A Novel Method for Rapid and Quantitative Mechanical Assessment of Soft Tissue for Diagnostic Purposes: A Computational Study

Biological tissues often experience drastic changes in their microstructure due to their pathophysiological conditions. Such microstructural changes could result in variations in mechanical properties, which can be used in diagnosing or monitoring a wide range of diseases, most notably cancer. This paves the avenue for non-invasive diagnosis by instrumented palpation although challenges remain in quantitatively assessing the amount of diseased tissue by means of mechanical characterization. This paper presents a framework for tissue diagnosis using a quantitative and efficient estimation of the fractions of cancerous and non-cancerous tissue without a priori knowledge of tissue microstructure. First, the sample is tested in a creep or stress relaxation experiment, and the behavior is characterized using a single term Prony series. A rule of mixtures, which relates tumor fraction to the apparent mechanical properties, is then obtained by minimizing the difference between strain energy of a heterogeneous system and an equivalent homogeneous one. Finally, the percentage of each tissue constituent is predicted by comparing the observed relaxation time with that calculated from the rule of mixtures. The proposed methodology is assessed using models reconstructed from histological samples and magnetic resonance imaging of prostate. Results show that estimation of cancerous tissue fraction can be obtained with a maximum error of 12% when samples of different sizes, geometries, and tumor fractions are presented. The proposed framework has the potential to be applied to a wide range of diseases such as rectal polyps, cirrhosis, or breast and prostate cancer whose current primary diagnosis remains qualitative.The support under grant nos. EP/I019472/1 and EP/I020101/1 from the Engineering and Physical Sciences Research Council (EPSRC) is greatly acknowledged. The authors also acknowledge Dr. M O'Donnell (Consultant Uropathologist, Western General Hospital) for the pathohistological analysis and Dr. Maurits Jansen and Ross Lennen from the University of Edinburgh for performing the MRI study

A pentapeptide as minimal antigenic determinant for MHC class I-restricted T lymphocytes

Peptides that are antigenic for T lymphocytes are ligands for two receptors, the class I or II glycoproteins that are encoded by genes in the major histocompatibility complex, and the idiotypic / chain T-cell antigen receptor1–9. That a peptide must bind to an MHC molecule to interact with a T-cell antigen receptor is the molecular basis of the MHC restriction of antigen-recognition by T lymphocytes10,11. In such a trimolecular interaction the amino-acid sequence of the peptide must specify the contact with both receptors: agretope residues bind to the MHC receptor and epitope residues bind to the T-cell antigen receptor12,13. From a compilation of known antigenic peptides, two algorithms have been proposed to predict antigenic sites in proteins. One algorithm uses linear motifs in the sequence14, whereas the other considers peptide conformation and predicts antigenicity for amphipathic -helices15,16. We report here that a systematic delimitation of an antigenic site precisely identifies a predicted pentapeptide motif as the minimal antigenic determinant presented by a class I MHC molecule and recognized by a cytolytic T lymphocyte clone

Quantum fields during black hole formation: how good an approximation is the Unruh state?

We study the quantum effects of a test Klein-Gordon field in a Vaidya space-time consisting of a collapsing null shell that forms a Schwazschild black hole, by explicitly obtaining, in a (1 + 1)-dimensional model, the Wightman function, the renormalised stress-energy tensor, and by analysing particle detector rates along stationary orbits in the exterior black hole region, and make a comparison with the folklore that the Unruh state is the state that emerges from black hole formation. In the causal future of the shell, we find a negative ingoing flux at the horizon that agrees precisely with the Unruh state calculation, and is the source of black hole radiation, while in the future null infinity we find that the radiation flux output in the Unruh state is an upper bound for the positive outgoing flux in the collapsing null shell spacetime. This indicates that back-reaction estimates based on Unruh state calculations over-estimate the energy output carried by so-called pre-Hawking radiation. The value of the output predicted by the Unruh state is however approached exponentially fast. Finally, we find that at late times, stationary observers in the exterior black hole region in the collapsing shell spacetime detect the local Hawking temperature, which is also well characterised by the Unruh state, coming from right-movers. Early-time discrepancies between the detector rates for the Unruh state and for the state in the collapsing shell spacetime are explored numerically

Observed Reductions in Schistosoma mansoni Transmission from Large-Scale Administration of Praziquantel in Uganda: A Mathematical Modelling Study

To date schistosomiasis control programmes based on chemotherapy have largely aimed at controlling morbidity in treated individuals rather than at suppressing transmission. In this study, a mathematical modelling approach was used to estimate reductions in the rate of Schistosoma mansoni reinfection following annual mass drug administration (MDA) with praziquantel in Uganda over four years (2003-2006). In doing this we aim to elucidate the benefits of MDA in reducing community transmission.Age-structured models were fitted to a longitudinal cohort followed up across successive rounds of annual treatment for four years (Baseline: 2003, TREATMENT: 2004-2006; n = 1,764). Instead of modelling contamination, infection and immunity processes separately, these functions were combined in order to estimate a composite force of infection (FOI), i.e., the rate of parasite acquisition by hosts.MDA achieved substantial and statistically significant reductions in the FOI following one round of treatment in areas of low baseline infection intensity, and following two rounds in areas with high and medium intensities. In all areas, the FOI remained suppressed following a third round of treatment.This study represents one of the first attempts to monitor reductions in the FOI within a large-scale MDA schistosomiasis morbidity control programme in sub-Saharan Africa. The results indicate that the Schistosomiasis Control Initiative, as a model for other MDA programmes, is likely exerting a significant ancillary impact on reducing transmission within the community, and may provide health benefits to those who do not receive treatment. The results obtained will have implications for evaluating the cost-effectiveness of schistosomiasis control programmes and the design of monitoring and evaluation approaches in general

Clinical implementation of a knowledge based planning tool for prostate VMAT

Abstract Background A knowledge based planning tool has been developed and implemented for prostate VMAT radiotherapy plans providing a target average rectum dose value based on previously achievable values for similar rectum/PTV overlap. The purpose of this planning tool is to highlight sub-optimal clinical plans and to improve plan quality and consistency. Methods A historical cohort of 97 VMAT prostate plans was interrogated using a RayStation script and used to develop a local model for predicting optimum average rectum dose based on individual anatomy. A preliminary validation study was performed whereby historical plans identified as “optimal” and “sub-optimal” by the local model were replanned in a blinded study by four experienced planners and compared to the original clinical plan to assess whether any improvement in rectum dose was observed. The predictive model was then incorporated into a RayStation script and used as part of the clinical planning process. Planners were asked to use the script during planning to provide a patient specific prediction for optimum average rectum dose and to optimise the plan accordingly. Results Plans identified as “sub-optimal” in the validation study observed a statistically significant improvement in average rectum dose compared to the clinical plan when replanned whereas plans that were identified as “optimal” observed no improvement when replanned. This provided confidence that the local model can identify plans that were suboptimal in terms of rectal sparing. Clinical implementation of the knowledge based planning tool reduced the population-averaged mean rectum dose by 5.6Gy. There was a small but statistically significant increase in total MU and femoral head dose and a reduction in conformity index. These did not affect the clinical acceptability of the plans and no significant changes to other plan quality metrics were observed. Conclusions The knowledge-based planning tool has enabled substantial reductions in population-averaged mean rectum dose for prostate VMAT patients. This suggests plans are improved when planners receive quantitative feedback on plan quality against historical data

Fast and slow responses of Southern Ocean sea surface temperature to SAM in coupled climate models

We investigate how sea surface temperatures (SSTs) around Antarctica respond to the Southern An- nular Mode (SAM) on multiple timescales. To that end we examine the relationship between SAM and SST within unperturbed preindustrial control simulations of coupled general circulation models (GCMs) included in the Climate Modeling Intercomparison Project phase 5 (CMIP5). We develop a technique to extract the re- sponse of the Southern Ocean SST (55◦S−70◦S) to a hypothetical step increase in the SAM index. We demonstrate that in many GCMs, the expected SST step re- sponse function is nonmonotonic in time. Following a shift to a positive SAM anomaly, an initial cooling regime can transition into surface warming around Antarctica. However, there are large differences across the CMIP5 ensemble. In some models the step response function never changes sign and cooling persists, while in other GCMs the SST anomaly crosses over from negative to positive values only three years after a step increase in the SAM. This intermodel diversity can be related to differences in the models’ climatological thermal ocean stratification in the region of seasonal sea ice around Antarctica. Exploiting this relationship, we use obser- vational data for the time-mean meridional and vertical temperature gradients to constrain the real Southern Ocean response to SAM on fast and slow timescales

Bacterial adaptation is constrained in complex communities

© 2020, The Author(s). A major unresolved question is how bacteria living in complex communities respond to environmental changes. In communities, biotic interactions may either facilitate or constrain evolution depending on whether the interactions expand or contract the range of ecological opportunities. A fundamental challenge is to understand how the surrounding biotic community modifies evolutionary trajectories as species adapt to novel environmental conditions. Here we show that community context can dramatically alter evolutionary dynamics using a novel approach that ‘cages’ individual focal strains within complex communities. We find that evolution of focal bacterial strains depends on properties both of the focal strain and of the surrounding community. In particular, there is a stronger evolutionary response in low-diversity communities, and when the focal species have a larger genome and are initially poorly adapted. We see how community context affects resource usage and detect genetic changes involved in carbon metabolism and inter-specific interaction. The findings demonstrate that adaptation to new environmental conditions should be investigated in the context of interspecific interactions

Increased Expression of Musashi-1 Evidences Mesenchymal Repair in Maxillary Sinus Floor Elevation

This study aimed to analyze the expression of Musashi-1 (MSI1) in maxillary native bone and grafted bone after maxillary sinus floor elevation. To do so, fifty-seven bone biopsies from 45 participants were studied. Eighteen samples were collected from native bone while 39 were obtained 6 months after maxillary sinus grafting procedures. Musashi-1 was analyzed by immunohistochemistry and RT-PCR. MSI1 was detected in osteoblasts and osteocytes in 97.4% (38/39) of grafted areas. In native bone, MSI1 was detected in only 66.6% (12/18) of the biopsies, mainly in osteocytes. Detection of MSI1 was significantly higher in osteoprogenitor mesenchymal cells of grafted biopsies (p < 0.001) but minor in smooth muscle and endothelial cells; no expression was detected in adipocytes. The mesenchymal cells of the non-mineralized tissue of native bone showed very low nuclear expression of MSI1, in comparison to fusiform cells in grafted areas (0.28(0.13) vs. 2.10(0.14), respectively; p < 0.001). Additionally, the detection of MSI1 mRNA was significantly higher in biopsies from grafted areas than those from native bone (1.00(0.51) vs. 60.34(35.2), respectively; p = 0.029). Thus, our results regardig the significantly higher detection of Musashi-1 in grafted sites than in native bone reflects its importance in the remodeling/repair events that occur after maxillary sinus floor elevation in humans.This investigation was partially supported by Research Groups #CTS-138 and #CTS-1028 (Junta de Andalucía, Spain). MPM was supported by the Andalucía Talent Hub Program from the Andalusian Knowledge Agency (co-funded by the European Union’s Seventh Framework Program, Marie Skłodowska-Curie actions (COFUND – Grant Agreement n° 291780) and the Ministry of Economy, Innovation, Science and Employment of the Junta de Andalucía)

Mining the Gene Wiki for functional genomic knowledge

<p>Abstract</p> <p>Background</p> <p>Ontology-based gene annotations are important tools for organizing and analyzing genome-scale biological data. Collecting these annotations is a valuable but costly endeavor. The Gene Wiki makes use of Wikipedia as a low-cost, mass-collaborative platform for assembling text-based gene annotations. The Gene Wiki is comprised of more than 10,000 review articles, each describing one human gene. The goal of this study is to define and assess a computational strategy for translating the text of Gene Wiki articles into ontology-based gene annotations. We specifically explore the generation of structured annotations using the Gene Ontology and the Human Disease Ontology.</p> <p>Results</p> <p>Our system produced 2,983 candidate gene annotations using the Disease Ontology and 11,022 candidate annotations using the Gene Ontology from the text of the Gene Wiki. Based on manual evaluations and comparisons to reference annotation sets, we estimate a precision of 90-93% for the Disease Ontology annotations and 48-64% for the Gene Ontology annotations. We further demonstrate that this data set can systematically improve the results from gene set enrichment analyses.</p> <p>Conclusions</p> <p>The Gene Wiki is a rapidly growing corpus of text focused on human gene function. Here, we demonstrate that the Gene Wiki can be a powerful resource for generating ontology-based gene annotations. These annotations can be used immediately to improve workflows for building curated gene annotation databases and knowledge-based statistical analyses.</p

Ventilatory Chaos Is Impaired in Carotid Atherosclerosis

Ventilatory chaos is strongly linked to the activity of central pattern generators, alone or influenced by respiratory or cardiovascular afferents. We hypothesized that carotid atherosclerosis should alter ventilatory chaos through baroreflex and autonomic nervous system dysfunctions. Chaotic dynamics of inspiratory flow was prospectively evaluated in 75 subjects undergoing carotid ultrasonography: 27 with severe carotid stenosis (>70%), 23 with moderate stenosis (<70%), and 25 controls. Chaos was characterized by the noise titration method, the correlation dimension and the largest Lyapunov exponent. Baroreflex sensitivity was estimated in the frequency domain. In the control group, 92% of the time series exhibit nonlinear deterministic chaos with positive noise limit, whereas only 68% had a positive noise limit value in the stenoses groups. Ventilatory chaos was impaired in the groups with carotid stenoses, with significant parallel decrease in the noise limit value, correlation dimension and largest Lyapunov exponent, as compared to controls. In multiple regression models, the percentage of carotid stenosis was the best in predicting the correlation dimension (p<0.001, adjusted R2: 0.35) and largest Lyapunov exponent (p<0.001, adjusted R2: 0.6). Baroreflex sensitivity also predicted the correlation dimension values (p = 0.05), and the LLE (p = 0.08). Plaque removal after carotid surgery reversed the loss of ventilatory complexity. To conclude, ventilatory chaos is impaired in carotid atherosclerosis. These findings depend on the severity of the stenosis, its localization, plaque surface and morphology features, and is independently associated with baroreflex sensitivity reduction. These findings should help to understand the determinants of ventilatory complexity and breathing control in pathological conditions