Intranasal immunisation with Outer Membrane Vesicles (OMV) protects against airway colonisation and systemic infection with Acinetobacter baumannii.

OBJECTIVES: The multi-drug resistant bacteria Acinetobacter baumannii is a major cause of hospital associated infection; a vaccine could significantly reduce this burden. The aim was to develop a clinically relevant model of A. baumannii respiratory tract infection and to test the impact of different immunisation routes on protective immunity provided by an outer membrane vesicle (OMV) vaccine. METHODS: BALB/c mice were intranasally challenged with isolates of oxa23-positive global clone GC2 A. baumannii from the lungs of patients with ventilator associated pneumonia. Mice were immunised with OMVs by the intramuscular, subcutaneous or intranasal routes; protection was determined by measuring local and systemic bacterial load. RESULTS: Infection with A. baumannii clinical isolates led to a more disseminated infection than the prototype A. baumannii strain ATCC17978; with bacteria detectable in upper and lower airways and the spleen. Intramuscular immunisation induced an antibody response but did not protect against bacterial infection. However, intranasal immunisation significantly reduced airway colonisation and prevented systemic bacterial dissemination. CONCLUSION: Use of clinically relevant isolates of A. baumannii provides stringent model for vaccine development. Intranasal immunisation with OMVs was an effective route for providing protection, demonstrating that local immunity is important in preventing A. baumannii infection

Vaccines for COVID-19

Since the emergence of COVID-19, caused by the SARS-CoV-2 virus, at the end of 2019 there has been an explosion of vaccine development. By the 1st September 2020, a staggering number of vaccines (over 200) had started pre-clinical development of which 39 had entered clinical trials, including some approaches that have not previously been licensed for human vaccines. Vaccines have been widely considered as part of the exit strategy to enable the return to previous patterns of working, schooling and socialising. Importantly, to effectively control the COVID-19 pandemic, production needs to be scaled up from a small number of pre-clinical doses to enough filled vials to immunise the world's population, which requires close engagement with manufacturers and regulators. It will require a global effort to control the virus, necessitating equitable access for all countries to effective vaccines. This review explores the immune responses required to protect against SARS-CoV-2 and the potential for vaccine-induced immunopathology. It describes the profile of the different platforms and the advantages and disadvantages of each approach. The review also addresses the critical steps between promising pre-clinical leads and manufacturing at scale. The issues faced during this pandemic and the platforms being developed to address it will be invaluable for future outbreak control. Nine months after the outbreak began, we are at a point where pre-clinical and early clinical data is being generated for the vaccines, an overview of this important area will help our understanding of the next phases

An algorithm to compute the polar decomposition of a 3 × 3 matrix

We propose an algorithm for computing the polar decomposition of a 3 × 3 real matrix that is based on the connection between orthogonal matrices and quaternions. An important application is to 3D transformations in the level 3 Cascading Style Sheets specification used in web browsers. Our algorithm is numerically reliable and requires fewer arithmetic operations than the alternative of computing the polar decomposition via the singular value decomposition

Acceleration of generalized hypergeometric functions through precise remainder asymptotics

We express the asymptotics of the remainders of the partial sums {s_n} of the generalized hypergeometric function q+1_F_q through an inverse power series z^n n^l \sum_k c_k/n^k, where the exponent l and the asymptotic coefficients {c_k} may be recursively computed to any desired order from the hypergeometric parameters and argument. From this we derive a new series acceleration technique that can be applied to any such function, even with complex parameters and at the branch point z=1. For moderate parameters (up to approximately ten) a C implementation at fixed precision is very effective at computing these functions; for larger parameters an implementation in higher than machine precision would be needed. Even for larger parameters, however, our C implementation is able to correctly determine whether or not it has converged; and when it converges, its estimate of its error is accurate.Comment: 36 pages, 6 figures, LaTeX2e. Fixed sign error in Eq. (2.28), added several references, added comparison to other methods, and added discussion of recursion stabilit

Mathematical modelling of polyamine metabolism in bloodstream-form trypanosoma brucei: An application to drug target identification

© 2013 Gu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedThis article has been made available through the Brunel Open Access Publishing Fund.We present the first computational kinetic model of polyamine metabolism in bloodstream-form Trypanosoma brucei, the causative agent of human African trypanosomiasis. We systematically extracted the polyamine pathway from the complete metabolic network while still maintaining the predictive capability of the pathway. The kinetic model is constructed on the basis of information gleaned from the experimental biology literature and defined as a set of ordinary differential equations. We applied Michaelis-Menten kinetics featuring regulatory factors to describe enzymatic activities that are well defined. Uncharacterised enzyme kinetics were approximated and justified with available physiological properties of the system. Optimisation-based dynamic simulations were performed to train the model with experimental data and inconsistent predictions prompted an iterative procedure of model refinement. Good agreement between simulation results and measured data reported in various experimental conditions shows that the model has good applicability in spite of there being gaps in the required data. With this kinetic model, the relative importance of the individual pathway enzymes was assessed. We observed that, at low-to-moderate levels of inhibition, enzymes catalysing reactions of de novo AdoMet (MAT) and ornithine production (OrnPt) have more efficient inhibitory effect on total trypanothione content in comparison to other enzymes in the pathway. In our model, prozyme and TSHSyn (the production catalyst of total trypanothione) were also found to exhibit potent control on total trypanothione content but only when they were strongly inhibited. Different chemotherapeutic strategies against T. brucei were investigated using this model and interruption of polyamine synthesis via joint inhibition of MAT or OrnPt together with other polyamine enzymes was identified as an optimal therapeutic strategy.The work was carried out under a PhD programme partly funded by Prof. Ray Welland, School of Computing Science, University of Glasgo

Neandertal-Modern Human Contact in Western Eurasia: Issues of Dating, Taxonomy, and Cultural Associations

Supporting Assimilation views of Neandertal/modern human interaction, chronostratigraphic reasoning indicates that the “transitional” industries of Europe predate modern human immigration, in agreement with their association with Neandertals in the Châtelperronian at the Grotte du Renne and St.-Césaire. Supporting the Neandertals' species separateness and less developed cognition, those industries are alternatively claimed to relate to pioneer groups of modern humans; the latter would have been the true makers of the precocious instances of symbolic material culture that, under Assimilation, are assigned to the Neandertals. However, the taxonomy of the Kent's Cavern and Grotta del Cavallo dental remains is uncertain, and their poor stratigraphic context precludes dating by association. The opposite happens at the Grotte du Renne, whose stratigraphic integrity is corroborated by both taphonomy and dating. Not questioning that the Early Ahmarian is a cultural proxy for modern humans and a source for the Protoaurignacian of Europe, its claimed emergence ~46–49 ka ago at Kebara refl ects the dating of Middle Paleolithic charcoal—to be expected, because the Early Ahmarian units at the back of the cave are made up of reworked Middle Paleolithic sediments derived from the entrance. The dating of inherited material also explains the old results for the Aurignacian of Willendorf II and Geissenklösterle. At the latter, the dates on anthropically modified samples of the hunted taxa (reindeer and horse) place its Aurignacian occupations in the same time range as elsewhere in Europe, after ~40 ka ago. The hypothesis that Neandertal/modern human contact in Europe resulted in a process of assimilation in connection with the spread of the Protoaurignacian ~41.5 ka ago remains unfalsified.info:eu-repo/semantics/publishedVersio

Tumor Necrosis Factor-α +489G/A gene polymorphism is associated with chronic obstructive pulmonary disease

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by a chronic inflammatory process, in which the pro-inflammatory cytokine Tumor Necrosis Factor (TNF)-α is considered to play a role. In the present study the putative involvement of TNF-α gene polymorphisms in pathogenesis of COPD was studied by analysis of four TNF-α gene polymorphisms in a Caucasian COPD population. METHODS: TNF-α gene polymorphisms at positions -376G/A, -308G/A, -238G/A, and +489G/A were examined in 169 Dutch COPD patients, who had a mean forced expiratory volume in one second (FEV1) of 37 ± 13%, and compared with a Dutch population control group of 358 subjects. RESULTS: The data showed that the TNF-α +489G/A genotype frequency tended to be different in COPD patients as compared to population controls, which was due to an enhanced frequency of the GA genotype. In line herewith, carriership of the minor allele was associated with enhanced risk of development of COPD (odds ratio = 1.9, p = 0.009). The other TNF-α gene polymorphisms studied revealed no discrimination between patients and controls. No differences in the examined four TNF-α polymorphisms were found between subtypes of COPD, which were stratified for the presence of radiological emphysema. However, comparison of the COPD subtypes with controls showed a significant difference in the TNF-α +489G/A genotype in patients without radiological emphysema (χ(2)-test: p < 0.025 [Bonferroni adjusted]), while no differences between COPD patients with radiological emphysema and controls were observed. CONCLUSION: Based on the reported data, it is concluded that COPD, and especially a subgroup of COPD patients without radiological emphysema, is associated with TNF-α +489G/A gene polymorphism

Initial Upper Palaeolithic Homo sapiens from Bacho Kiro Cave, Bulgaria

The Middle to Upper Palaeolithic transition in Europe witnessed the replacement and partial absorption of local Neanderthal populations by Homo sapiens populations of African origin. However, this process probably varied across regions and its details remain largely unknown. In particular, the duration of chronological overlap between the two groups is much debated, as are the implications of this overlap for the nature of the biological and cultural interactions between Neanderthals and H. sapiens. Here we report the discovery and direct dating of human remains found in association with Initial Upper Palaeolithic artefacts, from excavations at Bacho Kiro Cave (Bulgaria). Morphological analysis of a tooth and mitochondrial DNA from several hominin bone fragments, identified through proteomic screening, assign these finds to H. sapiens and link the expansion of Initial Upper Palaeolithic technologies with the spread of H. sapiens into the mid-latitudes of Eurasia before 45 thousand years ago. The excavations yielded a wealth of bone artefacts, including pendants manufactured from cave bear teeth that are reminiscent of those later produced by the last Neanderthals of western Europe. These finds are consistent with models based on the arrival of multiple waves of H. sapiens into Europe coming into contact with declining Neanderthal populations