An Integrative Approach to Computational Modelling of the Gene Regulatory Network Controlling Clostridium botulinum Type A1 Toxin Production

Clostridium botulinum produces botulinum neurotoxins (BoNTs), highly potent substances responsible for botulism. Currently, mathematical models of C. botulinum growth and toxigenesis are largely aimed at risk assessment and do not include explicit genetic information beyond group level but integrate many component processes, such as signalling, membrane permeability and metabolic activity. In this paper we present a scheme for modelling neurotoxin production in C. botulinum Group I type A1, based on the integration of diverse information coming from experimental results available in the literature. Experiments show that production of BoNTs depends on the growth-phase and is under the control of positive and negative regulatory elements at the intracellular level. Toxins are released as large protein complexes and are associated with non-toxic components. Here, we systematically review and integrate those regulatory elements previously described in the literature for C. botulinum Group I type A1 into a population dynamics model, to build the very first computational model of toxin production at the molecular level. We conduct a validation of our model against several items of published experimental data for different wild type and mutant strains of C. botulinum Group I type A1. The result of this process underscores the potential of mathematical modelling at the cellular level, as a means of creating opportunities in developing new strategies that could be used to prevent botulism; and potentially contribute to improved methods for the production of toxin that is used for therapeutics

Digital photographic technique for the production of an artificial eye

The use of hand painting an iris button using oil paint remains the conventional method of artificial eye manufacturing. The authors found that replacing this technique with a digital photograph taken of a patient’s unaffected eye offers several advantages over the conventional method but the process from capture to print must be standardised and colour accurate. The authors of this paper suggest a tried and tested formulated photographic process of capture and printing prior to polymerisation. It discusses issues that can arise and how these can be overcome in order to achieve a high-quality print that can be used to produce a ‘life like’ ocular prosthesis

CC+: a relational database of coiled-coil structures

We introduce the CC+ Database, a detailed, searchable repository of coiled-coil assignments, which is freely available at http://coiledcoils.chm.bris.ac.uk/ccplus. Coiled coils were identified using the program SOCKET, which locates coiled coils based on knobs-into-holes packing of side chains between α-helices. A method for determining the overall sequence identity of coiled-coil sequences was introduced to reduce statistical bias inherent in coiled-coil data sets. There are two points of entry into the CC+ Database: the ‘Periodic Table of Coiled-coil Structures’, which presents a graphical path through coiled-coil space based on manually validated data, and the ‘Dynamic Interface’, which allows queries of the database at different levels of complexity and detail. The latter entry level, which is the focus of this article, enables the efficient and rapid compilation of subsets of coiled-coil structures. These can be created and interrogated with increasingly sophisticated pull-down, keyword and sequence-based searches to return detailed structural and sequence information. Also provided are means for outputting the retrieved coiled-coil data in various formats, including PyMOL and RasMol scripts, and Position-Specific Scoring Matrices (or amino-acid profiles), which may be used, for example, in protein-structure prediction

Recent Advances in Graph Partitioning

We survey recent trends in practical algorithms for balanced graph partitioning together with applications and future research directions

Induction immunosuppression in adults undergoing liver transplantation: a network meta-analysis

BACKGROUND: Liver transplantation is considered the definitive treatment for people with liver failure. As part of post-liver transplantation management, immunosuppression (suppressing the host immunity) is given to prevent graft rejections. Immunosuppressive drugs can be classified into those that are used for a short period during the beginning phase of immunosuppression (induction immunosuppression) and those that are used over the entire lifetime of the individual (maintenance immunosuppression), because it is widely believed that graft rejections are more common during the first few months after liver transplantation. Some drugs such as glucocorticosteroids may be used for both induction and maintenance immunosuppression because of their multiple modalities of action. There is considerable uncertainty as to whether induction immunosuppression is necessary and if so, the relative efficacy of different immunosuppressive agents. OBJECTIVES: To assess the comparative benefits and harms of different induction immunosuppressive regimens in adults undergoing liver transplantation through a network meta-analysis and to generate rankings of the different induction immunosuppressive regimens according to their safety and efficacy. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until July 2019 to identify randomised clinical trials in adults undergoing liver transplantation. SELECTION CRITERIA: We included only randomised clinical trials (irrespective of language, blinding, or status) in adults undergoing liver transplantation. We excluded randomised clinical trials in which participants had multivisceral transplantation and those who already had graft rejections. DATA COLLECTION AND ANALYSIS: We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio (OR), rate ratio, and hazard ratio (HR) with 95% credible intervals (CrIs) based on an available case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS: We included a total of 25 trials (3271 participants; 8 treatments) in the review. Twenty-three trials (3017 participants) were included in one or more outcomes in the review. The trials that provided the information included people undergoing primary liver transplantation for various indications and excluded those with HIV and those with renal impairment. The follow-up in the trials ranged from three to 76 months, with a median follow-up of 12 months among trials. All except one trial were at high risk of bias, and the overall certainty of evidence was very low. Overall, approximately 7.4% of people who received the standard regimen of glucocorticosteroid induction died and 12.2% developed graft failure. All-cause mortality and graft failure was lower with basiliximab compared with glucocorticosteroid induction: all-cause mortality (HR 0.53, 95% CrI 0.31 to 0.93; network estimate, based on 2 direct comparison trials (131 participants; low-certainty evidence)); and graft failure (HR 0.44, 95% CrI 0.28 to 0.70; direct estimate, based on 1 trial (47 participants; low-certainty evidence)). There was no evidence of differences in all-cause mortality and graft failure between other induction immunosuppressants and glucocorticosteroids in either the direct comparison or the network meta-analysis (very low-certainty evidence). There was also no evidence of differences in serious adverse events (proportion), serious adverse events (number), renal failure, any adverse events (proportion), any adverse events (number), liver retransplantation, graft rejections (any), or graft rejections (requiring treatment) between other induction immunosuppressants and glucocorticosteroids in either the direct comparison or the network meta-analysis (very low-certainty evidence). However, because of the wide CrIs, clinically important differences in these outcomes cannot be ruled out. None of the studies reported health-related quality of life. FUNDING: the source of funding for 14 trials was drug companies who would benefit from the results of the study; two trials were funded by neutral organisations who have no vested interests in the results of the study; and the source of funding for the remaining nine trials was unclear. AUTHORS' CONCLUSIONS: Based on low-certainty evidence, basiliximab induction may decrease mortality and graft failure compared to glucocorticosteroids induction in people undergoing liver transplantation. However, there is considerable uncertainty about this finding because this information is based on small trials at high risk of bias. The evidence is uncertain about the effects of different induction immunosuppressants on other clinical outcomes, including graft rejections. Future randomised clinical trials should be adequately powered, employ blinding, avoid post-randomisation dropouts (or perform intention-to-treat analysis), and use clinically important outcomes such as mortality, graft failure, and health-related quality of life

A unified data representation theory for network visualization, ordering and coarse-graining

Representation of large data sets became a key question of many scientific disciplines in the last decade. Several approaches for network visualization, data ordering and coarse-graining accomplished this goal. However, there was no underlying theoretical framework linking these problems. Here we show an elegant, information theoretic data representation approach as a unified solution of network visualization, data ordering and coarse-graining. The optimal representation is the hardest to distinguish from the original data matrix, measured by the relative entropy. The representation of network nodes as probability distributions provides an efficient visualization method and, in one dimension, an ordering of network nodes and edges. Coarse-grained representations of the input network enable both efficient data compression and hierarchical visualization to achieve high quality representations of larger data sets. Our unified data representation theory will help the analysis of extensive data sets, by revealing the large-scale structure of complex networks in a comprehensible form.Comment: 13 pages, 5 figure

Unravelling the specificity and mechanism of sialic acid recognition by the gut symbiont Ruminococcus gnavus

Ruminococcus gnavus is a human gut symbiont which ability to degrade mucins is mediated by an intramolecular trans-sialidase (RgNanH). RgNanH comprises a GH33 catalytic domain and a sialic acid binding carbohydrate binding module (CBM40). Here we used glycan arrays, STD NMR, X-ray crystallography, mutagenesis, and binding assays to determine the structure and function of RgNanH_CBM40 (RgCBM40). RgCBM40 displays the canonical CBM40 b-sandwich fold and broad specificity towards sialoglycans with millimolar binding affinity towards α2,3- or α2,6-sialyllactose. RgCBM40 binds to mucus produced by goblet cells and to purified mucins, providing direct evidence for a CBM40 as a novel bacterial mucus adhesin. Bioinformatics data show that RgCBM40 canonical type domains are widespread among Firmicutes. Furthermore, binding of R. gnavus ATCC 29149 to intestinal mucus is sialic acid mediated. Together, this study reveals novel features of CBMs which may contribute to the biogeography of symbiotic bacteria in the gut

Old magma and a new, intrusive trigger: using diffusion chronometry to understand the rapid-onset Calbuco eruption, April 2015 (Southern Chile)

In April 2015, an unpredicted rapid-onset eruption occurred at Calbuco Volcano, Southern Andes of Chile. This event consisted of two, sub-Plinian eruptions separated by a few hours. By analysis of Fe–Ti exchange between ilmenite and titanomagnetite crystals in samples of erupted material, we determine timescales of pre-eruptive heating experienced at the partially solidified chamber base and constrain the magma residence time for the bulk of the carrier magma. Analysis of the Fe–Ti oxide pairs from a sample retrieved from a pyroclastic density current deposit (Cal-160) shows that it was affected by a significant heating event (recording 70–220 °C of heating), while other collected samples did not record this late heating. This sample is interpreted to represent a piece of crystal mush located at the bottom of a prolate, ellipsoidal mush reservoir, mobilised < 4 days before the eruption by a triggering pulse of mafic magma considerably hotter than the typical magmatic temperature of the reservoir. Another two fall deposit samples (lapillus, Cal-149Tb and Cal-155) of the eruption are interpreted to represent resident, eruptible magmas that did not interact with any magma recharge immediately prior to or during the eruption. We infer that these magmas had been at eruption temperature for some years based on their extensively equilibrated Fe–Ti oxides