Self-stabilization Overhead: an Experimental Case Study on Coded Atomic Storage

Shared memory emulation can be used as a fault-tolerant and highly available distributed storage solution or as a low-level synchronization primitive. Attiya, Bar-Noy, and Dolev were the first to propose a single-writer, multi-reader linearizable register emulation where the register is replicated to all servers. Recently, Cadambe et al. proposed the Coded Atomic Storage (CAS) algorithm, which uses erasure coding for achieving data redundancy with much lower communication cost than previous algorithmic solutions. Although CAS can tolerate server crashes, it was not designed to recover from unexpected, transient faults, without the need of external (human) intervention. In this respect, Dolev, Petig, and Schiller have recently developed a self-stabilizing version of CAS, which we call CASSS. As one would expect, self-stabilization does not come as a free lunch; it introduces, mainly, communication overhead for detecting inconsistencies and stale information. So, one would wonder whether the overhead introduced by self-stabilization would nullify the gain of erasure coding. To answer this question, we have implemented and experimentally evaluated the CASSS algorithm on PlanetLab; a planetary scale distributed infrastructure. The evaluation shows that our implementation of CASSS scales very well in terms of the number of servers, the number of concurrent clients, as well as the size of the replicated object. More importantly, it shows (a) to have only a constant overhead compared to the traditional CAS algorithm (which we also implement) and (b) the recovery period (after the last occurrence of a transient fault) is as fast as a few client (read/write) operations. Our results suggest that CASSS does not significantly impact efficiency while dealing with automatic recovery from transient faults and bounded size of needed resources

Differential Regulation of the Period Genes in Striatal Regions following Cocaine Exposure

Several studies have suggested that disruptions in circadian rhythms contribute to the pathophysiology of multiple psychiatric diseases, including drug addiction. In fact, a number of the genes involved in the regulation of circadian rhythms are also involved in modulating the reward value for drugs of abuse, like cocaine. Thus, we wanted to determine the effects of chronic cocaine on the expression of several circadian genes in the Nucleus Accumbens (NAc) and Caudate Putamen (CP), regions of the brain known to be involved in the behavioral responses to drugs of abuse. Moreover, we wanted to explore the mechanism by which these genes are regulated following cocaine exposure. Here we find that after repeated cocaine exposure, expression of the Period (Per) genes and Neuronal PAS Domain Protein 2 (Npas2) are elevated, in a somewhat regionally selective fashion. Moreover, NPAS2 (but not CLOCK (Circadian Locomotor Output Cycles Kaput)) protein binding at Per gene promoters was enhanced following cocaine treatment. Mice lacking a functional Npas2 gene failed to exhibit any induction of Per gene expression after cocaine, suggesting that NPAS2 is necessary for this cocaine-induced regulation. Examination of Per gene and Npas2 expression over twenty-four hours identified changes in diurnal rhythmicity of these genes following chronic cocaine, which were regionally specific. Taken together, these studies point to selective disruptions in Per gene rhythmicity in striatial regions following chronic cocaine treatment, which are mediated primarily by NPAS2. © 2013 Falcon et al

Transient peak-strain matching partially recovers the age-impaired mechanoadaptive cortical bone response

Mechanoadaptation maintains bone mass and architecture; its failure underlies age-related decline in bone strength. It is unclear whether this is due to failure of osteocytes to sense strain, osteoblasts to form bone or insufficient mechanical stimulus. Mechanoadaptation can be restored to aged bone by surgical neurectomy, suggesting that changes in loading history can rescue mechanoadaptation. We use non-biased, whole-bone tibial analyses, along with characterisation of surface strains and ensuing mechanoadaptive responses in mice at a range of ages, to explore whether sufficient load magnitude can activate mechanoadaptation in aged bone. We find that younger mice adapt when imposed strains are lower than in mature and aged bone. Intriguingly, imposition of short-term, high magnitude loading effectively primes cortical but not trabecular bone of aged mice to respond. This response was regionally-matched to highest strains measured by digital image correlation and to osteocytic mechanoactivation. These data indicate that aged bone’s loading response can be partially recovered, non-invasively by transient, focal high strain regions. Our results indicate that old murine bone does respond to load when the loading is of sufficient magnitude, and bones’ age-related adaptation failure may be due to insufficient mechanical stimulus to trigger mechanoadaptation

The combinatorics of resource sharing

We discuss general models of resource-sharing computations, with emphasis on the combinatorial structures and concepts that underlie the various deadlock models that have been proposed, the design of algorithms and deadlock-handling policies, and concurrency issues. These structures are mostly graph-theoretic in nature, or partially ordered sets for the establishment of priorities among processes and acquisition orders on resources. We also discuss graph-coloring concepts as they relate to resource sharing.Comment: R. Correa et alii (eds.), Models for Parallel and Distributed Computation, pp. 27-52. Kluwer Academic Publishers, Dordrecht, The Netherlands, 200

Accelerating root system phenotyping of seedlings through a computer-assisted processing pipeline

Background: There are numerous systems and techniques to measure the growth of plant roots. However, phenotyping large numbers of plant roots for breeding and genetic analyses remains challenging. One major difficulty is to achieve high throughput and resolution at a reasonable cost per plant sample. Here we describe a cost-effective root phenotyping pipeline, on which we perform time and accuracy benchmarking to identify bottlenecks in such pipelines and strategies for their acceleration. Results: Our root phenotyping pipeline was assembled with custom software and low cost material and equipment. Results show that sample preparation and handling of samples during screening are the most time consuming task in root phenotyping. Algorithms can be used to speed up the extraction of root traits from image data, but when applied to large numbers of images, there is a trade-off between time of processing the data and errors contained in the database. Conclusions: Scaling-up root phenotyping to large numbers of genotypes will require not only automation of sample preparation and sample handling, but also efficient algorithms for error detection for more reliable replacement of manual interventions

Interviews with Irish healthcare workers from different disciplines about palliative care for people with Parkinson’s disease: a definite role but uncertainty around terminology and timing

Background: An integrated palliative care approach is recommended in all life-limiting diseases, including Parkinson’s disease (PD). However research shows that people with PD have unmet palliative care needs. The study aimed to explore multidisciplinary healthcare workers’ (HCWs) views on palliative care for people with PD, identifying perceived barriers and facilitators. Methods: A qualitative design was used; data was analysed using Thematic Analysis. Semi-structured interviews were conducted with 30 HCWs, working either with people with PD or in a palliative care setting in Ireland. Results: A number of perceived barriers were evident helping to account for the previously reported unmet palliative care needs in PD. A lack of education about PD and palliative care meant that HCWs were unsure of the appropriateness of referral, and patients and carers weren’t equipped with information to seek palliative care. A lack of communication between PD and palliative care specialists was seen to impede collaboration between the disciplines. Uncertainty about the timing of palliative care meant that it was often not introduced until a crisis point, despite the recognised need for early planning due to increased prevalence of dementia. Conclusions: Most HCWs recognised a need for palliative care for people with PD; however several barriers to implementing a palliative care approach in this population need to be addressed. Implications for clinical practice and policy include the need for an integrated model of care, and education for all HCWs, patients, carers, and the public on both the nature of advanced PD, and the potential of palliative care in support of patients and their family members

Proliferation of Ty3/gypsy-like retrotransposons in hybrid sunflower taxa inferred from phylogenetic data

<p>Abstract</p> <p>Background</p> <p>Long terminal repeat (LTR) retrotransposons are a class of mobile genetic element capable of autonomous transposition via an RNA intermediate. Their large size and proliferative ability make them important contributors to genome size evolution, especially in plants, where they can reach exceptionally high copy numbers and contribute substantially to variation in genome size even among closely related taxa. Using a phylogenetic approach, we characterize dynamics of proliferation events of <it>Ty3/gypsy</it>-like LTR retrotransposons that led to massive genomic expansion in three <it>Helianthus </it>(sunflower) species of ancient hybrid origin. The three hybrid species are independently derived from the same two parental species, offering a unique opportunity to explore patterns of retrotransposon proliferation in light of reticulate evolutionary events in this species group.</p> <p>Results</p> <p>We demonstrate that <it>Ty3/gypsy</it>-like retrotransposons exist as multiple well supported sublineages in both the parental and hybrid derivative species and that the same element sublineage served as the source lineage of proliferation in each hybrid species' genome. This inference is based on patterns of species-specific element numerical abundance within different phylogenetic sublineages as well as through signals of proliferation events present in the distributions of element divergence values. Employing methods to date paralogous sequences within a genome, proliferation events in the hybrid species' genomes are estimated to have occurred approximately 0.5 to 1 million years ago.</p> <p>Conclusion</p> <p>Proliferation of the same retrotransposon major sublineage in each hybrid species indicates that similar dynamics of element derepression and amplification likely occurred in each hybrid taxon during their formation. Temporal estimates of these proliferation events suggest an earlier origin for these hybrid species than previously supposed.</p

Integrating complex genomic datasets and tumour cell sensitivity profiles to address a 'simple' question: which patients should get this drug?

It is becoming increasingly apparent that cancer drug therapies can only reach their full potential through appropriate patient selection. Matching drugs and cancer patients has proven to be a complex challenge, due in large part to the substantial molecular heterogeneity inherent to human cancers. This is not only a major hurdle to the improvement of the use of current treatments but also for the development of novel therapies and the ability to steer them to the relevant clinical indications. In this commentary we discuss recent studies from Kuo et al., published this month in BMC Medicine, in which they used a panel of cancer cell lines as a model for capturing patient heterogeneity at the genomic and proteomic level in order to identify potential biomarkers for predicting the clinical activity of a novel candidate chemotherapeutic across a patient population. The findings highlight the ability of a 'systems approach' to develop a better understanding of the properties of novel candidate therapeutics and to guide clinical testing and application

PKCδ regulates force signaling during VEGF/CXCL4 induced dissociation of endothelial tubes

Wound healing requires the vasculature to re-establish itself from the severed ends; endothelial cells within capillaries must detach from neighboring cells before they can migrate into the nascent wound bed to initiate angiogenesis. The dissociation of these endothelial capillaries is driven partially by platelets' release of growth factors and cytokines, particularly the chemokine CXCL4/platelet factor-4 (PF4) that increases cell-cell de-adherence. As this retraction is partly mediated by increased transcellular contractility, the protein kinase c-δ/myosin light chain-2 (PKCδ/MLC-2) signaling axis becomes a candidate mechanism to drive endothelial dissociation. We hypothesize that PKCδ activation induces contractility through MLC-2 to promote dissociation of endothelial cords after exposure to platelet-released CXCL4 and VEGF. To investigate this mechanism of contractility, endothelial cells were allowed to form cords following CXCL4 addition to perpetuate cord dissociation. In this study, CXCL4-induced dissociation was reduced by a VEGFR inhibitor (sunitinib malate) and/or PKCδ inhibition. During combined CXCL4+VEGF treatment, increased contractility mediated by MLC-2 that is dependent on PKCδ regulation. As cellular force is transmitted to focal adhesions, zyxin, a focal adhesion protein that is mechano-responsive, was upregulated after PKCδ inhibition. This study suggests that growth factor regulation of PKCδ may be involved in CXCL4-mediated dissociation of endothelial cords. © 2014 Jamison et al

Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis

Aims/hypothesis The innate immune cells, invariant natural killer T cells (iNKT cells), are implicated in the pathogenesis of psoriasis, an inflammatory condition associated with obesity and other metabolic diseases, such as diabetes and dyslipidaemia. We observed an improvement in psoriasis severity in a patient within days of starting treatment with an incretin-mimetic, glucagon-like peptide-1 (GLP-1) receptor agonist. This was independent of change in glycaemic control. We proposed that this unexpected clinical outcome resulted from a direct effect of GLP-1 on iNKTcells. Methods We measured circulating and psoriatic plaque iNKT cell numbers in two patients with type 2 diabetes and psoriasis before and after commencing GLP-1 analogue therapy. In addition, we investigated the in vitro effects of GLP-1 on iNKT cells and looked for a functional GLP-1 receptor on these cells. Results The Psoriasis Area and Severity Index improved in both patients following 6 weeks of GLP-1 analogue therapy. This was associated with an alteration in iNKT cell number, with an increased number in the circulation and a decreased number in psoriatic plaques. The GLP-1 receptor was expressed on iNKT cells, and GLP-1 induced a dose-dependent inhibition of iNKT cell cytokine secretion, but not cytolytic degranulation in vitro. Conclusions/interpretation The clinical effect observed and the direct interaction between GLP-1 and the immune system raise the possibility of therapeutic applications for GLP-1 in inflammatory conditions such as psoriasis