In silico modelling of in-host tuberculosis dynamics : towards building the virtual patient

Tuberculosis (TB) accounts for over 1 million deaths each year, despite effective treatment regimens being available. Improving the treatment of TB will require new regimens, each of which will need to be put through expensive and lengthy clinical trials, with no guarantee of success. The ability to predict which of many novel regimens to progress through the clinical trial stages would be an important tool to TB research. as current models are constrained in their ability to reflect the whole spectrum of pathophysiology, particularly as there remains uncertainty around the events that occur. This thesis explores the use of computational techniques to model a pulmonary human TB infection. We introduce the first in silico model of TB occurring over the whole lung that incorporates both the environmental heterogeneity that is exhibited within different spatial regions of the organ, and the different bacterial dissemination routes, in order to understand how bacteria move during infection and why post-primary disease is typically localised towards the apices of the lung. Our results show that including environmental heterogeneity within the lung can have profound effects on the results of an infection, by creating a region towards the apex which is preferential for bacterial proliferation. We also present a further iteration of the model, whereby the environment is made more granular to better understand the regions which are afflicted during infection, and show how sensitivity analysis can determine the factors that contribute most to disease outcomes. We show that in order to simulate TB disease within a human lung with sufficient accuracy, better understanding of the dynamics is required. The model presented in this thesis is intended to provide insight into these complicated dynamics, and thus make progress towards an end goal of a virtual clinical trial, consisting of a heterogeneous population of synthetic virtual patients."“This work was supported by the PreDiCT TB consortium (IMI Joint undertaking grant agreement number 115337, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EF-PIA companies’ in kind contribution.)” -- Acknowledgement

Extrinsic bronchial compression by primary tuberculous adenopathy, simulating foreign-body aspiration

A 5-month-old boy was well until the day before admission, when he developed a cough. On the morning of admission he was irritable and his mother noticed a blue tinge to his lips during episodes of crying. This prompted her to bring him to the emergency unit at Red Cross Children's Hospital, where he was found to be distressed and cyanosed, with a respiratory rate of 60 beats per minute, a heart rate of 200/minute and alar flaring. His left chest showed decreased air entry, bronchial breathing and dullness to percussion. Oxygen saturation was 66%, improving to 88% on face-mask oxygen. His weight was on the 50th percentile. He was well hydrated, well perfused and had no significant background medical history. A mobile chest radiograph (Fig. 1) showed complete opacification of the left hemithorax, mediastinal deviation to the left and overexpansion of the right lung, which had herniated across the midline. A penetrated anteroposterior (AP) chest radiograph (Fig. 2) showed abrupt 'cut-off' of the left main bronchus

Regulation of Membrane Targeting of the G Protein-coupled Receptor Kinase 2 by Protein Kinase A and Its Anchoring Protein AKAP79

The beta 2 adrenergic receptor (beta 2AR) undergoes desensitization by a process involving its phosphorylation by both protein kinase A (PKA) and G protein-coupled receptor kinases (GRKs). The protein kinase A-anchoring protein AKAP79 influences beta 2AR phosphorylation by complexing PKA with the receptor at the membrane. Here we show that AKAP79 also regulates the ability of GRK2 to phosphorylate agonist-occupied receptors. In human embryonic kidney 293 cells, overexpression of AKAP79 enhances agonist-induced phosphorylation of both the beta 2AR and a mutant of the receptor that cannot be phosphorylated by PKA (beta 2AR/PKA-). Mutants of AKAP79 that do not bind PKA or target to the beta 2AR markedly inhibit phosphorylation of beta 2AR/PKA-. We show that PKA directly phosphorylates GRK2 on serine 685. This modification increases Gbeta gamma subunit binding to GRK2 and thus enhances the ability of the kinase to translocate to the membrane and phosphorylate the receptor. Abrogation of the phosphorylation of serine 685 on GRK2 by mutagenesis (S685A) or by expression of a dominant negative AKAP79 mutant reduces GRK2-mediated translocation to beta 2AR and phosphorylation of agonist-occupied beta 2AR, thus reducing subsequent receptor internalization. Agonist-stimulated PKA-mediated phosphorylation of GRK2 may represent a mechanism for enhancing receptor phosphorylation and desensitization

Tilt engineering of spontaneous polarization and magnetization above 300 K in a bulk layered perovskite

Crystalline materials that combine electrical polarization and magnetization could be advantageous in applications such as information storage, but these properties are usually considered to have incompatible chemical bonding and electronic requirements. Recent theoretical work on perovskite materials suggested a route for combining both properties. We used crystal chemistry to engineer specific atomic displacements in a layered perovskite, (CaySr1–y)1.15Tb1.85Fe2O7, that change its symmetry and simultaneously generate electrical polarization and magnetization above room temperature. The two resulting properties are magnetoelectrically coupled as they arise from the same displacements

The operational efficiency of commercial food refrigeration systems: a data mining approach

The energy demands of food retail buildings account for approximately 3% of the UK’s energy consumption and resultant carbon emissions. Previous studies (Spyrou et al. 2014, Tassou et al. 2011) demonstrate that the greatest component of the electricity demand of food retail buildings is the cooling demand of the food refrigeration systems (ranging from 30 to 50%). Therefore a better understanding of the electricity demand for refrigeration would enable the development of effective energy management tools, including the evaluation of service and maintenance interventions to reduce operational electricity demand. Various methodologies have been developed and employed in the past for the quick identification of faults during the operation of commercial refrigeration systems. The focus of these methodologies has traditionally been on the temperature of food on the shop floor. The aim of this work is to enhance the existing fault-finding methodologies employed by a global multichannel retail organization, by enabling the identification of events that cause an increase in electricity demand of the refrigeration systems. This paper presents a methodology that analyzes data from refrigeration systems and enables a more straightforward identification of faults. This includes data for electricity consumption, compressor run times, percentage of refrigerant in the receiver, temperature of air on and off the evaporator, discharge and suction pressures, etc. Control strategies and maintenance schedules as well as meteorological data for each site were also collected and analyzed. Data mining methods were employed to remove known operational patterns (e.g. defrost cycles) and seasonal variations. Events that have had an effect on the electricity consumption of the system were highlighted and faults that have been identified by the existing methodology were filtered out. The resulting data set was then analyzed further to understand the events that increase the electricity demand of the systems in order to create an automatic identification method

First documented occurrences of Cladonia krogiana and C. rangiformis in north America

Funding Information: We thank Scott LaGreca for providing a photograph of the specimen of C. rangiformis at BM that was reportedly collected on Bermuda; Bruce Allen and the late Ronald Pursell for allowing us to cite their collections of Homalothecium sericeum from Newfoundland; Zdeněk Palice for enabling us to compare his collection of C. krogiana from the Czech Republic with material from Canada and Norway; Nathalie Djan-Chékar (Provincial Museum of Newfoundland and Labrador) for co-organizing the 2007 Tuckerman Workshop; and Irwin Brodo, James Lendemer, and an anonymous reviewer for their helpful comments on the manuscript. Permission to collect lichens in Fundy National Park and New River Beach Provincial Park (NRBPP) was approved by Renee Wissink (Parks Canada) and Martin MacMullin (NB Department of Tourism, Heritage, and Culture). Fieldwork in NRBPP and follow-up studies were supported in part by the New Brunswick Wildlife Trust Fund and the New Brunswick Environmental Trust Fund. Publisher Copyright: © 2021, New York Botanical Garden. All rights reserved.– Cladonia krogiana, previously known only from Norway and the Czech Republic, is reported here for North America from two localities near the Bay of Fundy, New Brunswick, Canada. It occurs there on open, rocky banks of clear, free-flowing rivers, habitats similar to those in which it has been found in Norway. We also document the occurrence of C. rangiformis in North America, based on collections from two localities on the southwest coast of Conception Bay, on the Avalon Peninsula of the island of Newfoundland, Canada. It is possibly an accidental, but naturalized, introduction in this area, where European settlement began in the early 1600s. A molecular phylogenetic analysis confirmed the identity of one of the Newfoundland specimens. The IGS rDNA haplotype to which it belongs is the same as the most widely distributed haplotype of C. rangiformis in Europe and Macaronesia. Previous reports of C. rangiformis for continental North America are based on misidentifications. A 19th century collection reportedly made on the island of Bermuda, while correctly identified, is of uncertain provenance.Peer reviewe

A spatially heterogeneous network-based metapopulation software model applied to the simulation of a pulmonary tuberculosis infection

This work was supported by the PreDiCT-TB consortium (IMI Joint undertaking grant agreement number 115337, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution.Tuberculosis (TB) is an ancient disease that, although curable, still accounts for over 1 million deaths worldwide. Shortening treatment time is an important area of research but is hampered by the lack of models that mimic the full range of human pathology. TB shows distinct localisations during different stages of infection, the reasons for which are poorly understood. Greater understanding of how heterogeneity within the human lung influences disease progression may hold the key to improving treatment efficiency and reducing treatment times. In this work, we present a novel in silico software model which uses a networked metapopulation incorporating both spatial heterogeneity and dissemination possibilities to simulate a TB infection over the whole lung and associated lymphatics. The entire population of bacteria and immune cells is split into a network of patches: members interact within patches and are able to move between them. Patches and edges of the lung network include their own environmental attributes which influence the dynamics of interactions between the members of the subpopulations of the patches and the translocation of members along edges. In this work, we detail the initial findings of a whole-organ model that incorporates distinct spatial heterogeneity features which are not present in standard differential equation approaches to tuberculosis modelling. We show that the inclusion of heterogeneity within the lung landscape when modelling TB disease progression has significant outcomes on the bacterial load present: a greater differential of oxygen, perfusion and ventilation between the apices and the basal regions of the lungs creates micro-environments at the apex that are more preferential for bacteria, due to increased oxygen availability and reduced immune activity, leading to a greater overall bacterial load present once latency is established. These findings suggest that further whole-organ modelling incorporating more sophisticated heterogeneities within the environment and complex lung topologies will provide more insight into the environments in which TB bacteria persist and thus help develop new treatments which are factored towards these environmental conditions.Publisher PDFPeer reviewe

Is the abundance of Faecalibacterium prausnitzii relevant to Crohn's disease?

Reports that bacteria within the Firmicutes phylum, especially the species Faecalibacterium prausnitzii, are less abundant in Crohn’s disease (CD) patients and supernatants from cultures of this bacterium are anti-inflammatory prompted the investigation of the possible correlations between the abundance of F.prausnitzii and the response to treatment in patients with gut diseases and healthy controls. In a randomized, double-blind trial, faeces were collected from healthy volunteers, and from patients with active CD, ulcerative colitis (UC) and irritable bowel syndrome before and after treatment. The levels of F. prausnitzii DNA in faecal suspensions were determined by PCR. Treatment by an elemental diet was effective, resulting in decreases in both the Harvey and Bradshaw index (P<0.001) and the concentrations of serum C-reactive protein (P<0.05). The total levels of F. prausnitzii in faecal samples from CD patients at presentation were lower than those in the other groups both before and after the treatment. There was no correlation between F. prausnitzii abundance and the severity of CD before treatment. Clinical improvement unexpectedly correlated with a significant decrease in the abundance of F. prausnitzii, especially the A2-165 subgroup (P<0.05). Our data suggest that a paucity of F. prausnitzii in the gastrointestinal microbial communities is likely to be a minor aetiological factor in CD: recovery following elemental diet is attributed to lower levels of gut flora