Perturbation of Interaction Networks for Application to Cancer Therapy

We present a computational approach for studying the effect of potential drug combinations on the protein networks associated with tumor cells. The majority of therapeutics are designed to target single proteins, yet most diseased states are characterized by a combination of many interacting genes and proteins. Using the topology of protein-protein interaction networks, our methods can explicitly model the possible synergistic effect of targeting multiple proteins using drug combinations in different cancer types

Characterisation of carbon components and their isotopic composition in gas shales

Shales are an important reservoir of both organic and inorganic carbon that can be decoupled by incremental stepwise combustion without acid treatment. The study of shales from various depths of three cores of Haynesville-Bossier formation of Jurassic period indicates the presence of organic and inorganic carbon with comparable δ13C and nitrogen/carbon (N/C) ratios in all three. Both the isotopic and elemental ratios predominantly indicate a continental source but a minor N/C fraction corresponding to a marine/lacustrine source is also seen. This indicates either mixing from different sources and/or fractionation, perhaps due to preferential loss of nitrogen during organic matter degradation. Because some of the organic component is released at a high temperature of 1000-1200 °C although ungraphitised, it may be locked up in minerals like sulphides and K-feldspars, incorporated during diagenesis and hydrothermal alteration. Carbon locked in these minerals can be isolated from the carbon cycle for a longer period of time

Further evidence for a non-cortical origin of mirror movements after stroke.

Ejaz et al. (2018) are to be commended for showing no evidence for a cortical origin of post-stroke mirror movements. Using functional MRI during affected-finger presses in recovering adult-onset stroke patients, they found no consistent relationship between contralesional sensorimotor cortex (cSM1) activation and quantitative indices of mirror movements; specifically, mirror movements were not linked to the presence of cSM1 overactivation, arguing against the classic ‘transcallosal’ mechanism heretofore widely believed to cause mirror movements (Di Pino et al., 2014). We wish to report findings—previously published in abstract form (Calautti, 2008)—that further support the idea that mirror movements are not cortically mediated. We also present data that confirm that mirror movements can involve the affected (i.e. paretic) hand during movement of the unaffected (i.e. non-paretic) hand, also arguing in favour of disruption of a bilaterally-organized system

Development of core outcome sets for people undergoing major lower limb amputation for complications of peripheral vascular disease

Objective Every year, thousands of patients with peripheral vascular disease undergo major lower limb amputation. Despite this, evidence for optimal management is weak. Core outcome sets capture consensus on the most important outcomes for a patient group to improve the consistency and quality of research. The aim was to define short and medium term core outcome sets for studies involving patients undergoing major lower limb amputation. Methods A systematic review of the literature and focus groups involving patients, carers, and healthcare professionals were used to derive a list of potential outcomes. Findings informed a three round online Delphi consensus process, where outcomes were rated for both short and medium term studies. The results of the Delphi process were discussed at a face to face consensus meeting, and recommendations were made for each core outcome set. Results A systematic review revealed 45 themes to cazrry forward to the consensus survey. These were supplemented by a further five from focus groups. The consensus survey received responses from 123 participants in round one, and 91 individuals completed all three rounds. In the final round, nine outcomes were rated as “core” for short term studies and a further nine for medium term studies. Wound infection and healing were rated as “core” for both short and medium term studies. Outcomes related to mortality, quality of life, communication, and additional healthcare needs were also rated as “core” for short term studies. In medium term studies, outcomes related to quality of life, mobility, and social integration/independence were rated as “core”. The face to face stakeholder meeting ratified inclusion of all outcomes from the Delphi and suggested that deterioration of the other leg and psychological morbidity should also be reported for both short and medium term studies. Conclusion Consensus was established on 11 core outcomes for short and medium term studies. It is recommended that all future studies involving patients undergoing major lower limb amputation should report these outcomes

Structural and functional analysis of the tandem β-zipper interaction of a streptococcal protein with human fibronectin

Bacterial fibronectin-binding proteins (FnBPs) contain a large intrinsically disordered region (IDR) that mediates adhesion of bacteria to host tissues, and invasion of host cells, through binding to fibronectin (Fn). These FnBP IDRs consist of Fn-binding repeats (FnBRs) that form a highly extended tandem β-zipper interaction on binding to the N-terminal domain of Fn. Several FnBR residues are highly conserved across bacterial species, and here we investigate their contribution to the interaction. Mutation of these residues to alanine in SfbI-5 (a disordered FnBR from the human pathogen Streptococcus pyogenes) reduced binding, but for each residue the change in free energy of binding was <2 kcal/mol. The structure of an SfbI-5 peptide in complex with the second and third F1 modules from Fn confirms that the conserved FnBR residues play equivalent functional roles across bacterial species. Thus, in SfbI-5, the binding energy for the tandem β-zipper interaction with Fn is distributed across the interface rather than concentrated in a small number of "hot spot" residues that are frequently observed in the interactions of folded proteins. We propose that this might be a common feature of the interactions of IDRs and is likely to pose a challenge for the development of small molecule inhibitors of FnBP-mediated adhesion to and invasion of host cells

Discovery of a meteoritic ejecta layer containing unmelted impactor fragments at the base of Paleocene lavas, Isle of Skye, Scotland

Evidence for meteorite impacts in the geological record may include the presence of shocked minerals, spherule layers, and geochemical anomalies. However, it is highly unusual to nd unmelted crystals from the actual impactor within an ejecta layer. Here we detail the rst recorded occurrence of vanadium-rich osbornite (TiVN) on Earth, from two sites on Skye, northwest Scotland, which are interpreted as part of a meteoritic ejecta layer. TiVN has only previously been reported as dust from comet Wild 2, but on Skye it has been identi ed as an unmelted phase. Both ejecta layer sites also contain niobium-rich osbornite (TiNbN), which has not previously been reported. An extraterrestrial origin for these deposits is strongly supported by the presence of reidite (a high-pressure zircon polymorph), which is only found naturally at sites of meteorite impact. Barringerite [(Fe,Ni)2P], baddeleyite (ZrO2), alabandite (MnS), and carbon-bearing native iron spherules, together with planar deformation features and diaplectic glass in quartz, further support this thesis. We demonstrate through eld relationships and Ar-Ar dating that the meteorite strike occurred during the mid-Paleocene. This is the rst recorded mid-Paleocene impact event in the region and is coincident with the onset of magmatism in the British Palaeogene Igneous Province (BPIP). The Skye ejecta layer deposits provoke important questions regarding their lateral extent at the base of the BPIP and the possibility of their presence elsewhere beneath the much larger North Atlantic Igneous Province

Quantifying the anisotropy and tortuosity of permeable pathways in clay-rich mudstones using models based on X-ray tomography

The permeability of shales is important, because it controls where oil and gas resources can migrate to and where in the Earth hydrocarbons are ultimately stored. Shales have a well-known anisotropic directional permeability that is inherited from the depositional layering of sedimentary laminations, where the highest permeability is measured parallel to laminations and the lowest permeability is perpendicular to laminations. We combine state of the art laboratory permeability experiments with high-resolution X-ray computed tomography and for the first time can quantify the three-dimensional interconnected pathways through a rock that define the anisotropic behaviour of shales. Experiments record a physical anisotropy in permeability of one to two orders of magnitude. Two- and three-dimensional analyses of micro- and nano-scale X-ray computed tomography illuminate the interconnected pathways through the porous/permeable phases in shales. The tortuosity factor quantifies the apparent decrease in diffusive transport resulting from convolutions of the flow paths through porous media and predicts that the directional anisotropy is fundamentally controlled by the bulk rock mineral geometry. Understanding the mineral-scale control on permeability will allow for better estimations of the extent of recoverable reserves in shale gas plays globally

Prognostic risk modelling for patients undergoing major lower limb amputation: an analysis of the UK National Vascular Registry

Objective Major lower limb amputation is the highest risk lower limb procedure in vascular surgery. Despite this, few high quality studies have examined factors contributing to mortality. The aim was to identify independent risk factors for peri-operative morbidity and mortality and develop reliable models for estimating risk. Methods All patients undergoing lower limb amputation above the ankle entered into the UK National Vascular Registry (January 2014–December 2016) were included. Missing data were handled using multiple imputation. Models were developed to evaluate independent risk factors for mortality (the primary outcome) and morbidity using logistic regression, minimising the Bayesian information criterion to balance complexity and model fit. Ethical approval for the study was granted (Wales REC 3 ref:16/WA/0353). Results All 9549 above ankle joint amputations in the registry were included. Overall, 865 patients (9.1%) died before leaving hospital. Independent factors associated with mortality were emergency admission, bilateral operation, age, American Society of Anesthesiologists' grade, abnormal electrocardiogram, and increased white cell count or creatinine (p < .01 for all). Independent factors reducing mortality were transtibial operation, increased albumin or patient weight, and previous ipsilateral revascularisation procedures (p < .01 for all). A risk model incorporating these factors had good discrimination (C-statistic 0.79, 95% confidence interval 0.77–0.80) and excellent calibration. Morbidity rates were high, with 6.6%, 9.7%, and 4.3% of patients suffering cardiac, respiratory, and renal complications, respectively. The risk model was also predictive of morbidity outcomes (C-statistics 0.74, 0.69, and 0.74, respectively). Conclusion Morbidity and mortality after lower limb amputation are high in the UK. Some potentially modifiable factors for quality improvement initiatives have been identified and accurate predictive models that could assist patient counselling and decision making have been developed