \eg, "move towards the red landmark". Let $\chi_G(P)$, the chromatic number of $P$, denote the minimum number of colors required to color any guard cover of $P$. We show that determining, whether $\chi_G(P) \leq k$ is \NP-hard for all $k \geq 2$. Keeping the number of colors minimal is of great interest for robot navigation, because less types of landmarks lead to cheaper and more reliable recognition

Fibrosis in Atrial Fibrillation – Role of Reactive Species and MPO

Atrial fibrosis with enhanced turnover and deposition of matrix proteins leads to inhomogeneous atrial electrical conduction and gives rise to electrical reentry circuits resulting in atrial fibrillation. The multifactorial pathogenesis of atrial fibrosis involves resident cardiac cells as well as infiltrating leukocytes, both generating and sequestering matrix metalloproteinases (MMPs), a key enzyme family involved in fibrosis. A growing body of evidence points toward an important role of reactive oxygen species (ROS) in the release and activation of pro-MMPs and the stimulation of pro-fibrotic cascades. Myeloperoxidase (MPO), a bactericidal enzyme released from activated polymorphonuclear neutrophils (PMN) is not only associated with a variety of cardiovascular diseases, but has also been shown to be mechanistically linked to atrial fibrosis and fibrillation. MPO catalyzes the generation of reactive species like hypochlorous acid, which affect intracellular signaling cascades in various cells and advance activation of pro-MMPs and deposition of atrial collagen resulting in atrial arrhythmias. Thus, inflammatory mechanisms effectively promote atrial structural remodeling and importantly contribute to the initiation and perpetuation of atrial fibrillation

Metastability-containing circuits, parallel distance problems, and terrain guarding

We study three problems. The first is the phenomenon of metastability in digital circuits. This is a state of bistable storage elements, such as registers, that is neither logical 0 nor 1 and breaks the abstraction of Boolean logic. We propose a time- and value-discrete model for metastability in digital circuits and show that it reflects relevant physical properties. Further, we propose the fundamentally new approach of using logical masking to perform meaningful computations despite the presence of metastable upsets and analyze what functions can be computed in our model. Additionally, we show that circuits with masking registers grow computationally more powerful with each available clock cycle. The second topic are parallel algorithms, based on an algebraic abstraction of the Moore-Bellman-Ford algorithm, for solving various distance problems. Our focus are distance approximations that obey the triangle inequality while at the same time achieving polylogarithmic depth and low work. Finally, we study the continuous Terrain Guarding Problem. We show that it has a rational discretization with a quadratic number of guard candidates, establish its membership in NP and the existence of a PTAS, and present an efficient implementation of a solver.Wir betrachten drei Probleme, zunächst das Phänomen von Metastabilität in digitalen Schaltungen. Dabei geht es um einen Zustand in bistabilen Speicherelementen, z.B. Registern, welcher weder logisch 0 noch 1 entspricht und die Abstraktion Boolescher Logik unterwandert. Wir präsentieren ein zeit- und wertdiskretes Modell für Metastabilität in digitalen Schaltungen und zeigen, dass es relevante physikalische Eigenschaften abbildet. Des Weiteren präsentieren wir den grundlegend neuen Ansatz, trotz auftretender Metastabilität mit Hilfe von logischem Maskieren sinnvolle Berechnungen durchzuführen und bestimmen, welche Funktionen in unserem Modell berechenbar sind. Darüber hinaus zeigen wir, dass durch Maskingregister in zusätzlichen Taktzyklen mehr Funktionen berechenbar werden. Das zweite Thema sind parallele Algorithmen die, basierend auf einer Algebraisierung des Moore-Bellman-Ford-Algorithmus, diverse Distanzprobleme lösen. Der Fokus liegt auf Distanzapproximationen unter Einhaltung der Dreiecksungleichung bei polylogarithmischer Tiefe und niedriger Arbeit. Abschließend betrachten wir das kontinuierliche Terrain Guarding Problem. Wir zeigen, dass es eine rationale Diskretisierung mit einer quadratischen Anzahl von Wächterpositionen erlaubt, folgern dass es in NP liegt und ein PTAS existiert und präsentieren eine effiziente Implementierung, die es löst

Elevated prevalence of multidrug-resistant gram-negative organisms in HIV positive men

Background: Routes of transmission of multidrug-resistant gram-negative organisms (MDRGN) are not completely understood. Since sexual transmission of MDRGN might represent a potential mode that has not been noticed so far, this study evaluated transmission of MDRGN in HIV positive men. Methods: Between November 2014 and March 2016, we retrospectively investigated the MDRGN prevalence in rectal swabs of n = 109 males tested positive for HIV (HP). These findings were compared to the MDRGN prevalence in n = 109 rectal swabs in age-matched males tested negative for HIV (HN) within the same period. According to the infection control protocol of University Hospital Frankfurt, Germany (UHF), patients admitted to intensive/intermediate care units have to be screened for MDRGN on day of admittance. Patients without HIV testing or MDRGN screening were excluded. Results: MDRGN prevalence in rectal swabs was significantly higher (p = 0.002) in male HP (23.9%;95% confidence interval 16.2-32.9%) than in age-matched male HN (8.3%;3.8-15.1%). In total, 35 MDRGN species were detected. The most frequent MDRGN species was Escherichia coli with resistance due to ESBL expression and additional resistance to fluoroquinolones with n = 25/35 (71.4%;53.7-85.4%). Thereof, n = 19/26 (73.1%;52.2-88.4%) were detected in HP and n = 6/9 (66.7%;29.9-92.5%) in HN, respectively. Conclusions: Prevalence of MDRGN is significantly higher in male HIV positive than in male HIV negative individuals. This might indicate sexual transmission of MDRGN within the male HIV positive population. As treatment options in case of MRGN infections are limited, prevention of MDRGN transmission is strongly emphasized

On the Complexity of Hazard-free Circuits

The problem of constructing hazard-free Boolean circuits dates back to the 1940s and is an important problem in circuit design. Our main lower-bound result unconditionally shows the existence of functions whose circuit complexity is polynomially bounded while every hazard-free implementation is provably of exponential size. Previous lower bounds on the hazard-free complexity were only valid for depth 2 circuits. The same proof method yields that every subcubic implementation of Boolean matrix multiplication must have hazards. These results follow from a crucial structural insight: Hazard-free complexity is a natural generalization of monotone complexity to all (not necessarily monotone) Boolean functions. Thus, we can apply known monotone complexity lower bounds to find lower bounds on the hazard-free complexity. We also lift these methods from the monotone setting to prove exponential hazard-free complexity lower bounds for non-monotone functions. As our main upper-bound result, we show how to efficiently convert a Boolean circuit into a bounded-bit hazard-free circuit with only a polynomially large blow-up in the number of gates. Previously, the best known method yielded exponentially large circuits in the worst case, so our algorithm gives an exponential improvement. As a side result, we establish the NP-completeness of several hazard detection problems

Effects of b-lactam antibiotics and fluoroquinolones on human gut microbiota in relation to clostridium difficile associated diarrhea

Clostridium difficile infections are an emerging health problem in the modern hospital environment. Severe alterations of the gut microbiome with loss of resistance to colonization against C. difficile are thought to be the major trigger, but there is no clear concept of how C. difficile infection evolves and which microbiological factors are involved. We sequenced 16S rRNA amplicons generated from DNA and RNA/cDNA of fecal samples from three groups of individuals by FLX technology: (i) healthy controls (no antibiotic therapy); (ii) individuals receiving antibiotic therapy (Ampicillin/Sulbactam, cephalosporins, and fluoroquinolones with subsequent development of C. difficile infection or (iii) individuals receiving antibiotic therapy without C. difficile infection. We compared the effects of the three different antibiotic classes on the intestinal microbiome and the effects of alterations of the gut microbiome on C. difficile infection at the DNA (total microbiota) and rRNA (potentially active) levels. A comparison of antibiotic classes showed significant differences at DNA level, but not at RNA level. Among individuals that developed or did not develop a C. difficile infection under antibiotics we found no significant differences. We identified single species that were up- or down regulated in individuals receiving antibiotics who developed the infection compared to non-infected individuals. We found no significant differences in the global composition of the transcriptionally active gut microbiome associated with C. difficile infections. We suggest that up- and down regulation of specific bacterial species may be involved in colonization resistance against C. difficile providing a potential therapeutic approach through specific manipulation of the intestinal microbiome.This work was supported by the ERANET Project PathoGenoMics program grant number 0315441A.Peer Reviewe

Functional consequences of microbial shifts in the human gastrointestinal tract linked to antibiotic treatment and obesity

The microbiomes in the gastrointestinal tract (GIT) of individuals receiving antibiotics and those in obese subjects undergo compositional shifts, the metabolic effects and linkages of which are not clearly understood. Herein, we set to gain insight into these effects, particularly with regard to carbohydrate metabolism, and to contribute to unravel the underlying mechanisms and consequences for health conditions. We measured the activity level of GIT carbohydrate-active enzymes toward 23 distinct sugars in adults patients (n = 2) receiving 14-d β-lactam therapy and in obese (n = 7) and lean (n = 5) adolescents. We observed that both 14 d antibiotic-treated and obese subjects showed higher and less balanced sugar anabolic capacities, with 40% carbohydrates being preferentially processed as compared with non-treated and lean patients. Metaproteome-wide metabolic reconstructions confirmed that the impaired utilization of sugars propagated throughout the pentose phosphate metabolism, which had adverse consequences for the metabolic status of the GIT microbiota. The results point to an age-independent positive association between GIT glycosidase activity and the body mass index, fasting blood glucose and insulin resistance (r2 ≥ 0.95). Moreover, antibiotics altered the active fraction of enzymes controlling the thickness, composition and consistency of the mucin glycans. Our data and analyses provide biochemical insights into the effects of antibiotic usage on the dynamics of the GIT microbiota and pin-point presumptive links to obesity. The knowledge and the hypotheses generated herein lay a foundation for subsequent, systematic research that will be paramount for the design of “smart” dietary and therapeutic interventions to modulate host-microbe metabolic co-regulation in intestinal homeostasis

Interference with Activator Protein-2 transcription factors leads to induction of apoptosis and an increase in chemo- and radiation-sensitivity in breast cancer cells

<p>Abstract</p> <p>Background</p> <p>Activator Protein-2 (AP-2) transcription factors are critically involved in a variety of fundamental cellular processes such as proliferation, differentiation and apoptosis and have also been implicated in carcinogenesis. Expression of the family members AP-2α and AP-2γ is particularly well documented in malignancies of the female breast. Despite increasing evaluation of single AP-2 isoforms in mammary tumors the functional role of concerted expression of multiple AP-2 isoforms in breast cancer remains to be elucidated. AP-2 proteins can form homo- or heterodimers, and there is growing evidence that the net effect whether a cell will proliferate, undergo apoptosis or differentiate is partly dependent on the balance between different AP-2 isoforms.</p> <p>Methods</p> <p>We simultaneously interfered with all AP-2 isoforms expressed in ErbB-2-positive murine N202.1A breast cancer cells by conditionally over-expressing a dominant-negative AP-2 mutant.</p> <p>Results</p> <p>We show that interference with AP-2 protein function lead to reduced cell number, induced apoptosis and increased chemo- and radiation-sensitivity. Analysis of global gene expression changes upon interference with AP-2 proteins identified 139 modulated genes (90 up-regulated, 49 down-regulated) compared with control cells. Gene Ontology (GO) investigations for these genes revealed <it>Cell Death </it>and <it>Cell Adhesion and Migration </it>as the main functional categories including 25 and 12 genes, respectively. By using information obtained from Ingenuity Pathway Analysis Systems we were able to present proven or potential connections between AP-2 regulated genes involved in cell death and response to chemo- and radiation therapy, (i.e. <it>Ctgf, Nrp1</it>, <it>Tnfaip3, Gsta3</it>) and AP-2 and other main apoptosis players and to create a unique network.</p> <p>Conclusions</p> <p>Expression of AP-2 transcription factors in breast cancer cells supports proliferation and contributes to chemo- and radiation-resistance of tumor cells by impairing the ability to induce apoptosis. Therefore, interference with AP-2 function could increase the sensitivity of tumor cells towards therapeutic intervention.</p