Applications of percolation theory to fungal spread with synergy

There is increasing interest in the use of the percolation paradigm to analyze and predict the progress of disease spreading in spatially-structured populations of animals and plants. The wider utility of the approach has been limited, however, by several restrictive assumptions, foremost of which is a strict requirement for simple nearest-neighbour transmission, in which the disease history of an individual is in uenced only by that of its neighbours. In a recent paper the percolation paradigm has been generalised to incorporate synergistic interactions in host infectivity and susceptibility and the impact of these interactions on the invasive dynamics of an epidemic has been demonstrated. In the current paper we elicit evidence that such synergistic interactions may underlie transmission dynamics in real-world systems by rst formulating a model for the spread of a ubiquitous parasitic and saprotrophic fungus through replicated populations of nutrient sites and subsequently tting and testing the model using data from experimental microcosms. Using Bayesian computational methods for model tting, we demonstrate that synergistic interactions are necessary to explain the dynamics observed in the replicate experiments. The broader implications of this work in identifying disease control strategies that de ect epidemics from invasive to non-invasive regimes are discussed

Acute systemic inflammation enhances tissue plasminogen activator release in man

Digitalitzat per Artypla

Clinical perspectives of emerging pathogens in bleeding disorders.

As a result of immunological and nucleic-acid screening of plasma donations for transfusion-transmissible viruses, and the incorporation of viral reduction processes during plasma fractionation, coagulation-factor concentrates (CFC) are now judged safe in terms of many known infectious agents, including hepatitis B and C viruses, HIV, and human T-cell lymphotropic virus. However, emerging pathogens could pose future threats, particularly those with blood-borne stages that are resistant to viral-inactivation steps in the manufacturing process, such as non-lipid-coated viruses. As outlined in this Review, better understanding of infectious diseases allows challenges from newly described agents of potential concern in the future to be anticipated, but the processes of zoonotic transmission and genetic selection or modification ensure that plasma-derived products will continue to be subject to infectious concerns. Manufacturers of plasma-derived CFC have addressed the issue of emerging infectious agents by developing recombinant products that limit the need for human plasma during production. Such recombinant products have extended the safety profile of their predecessors by ensuring that all reagents used for cell culture, purification steps, and stabilisation and storage buffers are completely independent of human plasma

The European Association for Haemophilia and Allied Disorders (EAHAD) Coagulation Factor Variant Databases: Important resources for haemostasis clinicians and researchers

Haemophilia published by John Wiley & Sons Ltd Introduction: Advances in genomic sequencing have facilitated the sequencing of genes associated with disorders of haemostasis. The identification of variants within genes and access to curated data incorporating structural, functional, evolutionary as well as phenotypic data has become increasingly important in order to ascribe pathogenicity. Aim: The European Association for Haemophilia and Allied Disorders (EAHAD) Coagulation Factor Variant Database Project aims to provide a single port of entry to a web-accessible resource for variants in genes involved in clinical bleeding disorders. Results: New databases have evolved from previously developed single gene variant coagulation database projects, incorporating new data, new analysis tools and a new common database architecture with new interfaces and filters. These new databases currently present information about the genotype, phenotype (laboratory and clinical) and structural and functional effects of variants described in the genes of factor (F) VII (F7), FVIII (F8), FIX (F9) and von Willebrand factor (VWF). Conclusion: The project has improved the quality and quantity of information available to the haemostasis research and clinical communities, thereby enabling accurate classification of disease severity in order to make assessments of likely pathogenicity

Synergy in spreading processes: from exploitative to explorative foraging strategies

An epidemiological model which incorporates synergistic effects that allow the infectivity and/or susceptibility of hosts to be dependent on the number of infected neighbours is proposed. Constructive synergy induces an exploitative behaviour which results in a rapid invasion that infects a large number of hosts. Interfering synergy leads to a slower and sparser explorative foraging strategy that traverses larger distances by infecting fewer hosts. The model can be mapped to a dynamical bond-percolation with spatial correlations that affect the mechanism of spread but do not influence the critical behaviour of epidemics.Comment: 16 pages, 15 figures. 4 pages for main text and 6 appendices published as supplemental material at http://link.aps.org/supplemental/10.1103/PhysRevLett.106.21870

The EAHAD blood coagulation factor VII variant database

Hereditary blood coagulation factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder resulting from variants in the gene encoding FVII (F7 ). Integration of genetic variation with functional consequences on protein function is essential for the interpretation of the pathogenicity of novel variants. Here, we describe the integration of previous locus‐specific databases for F7 into a single curated database with enhanced features. The database provides access to in silico analyses that may be useful in the prediction of variant pathogenicity as well as cross‐species sequence alignments, structural information, and functional and clinical severity described for each variant, where appropriate. The variant data is shared with the F7 Leiden Open Variation Database. The updated database now includes 221 unique variants, representing gene variants identified in 728 individuals. Single nucleotide variants are the most common type (88%) with missense representing 74% of these variants. A number of variants are found with relatively high minor allele frequencies that are not pathogenic but contribute significantly to the likely pathogenicity of coinherited variants due to their effect on FVII plasma levels. This comprehensive collection of curated information significantly aids the assessment of pathogenicity

Role of the endothelium in the vascular effects of the thrombin receptor (protease-activated receptor type 1) in humans

ObjectivesThe purpose of this study was to determine the role of the endothelium in the vascular actions of protease-activated receptor type 1 (PAR-1) activation in vivo in man.BackgroundThrombin is central to the pathophysiology of atherothrombosis. Its cellular actions are mediated via PAR-1. Protease-activated receptor type 1 activation causes arterial vasodilation, venoconstriction, platelet activation, and tissue-type plasminogen activator release in man.MethodsDorsal hand vein diameter was measured in 6 healthy volunteers before and after endothelial denudation. Forearm arterial blood flow, plasma fibrinolytic factors, and platelet activation were measured in 24 healthy volunteers during venous occlusion plethysmography. The effects of inhibition of prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor on PAR-1 responses were assessed during coadministration of aspirin, the “NO clamp” (L-NG-monomethyl arginine and sodium nitroprusside), and tetraethylammonium ion, respectively.ResultsEndothelial denudation did not affect PAR-1–evoked venoconstriction (SFLLRN; 0.05 to 15 nmol/min). Although aspirin had no effect, SFLLRN-induced vasodilation (5 to 50 nmol/min) was attenuated by the NO clamp (p < 0.0001) and tetraethylammonium ion (p < 0.05) and abolished by their combination (p < 0.01). The NO clamp augmented SFLLRN-induced tissue-type plasminogen activator and plasminogen activator inhibitor type 1 antigen (p < 0.0001) release, but tetraethylammonium ion and aspirin had no effect. SFLLRN-induced platelet activation was unaffected by NO or prostacyclin inhibition.ConclusionsActing via PAR-1, thrombin causes contrasting effects in the human vasculature and has a major interaction with the endothelium. This highlights the critical importance of endothelial function during acute arterial injury and intravascular thrombosis, as occurs in cardiovascular events including myocardial infarction and stroke

European retrospective study of real-life haemophilia treatment

IntroductionHaemophilia treatment varies significantly between individuals, countries and regions and details of bleed rates, factor consumption and injection frequency are often not available.AimTo provide an overview of the FVIII/FIX treatment practice and outcome for patients with haemophilia A (HA) or haemophilia B (HB) across Europe.MethodsNon‐interventional, 12‐month retrospective study where anonymized data were retrieved from haemophilia centres/registers in Belgium, France, Germany, Italy, Spain, Sweden and the United Kingdom. Male patients (all ages) receiving coagulation factor treatment 24 months prior to the study, with basal FVIII/FIX levels ≤5 IU dL−1, without inhibitors, were included. Data were summarized descriptively.ResultsIn total, 1346 patients with HA and 312 with HB were included in the analysis; 75% and 57% had severe disease (FVIII/FIX < 1 IU dL−1) respectively. Prophylaxis was most common for severe haemophilia, especially for children, whereas on‐demand treatment was more common for moderate haemophilia in most countries. The mean (SD) prescribed prophylactic treatment ranged from 67.9 (30.4) to 108.4 (78.1) (HA) and 32.3 (10.2) to 97.7 (32.1) (HB) IU kg−1 per week, across countries. Most patients on prophylaxis were treated ≥3 times/week (HA) or two times/week (HB). The median annual bleeding rate (ABR) for patients on prophylaxis ranged from 1.0 to 4.0 for severe HA, and from 1.0 to 6.0 for severe HB, while those with moderate haemophilia generally had slightly higher ABRs. Median ABRs for on‐demand‐treated severe HA ranged from 4.5 to 18.0, and for HB, 1.5 to 14.0.ConclusionTreatment practice varied greatly between centres and countries and patients treated on‐demand and prophylactically both experienced bleeds, emphasizing the need for further optimization of care

Protein folding on the ribosome studied using NMR spectroscopy

NMR spectroscopy is a powerful tool for the investigation of protein folding and misfolding, providing a characterization of molecular structure, dynamics and exchange processes, across a very wide range of timescales and with near atomic resolution. In recent years NMR methods have also been developed to study protein folding as it might occur within the cell, in a de novo manner, by observing the folding of nascent polypeptides in the process of emerging from the ribosome during synthesis. Despite the 2.3 MDa molecular weight of the bacterial 70S ribosome, many nascent polypeptides, and some ribosomal proteins, have sufficient local flexibility that sharp resonances may be observed in solution-state NMR spectra. In providing information on dynamic regions of the structure, NMR spectroscopy is therefore highly complementary to alternative methods such as X-ray crystallography and cryo-electron microscopy, which have successfully characterized the rigid core of the ribosome particle. However, the low working concentrations and limited sample stability associated with ribosome-nascent chain complexes means that such studies still present significant technical challenges to the NMR spectroscopist. This review will discuss the progress that has been made in this area, surveying all NMR studies that have been published to date, and with a particular focus on strategies for improving experimental sensitivity