An objective approach to model reduction: application to the Sirius wheat model

An existing simulation model of wheat growth and development, Sirius, was evaluated through a systematic model reduction procedure. The model was automatically manipulated under software control to replace variables within the model structure with constants, individually and in combination. Predictions of the resultant models were compared to growth analysis observations of total biomass, grain yield, and canopy leaf area derived from 9 trials conducted in the UK and New Zealand under optimal, nitrogen limiting and drought conditions. Model performance in predicting these observations was compared in order to evaluate whether individual model variables contributed positively to the overall prediction. Of the 1 1 1 model variables considered 16 were identified as potentially redundant. Areas of the model where there was evidence of redundancy were: (a) translocation of biomass carbon to grain; (b) nitrogen physiology; (c) adjustment of air temperature for various modelled processes; (d) allowance for diurnal variation in temperature; (e) vernalisation (f) soil nitrogen mineralisation (g) soil surface evaporation. It is not suggested that these are not important processes in real crops, rather, that their representation in the model cannot be justified in the context of the analysis. The approach described is analogous to a detailed model inter-comparison although it would be better described as a model intra-comparison as it is based on the comparison of many simplified forms of the same model. The approach provides automation to increase the efficiency of the evaluation and a systematic means of increasing the rigour of the evaluation

SVD-based Anatomy of Gene Expressions for Correlation Analysis in Arabidopsis thaliana

Gene co-expression analysis has been widely used in recent years for predicting unknown gene function and its regulatory mechanisms. The predictive accuracy depends on the quality and the diversity of data set used. In this report, we applied singular value decomposition (SVD) to array experiments in public databases to find that co-expression linkage could be estimated by a much smaller number of array data. Correlations of co-expressed gene were assessed using two regulatory mechanisms (feedback loop of the fundamental circadian clock and a global transcription factor Myb28), as well as metabolic pathways in the AraCyc database. Our conclusion is that a smaller number of informative arrays across tissues can suffice to reproduce comparable results with a state-of-the-art co-expression software tool. In our SVD analysis on Arabidopsis data set, array experiments that contributed most as the principal components included stamen development, germinating seed and stress responses on leaf

Investigating putative depression-like states in the domestic dog: does greater time spent displaying waking inactivity in the home kennel co-vary with negative judgment of ambiguity?

12 months embargo applie

Could Greater Time Spent Displaying Waking Inactivity in the Home Environment Be a Marker for a Depression-Like State in the Domestic Dog?

Dogs exposed to aversive events can become inactive and unresponsive and are commonly referred to as being “depressed”, but this association remains to be tested. We investigated whether shelter dogs spending greater time inactive “awake but motionless” (ABM) in their home-pen show anhedonia (the core reduction of pleasure reported in depression), as tested by reduced interest in, and consumption of, palatable food (KongTM test). We also explored whether dogs being qualitatively perceived by experts as disinterested in the food would spend greater time ABM (experts blind to actual inactivity levels). Following sample size estimations and qualitative behaviour analysis (n = 14 pilot dogs), forty-three dogs (6 shelters, 22F:21M) were included in the main study. Dogs relinquished by their owners spent more time ABM than strays or legal cases (F = 8.09, p = 0.032). One significant positive association was found between the KongTM measure for average length of KongTM bout and ABM, when length of stay in the shelter was accounted for as a confounder (F = 3.66, p = 0.035). Time spent ABM also correlated with scores for “depressed” and “bored” in the qualitative results, indirectly suggesting that experts associate greater waking inactivity with negative emotional states. The hypothesis that ABM reflects a depression-like syndrome is not supported; we discuss how results might tentatively support a “boredom-like” state and further research directions.</jats:p

GPX-Macrophage Expression Atlas: A database for expression profiles of macrophages challenged with a variety of pro-inflammatory, anti-inflammatory, benign and pathogen insults

BACKGROUND: Macrophages play an integral role in the host immune system, bridging innate and adaptive immunity. As such, they are finely attuned to extracellular and intracellular stimuli and respond by rapidly initiating multiple signalling cascades with diverse effector functions. The macrophage cell is therefore an experimentally and clinically amenable biological system for the mapping of biological pathways. The goal of the macrophage expression atlas is to systematically investigate the pathway biology and interaction network of macrophages challenged with a variety of insults, in particular via infection and activation with key inflammatory mediators. As an important first step towards this we present a single searchable database resource containing high-throughput macrophage gene expression studies. DESCRIPTION: The GPX Macrophage Expression Atlas (GPX-MEA) is an online resource for gene expression based studies of a range of macrophage cell types following treatment with pathogens and immune modulators. GPX-MEA follows the MIAME standard and includes an objective quality score with each experiment. It places special emphasis on rigorously capturing the experimental design and enables the searching of expression data from different microarray experiments. Studies may be queried on the basis of experimental parameters, sample information and quality assessment score. The ability to compare the expression values of individual genes across multiple experiments is provided. In addition, the database offers access to experimental annotation and analysis files and includes experiments and raw data previously unavailable to the research community. CONCLUSION: GPX-MEA is the first example of a quality scored gene expression database focussed on a macrophage cellular system that allows efficient identification of transcriptional patterns. The resource will provide novel insights into the phenotypic response of macrophages to a variety of benign, inflammatory, and pathogen insults. GPX-MEA is available through the GPX website at

Molecular profiling of the human testis reveals stringent pathway-specific regulation of RNA expression following gonadotropin suppression and progestogen treatment

Gonadotropin withdrawal induces changes in gene expression in all 3 major cell types of the testis. Knowledge of the genes affected, in both the presence and absence of additional progestogen, will give insight into the regulation of human testicular function and aid development of novel contraceptive methods. We have undertaken a whole‐genome analysis of RNA expression in testicular biopsies from normal men and after 4 weeks of gonadotropin suppression induced by gonadotropin‐releasing hormone antagonist plus testosterone administration sufficient to cause marked suppression of spermatogenesis. Microarray analysis shows that interindividual variability is markedly low, and the response to treatment is focused on a small subset of genes particularly related to pathways in steroidogenesis and cholesterol biosynthesis or metabolism, the Leydig cell gene INSL3, and genes involved in early meiosis or Sertoli—germ cell junctions. These changes in expression were confirmed by quantitative reverse transcriptase polymerase chain reaction. No major changes in gene expression were identified in men additionally treated with a progestogen, although FLJ35767, an expressed sequence tag that is expressed in the germ cell compartment, did show a small but significant additional effect of progestogen. Overall, the results of this investigation disclose a remarkably stringent regulation of testicular gene expression, revealing the genes most sensitive to gonadotropin withdrawal, and might reflect the most labile pathways in the regulation of testicular functio

Reflexive governance architectures: considering the ethical implications of autonomous technology adoption in food supply chains

Background: The application of autonomous technology in food supply chains gives rise to a number of ethical considerations associated with the interaction between human and technology, human-technology-plant and human-technology-animal. These considerations and their implications influence technology design, the ways in which technology is applied, how the technology changes food supply chain practices, decision-making and the associated ethical aspects and outcomes. Scope and approach: Using the concept of reflexive governance, this paper has critiqued existing reflective food-related ethical assessment tools and proposed the structural elements required for reflexive governance architectures which address both the sharing of data, and the use of artificial intelligence (AI) and machine learning in food supply chains. Key findings and conclusions: Considering the ethical implications of using autonomous technology in real life contexts is challenging. The current approach, focusing on discrete ethical elements in isolation e.g., ethical aspects or outcomes, normative standards or ethically orientated compliance-based business strategies is not sufficient in itself. Alternatively, the application of more holistic, reflexive governance architectures can inform consideration of ethical aspects, potential ethical outcomes, in particular how they are interlinked and/or interdependent, and the need for mitigation at all lifecycle stages of technology and food product conceptualisation, design, realisation and adoption in the food supply chain. This research is of interest to those who are undertaking ethical deliberation on data sharing, and the use of AI and machine learning in food supply chains

Targeted protein degradation via intramolecular bivalent glues

Targeted protein degradation is a pharmacological modality that is based on the induced proximity of an E3 ubiquitin ligase and a target protein to promote target ubiquitination and proteasomal degradation. This has been achieved either via proteolysis-targeting chimeras (PROTACs)—bifunctional compounds composed of two separate moieties that individually bind the target and E3 ligase, or via molecular glues that monovalently bind either the ligase or the target 1–4. Here, using orthogonal genetic screening, biophysical characterization and structural reconstitution, we investigate the mechanism of action of bifunctional degraders of BRD2 and BRD4, termed intramolecular bivalent glues (IBGs), and find that instead of connecting target and ligase in trans as PROTACs do, they simultaneously engage and connect two adjacent domains of the target protein in cis. This conformational change ‘glues’ BRD4 to the E3 ligases DCAF11 or DCAF16, leveraging intrinsic target–ligase affinities that do not translate to BRD4 degradation in the absence of compound. Structural insights into the ternary BRD4–IBG1–DCAF16 complex guided the rational design of improved degraders of low picomolar potency. We thus introduce a new modality in targeted protein degradation, which works by bridging protein domains in cis to enhance surface complementarity with E3 ligases for productive ubiquitination and degradation.</p

Targeted protein degradation via intramolecular bivalent glues

Targeted protein degradation is a pharmacological modality that is based on the induced proximity of an E3 ubiquitin ligase and a target protein to promote target ubiquitination and proteasomal degradation. This has been achieved either via proteolysis-targeting chimeras (PROTACs)—bifunctional compounds composed of two separate moieties that individually bind the target and E3 ligase, or via molecular glues that monovalently bind either the ligase or the target 1–4. Here, using orthogonal genetic screening, biophysical characterization and structural reconstitution, we investigate the mechanism of action of bifunctional degraders of BRD2 and BRD4, termed intramolecular bivalent glues (IBGs), and find that instead of connecting target and ligase in trans as PROTACs do, they simultaneously engage and connect two adjacent domains of the target protein in cis. This conformational change ‘glues’ BRD4 to the E3 ligases DCAF11 or DCAF16, leveraging intrinsic target–ligase affinities that do not translate to BRD4 degradation in the absence of compound. Structural insights into the ternary BRD4–IBG1–DCAF16 complex guided the rational design of improved degraders of low picomolar potency. We thus introduce a new modality in targeted protein degradation, which works by bridging protein domains in cis to enhance surface complementarity with E3 ligases for productive ubiquitination and degradation.</p

A systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus causing vesicular oral or genital skin lesions, meningitis and other diseases particularly harmful in immunocompromised individuals. To comprehensively investigate the complex interaction between HSV-1 and its host we combined two genome-scale screens for host factors (HFs) involved in virus replication. A yeast two-hybrid screen for protein interactions and a RNA interference (RNAi) screen with a druggable genome small interfering RNA (siRNA) library confirmed existing and identified novel HFs which functionally influence HSV-1 infection. Bioinformatic analyses found the 358 HFs were enriched for several pathways and multi-protein complexes. Of particular interest was the identification of Med23 as a strongly anti-viral component of the largely pro-viral Mediator complex, which links specific transcription factors to RNA polymerase II. The anti-viral effect of Med23 on HSV-1 replication was confirmed in gain-of-function gene overexpression experiments, and this inhibitory effect was specific to HSV-1, as a range of other viruses including Vaccinia virus and Semliki Forest virus were unaffected by Med23 depletion. We found Med23 significantly upregulated expression of the type III interferon family (IFN-λ) at the mRNA and protein level by directly interacting with the transcription factor IRF7. The synergistic effect of Med23 and IRF7 on IFN-λ induction suggests this is the major transcription factor for IFN-λ expression. Genotypic analysis of patients suffering recurrent orofacial HSV-1 outbreaks, previously shown to be deficient in IFN-λ secretion, found a significant correlation with a single nucleotide polymorphism in the IFN-λ3 (IL28b) promoter strongly linked to Hepatitis C disease and treatment outcome. This paper describes a link between Med23 and IFN-λ, provides evidence for the crucial role of IFN-λ in HSV-1 immune control, and highlights the power of integrative genome-scale approaches to identify HFs critical for disease progression and outcome