Serializability, not Serial: Concurrency Control and Availability in Multi-Datacenter Datastores

We present a framework for concurrency control and availability in multi-datacenter datastores. While we consider Google's Megastore as our motivating example, we define general abstractions for key components, making our solution extensible to any system that satisfies the abstraction properties. We first develop and analyze a transaction management and replication protocol based on a straightforward implementation of the Paxos algorithm. Our investigation reveals that this protocol acts as a concurrency prevention mechanism rather than a concurrency control mechanism. We then propose an enhanced protocol called Paxos with Combination and Promotion (Paxos-CP) that provides true transaction concurrency while requiring the same per instance message complexity as the basic Paxos protocol. Finally, we compare the performance of Paxos and Paxos-CP in a multi-datacenter experimental study, and we demonstrate that Paxos-CP results in significantly fewer aborted transactions than basic Paxos.Comment: VLDB201

The human papillomavirus (HPV) oncoproteins: a review of the host pathways targeted on the road to transformation

Persistent infection with high-risk human papillomaviruses (HR-HPVs) is the causal factor in over 99 % of cervical cancer cases, and a significant proportion of oropharyngeal and anogenital cancers. The key drivers of HPV-mediated transformation are the oncoproteins E5, E6 and E7. Together, they act to prolong cell-cycle progression, delay differentiation and inhibit apoptosis in the host keratinocyte cell in order to generate an environment permissive for viral replication. The oncoproteins also have key roles in mediating evasion of the host immune response, enabling infection to persist. Moreover, prolonged infection within the cellular environment established by the HR-HPV oncoproteins can lead to the acquisition of host genetic mutations, eventually culminating in transformation to malignancy. In this review, we outline the many ways in which the HR-HPV oncoproteins manipulate the host cellular environment, focusing on how these activities can contribute to carcinogenesis

Snapshot Profiling of the Antileishmanial Potency of Lead Compounds and Drug Candidates against Intracellular <i>Leishmania donovani</i> Amastigotes, with a Focus on Human-Derived Host Cells

This study characterised in vitro potencies of anti-leishmanial agents against intracellular Leishmania donovani amastigotes in primary human macrophages, obtained with or without CD14-positive monocyte enrichment, phorbol 12-myristate 13-acetate (PMA) differentiated THP-1 cells and mouse peritoneal exudate macrophages (PEMs). Host cell dependent potency was confirmed for pentavalent and trivalent antimony. Fexinidazole was inactive against intracellular amastigotes across the host cell panel. Fexinidazole sulfone, (R)-PA-824, (S)-PA-824 and VL-2098 displayed similar potency in all host cells tested

Polyubiquitin binding to ABIN1 is required to prevent autoimmunity

The protein ABIN1 possesses a polyubiquitin-binding domain homologous to that present in nuclear factor kappa B (NF-kappa B) essential modulator (NEMO), a component of the inhibitor of NF-kappa B (I kappa B) kinase (IKK) complex. To address the physiological significance of polyubiquitin binding, we generated knockin mice expressing the ABIN1[D485N] mutant instead of the wild-type (WT) protein. These mice developed all the hallmarks of autoimmunity, including spontaneous formation of germinal centers, isotype switching, and production of autoreactive antibodies. Autoimmunity was suppressed by crossing to MyD88(-/-) mice, demonstrating that toll-like receptor (TLR)-MyD88 signaling pathways are needed for the phenotype to develop. The B cells and myeloid cells of the ABIN1[D485N] mice showed enhanced activation of the protein kinases TAK, IKK-alpha/beta, c-Jun N-terminal kinases, and p38 alpha mitogen-activated protein kinase and produced more IL-6 and IL-12 than WT. The mutant B cells also proliferated more rapidly in response to TLR ligands. Our results indicate that the interaction of ABIN1 with polyubiquitin is required to limit the activation of TLR-MyD88 pathways and prevent autoimmunity

Classic and spatial shift-share analysis of state-level employment change in Brazil

This paper combines classic and spatial shift-share decompositions of 1981 to 2006 employment change across the 27 states of Brazil. The classic shift-share method shows higher employment growth rates for underdeveloped regions that are due to an advantageous industry-mix and also due to additional job creation, commonly referred to as the competitive effect. Alternative decompositions proposed in the literature do not change this broad conclusion. Further examination employing exploratory spatial data analysis (ESDA) shows spatial correlation of both the industry-mix and the competitive effects. Considering that until the 1960s economic activities were more concentrated in southern regions of Brazil than they are nowadays, these results support beta convergence theories but also find evidence of agglomeration effects. Additionally, a very simple spatial decomposition is proposed that accounts for the spatially-weighted growth of surrounding states. Favourable growth in northern and centre-western states is basically associated with those states’ strengths in potential spatial spillover effect and in spatial competitive effect

Size and shape constancy in consumer virtual reality

With the increase in popularity of consumer virtual reality headsets, for research and other applications, it is important to understand the accuracy of 3D perception in VR. We investigated the perceptual accuracy of near-field virtual distances using a size and shape constancy task, in two commercially available devices. Participants wore either the HTC Vive or the Oculus Rift and adjusted the size of a virtual stimulus to match the geometric qualities (size and depth) of a physical stimulus they were able to refer to haptically. The judgments participants made allowed for an indirect measure of their perception of the egocentric, virtual distance to the stimuli. The data show under-constancy and are consistent with research from carefully calibrated psychophysical techniques. There was no difference in the degree of constancy found in the two headsets. We conclude that consumer virtual reality headsets provide a sufficiently high degree of accuracy in distance perception, to allow them to be used confidently in future experimental vision science, and other research applications in psychology

The anti-tubercular drug delamanid as a potential oral treatment for visceral leishmaniasis

There is an urgent requirement for safe, oral and cost-effective drugs for the treatment of visceral leishmaniasis (VL). We report that delamanid (OPC-67683), an approved drug for multi-drug resistant tuberculosis, is a potent inhibitor of Leishmania donovani both in vitro and in vivo. Twice-daily oral dosing of delamanid at 30 mg kg(-1) for 5 days resulted in sterile cures in a mouse model of VL. Treatment with lower doses revealed a U-shaped (hormetic) dose-response curve with greater parasite suppression at 1 mg kg(-1) than at 3 mg kg(-1) (5 or 10 day dosing). Dosing delamanid for 10 days confirmed the hormetic dose-response and improved the efficacy at all doses investigated. Mechanistic studies reveal that delamanid is rapidly metabolised by parasites via an enzyme, distinct from the nitroreductase that activates fexinidazole. Delamanid has the potential to be repurposed as a much-needed oral therapy for VL. DOI: http://dx.doi.org/10.7554/eLife.09744.00

Injection Drug Use as a Mediator Between Client-perpetrated Abuse and HIV Status Among Female Sex Workers in Two Mexico-US Border Cities

We examined relationships between client-perpetrated emotional, physical, and sexual abuse, injection drug use, and HIV-serostatus among 924 female sex workers (FSWs) in Tijuana and Ciudad Juarez, two large Mexico-US border cities. We hypothesized that FSWs’ injection drug use would mediate the relationship between client-perpetrated abuse and HIV-seropositivity. The prevalence of client-perpetrated emotional, physical, and sexual abuse in the past 6 months was 26, 18, and 10% respectively; prevalence of current injection drug use and HIV was 12 and 6%, respectively. Logistic regression analyses revealed that client-perpetrated sexual abuse was significantly associated with HIV-seropositivity and injection drug use, and that injection drug use was positively associated with HIV-seropositivity. Injection drug use partially mediated the relationship between client-perpetrated sexual abuse and HIV-seropositivity. Results suggest the need to address client-perpetrated violence and injection drug use when assessing HIV risk among FSWs

Processing-Induced Disorder in Pharmaceutical Materials

This chapter focuses on the major types of pharmaceutical processing methods that have been widely reported to produce disordered material either intentionally or unintentionally. Milling is one of the most frequently used unit operations used by the pharmaceutical industry for reducing the particle size of solids. Thermal processing techniques are mainly used for controlling or improving the release and the subsequent bioavailability of an active pharmaceutical ingredient (API). Techniques such as melt-mixing, spray-congealing, sintering, melt-granulation, and hot-melt extrusion (HME) have developed and evolved rapidly for large-scale pharmaceutical production. Solvent-evaporation-based methods are important processing techniques for both raw materials, such as crystallization of the raw drug, and formulation manufacturing in the pharmaceutical industry. The chapter discusses the processing that can potentially induce the formation of the disordered state during the manufacture of formulations. The widely used solvent-evaporation-based processing techniques in pharmaceutical formulation production include spray-drying, freeze-drying, film casting, and film coating