Lifelong Multi-Agent Path Finding in Large-Scale Warehouses

Multi-Agent Path Finding (MAPF) is the problem of moving a team of agents to their goal locations without collisions. In this paper, we study the lifelong variant of MAPF, where agents are constantly engaged with new goal locations, such as in large-scale automated warehouses. We propose a new framework Rolling-Horizon Collision Resolution (RHCR) for solving lifelong MAPF by decomposing the problem into a sequence of Windowed MAPF instances, where a Windowed MAPF solver resolves collisions among the paths of the agents only within a bounded time horizon and ignores collisions beyond it. RHCR is particularly well suited to generating pliable plans that adapt to continually arriving new goal locations. We empirically evaluate RHCR with a variety of MAPF solvers and show that it can produce high-quality solutions for up to 1,000 agents (= 38.9\% of the empty cells on the map) for simulated warehouse instances, significantly outperforming existing work.Comment: Published at AAAI 202

How the Western Was Won: Evidence for Netrin Signaling Machinery in Tetrahymena thermophila

Netrins are pleiotropic signaling molecules with diverse roles in animal development. Netrin signals through a number of receptors in animals, including the UNC-5 family, neogenin, DSCAM, and DCC. Previous studies have shown that netrin-1-peptide, netrin-3-peptide, and recombinant netrin-4 all act as chemorepellents in Tetrahymena (Kuruvilla et al., 2016, Khol et al., 2018; Bradley and Kuruvilla, 2020). In addition, netrin-1 peptide appears to signal through a tyrosine kinase in this organism (Kuruvilla et al., 2016), similar to vertebrate signaling through UNC-5, which uses the tyrosine kinase, src. In light of these data, we hypothesized that Tetrahymena thermophila possess netrin signaling machinery, including a tyrosine kinase. In order to investigate this hypothesis, we searched for various netrin receptors, as well as a src homologue, in Tetrahymena using immunofluorescence (Khol et al., 2018). We found that anti-UNC-5 and anti-neogenin antibodies showed fluorescence, while anti-DCC and anti-DSCAM antibodies did not. In addition, an anti-src antibody showed significant fluorescence in Tetrahymena (Khol et al., 2018. In our current study, we searched the Tetrahymena Genome Database for homologs of UNC-5, neogenin, and src. We also used Western blotting to screen for potential homologues of these proteins. At the present time, there are several proteins of interest which we would like to study further

Biochemical Evidence for Netrin-Signaling Homologues in Tetrahymena thermophila

Netrins are pleiotropic guidance proteins that are involved in developmental signaling of branched structures within vertebrates. However, like many developmental pathways, dysregulation of the netrin pathway has been implicated in cancer progression and metastasis. Since Tetrahymena respond to guidance proteins, showing chemoattractant and chemorepellent behavior, we hypothesized that we could use these organisms as a model system for cancer signaling. We have previously found that netrin-1-peptided, netrin-3-peptide, and recombinant netrin-4 are all chemorepellents in this organism. Since netrin-1-peptide signals through a tyrosine kinase in Tetrahymena, we hypothesized that Tetrahymena might possess tyrosine kinases as well as a receptor homologous to UNC-5, a netrin receptor which relays signals via tyrosine kinases in vertebrates. Using immunoprecipitation with a polyclonal anti-UNC-5-B antibody, we purified a 250 kD protein from Tetrahymena whole cell extract. Similarly, we immunoprecipitated several proteins, including a 60 kD protein and a 75 kD protein using a polyclonal anti-src-antibody. Our purified samples were sent out for identification by mass spectroscopy. Mass spectroscopy indicated that we have purified a number of novel peptides not currently found in the Tetrahymena Genome Database. Our data indicate that the proteome database in this organism is incomplete, and that there are additional proteins waiting to be discovered in this organism

Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: Two randomised, double-blind, phase 3, non-inferiority trials

none27siBackground Tenofovir disoproxil fumarate can cause renal and bone toxic effects related to high plasma tenofovir concentrations. Tenofovir alafenamide is a novel tenofovir prodrug with a 90% reduction in plasma tenofovir concentrations. Tenofovir alafenamide-containing regimens can have improved renal and bone safety compared with tenofovir disoproxil fumarate-containing regimens. Methods In these two controlled, double-blind phase 3 studies, we recruited treatment-naive HIV-infected patients with an estimated creatinine clearance of 50 mL per min or higher from 178 outpatient centres in 16 countries. Patients were randomly assigned (1:1) to receive once-daily oral tablets containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide (E/C/F/tenofovir alafenamide) or 300 mg tenofovir disoproxil fumarate (E/C/F/tenofovir disoproxil fumarate) with matching placebo. Randomisation was done by a computer-generated allocation sequence (block size 4) and was stratified by HIV-1 RNA, CD4 count, and region (USA or ex-USA). Investigators, patients, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug were included in the primary intention-to-treat efficacy and safety analyses. The main outcomes were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48 as defined by the the US Food and Drug Adminstration (FDA) snapshot algorithm (pre-specified non-inferiority margin of 12%) and pre-specified renal and bone endpoints at 48 weeks. These studies are registered with ClinicalTrials.gov, numbers NCT01780506 and NCT01797445. Findings We recruited patients from Jan 22, 2013, to Nov 4, 2013 (2175 screened and 1744 randomly assigned), and gave treatment to 1733 patients (866 given E/C/F/tenofovir alafenamide and 867 given E/C/F/tenofovir disoproxil fumarate). E/C/F/tenofovir alafenamide was non-inferior to E/C/F/tenofovir disoproxil fumarate, with 800 (92%) of 866 patients in the tenofovir alafenamide group and 784 (90%) of 867 patients in the tenofovir disoproxil fumarate group having plasma HIV-1 RNA less than 50 copies per mL (adjusted difference 2·0%, 95% CI -0·7 to 4·7). Patients given E/C/F/tenofovir alafenamide had significantly smaller mean serum creatinine increases than those given E/C/F/tenofovir disoproxil fumarate (0·08 vs 0·12 mg/dL; p<0·0001), significantly less proteinuria (median % change -3 vs 20; p<0·0001), and a significantly smaller decrease in bone mineral density at spine (mean % change -1·30 vs -2·86; p<0·0001) and hip (-0·66 vs -2·95; p<0·0001) at 48 weeks. Interpretation Through 48 weeks, more than 90% of patients given E/C/F/tenofovir alafenamide or E/C/F/tenofovir disoproxil fumarate had virological success. Renal and bone effects were significantly reduced in patients given E/C/F/tenofovir alafenamide. Although these studies do not have the power to assess clinical safety events such as renal failure and fractures, our data suggest that E/C/F/tenofovir alafenamide will have a favourable long-term renal and bone safety profile. Funding Gilead Sciences.openSax, Paul E; Wohl, David; Yin, Michael T.; Post, Frank; Dejesus, Edwin; Saag, Michael; Pozniak, Anton; Thompson, Melanie; Podzamczer, Daniel; Molina, Jean Michel; Oka, Shinichi; Koenig, Ellen; Trottier, Benoit; Andrade-Villanueva, Jaime; Crofoot, Gordon; Custodio, Joseph M.; Plummer, Andrew; Zhong, Lijie; Cao, Huyen; Martin, Hal; Callebaut, Christian; Cheng, Andrew K.; Fordyce, Marshall W.; Mccallister, Scott; for the GS-US-292-0104/0111 Study Team [...; Pierluigi Viale; ...]Sax, Paul E; Wohl, David; Yin, Michael T.; Post, Frank; Dejesus, Edwin; Saag, Michael; Pozniak, Anton; Thompson, Melanie; Podzamczer, Daniel; Molina, Jean Michel; Oka, Shinichi; Koenig, Ellen; Trottier, Benoit; Andrade-Villanueva, Jaime; Crofoot, Gordon; Custodio, Joseph M.; Plummer, Andrew; Zhong, Lijie; Cao, Huyen; Martin, Hal; Callebaut, Christian; Cheng, Andrew K.; Fordyce, Marshall W.; Mccallister, Scott; for the GS-US-292-0104/0111 Study Team [..; Pierluigi Viale; ..

6-Year Periodicity and Variable Synchronicity in a Mass-Flowering Plant

Periodical organisms, such as bamboos and periodical cicadas, are very famous for their synchronous reproduction. In bamboos and other periodical plants, the synchronicity of mass-flowering and withering has been often reported indicating these species are monocarpic (semelparous) species. Therefore, synchronicity and periodicity are often suspected to be fairly tightly coupled traits in these periodical plants. We investigate the periodicity and synchronicity of Strobilanthes flexicaulis, and a closely related species S. tashiroi on Okinawa Island, Japan. The genus Strobilanthes is known for several periodical species. Based on 32-year observational data, we confirmed that S. flexicaulis is 6-year periodical mass-flowering monocarpic plant. All the flowering plants had died after flowering. In contrast, we found that S. tashiroi is a polycarpic perennial with no mass-flowering from three-year individual tracking. We also surveyed six local populations of S. flexicaulis and found variation in the synchronicity from four highly synchronized populations (>98% of plants flowering in the mass year) to two less synchronized one with 11–47% of plants flowering before and after the mass year. This result might imply that synchrony may be selected for when periodicity is established in monocarpic species. We found the selective advantages for mass-flowering in pollinator activities and predator satiation. The current results suggest that the periodical S. flexicaulis might have evolved periodicity from a non-periodical close relative. The current report should become a key finding for understanding the evolution of periodical plants

Intimate partner violence against women in western Ethiopia: prevalence, patterns, and associated factors

<p>Abstract</p> <p>Background</p> <p>Intimate partner violence against women is the psychological, physical, and sexual abuse directed to spouses. Globally it is the most pervasive yet underestimated human rights violation. This study was aimed at investigating the prevalence, patterns and associated factors of intimate partner violence against women in Western Ethiopia.</p> <p>Methods</p> <p>A cross-sectional, population based household survey was conducted from January to April, 2011 using standard WHO multi-country study questionnaire. A sample of 1540 ever married/cohabited women aged 15-49 years was randomly selected from urban and rural settings of East Wollega Zone, Western Ethiopia. Data were principally analyzed using logistic regression.</p> <p>Results</p> <p>Lifetime and past 12 months prevalence of intimate partner violence against women showed 76.5% (95% CI: 74.4-78.6%) and 72.5% (95% CI: 70.3-74.7%), respectively. The overlap of psychological, physical, and sexual violence was 56.9%. The patterns of the three forms of violence are similar across the time periods. Rural residents (AOR 0.58, 95% CI 0.34-0.98), literates (AOR 0.65, 95% CI 0.48-0.88), female headed households <b>(</b>AOR 0.46, 95% CI 0.27-0.76) were at decreased likelihood to have lifetime intimate partner violence. Yet, older women were nearly four times (AOR 3.36, 95% CI 1.27-8.89) more likely to report the incident. On the other hand, abduction (AOR 3.71, 95% CI 1.01-13.63), polygamy (AOR 3.79, 95% CI 1.64-0.73), spousal alcoholic consumption (AOR 1.98, 95% CI 1.21-3.22), spousal hostility (AOR 3.96, 95% CI 2.52-6.20), and previous witnesses of parental violence (AOR 2.00, 95% CI 1.54-2.56) were factors associated with an increased likelihood of lifetime intimate partner violence against women.</p> <p>Conclusion</p> <p>In their lifetime, three out of four women experienced at least one incident of intimate partner violence. This needs an urgent attention at all levels of societal hierarchy including policymakers, stakeholders and professionals to alleviate the situation.</p

CRP identifies homeostatic immune oscillations in cancer patients: a potential treatment targeting tool?

The search for a suitable biomarker which indicates immune system responses in cancer patients has been long and arduous, but a widely known biomarker has emerged as a potential candidate for this purpose. C-Reactive Protein (CRP) is an acute-phase plasma protein that can be used as a marker for activation of the immune system. The short plasma half-life and relatively robust and reliable response to inflammation, make CRP an ideal candidate marker for inflammation. The high- sensitivity test for CRP, termed Low-Reactive Protein (LRP, L-CRP or hs-CRP), measures very low levels of CRP more accurately, and is even more reliable than standard CRP for this purpose. Usually, static sampling of CRP has been used for clinical studies and these can predict disease presence or recurrence, notably for a number of cancers. We have used frequent serial L-CRP measurements across three clinical laboratories in two countries and for different advanced cancers, and have demonstrated similar, repeatable observations of a cyclical variation in CRP levels in these patients. We hypothesise that these L-CRP oscillations are part of a homeostatic immune response to advanced malignancy and have some preliminary data linking the timing of therapy to treatment success. This article reviews CRP, shows some of our data and advances the reasoning for the hypothesis that explains the CRP cycles in terms of homeostatic immune regulatory cycles. This knowledge might also open the way for improved timing of treatment(s) for improved clinical efficacy

Drug Discovery for Duchenne Muscular Dystrophy via Utrophin Promoter Activation Screening

Background: Duchenne muscular dystrophy (DMD) is a devastating muscle wasting disease caused by mutations in dystrophin, a muscle cytoskeletal protein. Utrophin is a homologue of dystrophin that can functionally compensate for its absence when expressed at increased levels in the myofibre, as shown by studies in dystrophin-deficient mice. Utrophin upregulation is therefore a promising therapeutic approach for DMD. The use of a small, drug-like molecule to achieve utrophin upregulation offers obvious advantages in terms of delivery and bioavailability. Furthermore, much of the time and expense involved in the development of a new drug can be eliminated by screening molecules that are already approved for clinical use. Methodology/Principal Findings: We developed and validated a cell-based, high-throughput screening assay for utrophin promoter activation, and used it to screen the Prestwick Chemical Library of marketed drugs and natural compounds. Initial screening produced 20 hit molecules, 14 of which exhibited dose-dependent activation of the utrophin promoter and were confirmed as hits. Independent validation demonstrated that one of these compounds, nabumetone, is able to upregulate endogenous utrophin mRNA and protein, in C2C12 muscle cells. Conclusions/Significance: We have developed a cell-based, high-throughput screening utrophin promoter assay. Using this assay, we identified and validated a utrophin promoter-activating drug, nabumetone, for which pharmacokinetics an

MASTREE+: time-series of plant reproductive effort from six continents

Significant gaps remain in understanding the response of plant reproduction to environmental change. This is partly because measuring reproduction in long-lived plants requires direct observation over many years and such datasets have rarely been made publicly available. Here we introduce MASTREE+, a data set that collates reproductive time-series data from across the globe and makes these data freely available to the community. MASTREE+ includes 73,828 georeferenced observations of annual reproduction (e.g. seed and fruit counts) in perennial plant populations worldwide. These observations consist of 5971 population-level time-series from 974 species in 66 countries. The mean and median time-series length is 12.4 and 10 years respectively, and the data set includes 1122 series that extend over at least two decades (≥20 years of observations). For a subset of well-studied species, MASTREE+ includes extensive replication of time-series across geographical and climatic gradients. Here we describe the open-access data set, available as a.csv file, and we introduce an associated web-based app for data exploration. MASTREE+ will provide the basis for improved understanding of the response of long-lived plant reproduction to environmental change. Additionally, MASTREE+ will enable investigation of the ecology and evolution of reproductive strategies in perennial plants, and the role of plant reproduction as a driver of ecosystem dynamics.Additional co-authors: Ciprian Palaghianu, Mario Pesendorfer, Akiko Satake, Eliane Schermer, Andrew J. Tanentzap, Peter A. Thomas, Davide Vecchio, Andreas P. Wion, Thomas Wohlgemuth, Tingting Xue, Marie-Claire Aravena Acuña, Marcelo Daniel Barrera, Jessica H. Barton, Stan Boutin, Emma R. Bush, Sergio Donoso Calderón, Felipe S. Carevic, Carolina Volkmer de Castilho, Juan Manuel Cellini, Colin A. Chapman, Hazel Chapman, Francesco Chianucci, Patricia da Costa, Luc Croisé, Andrea Cutini, Ben Dantzer, R. Justin DeRose, Jean-Thoussaint Dikangadissi, Edmond Dimoto, Fernanda Lopes da Fonseca, Leonardo Gallo, Georg Gratzer, David F. Greene, Martín A. Hadad, Alejandro Huertas Herrera, Jill F. Johnstone, Urs Kalbitzer, Władysław Kantorowicz, Christie A. Klimas, Jonathan G. A. Lageard, Jeffrey Lane, Katharina Lapin, Mateusz Ledwoń, Abigail C. Leeper, Maria Vanessa Lencinas, Ana Cláudia Lira-Guedes, Michael C. Lordon, Paula Marchelli, Shealyn Marino, Harald Schmidt Van Marle, Andrew G. McAdam, Ludovic R. W. Momont, Manuel Nicolas, Lúcia Helena de Oliveira Wadt, Parisa Panahi, Guillermo Martínez Pastur, Thomas Patterson, Pablo Luis Peri, Łukasz Piechnik, Mehdi Pourhashemi, Claudia Espinoza Quezada, Fidel A. Roig, Karen Peña Rojas, Yamina Micaela Rosas, Silvio Schueler, Barbara Seget, Rosina Soler, Michael A. Steele, Mónica Toro-Manríquez, Caroline E. G. Tutin, Tharcisse Ukizintambara, Biplang Yadok, John L. Willis, Anita Zolles, Magdalena Żywiec, Davide Ascol