Game theoretic analysis of collusions in nonneutral networks

This paper studies the impact of exclusive contracts between a content provider (CP) and an internet service provider (ISP) in a nonneutral network. We consider a simple linear demand function for the CPs. We studywhen an exclusive contract is benefcial to the colluding pair and evaluate its impact on the noncolluding players at equilibrium. For the case of two CPs and one ISP we show that collusion may not always be benefcial. We derive an explicit condition in terms of the advertisement revenues of the CPs that tells when a collusion is proftable to the colluding entities.

Endoplasmic Reticulum Stress-Mediated Activation of p38 MAPK, Caspase-2 and Caspase-8 Leads to Abrin-Induced Apoptosis

Abrin from Abrus precatorius plant is a potent protein synthesis inhibitor and induces apoptosis in cells. However, the relationship between inhibition of protein synthesis and apoptosis is not well understood. Inhibition of protein synthesis by abrin can lead to accumulation of unfolded protein in the endoplasmic reticulum causing ER stress. The observation of phosphorylation of eukaryotic initiation factor 2 alpha and upregulation of CHOP (CAAT/enhancer binding protein (C/EBP) homologous protein), important players involved in ER stress signaling by abrin, suggested activation of ER stress in the cells. ER stress is also known to induce apoptosis via stress kinases such as p38 MAPK and JNK. Activation of both the pathways was observed upon abrin treatment and found to be upstream of the activation of caspases. Moreover, abrin-induced apoptosis was found to be dependent on p38 MAPK but not JNK. We also observed that abrin induced the activation of caspase-2 and caspase-8 and triggered Bid cleavage leading to mitochondrial membrane potential loss and thus connecting the signaling events from ER stress to mitochondrial death machinery.

Chaperoning mitochondrial permeability transition: regulation of transition pore complex by a J-protein, DnaJC15

Mitochondria have a central role in the intrinsic pathway of apoptosis and involve activation of several transmembrane channels leading to release of death factors. Reduced expression of a mitochondrial J-protein DnaJC15 was associated with the development of chemoresistance in ovarian cancer cells. DnaJC15 was found to be a part of mitochondrial protein-transport machinery, though its connection with cell death mechanisms is still unclear. In the present study, we have provided evidence towards a novel function of DnaJC15 in regulation of mitochondrial permeability transition pore (MPTP) complex in normal and cancer cells. Overexpression of DnaJC15 resulted in MPTP opening and induction of apoptosis, whereas reduced amount of protein suppressed MPTP activation, upon cisplatin treatment. DnaJC15 was found to exert its proapoptotic function through the essential component of MPTP, cyclophilin D (CypD). Our results reveal a specific role of DnaJC15 in recruitment and coupling of CypD with mitochondrial permeability transition. In summary, our analysis provides first-time insights on the functional connection between mitochondrial inner membrane protein translocation machinery-associated J-protein DnaJC15 and regulation of cell death pathways.

Automatic Data Allocation and Buffer Management for Multi-GPU Machines

Multi-GPU machines are being increasingly used in high-performance computing. Each GPU in such a machine has its own memory and does not share the address space either with the host CPU or other GPUs. Hence, applications utilizing multiple GPUs have to manually allocate and manage data on each GPU. Existing works that propose to automate data allocations for GPUs have limitations and inefficiencies in terms of allocation sizes, exploiting reuse, transfer costs, and scalability. We propose a scalable and fully automatic data allocation and buffer management scheme for affine loop nests on multi-GPU machines. We call it the Bounding-Box-based Memory Manager (BBMM). BBMM can perform at runtime, during standard set operations like union, intersection, and difference, finding subset and superset relations on hyperrectangular regions of array data (bounding boxes). It uses these operations along with some compiler assistance to identify, allocate, and manage data required by applications in terms of disjoint bounding boxes. This allows it to (1) allocate exactly or nearly as much data as is required by computations running on each GPU, (2) efficiently track buffer allocations and hence maximize data reuse across tiles and minimize data transfer overhead, and (3) and as a result, maximize utilization of the combined memory on multi-GPU machines. BBMM can work with any choice of parallelizing transformations, computation placement, and scheduling schemes, whether static or dynamic. Experiments run on a four-GPU machine with various scientific programs showed that BBMM reduces data allocations on each GPU by up to 75% compared to current allocation schemes, yields performance of at least 88% of manually written code, and allows excellent weak scaling.

Unraveling the Intricate Organization of Mammalian Mitochondrial Presequence Translocases: Existence of Multiple Translocases for Maintenance of Mitochondrial Function

Mitochondria are indispensable organelles implicated in multiple aspects of cellular processes, including tumorigenesis. Heat shock proteins play a critical regulatory role in accurately delivering the nucleus-encoded proteins through membrane-bound presequence translocase (Tim23 complex) machinery. Although altered expression of mammalian presequence translocase components had been previously associated with malignant phenotypes, the overall organization of Tim23 complexes is still unsolved. In this report, we show the existence of three distinct Tim23 complexes, namely, B1, B2, and A, involved in the maintenance of normal mitochondrial function. Our data highlight the importance of Magmas as a regulator of translocase function and in dynamically recruiting the J-proteins DnaJC19 and DnaJC15 to individual translocases. The basic housekeeping function involves translocases B1 and B2 composed of Tim17b isoforms along with DnaJC19, whereas translocase A is nonessential and has a central role in oncogenesis. Translocase B, having a normal import rate, is essential for constitutive mitochondrial functions such as maintenance of electron transport chain complex activity, organellar morphology, iron-sulfur cluster protein biogenesis, and mitochondrial DNA. In contrast, translocase A, though dispensable for housekeeping functions with a comparatively lower import rate, plays a specific role in translocating oncoproteins lacking presequence, leading to reprogrammed mitochondrial functions and hence establishing a possible link between the TIM23 complex and tumorigenicity.

Homeostasis of functional maps in active dendrites emerges in the absence of individual channelostasis

The maintenance of ion channel homeostasis, or channelostasis, is a complex puzzle in neurons with extensive dendritic arborization, encompassing a combinatorial diversity of proteins that encode these channels and their auxiliary subunits, their localization profiles, and associated signaling machinery. Despite this, neurons exhibit amazingly stereotypic, topographically continuous maps of several functional properties along their active dendritic arbor. Here, we asked whether the membrane composition of neurons, at the level of individual ion channels, is constrained by this structural requirement of sustaining several functional maps along the same topograph. We performed global sensitivity analysis on morphologically realistic conductance-based models of hippocampal pyramidal neurons that coexpressed six well-characterized functional maps along their trunk. We generated randomized models by varying 32 underlying parameters and constrained these models with quantitative experimental measurements from the soma and dendrites of hippocampal pyramidal neurons. Analyzing valid models that satisfied experimental constraints on all six functional maps, we found topographically analogous functional maps to emerge from disparate model parameters with weak pairwise correlations between parameters. Finally, we derived a methodology to assess the contribution of individual channel conductances to the various functional measurements, using virtual knockout simulations on the valid model population. We found that the virtual knockout of individual channels resulted in variable, measurement and location-specific impacts across the population. Our results suggest collective channelostasis as a mechanism behind the robust emergence of analogous functional maps and have significant ramifications for the localization and targeting of ion channels and enzymes that regulate neural coding and homeostasis.

Endoplasmic Reticulum Stress Triggers Gametocytogenesis in the Malaria Parasite

The malaria parasite experiences a significant amount of redox stress during its growth in human erythrocytes and heavily relies on secretory functions for pathogenesis. Most certainly, the parasite is equipped with machinery to tackle perturbations in the secretory pathway, like the unfolded protein response pathway in higher eukaryotes. Our bioinformatics analysis revealed the complete absence of genes involved in the canonical unfolded protein response pathway in Plasmodium falciparum. Accordingly, the parasite was unable to up-regulate endoplasmic reticulum (ER) chaperones or ER-associated degradation in response to DTT-mediated ER stress. Global profiling of gene expression upon DTT treatment revealed a network of AP2 transcription factors and their targets being activated. The overall outcome was up-regulation of genes involved in protein export and the sexual stage of the parasite life cycle culminating in gametocytogenesis. Our results suggest that the malaria parasite uses ER stress as a cue to switch to the transmissible sexual stages.

DNA binders in clinical trials and chemotherapy

Cancer has always been a dreadful disease and continues to attract extensive research investigations. Various targets have been identified to restrain cancer. Among these DNA happens to be the most explored one. A wide variety of small molecules, often referred to as `ligands', has been synthesized to target numerous structural features of DNA. The sole purpose of such molecular design has been to interfere with the transcriptional machinery in order to drive the cancer cell toward apoptosis. The mode of action of the DNA targeting ligands focuses either on the sequence-specificity by groove binding and strand cleavage, or by identifying the morphologically distinct higher order structures like that of the G-quadruplex DNA. However, in spite of the extensive research, only a tiny fraction of the molecules have been able to reach clinical trials and only a handful are used in chemotherapy. This review attempts to record the journey of the DNA binding small molecules from its inception to cancer therapy via various modifications at the molecular level. Nevertheless, factors like limited bioavailability, severe toxicities, unfavorable pharmacokinetics etc. still prove to be the major impediments in the field which warrant considerable scope for further research investigations. (C) 2014 Published by Elsevier Ltd.

Comparison of CO2 and steam in transcritical Rankine cycles for concentrated solar power

High temperature, high pressure transcritical condensing CO2 cycle (TC-CO2) is compared with transcritical steam (TC-steam) cycle. Performance indicators such as thermal efficiency, volumetric flow rates and entropy generation are used to analyze the power cycle wherein, irreversibilities in turbo-machinery and heat exchangers are taken into account. Although, both cycles yield comparable thermal efficiencies under identical operating conditions, TC-CO2 plant is significantly compact compared to a TC-steam plant. Large specific volume of steam is responsible for a bulky system. It is also found that the performance of a TC-CO2 cycle is less sensitive to source temperature variations, which is an important requirement of a solar thermal system. In addition, issues like wet expansion in turbine and vacuum in condenser are absent in case of a TC-CO2 cycle. External heat addition to working fluid is assumed to take place through a heat transfer fluid (HTF) which receives heat from a solar receiver. A TC-CO2 system receives heat though a single HTF loop, whereas, for TC-steam cycle two HTF loops in series are proposed to avoid high temperature differential between the steam and HTF. (C) 2013 P. Garg. Published by Elsevier Ltd.

Magmas functions as a ROS regulator and provides cytoprotection against oxidative stress-mediated damages

Redox imbalance generates multiple cellular damages leading to oxidative stress-mediated pathological conditions such as neurodegenerative diseases and cancer progression. Therefore, maintenance of reactive oxygen species (ROS) homeostasis is most important that involves well-defined antioxidant machinery. In the present study, we have identified for the first time a component of mammalian protein translocation machinery Magmas to perform a critical ROS regulatory function. Magmas overexpression has been reported in highly metabolically active tissues and cancer cells that are prone to oxidative damage. We found that Magmas regulates cellular ROS levels by controlling its production as well as scavenging. Magmas promotes cellular tolerance toward oxidative stress by enhancing antioxidant enzyme activity, thus preventing induction of apoptosis and damage to cellular components. Magmas enhances the activity of electron transport chain (ETC) complexes, causing reduced ROS production. Our results suggest that J-like domain of Magmas is essential for maintenance of redox balance. The function of Magmas as a ROS sensor was found to be independent of its role in protein import. The unique ROS modulatory role of Magmas is highlighted by its ability to increase cell tolerance to oxidative stress even in yeast model organism. The cytoprotective capability of Magmas against oxidative damage makes it an important candidate for future investigation in therapeutics of oxidative stress-related diseases.

BELIEF PROPAGATION FOR OPTIMAL EDGE COVER IN THE RANDOM COMPLETE GRAPH

We apply the objective method of Aldous to the problem of finding the minimum-cost edge cover of the complete graph with random independent and identically distributed edge costs. The limit, as the number of vertices goes to infinity, of the expected minimum cost for this problem is known via a combinatorial approach of Hessler and Wastlund. We provide a proof of this result using the machinery of the objective method and local weak convergence, which was used to prove the (2) limit of the random assignment problem. A proof via the objective method is useful because it provides us with more information on the nature of the edge's incident on a typical root in the minimum-cost edge cover. We further show that a belief propagation algorithm converges asymptotically to the optimal solution. This can be applied in a computational linguistics problem of semantic projection. The belief propagation algorithm yields a near optimal solution with lesser complexity than the known best algorithms designed for optimality in worst-case settings.

Race Detection for Android Applications

Programming environments for smartphones expose a concurrency model that combines multi-threading and asynchronous event-based dispatch. While this enables the development of efficient and feature-rich applications, unforeseen thread interleavings coupled with non-deterministic reorderings of asynchronous tasks can lead to subtle concurrency errors in the applications. In this paper, we formalize the concurrency semantics of the Android programming model. We further define the happens-before relation for Android applications, and develop a dynamic race detection technique based on this relation. Our relation generalizes the so far independently studied happens-before relations for multi-threaded programs and single-threaded event-driven programs. Additionally, our race detection technique uses a model of the Android runtime environment to reduce false positives. We have implemented a tool called DROIDRACER. It generates execution traces by systematically testing Android applications and detects data races by computing the happens-before relation on the traces. We analyzed 1 5 Android applications including popular applications such as Facebook, Twitter and K-9 Mail. Our results indicate that data races are prevalent in Android applications, and that DROIDRACER is an effective tool to identify data races.

Compiler/Runtime Framework for Dynamic Dataflow Parallelization of Tiled Programs

Task-parallel languages are increasingly popular. Many of them provide expressive mechanisms for intertask synchronization. For example, OpenMP 4.0 will integrate data-driven execution semantics derived from the StarSs research language. Compared to the more restrictive data-parallel and fork-join concurrency models, the advanced features being introduced into task-parallelmodels in turn enable improved scalability through load balancing, memory latency hiding, mitigation of the pressure on memory bandwidth, and, as a side effect, reduced power consumption. In this article, we develop a systematic approach to compile loop nests into concurrent, dynamically constructed graphs of dependent tasks. We propose a simple and effective heuristic that selects the most profitable parallelization idiom for every dependence type and communication pattern. This heuristic enables the extraction of interband parallelism (cross-barrier parallelism) in a number of numerical computations that range from linear algebra to structured grids and image processing. The proposed static analysis and code generation alleviates the burden of a full-blown dependence resolver to track the readiness of tasks at runtime. We evaluate our approach and algorithms in the PPCG compiler, targeting OpenStream, a representative dataflow task-parallel language with explicit intertask dependences and a lightweight runtime. Experimental results demonstrate the effectiveness of the approach.

Multithreaded Test Synthesis for Deadlock Detection

Designing and implementing thread-safe multithreaded libraries can be a daunting task as developers of these libraries need to ensure that their implementations are free from concurrency bugs, including deadlocks. The usual practice involves employing software testing and/or dynamic analysis to detect. deadlocks. Their effectiveness is dependent on well-designed multithreaded test cases. Unsurprisingly, developing multithreaded tests is significantly harder than developing sequential tests for obvious reasons. In this paper, we address the problem of automatically synthesizing multithreaded tests that can induce deadlocks. The key insight to our approach is that a subset of the properties observed when a deadlock manifests in a concurrent execution can also be observed in a single threaded execution. We design a novel, automatic, scalable and directed approach that identifies these properties and synthesizes a deadlock revealing multithreaded test. The input to our approach is the library implementation under consideration and the output is a set of deadlock revealing multithreaded tests. We have implemented our approach as part of a tool, named OMEN1. OMEN is able to synthesize multithreaded tests on many multithreaded Java libraries. Applying a dynamic deadlock detector on the execution of the synthesized tests results in the detection of a number of deadlocks, including 35 real deadlocks in classes documented as thread-safe. Moreover, our experimental results show that dynamic analysis on multithreaded tests that are either synthesized randomly or developed by third-party programmers are ineffective in detecting the deadlocks.

Trace Driven Dynamic Deadlock Detection and Reproduction

Dynamic analysis techniques have been proposed to detect potential deadlocks. Analyzing and comprehending each potential deadlock to determine whether the deadlock is feasible in a real execution requires significant programmer effort. Moreover, empirical evidence shows that existing analyses are quite imprecise. This imprecision of the analyses further void the manual effort invested in reasoning about non-existent defects. In this paper, we address the problems of imprecision of existing analyses and the subsequent manual effort necessary to reason about deadlocks. We propose a novel approach for deadlock detection by designing a dynamic analysis that intelligently leverages execution traces. To reduce the manual effort, we replay the program by making the execution follow a schedule derived based on the observed trace. For a real deadlock, its feasibility is automatically verified if the replay causes the execution to deadlock. We have implemented our approach as part of WOLF and have analyzed many large (upto 160KLoC) Java programs. Our experimental results show that we are able to identify 74% of the reported defects as true (or false) positives automatically leaving very few defects for manual analysis. The overhead of our approach is negligible making it a compelling tool for practical adoption.