Causal synchrony in the design of distributed programs

The outcome of any computation is determined by the order of the events in the computation and the state of the component variables of the computation at those events. The level of knowledge that can be obtained about event order and process state influences protocol design and operation. In a centralized system, the presence of a physical clock makes it easy to determine event order. It is a more difficult task in a distributed system because there is normally no global time. Hence, there is no common time reference to be used for ordering events. as a consequence, distributed protocols are often designed without explicit reference to event order. Instead they are based on some approximation of global state. Because global state is also difficult to identify in a distributed system, the resulting protocols are not as efficient or clear as they could be.;We subscribe to Lamport\u27s proposition that the relevant temporal ordering of any two events is determined by their causal relationship and that knowledge of the causal order can be a powerful tool in protocol design. Mattern\u27s vector time can be used to identify the causal order, thereby providing the common frame of reference needed to order events in a distributed computation. In this dissertation we present a consistent methodology for analysis and design of distributed protocols that is based on the causal order and vector time. Using it we can specify conditions which must be met for a protocol to be correct, we can define the axiomatic protocol specifications, and we can structure reasoning about the correctness of the specified protocol. Employing causality as a unifying concept clarifies protocol specifications and correctness arguments because it enables them to be defined purely in terms of local states and local events.;We have successfully applied this methodology to the problems of distributed termination detection, distributed deadlock detection and resolution, and optimistic recovery. In all cases, the causally synchronous protocols we have presented are efficient and demonstrably correct

Narratives as a Fundamental Component of Consciousness

In this paper, we propose a conceptual architecture that models human (spatially-temporally-modally) cohesive narrative development using a computer representation of quale properties. Qualia are proposed to be the fundamental "cognitive" components humans use to generate cohesive narratives. The engineering approach is based on cognitively inspired technologies and incorporates the novel concept of quale representation for computation of primitive cognitive components of narrative. The ultimate objective of this research is to develop an architecture that emulates the human ability to generate cohesive narratives with incomplete or perturbated information

Maternal Influences on Nausea and Vomiting in Early Pregnancy

Symptoms of nausea and vomiting in early pregnancy (NVP) are common among pregnant women, but whether some women are more likely than others to experience these symptoms has not been well established. We examined potential risk factors for NVP symptom severity, timing of onset, and duration. We included 2,407 newly pregnant women who participated in a prospective cohort study on early pregnancy health between 2000 and 2004 in three U.S. cities. Data on NVP and other health information were collected through telephone interviews, early gestation ultrasound, and medical record abstractions. Generalized linear models were used to model possible risk factors for each NVP characteristic. Eighty-nine percent of women had NVP; for 99% of these, symptoms started in the first trimester. None of the characteristics examined were associated with having NVP. Among those with NVP, increasing risk of delayed symptoms onset was associated with advancing maternal age; increased risks were also seen among non-Hispanic Black [Risk ratio (RR) = 4.3, 95% confidence interval (CI): 1.6,11.6] and Hispanic women (RR = 2.3, 95% CI:0.4,11.5). NVP symptoms for multigravidae were more likely to last beyond the first trimester with each additional pregnancy. Most pregnant women experienced NVP. Nearly all of them, regardless of characteristics examined, had symptoms beginning in the first trimester. Maternal age, race/ethnicity, and gravidity were associated with delayed onset and symptoms that persisted into the second trimester

Safety and efficacy of an oxycodone vaccine: Addressing some of the unique considerations posed by opioid abuse

Among vaccines aimed at treating substance use disorders, those targeting opioids present several unique medication development challenges. 1) Opioid overdose is a common complication of abuse, so it is desirable for an opioid vaccine to block the toxic as well as the addictive effects of opioids. 2) It is important that an opioid vaccine not interfere with the action of opioid antagonists used to reverse opioid overdose or treat addiction. 3) Some opioids are immunosuppressive and chronic ongoing opioid use could interfere with vaccine immunogenicity. 4) Although antibody-bound oxycodone is unable to enter the brain because of its size, it might still be able to activate peripheral opioid receptors. To assess vaccine impact on opioid toxicity, rats vaccinated with oxycodone conjugated to keyhole limpet hemocyanin subunit dimer (OXY-dKLH) adsorbed to alum or controls vaccinated with dKLH were compared with regard to oxycodone-induced hotplate analgesia and oxycodone-induced respiratory depression and bradycardia. Vaccination shifted the dose-response curves to the right, representing protection, for each of these endpoints. Naloxone was equally effective in both OXY-dKLH and control groups, providing complete and rapid reversal of respiratory depression. The administration of a long-acting naltrexone formulation during vaccination did not impair vaccine immunogenicity in mice. Similarly, serum anti-oxycodone antibody titers were not altered by continuous morphine infusion during vaccination compared to opioid-naïve controls. Competitive ELISA assay showed negligible or low affinity of immune antiserum for endogenous opioids or opioid antagonists. In vitro receptor binding assays showed that antibody-bound oxycodone does not activate mu opioid receptors. These data support further study of OXY-dKLH as a potential treatment for oxycodone abuse and suggest that vaccination might also reduce the severity of oxycodone overdose

Microevolution of Helicobacter pylori during prolonged infection of single hosts and within families

Our understanding of basic evolutionary processes in bacteria is still very limited. For example, multiple recent dating estimates are based on a universal inter-species molecular clock rate, but that rate was calibrated using estimates of geological dates that are no longer accepted. We therefore estimated the short-term rates of mutation and recombination in Helicobacter pylori by sequencing an average of 39,300 bp in 78 gene fragments from 97 isolates. These isolates included 34 pairs of sequential samples, which were sampled at intervals of 0.25 to 10.2 years. They also included single isolates from 29 individuals (average age: 45 years) from 10 families. The accumulation of sequence diversity increased with time of separation in a clock-like manner in the sequential isolates. We used Approximate Bayesian Computation to estimate the rates of mutation, recombination, mean length of recombination tracts, and average diversity in those tracts. The estimates indicate that the short-term mutation rate is 1.4×10−6 (serial isolates) to 4.5×10−6 (family isolates) per nucleotide per year and that three times as many substitutions are introduced by recombination as by mutation. The long-term mutation rate over millennia is 5–17-fold lower, partly due to the removal of non-synonymous mutations due to purifying selection. Comparisons with the recent literature show that short-term mutation rates vary dramatically in different bacterial species and can span a range of several orders of magnitude

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN