Using large-scale perturbations in gene network reconstruction

Background: Recent analysis of the yeast gene network shows that most genes have few inputs, indicating that enumerative gene reconstruction methods are both useful and computationally feasible. A simple enumerative reconstruction method based on a discrete dynamical system model is used to study how microarray experiments involving modulated global perturbations can be designed to obtain reasonably accurate reconstructions. The method is tested on artificial gene networks with biologically realistic in/out degree characteristics.Results: It was found that a relatively small number of perturbations significantly improve inference accuracy, particularly for low-order inputs of one or two genes. The perturbations themselves should alter the expression level of approximately 50-60% of the genes in the network.Conclusions: Time-series obtained from perturbations are a common form of expression data. This study illustrates how gene networks can be significantly reconstructed from such time-series while requiring only a relatively small number of calibrated perturbations, even for large networks, thus reducing experimental costs

Formal Derivation of Concurrent Garbage Collectors

Concurrent garbage collectors are notoriously difficult to implement correctly. Previous approaches to the issue of producing correct collectors have mainly been based on posit-and-prove verification or on the application of domain-specific templates and transformations. We show how to derive the upper reaches of a family of concurrent garbage collectors by refinement from a formal specification, emphasizing the application of domain-independent design theories and transformations. A key contribution is an extension to the classical lattice-theoretic fixpoint theorems to account for the dynamics of concurrent mutation and collection.Comment: 38 pages, 21 figures. The short version of this paper appeared in the Proceedings of MPC 201

Parameterizing LivSim for simulating growth of the Ghana shorthorn cattle

An important component of the farming system in Ghana is livestock production. Livestock, especially cattle production is heavily dependent on rainfall for the production of forages to feed them. Projected increase in temperature and shifts in rainfall patterns due to climate change is expected to affect the level of livestock production and livelihood of the resource poor animal herders in Ghana. To gain insight into the livestock-climate nexus, we conducted a study in Tamale in the Northern region of Ghana to parameterize the LivSim (Livestock Simulator) model for the simulation of growth of the Ghana Shorthorn cattle. The main objective was to quantify milk and calf production by the various smallholder farmers in the community. A survey of 261 households out of which 96 owned livestock was conducted to obtain observed data on milk yield, calving frequencies, among others. Other data required by LivSIM such as the minimum and maximum bodyweights of both male and female Ghana Shorthorn were obtained from the literature. The number of cattle owned by the households interviewed ranged from 2-47 with majority having a herd size less than twelve. The herd composition was estimated to be 72% female and 28% male. Preliminary simulation results showed that the herd dynamics could be well captured for an initial period of 5 years, after which there was divergence between the simulated and the observed. Further current efforts are directed to the improvement in parameter values especially those relating to the potential growth rates and the compensatory growth rate

How are gender equality and human rights interventions included in sexual and reproductive health programmes and policies: A systematic review of existing research foci and gaps

The importance of promoting gender equality and human rights in sexual and reproductive health (SRH) programmes and policies has been affirmed in numerous international and regional agreements, most recently the 2030 Agenda for Sustainable Development. Given the critical role of research to determine what works, we aimed to identify research gaps as part of a broader priority setting exercise on integrating gender equality and human rights approaches in SRH programmes and policies. A systematic literature review of reviews was conducted to examine the question: what do we know about how research in the context of SRH programmes and policies has addressed gender equality and human rights and what are the current gaps in research. We searched three databases for reviews that addressed the research question, were published between 1994-2014, and met methodological standards for systematic reviews, qualitative meta-syntheses and other reviews of relevance to the research question. Additional grey literature was identified based on expert input. Articles were appraised by the primary author and examined by an expert panel. An abstraction and thematic analysis process was used to synthesize findings. Of the 3,073 abstracts identified, 56 articles were reviewed in full and 23 were included along with 10 from the grey literature. The majority focused on interventions addressing gender inequalities; very few reviews explicitly included human rights based interventions. Across both topics, weak study designs and use of intermediate outcome measures limited evidence quality. Further, there was limited evidence on interventions that addressed marginalized groups. Better quality studies, longer-term indicators, and measurement of unintended consequences are needed to better understand the impact of these types of interventions on SRH outcomes. Further efforts are needed to cover research on gender equality and human rights issues as they pertain to a broader set of SRH topics and populations.Scopu

AID Overlapping and Polη Hotspots Are Key Features of Evolutionary Variation Within the Human Antibody Heavy Chain (IGHV) Genes

© Copyright © 2020 Tang, Bagnara, Chiorazzi, Scharff and MacCarthy. Somatic hypermutation (SHM) of the immunoglobulin variable (IgV) loci is a key process in antibody affinity maturation. The enzyme activation-induced deaminase (AID), initiates SHM by creating C → U mismatches on single-stranded DNA (ssDNA). AID has preferential hotspot motif targets in the context of WRC/GYW (W = A/T, R = A/G, Y = C/T) and particularly at WGCW overlapping hotspots where hotspots appear opposite each other on both strands. Subsequent recruitment of the low-fidelity DNA repair enzyme, Polymerase eta (Polη), during mismatch repair, creates additional mutations at WA/TW sites. Although there are more than 50 functional immunoglobulin heavy chain variable (IGHV) segments in humans, the fundamental differences between these genes and their ability to respond to all possible foreign antigens is still poorly understood. To better understand this, we generated profiles of WGCW hotspots in each of the human IGHV genes and found the expected high frequency in complementarity determining regions (CDRs) that encode the antigen binding sites but also an unexpectedly high frequency of WGCW in certain framework (FW) sub-regions. Principal Components Analysis (PCA) of these overlapping AID hotspot profiles revealed that one major difference between IGHV families is the presence or absence of WGCW in a sub-region of FW3 sometimes referred to as “CDR4.” Further differences between members of each family (e.g., IGHV1) are primarily determined by their WGCW densities in CDR1. We previously suggested that the co-localization of AID overlapping and Polη hotspots was associated with high mutability of certain IGHV sub-regions, such as the CDRs. To evaluate the importance of this feature, we extended the WGCW profiles, combining them with local densities of Polη (WA) hotspots, thus describing the co-localization of both types of hotspots across all IGHV genes. We also verified that co-localization is associated with higher mutability. PCA of the co-localization profiles showed CDR1 and CDR2 as being the main contributors to variance among IGHV genes, consistent with the importance of these sub-regions in antigen binding. Our results suggest that AID overlapping (WGCW) hotspots alone or in conjunction with Polη (WA/TW) hotspots are key features of evolutionary variation between IGHV genes

Differential regulation drives plasticity in sex determination gene networks

Background: Sex determination networks evolve rapidly and have been studied intensely across many species, particularly in insects, thus presenting good models to study the evolutionary plasticity of gene networks.Results: We study the evolution of an unlinked gene capable of regulating an existing diploid sex determination system. Differential gene expression determines phenotypic sex and fitness, dramatically reducing the number of assumptions of previous models. It allows us to make a quantitative evaluation of the full range of evolutionary outcomes of the system and an assessment of the likely contribution of sexual conflict to change in sex determination systems. Our results show under what conditions network mutations causing differential regulation can lead to the reshaping of sex determination networks.Conclusion: The analysis demonstrates the complex relationship between mutation and outcome: the same mutation can produce many different evolved populations, while the same evolved population can be produced by many different mutations. Existing network structure alters the constraints and frequency of evolutionary changes, which include the recruitment of new regulators, changes in heterogamety, protected polymorphisms, and transitions to a new locus that controls sex determination

Mean-VaR portfolio optimization: A nonparametric approach

Portfolio optimization involves the optimal assignment of limited capital to different available financial assets to achieve a reasonable trade-off between profit and risk. We consider an alternative Markowitz’s mean–variance model in which the variance is replaced with an industry standard risk measure, Value-at-Risk (VaR), in order to better assess market risk exposure associated with financial and commodity asset price fluctuations. Realistic portfolio optimization in the mean-VaR framework is a challenging problem since it leads to a non-convex NP-hard problem which is computationally intractable. In this work, an efficient learning-guided hybrid multi-objective evolutionary algorithm (MODE-GL) is proposed to solve mean-VaR portfolio optimization problems with real-world constraints such as cardinality, quantity, pre-assignment, round-lot and class constraints. A learning-guided solution generation strategy is incorporated into the multi-objective optimization process to promote efficient convergence by guiding the evolutionary search towards promising regions of the search space. The proposed algorithm is compared with the Non-dominated Sorting Genetic Algorithm (NSGA-II) and the Strength Pareto Evolutionary Algorithm (SPEA2). Experimental results using historical daily financial market data from S & P 100 and S & P 500 indices are presented. The results show that MODE-GL outperforms two existing techniques for this important class of portfolio investment problems in terms of solution quality and computational time. The results highlight that the proposed algorithm is able to solve the complex portfolio optimization without simplifications while obtaining good solutions in reasonable time and has significant potential for use in practice

The Mantle Transition Zone Beneath West Antarctica: Seismic Evidence for Hydration and Thermal Upwellings

Although prior work suggests that a mantle plume is associated with Cenozoic rifting and volcanism in West Antarctica, the existence of a plume remains conjectural. Here we use P wave receiver functions (PRFs) from the Antarctic POLENET array to estimate mantle transition zone thickness, which is sensitive to temperature perturbations, throughout previously unstudied parts of West Antarctica. We obtain over 8000 high-quality PRFs using an iterative, time domain deconvolution method filtered with a Gaussian width of 0.5 and 1.0, corresponding to frequencies less than ∼0.24 and ∼0.48 Hz, respectively. Single-station and common conversion point stacks, migrated to depth using the AK135 velocity model, indicate that mantle transition zone thickness throughout most of West Antarctica does not differ significantly from the global average, except in two locations; one small region exhibits a vertically thinned (210 ± 15 km) transition zone beneath the Ruppert Coast of Marie Byrd Land and another laterally broader region shows slight, vertical thinning (225 ± 25 km) beneath the Bentley Subglacial Trench. We also observe the 520 discontinuity and a prominent negative peak above the mantle transition zone throughout much of West Antarctica. These results suggest that the mantle transition zone may be hotter than average in two places, possibly due to upwelling from the lower mantle, but not broadly across West Antarctica. Furthermore, we propose that the transition zone may be hydrated due to \u3e100 million years of subduction beneath the region during the early Mesozoic

Identifying dynamical instabilities in supply networks using generalized modeling

Abstract Supply networks need to exhibit stability in order to remain functional. Here, we apply a generalized modeling (GM) approach, which has a strong pedigree in the analysis of dynamical systems, to study the stability of real-world supply networks. It goes beyond purely structural network analysis approaches by incorporating material flows, which are defining characteristics of supply networks. The analysis focuses on the network of interactions between material flows, providing new conceptualizations to capture key aspects of production and inventory policies. We provide stability analyses of two contrasting real-world networks?that of an industrial engine manufacturer and an industry-level network in the luxury goods sector. We highlight the criticality of links with suppliers that involve the dispatch, processing, and return of parts or sub-assemblies, cyclic motifs that involve separate paths from a common supplier to a common firm downstream, and competing demands of different end products at specific nodes. Based on a critical discussion of our findings in the context of the supply chain management literature, we generate five propositions to advance knowledge and understanding of supply network stability. We discuss the implications of the propositions for the effective management, control, and development of supply networks. The GM approach enables fast screening to identify hidden vulnerabilities in extensive supply networks