Network modeling of BVD transmission

Endemic diseases of cattle, such as bovine viral diarrhea, have significant impact on production efficiency of food of animal origin with consequences for animal welfare and climate change reduction targets. Many modeling studies focus on the local scale, examining the on-farm dynamics of this infectious disease. However, insight into prevalence and control across a network of farms ultimately requires a network level approach. Here, we implement understanding of infection dynamics, gained through these detailed on-farm modeling studies, to produce a national scale model of bovine viral diarrhea virus transmission. The complex disease epidemiology and on-farm dynamics are approximated using SIS dynamics with each farm treated as a single unit. Using a top down approach, we estimate on-farm parameters associated with contraction and subsequent clearance from infection at herd level. We examine possible control strategies associated with animal movements between farms and find measures targeted at a small number of high-movement farms efficient for rapid and sustained prevalence reduction

An Evolutionary-Network Model Reveals Stratified Interactions in the V3 Loop of the HIV-1 Envelope

The third variable loop (V3) of the human immunodeficiency virus type 1 (HIV-1) envelope is a principal determinant of antibody neutralization and progression to AIDS. Although it is undoubtedly an important target for vaccine research, extensive genetic variation in V3 remains an obstacle to the development of an effective vaccine. Comparative methods that exploit the abundance of sequence data can detect interactions between residues of rapidly evolving proteins such as the HIV-1 envelope, revealing biological constraints on their variability. However, previous studies have relied implicitly on two biologically unrealistic assumptions: (1) that founder effects in the evolutionary history of the sequences can be ignored, and; (2) that statistical associations between residues occur exclusively in pairs. We show that comparative methods that neglect the evolutionary history of extant sequences are susceptible to a high rate of false positives (20%–40%). Therefore, we propose a new method to detect interactions that relaxes both of these assumptions. First, we reconstruct the evolutionary history of extant sequences by maximum likelihood, shifting focus from extant sequence variation to the underlying substitution events. Second, we analyze the joint distribution of substitution events among positions in the sequence as a Bayesian graphical model, in which each branch in the phylogeny is a unit of observation. We perform extensive validation of our models using both simulations and a control case of known interactions in HIV-1 protease, and apply this method to detect interactions within V3 from a sample of 1,154 HIV-1 envelope sequences. Our method greatly reduces the number of false positives due to founder effects, while capturing several higher-order interactions among V3 residues. By mapping these interactions to a structural model of the V3 loop, we find that the loop is stratified into distinct evolutionary clusters. We extend our model to detect interactions between the V3 and C4 domains of the HIV-1 envelope, and account for the uncertainty in mapping substitutions to the tree with a parametric bootstrap

Evolutionary Interactions between N-Linked Glycosylation Sites in the HIV-1 Envelope

The addition of asparagine (N)-linked polysaccharide chains (i.e., glycans) to the gp120 and gp41 glycoproteins of human immunodeficiency virus type 1 (HIV-1) envelope is not only required for correct protein folding, but also may provide protection against neutralizing antibodies as a “glycan shield.” As a result, strong host-specific selection is frequently associated with codon positions where nonsynonymous substitutions can create or disrupt potential N-linked glycosylation sites (PNGSs). Moreover, empirical data suggest that the individual contribution of PNGSs to the neutralization sensitivity or infectivity of HIV-1 may be critically dependent on the presence or absence of other PNGSs in the envelope sequence. Here we evaluate how glycan–glycan interactions have shaped the evolution of HIV-1 envelope sequences by analyzing the distribution of PNGSs in a large-sequence alignment. Using a “covarion”-type phylogenetic model, we find that the rates at which individual PNGSs are gained or lost vary significantly over time, suggesting that the selective advantage of having a PNGS may depend on the presence or absence of other PNGSs in the sequence. Consequently, we identify specific interactions between PNGSs in the alignment using a new paired-character phylogenetic model of evolution, and a Bayesian graphical model. Despite the fundamental differences between these two methods, several interactions are jointly identified by both. Mapping these interactions onto a structural model of HIV-1 gp120 reveals that negative (exclusive) interactions occur significantly more often between colocalized glycans, while positive (inclusive) interactions are restricted to more distant glycans. Our results imply that the adaptive repertoire of alternative configurations in the HIV-1 glycan shield is limited by functional interactions between the N-linked glycans. This represents a potential vulnerability of rapidly evolving HIV-1 populations that may provide useful glycan-based targets for neutralizing antibodies

Introducing a drift and diffusion framework for childhood growth research

Acknowledgements We thank the participants and staff of the MAL-ED study for their vital contributions and we thank Prof. Laura Caulfield for her insightful and constructive input. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the U.S. National Institutes of Health or Department of Health and Human Services. Publisher Copyright: © 2020 Lewis FI et al.Peer reviewedPublisher PD

Interaction of eukaryotic translation initiation factor 4G with the nuclear cap-binding complex provides a link between nuclear and cytoplasmic functions of the m7 guanosine cap

In eukaryotes the majority of mRNAs have an m7G cap that is added cotranscriptionally and that plays an important role in many aspects of mRNA metabolism. The nuclear cap-binding complex (CBC; consisting of CBP20 and CBP80) mediates the stimulatory functions of the cap in pre-mRNA splicing, 3' end formation, and U snRNA export. As little is known about how nuclear CBC mediates the effects of the cap in higher eukaryotes, we have characterized proteins that interact with CBC in HeLa cell nuclear extracts as potential mediators of its function. Using cross-linking and coimmunoprecipitation, we show that eukaryotic translation initiation factor 4G (eIF4G), in addition to its function in the cytoplasm, is a nuclear CBC-interacting protein. We demonstrate that eIF4G interacts with CBC in vitro and that, in addition to its cytoplasmic localization, there is a significant nuclear pool of eIF4G in mammalian cells in vivo. Immunoprecipitation experiments suggest that, in contrast to the cytoplasmic pool, much of the nuclear eIF4G is not associated with eIF4E (translation cap binding protein of eIF4F) but is associated with CBC. While eIF4G stably associates with spliceosomes in vitro and shows close association with spliceosomal snRNPs and splicing factors in vivo, depletion studies show that it does not participate directly in the splicing reaction. Taken together the data indicate that nuclear eIF4G may be recruited to pre-mRNAs via its interaction with CBC and accompanies the mRNA to the cytoplasm, facilitating the switching of CBC for eIF4F. This may provide a mechanism to couple nuclear and cytoplasmic functions of the mRNA cap structure

A high-hard outburst of the black hole X-ray binary GS 1354-64

We study in detail the evolution of the 2015 outburst of GS 1354−64 (BW Cir) at optical, UV and X-ray wavelengths using Faulkes Telescope South/Las Cumbres Observatory Global Telescope Network, Small & Moderate Aperture Research Telescope System and Swift. The outburst was found to stay in the hard X-ray state, albeit being anomalously luminous with a peak luminosity of LX > 0.15 LEdd, which could be the most luminous hard state observed in a black hole X-ray binary. We found that the optical/UV emission is tightly correlated with the X-ray emission, consistent with accretion disc irradiation and/or a jet producing the optical emission. The X-ray spectra can be fitted well with a Comptonization model, and show softening towards the end of the outburst. In addition, we detect a QPO in the X-ray light curves with increasing centroid frequency during the peak and decay periods of the outburst. The long-term optical light curves during quiescence show a statistically significant, slow rise of the source brightness over the 7 years prior to the 2015 outburst. This behaviour as well as the outburst evolution at all wavelengths studied can be explained by the disc instability model with irradiation and disc evaporation/condensation

Robotic milking technologies and renegotiating situated ethical relationships on UK dairy farms

Robotic or automatic milking systems (AMS) are novel technologies that take over the labor of dairy farming and reduce the need for human-animal interactions. Because robotic milking involves the replacement of 'conventional' twice-a-day milking managed by people with a system that supposedly allows cows the freedom to be milked automatically whenever they choose, some claim robotic milking has health and welfare benefits for cows, increases productivity, and has lifestyle advantages for dairy farmers. This paper examines how established ethical relations on dairy farms are unsettled by the intervention of a radically different technology such as AMS. The renegotiation of ethical relationships is thus an important dimension of how the actors involved are re-assembled around a new technology. The paper draws on in-depth research on UK dairy farms comparing those using conventional milking technologies with those using AMS. We explore the situated ethical relations that are negotiated in practice, focusing on the contingent and complex nature of human-animal-technology interactions. We show that ethical relations are situated and emergent, and that as the identities, roles, and subjectivities of humans and animals are unsettled through the intervention of a new technology, the ethical relations also shift. © 2013 Springer Science+Business Media Dordrecht

Exploring the Concepts of Recognition and Shame for Social Work

© 2016 GAPS. Recognition and shame are both concepts that potentially offer social workers a structure to build practice on; two states experienced by both social workers and service users. ‘Recognition’, within social, political and economic thought, has been established as a field in which inequality and exclusion can be analysed. Social work theorists have also made inroads into exploring its reach. ‘Shame’ in twentieth century and contemporary sociological and psychoanalytical accounts, is understood as a force in limiting human agency, well-being and capacity This paper briefly outlines some of the defining ideas in circulation in relation to recognition and shame, and then briefly considers how psychoanalytical and contemporary social structural analysis builds on this, making links to contemporary social work thinking throughout. The paper also specifically considers some of the uses of recognition and shame for thinking about social worker and service user ‘well-being’, and the connections, through both the relational and the socio-political, which inflect social work practice

Complex and unexpected dynamics in simple genetic regulatory networks

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Complement is activated in progressive multiple sclerosis cortical grey matter lesions

The symptoms of multiple sclerosis (MS) are caused by damage to myelin and nerve cells in the brain and spinal cord. Inflammation is tightly linked with neurodegeneration, and it is the accumulation of neurodegeneration that underlies increasing neurological disability in progressive MS. Determining pathological mechanisms at play in MS grey matter is therefore a key to our understanding of disease progression