Breaking beta: deconstructing the parasite transmission function

Transmission is a fundamental step in the life cycle of every parasite but it is also one of the most challenging processes to model and quantify. In most host–parasite models, the transmission process is encapsulated by a single parameterβ. Many different biological processes and interactions, acting on both hosts and infectious organisms, are subsumed in this single term. There are, however, at least two undesirable consequences of this high level of abstraction. First, nonlinearities and heterogeneities that can be critical to the dynamic behaviour of infections are poorly represented; second, estimating the transmission coefficientβfrom field data is often very difficult. In this paper, we present a conceptual model, which breaks the transmission process into its component parts. This deconstruction enables us to identify circumstances that generate nonlinearities in transmission, with potential implications for emergent transmission behaviour at individual and population scales. Such behaviour cannot be explained by the traditional linear transmission frameworks. The deconstruction also provides a clearer link to the empirical estimation of key components of transmission and enables the construction of flexible models that produce a unified understanding of the spread of both micro- and macro-parasite infectious disease agents

Comprehensive Biotransformation Analysis of Phenylalanine-Tyrosine Metabolism Reveals Alternative Routes of Metabolite Clearance in Nitisinone-Treated Alkaptonuria

Metabolomic analyses in alkaptonuria (AKU) have recently revealed alternative pathways in phenylalanine-tyrosine (phe-tyr) metabolism from biotransformation of homogentisic acid (HGA), the active molecule in this disease. The aim of this research was to study the phe-tyr metabolic pathway and whether the metabolites upstream of HGA, increased in nitisinone-treated patients, also undergo phase 1 and 2 biotransformation reactions. Metabolomic analyses were performed on serum and urine from patients partaking in the SONIA 2 phase 3 international randomised-controlled trial of nitisinone in AKU (EudraCT no. 2013-001633-41). Serum and urine samples were taken from the same patients at baseline (pre-nitisinone) then at 24 and 48 months on nitisinone treatment (patients N = 47 serum; 53 urine) or no treatment (patients N = 45 serum; 50 urine). Targeted feature extraction was performed to specifically mine data for the entire complement of theoretically predicted phase 1 and 2 biotransformation products derived from phenylalanine, tyrosine, 4-hydroxyphenylpyruvic acid and 4-hydroxyphenyllactic acid, in addition to phenylalanine-derived metabolites with known increases in phenylketonuria. In total, we observed 13 phase 1 and 2 biotransformation products from phenylalanine through to HGA. Each of these products were observed in urine and two were detected in serum. The derivatives of the metabolites upstream of HGA were markedly increased in urine of nitisinone-treated patients (fold change 1.2–16.2) and increases in 12 of these compounds were directly proportional to the degree of nitisinone-induced hypertyrosinaemia (correlation coefficient with serum tyrosine = 0.2–0.7). Increases in the urinary phenylalanine metabolites were also observed across consecutive visits in the treated group. Nitisinone treatment results in marked increases in a wider network of phe-tyr metabolites than shown before. This network comprises alternative biotransformation products from the major metabolites of this pathway, produced by reactions including hydration (phase 1) and bioconjugation (phase 2) of acetyl, methyl, acetylcysteine, glucuronide, glycine and sulfate groups. We propose that these alternative routes of phe-tyr metabolism, predominantly in urine, minimise tyrosinaemia as well as phenylalanaemia

Metabolomic studies in the inborn error of metabolism alkaptonuria reveal new biotransformations in tyrosine metabolism

Alkaptonuria (AKU) is an inherited disorder of tyrosine metabolism caused by lack of active enzyme homogentisate 1,2-dioxygenase (HGD). The primary consequence of HGD deficiency is increased circulating homogentisic acid (HGA), the main agent in the pathology of AKU disease. Here we report the first metabolomic analysis of AKU homozygous Hgd knockout (Hgd(−/−)) mice to model the wider metabolic effects of Hgd deletion and the implication for AKU in humans. Untargeted metabolic profiling was performed on urine from Hgd(−/−) AKU (n = 15) and Hgd(+/−) non-AKU control (n = 14) mice by liquid chromatography high-resolution time-of-flight mass spectrometry (Experiment 1). The metabolites showing alteration in Hgd(−/−) were further investigated in AKU mice (n = 18) and patients from the UK National AKU Centre (n = 25) at baseline and after treatment with the HGA-lowering agent nitisinone (Experiment 2). A metabolic flux experiment was carried out after administration of (13)C-labelled HGA to Hgd(−/−)(n = 4) and Hgd(+/−)(n = 4) mice (Experiment 3) to confirm direct association with HGA. Hgd(−/−) mice showed the expected increase in HGA, together with unexpected alterations in tyrosine, purine and TCA-cycle pathways. Metabolites with the greatest abundance increases in Hgd(−/−) were HGA and previously unreported sulfate and glucuronide HGA conjugates, these were decreased in mice and patients on nitisinone and shown to be products from HGA by the (13)C-labelled HGA tracer. Our findings reveal that increased HGA in AKU undergoes further metabolism by mainly phase II biotransformations. The data advance our understanding of overall tyrosine metabolism, demonstrating how specific metabolic conditions can elucidate hitherto undiscovered pathways in biochemistry and metabolism

maxdLoad2 and maxdBrowse: standards-compliant tools for microarray experimental annotation, data management and dissemination

BACKGROUND: maxdLoad2 is a relational database schema and Java(® )application for microarray experimental annotation and storage. It is compliant with all standards for microarray meta-data capture; including the specification of what data should be recorded, extensive use of standard ontologies and support for data exchange formats. The output from maxdLoad2 is of a form acceptable for submission to the ArrayExpress microarray repository at the European Bioinformatics Institute. maxdBrowse is a PHP web-application that makes contents of maxdLoad2 databases accessible via web-browser, the command-line and web-service environments. It thus acts as both a dissemination and data-mining tool. RESULTS: maxdLoad2 presents an easy-to-use interface to an underlying relational database and provides a full complement of facilities for browsing, searching and editing. There is a tree-based visualization of data connectivity and the ability to explore the links between any pair of data elements, irrespective of how many intermediate links lie between them. Its principle novel features are: • the flexibility of the meta-data that can be captured, • the tools provided for importing data from spreadsheets and other tabular representations, • the tools provided for the automatic creation of structured documents, • the ability to browse and access the data via web and web-services interfaces. Within maxdLoad2 it is very straightforward to customise the meta-data that is being captured or change the definitions of the meta-data. These meta-data definitions are stored within the database itself allowing client software to connect properly to a modified database without having to be specially configured. The meta-data definitions (configuration file) can also be centralized allowing changes made in response to revisions of standards or terminologies to be propagated to clients without user intervention. maxdBrowse is hosted on a web-server and presents multiple interfaces to the contents of maxd databases. maxdBrowse emulates many of the browse and search features available in the maxdLoad2 application via a web-browser. This allows users who are not familiar with maxdLoad2 to browse and export microarray data from the database for their own analysis. The same browse and search features are also available via command-line and SOAP server interfaces. This both enables scripting of data export for use embedded in data repositories and analysis environments, and allows access to the maxd databases via web-service architectures. CONCLUSION: maxdLoad2 and maxdBrowse are portable and compatible with all common operating systems and major database servers. They provide a powerful, flexible package for annotation of microarray experiments and a convenient dissemination environment. They are available for download and open sourced under the Artistic License

Studies in alkaptonuria reveal new roles beyond drug clearance for phase I and II biotransformations in tyrosine metabolism

AbstractBackground and Purposealkaptonuria (AKU) is an inherited disorder of tyrosine metabolism caused by lack of the enzyme homogentisate 1,2-dioxygenase (HGD). The primary biochemical consequence of HGD-deficiency is increased circulating homogentisic acid (HGA), which is central to AKU disease pathology. The aim of this study was to investigate the wider metabolic consequences of targeted Hgd disruption.Experimental Approachthe first metabolomic analysis of the Hgd−/− AKU mouse model was performed. Urinary metabolites altered in Hgd−/− were further validated by showing that the HGA-lowering drug nitisinone reversed their direction of alteration in AKUKey Resultscomparison of Hgd−/− (AKU) versus Hgd+/− (heterozygous control) urine revealed increases in HGA and a group of 8 previously unreported HGA-derived transformation products from phase I and II metabolism. HGA biotransformation products HGA-sulfate, HGA-glucuronide, HGA-hydrate and hydroxymethyl-HGA were also decreased in urine from both mice and patients with AKU on the HGA-lowering agent nitisinone. Hgd knockout also revealed a host of previously unrecognised associations between tyrosine, purine and TCA cycle metabolic pathways.Conclusion and ImplicationsAKU is rare, but our findings further what is currently understood about tyrosine metabolism more generally, and show for the first time that phase I and II detoxification is recruited to prevent accumulation of endogenously-produced metabolites in inborn errors of metabolism. The data highlight the misconception that phase I and II metabolic biotransformations are reserved solely for drug clearance; these are ancient mechanisms, which represent new potential treatment targets in inherited metabolic diseases.Abstract FigureBullet point summaryWhat is already known Increased circulating homogentisic acid is central to disease pathology in the inherited metabolic disease alkaptonuriaThe Hgd knockout mouse, created in our laboratory, accurately models human alkaptonuriaWhat this study adds Phase I and II biotransformations are recruited in alkaptonuria for detoxification of homogentisic acidThese data challenge misconceptions that phase I and II metabolism is solely for drug clearanceClinical significance Phase I and II metabolic processes represent new treatment targets in inherited metabolic diseasesThe molecular pathology of AKU extends much further than the known alteration to tyrosine metabolism</jats:sec

A feasibility study of acceptance and commitment therapy for emotional dysfunction following psychosis

The experience of psychosis can lead to depression, anxiety and fear. Acceptance and Commitment Therapy (ACT) facilitates individuals to accept difficult mental experiences and behave in ways that are consistent with personally held values. This study was a single (rater) blind pilot randomised controlled trial of ACT for emotional dysfunction following psychosis. Twenty-seven participants with psychosis were randomised to either: ten sessions of ACT plus treatment as usual (TAU) or TAU alone. The Hospital Anxiety and Depression Scale, Positive and Negative Syndrome Scale, Acceptance and Action Questionnaire, Kentucky Inventory of Mindfulness Skills and Working Alliance Inventory were used. Individuals were assessed at baseline and 3 months post-baseline. The individuals randomised to receive ACT found the intervention acceptable. A significantly greater proportion of the ACT group changed from being depressed at time of entry into the study to not being depressed at follow-up. The ACT group showed a significantly greater increase in mindfulness skills and reduction in negative symptoms. Results indicated that individuals randomised to ACT had significantly fewer crisis contacts over the study. Changes in mindfulness skills correlated positively with changes in depression. ACT appears to offer promise in reducing negative symptoms, depression and crisis contacts in psychosis

Dependence of the Ice Water Content and Snowfall Rate on Temperature, Globally: Comparison of In-Situ Observations, Satellite Active Remote Sensing Retrievals and Global Climate Model Simulations

Cloud ice microphysical properties measured or estimated from in-situ aircraft observations are compared to global climate models and satellite active remote sensor retrievals. Two large datasets, with direct measurements of the ice water content (IWC) and encompassing data from polar to tropical regions, are combined to yield a large database of in-situ measurements. The intention of this study is to identify strengths and weaknesses of the various methods used to derive ice cloud microphysical properties. The in-situ data are measured with total water hygrometers, condensed water probes, and particle spectrometers. Data from polar, midlatitude, and tropical locations are included. The satellite data are retrieved from CloudSat/CALIPSO (2C-ICE, 2C-SNOWPROFILE), and Global Precipitation Measurement (GPM) Level2A. Although the 2CICE retrieval is for IWC, we developed a method to use the IWC to get snowfall rates (S). The GPM retrievals are for snowfall rate only. Model results are derived using the Community Atmosphere Model (CAM5) and the UK Met Office Unified Model (GA7). The retrievals and model results are related to the in-situ observations using temperature and partitioned by geographical region. Specific variables compared between the in-situ observations, models, and retrievals are the IWC and S. The retrieved IWCs are reasonably close in value to the in-situ observations, whereas the models' values are relatively low by comparison. Differences between the in-situ IWCs and those from the other methods are compounded when S is considered, leading to model snowfall rates that are considerably lower than derived from the in-situ data. Anomalous trends with temperature are noted in some instances

Harnessing Interpretable and Unsupervised Machine Learning to Address Big Data from Modern X-ray Diffraction

The information content of crystalline materials becomes astronomical when collective electronic behavior and their fluctuations are taken into account. In the past decade, improvements in source brightness and detector technology at modern x-ray facilities have allowed a dramatically increased fraction of this information to be captured. Now, the primary challenge is to understand and discover scientific principles from big data sets when a comprehensive analysis is beyond human reach. We report the development of a novel unsupervised machine learning approach, XRD Temperature Clustering (X-TEC), that can automatically extract charge density wave (CDW) order parameters and detect intra-unit cell (IUC) ordering and its fluctuations from a series of high-volume X-ray diffraction (XRD) measurements taken at multiple temperatures. We apply X-TEC to XRD data on a quasi-skutterudite family of materials, (Ca$_x$Sr$_{1-x}$)$_3$Rh$_4$Sn$_{13}$, where a quantum critical point arising from charge order is observed as a function of Ca concentration. We further apply X-TEC to XRD data on the pyrochlore metal, Cd$_2$Re$_2$O$_7$, to investigate its two much debated structural phase transitions and uncover the Goldstone mode accompanying them. We demonstrate how unprecedented atomic scale knowledge can be gained when human researchers connect the X-TEC results to physical principles. Specifically, we extract from the X-TEC-revealed selection rule that the Cd and Re displacements are approximately equal in amplitude, but out of phase. This discovery reveals a previously unknown involvement of $5d^2$ Re, supporting the idea of an electronic origin to the structural order. Our approach can radically transform XRD experiments by allowing in-operando data analysis and enabling researchers to refine experiments by discovering interesting regions of phase space on-the-fly