Soft windowing application to improve analysis of high-throughput phenotyping data.

MOTIVATION: High-throughput phenomic projects generate complex data from small treatment and large control groups that increase the power of the analyses but introduce variation over time. A method is needed to utlize a set of temporally local controls that maximizes analytic power while minimizing noise from unspecified environmental factors. RESULTS: Here we introduce \u27soft windowing\u27, a methodological approach that selects a window of time that includes the most appropriate controls for analysis. Using phenotype data from the International Mouse Phenotyping Consortium (IMPC), adaptive windows were applied such that control data collected proximally to mutants were assigned the maximal weight, while data collected earlier or later had less weight. We applied this method to IMPC data and compared the results with those obtained from a standard non-windowed approach. Validation was performed using a resampling approach in which we demonstrate a 10% reduction of false positives from 2.5 million analyses. We applied the method to our production analysis pipeline that establishes genotype-phenotype associations by comparing mutant versus control data. We report an increase of 30% in significant P-values, as well as linkage to 106 versus 99 disease models via phenotype overlap with the soft-windowed and non-windowed approaches, respectively, from a set of 2082 mutant mouse lines. Our method is generalizable and can benefit large-scale human phenomic projects such as the UK Biobank and the All of Us resources. AVAILABILITY AND IMPLEMENTATION: The method is freely available in the R package SmoothWin, available on CRAN http://CRAN.R-project.org/package=SmoothWin. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online

The Transcription Factor Ultraspiracle Influences Honey Bee Social Behavior and Behavior-Related Gene Expression

Behavior is among the most dynamic animal phenotypes, modulated by a variety of internal and external stimuli. Behavioral differences are associated with large-scale changes in gene expression, but little is known about how these changes are regulated. Here we show how a transcription factor (TF), ultraspiracle (usp; the insect homolog of the Retinoid X Receptor), working in complex transcriptional networks, can regulate behavioral plasticity and associated changes in gene expression. We first show that RNAi knockdown of USP in honey bee abdominal fat bodies delayed the transition from working in the hive (primarily “nursing” brood) to foraging outside. We then demonstrate through transcriptomics experiments that USP induced many maturation-related transcriptional changes in the fat bodies by mediating transcriptional responses to juvenile hormone. These maturation-related transcriptional responses to USP occurred without changes in USP's genomic binding sites, as revealed by ChIP–chip. Instead, behaviorally related gene expression is likely determined by combinatorial interactions between USP and other TFs whose cis-regulatory motifs were enriched at USP's binding sites. Many modules of JH– and maturation-related genes were co-regulated in both the fat body and brain, predicting that usp and cofactors influence shared transcriptional networks in both of these maturation-related tissues. Our findings demonstrate how “single gene effects” on behavioral plasticity can involve complex transcriptional networks, in both brain and peripheral tissues

Think Again – Supplying War: Reappraising Military Logistics and Its Centrality to Strategy and War

This article argues that logistics constrains strategic opportunity while itself being heavily circumscribed by strategic and operational planning. With the academic literature all but ignoring the centrality of logistics to strategy and war, this article argues for a reappraisal of the critical role of military logistics, and posits that the study and conduct of war and strategy are incomplete at best or false at worst when they ignore this crucial component of the art of war. The article conceptualises the logistics–strategy nexus in a novel way, explores its contemporary manifestation in an age of uncertainty, and applies it to a detailed case study of UK operations in Iraq and Afghanistan since 2001

Mortality in Sickle Cell Anemia in Africa: A Prospective Cohort Study in Tanzania

Background: The World Health Organization has declared Sickle Cell Anemia (SCA) a public health priority. There are 300,000 births/year, over 75% in Africa, with estimates suggesting that 6 million Africans will be living with SCA if average survival reaches half the African norm. Countries such as United States of America and United Kingdom have reduced SCA mortality from 3 to 0.13 per 100 person years of observation (PYO), with interventions such as newborn screening, prevention of infections and comprehensive care, but implementation of interventions in African countries has been hindered by lack of locally appropriate information. The objective of this study was to determine the incidence and factors associated with death from SCA in Dar-es-Salaam.Methods and Findings: A hospital-based cohort study was conducted, with prospective surveillance of 1,725 SCA patients recruited from 2004 to 2009, with 209 (12%) lost to follow up, while 86 died. The mortality rate was 1.9 (95% CI 1.5, 2.9) per 100 PYO, highest under 5-years old [7.3 (4.8-11.0)], adjusting for dates of birth and study enrollment. Independent risk factors, at enrollment to the cohort, predicting death were low hemoglobin (= 102 mu mol/L) [1.7 (1.0-2.9); p = 0.044] as determined by logistic regression.Conclusions: Mortality in SCA in Africa is high, with the most vulnerable period being under 5-years old. This is most likely an underestimate, as this was a hospital cohort and may not have captured SCA individuals with severe disease who died in early childhood, those with mild disease who are undiagnosed or do not utilize services at health facilities. Prompt and effective treatment for anemia in SCA is recommended as it is likely to improve survival. Further research is required to determine the etiology, pathophysiology and the most appropriate strategies for management of anemia in SCA

A Feedback Control Model for Managing Quality of Service in Multimedia Communications

Advances in Internet Protocol (IP) multicasting provide a rich background for support of IP multipoint collaborative communications. IP multicast applications have traditionally been deployed over wired networks, however, new wireless technologies such as Local Multipoint Distribution Service (LMDS) are currently emerging as transport mechanisms for wireless video, voice, and application sharing environments. For multimedia wireless services to effectively evolve, management tools that can support Quality of Service (QoS) adaptation of increasingly complex network resources and customer application profiles are needed. In this paper, we present a control model which provides response time and bandwidth requirement adaptation of audio, video, and application sharing multipoint IP teleconferences for emerging wireless multimedia communications. Our study is innovative in that it integrates feedback controls between the application and network layers. Our model is based on revealing feedback controls for multimedia call preparation and subsequent real-time connection control. Case-based reasoning memory is used to match real-time congestion (connection) controls with call preparation controls and user profiles for improved QoS. Network agents are used to capture user and multimedia teleconference application call profiles at the application layer and transfer them to the case memory. Real Time Protocol (RTP) statistics are used to identify connection management feedback controls at the network layer. Receiver-based, real-time adaptation at the network layer and above is possible through the use of a hierarchical coding technique. The proposed adaptive management architecture is based upon a case memory representation of call preparation feedback controls, RTP feedback controls for providing audio stream bandwidth adaptation, and configuration descriptions for integrated experiments. We conclude that implementation of these techniques should lead to improved QoS of wireless IP multipoint teleconferences

Adaptive Management of QoS Requirements for Wireless Multimedia Communications

We present a control model, which provides response time and bandwidth requirement adaptation in audio, video, and application sharing multipoint IP teleconferences for emerging wireless multimedia communications. The model is based on revealing feedback controls for multimedia call preparation and subsequent real time connection control. Case-based reasoning memory is used to associate real time congestion (connection) controls with call preparation controls and user QoS profiles. Web agents are used to capture user and application multimedia call profiles observed at the application layer and transfer them into the case memory. RTP statistics are used to identify the connection management feedback controls for the network layer. Real-time adaptation at the network layer and above is made possible by using hierarchical coding techniques. The proposed adaptive management architecture is illustrated by a case memory representation of call preparation feedback controls, RTP feedback control tests for providing audio stream bandwidth adaptation, and configuration of integrated experiments

Influence of Glyphosate Rate, Application Date, and Spray Volume on Cattail Control

Cattail growth in lakes, wetlands, lake edges and drainage ditches in North Dakota is discussed. While part of a natural ecological environ, cattails can strangle out waterways, reduce oxygenation and microbial activity in these waterways. Therefore, cattails become a weed and, thus, must be controlled. Typical ways of crushing, mowing, burning and discing to control or to reduce cattail presence are short-lived and ineffective. Herbicides have proven the most effective method of controlling cattails infestation. Several trials were made spraying cattails with glyphosate at various stages of growth with various amounts of chemical. Late July to early September appeared the optimum period to apply the chemical. The amount of glyphosate appeared immaterial

1.55 Å-resolution structure of ent-copalyl diphosphate synthase and exploration of general acid function by site-directed mutagenesis

Background—The diterpene cyclase ent-copalyl diphosphate synthase (CPS) catalyzes the first committed step in the biosynthesis of gibberellins. The previously reported 2.25 Å resolution crystal structure of CPS complexed with (S)-15-aza-14,15-dihydrogeranylgeranyl thiolodiphosphate (1) established the αβγ domain architecture, but ambiguities regarding substrate analog binding remained. Method—Use of crystallization additives yielded CPS crystals diffracting to 1.55 Å resolution. Additionally, active site residues that hydrogen bond with D379, either directly or through hydrogen bonded water molecules, were probed by mutagenesis. Results—This work clarifies structure-function relationships that were ambiguous in the lower resolution structure. Well-defined positions for the diphosphate group and tertiary ammonium cation of 1 as well as extensive solvent structure, are observed. Conclusions—Two channels involving hydrogen bonded solvent and protein residues lead to the active site, forming hydrogen bonded proton wires that link general acid D379 with bulk solvent. These proton wires may facilitate proton transfer with the general acid during catalysis. Activity measurements made with mutant enzymes indicate that N425, which donates a hydrogen bond directly to D379, and T421, which hydrogen bonds with D379 through an intervening solvent molecule, help orient D379 for catalysis. Residues involved in hydrogen bonds with the proton wire, R340 and D503, are also important. Finally, conserved residue E211, which is located near the diphosphate group of 1 is proposed to be a ligand to Mg2+ required for optimal catalytic activity. General Significance—This work establishes structure-function relationships for class II terpenoid cyclases