Barrier Frank-Wolfe for Marginal Inference

We introduce a globally-convergent algorithm for optimizing the tree-reweighted (TRW) variational objective over the marginal polytope. The algorithm is based on the conditional gradient method (Frank-Wolfe) and moves pseudomarginals within the marginal polytope through repeated maximum a posteriori (MAP) calls. This modular structure enables us to leverage black-box MAP solvers (both exact and approximate) for variational inference, and obtains more accurate results than tree-reweighted algorithms that optimize over the local consistency relaxation. Theoretically, we bound the sub-optimality for the proposed algorithm despite the TRW objective having unbounded gradients at the boundary of the marginal polytope. Empirically, we demonstrate the increased quality of results found by tightening the relaxation over the marginal polytope as well as the spanning tree polytope on synthetic and real-world instances.Comment: 25 pages, 12 figures, To appear in Neural Information Processing Systems (NIPS) 2015, Corrected reference and cleaned up bibliograph

Optimal controller gain tuning for robust stability of spacecraft formation

The spacecraft formation control problem sets high demands to the performance, especially with respect to positional accuracy. The problem is further complicated due to scarce fuel resources and limited actuation effects, in addition to the many sources of disturbances. This paper addresses the problem of finding the optimal gains of spacecraft formation controllers. By optimal, we mean the gains that minimizes a cost functional which penalizes both the control efforts and the state deviation, while still guaranteeing stability of the closed-loop systems in the presence of disturbances

Global entrainment of transcriptional systems to periodic inputs

This paper addresses the problem of giving conditions for transcriptional systems to be globally entrained to external periodic inputs. By using contraction theory, a powerful tool from dynamical systems theory, it is shown that certain systems driven by external periodic signals have the property that all solutions converge to a fixed limit cycle. General results are proved, and the properties are verified in the specific case of some models of transcriptional systems. The basic mathematical results needed from contraction theory are proved in the paper, making it self-contained

Singularly Perturbed Monotone Systems and an Application to Double Phosphorylation Cycles

The theory of monotone dynamical systems has been found very useful in the modeling of some gene, protein, and signaling networks. In monotone systems, every net feedback loop is positive. On the other hand, negative feedback loops are important features of many systems, since they are required for adaptation and precision. This paper shows that, provided that these negative loops act at a comparatively fast time scale, the main dynamical property of (strongly) monotone systems, convergence to steady states, is still valid. An application is worked out to a double-phosphorylation ``futile cycle'' motif which plays a central role in eukaryotic cell signaling.Comment: 21 pages, 3 figures, corrected typos, references remove

HIV stigma in UK press reporting of a case of intentional HIV transmission

The UK has set itself the ambitious target of zero new HIV transmissions by 2030. HIV stigma is a significant barrier to achieving this target. Media reporting plays an important role in shaping social representations of HIV and of stigma. Between 2016 and 2018, the media in the UK reported on the Daryll Rowe case – the first criminal prosecution for intentional transmission of HIV in the UK. This article examines the way that UK newspapers reported this case, which may have exacerbated HIV stigma. Using Nexis, 178 UK newspaper articles were extracted and subjected to qualitative thematic analysis through a social constructionist lens. Informed by social representations theory, the analysis yielded three discursive themes: (1) Representing the perpetrator through HIV-focussed metaphors; (2) Constructing volitional ambiguity; and (3) Anchoring the lived experience of HIV to misery and death. UK newspapers constructed an ‘evil vs victimhood’ dichotomy in relation to Rowe and the men infected with HIV, respectively. This article argues that news coverage of the Rowe story constructs HIV in ways that are inconsistent with public health messaging. Reporting failed to note innovations in HIV treatment and prevention but instead disseminated stigmatising social representations of HIV. This is important because stigma impedes effective HIV prevention, engagement with HIV care and ultimately our ability to achieve the zero-infections target

Detection of Mutant-Huntingtin Aggregation Conformers and Modulation of SDS-Soluble Fibrillar Oligomers by Small Molecules

The Huntington’s disease (HD) mutation leads to a complex process of Huntingtin (Htt) aggregation into multimeric species that eventually form visible inclusions in cytoplasm, nuclei and neuronal processes. One hypothesis is that smaller, soluble forms of amyloid proteins confer toxic effects and contribute to early cell dysfunction. However, analysis of mutant Htt aggregation intermediates to identify conformers that may represent toxic forms of the protein and represent potential drug targets remains difficult. We performed a detailed analysis of aggregation conformers in multiple in vitro, cell and ex vivo models of HD. Conformation-specific antibodies were used to identify and characterize aggregation species, allowing assessment of multiple conformers present during the aggregation process. Using a series of assays together with these antibodies, several forms could be identified. Fibrillar oligomers, defined as having ab-sheet rich conformation, are observed in vitro using recombinant protein and in protein extracts from cells in culture or mouse brain and shown to be globular, soluble and non-sedimentable structures. Compounds previously described to modulate visible inclusion body formation and reduce toxicity in HD models were also tested and consistently found to alter the formation of fibrillar oligomers. Interestingly, these compounds did not alter the rate of visible inclusion formation, indicating that fibrillar oligomers are not necessarily the rate limiting step of inclusion body formation. Taken together, we provide insights into the structure and formation of mutant Htt fibrillar oligomers that can be modulated by small molecules with protective potential in HD models

Alterations of nocturnal activity in rats following subchronic oral administration of the neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-β-carboline

1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo) is neurotoxic when administered to the brain and alters motor behaviour following intraperitoneal administration. We have assessed the long-term effects of oral TaClo administration on nocturnal motor behaviour in rats. Two groups of rats received TaClo orally at a dose of either 0.2 or 0.4 mg/kg twice daily for 7 weeks. The control group was given saline. No change in locomotor activity was observed 4–9 days after the end of the 7-week administration of TaClo. In addition, the spontaneous motor activity was altered dose-dependently 9 months after oral TaClo administration, with an increase in the low-dose TaClo group and a decrease in the high-dose group. Oral administration of TaClo in rats may be useful in investigating the hypothesis that in Parkinson’s disease, an unknown pathogenic factor crossing the intestinal mucosa barrier can induce neurodegenerative processes eventually affecting the entire brain