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Extracellular vesicles (EVs) are nano-sized vesicles containing nucleic acid and protein cargo that are released from a multitude of cell types and have gained significant interest as potential diagnostic biomarkers. Human serum is a rich source of readily accessible EVs; however, the separation of EVs from serum proteins and non-EV lipid particles represents a considerable challenge. In this study, we compared the most commonly used isolation techniques, either alone or in combination, for the isolation of EVs from 200 µl of human serum and their separation from non-EV protein and lipid particles present in serum. The size and yield of particles isolated by each method was determined by nanoparticle tracking analysis, with the variation in particle size distribution being used to determine the relative impact of lipoproteins and protein aggregates on the isolated EV population. Purification of EVs from soluble protein was determined by calculating the ratio of EV particle count to protein concentration. Finally, lipoprotein particles co-isolated with EVs was determined by Western blot analysis of lipoprotein markers APOB and APOE. Overall, this study reveals that the choice of EV isolation procedure significantly impacts EV yield from human serum, together with the presence of lipoprotein and protein contaminants.

The motion of extended defects called dislocations controls the mechanical properties of crystalline materials such as strength and ductility. Under moderate applied loads, this motion proceeds via the thermal nucleation of kink pairs. The nucleation rate is known to be a highly nonlinear function of the applied load, and its calculation has long been a theoretical challenge. In this article, a stochastic path integral approach is used to derive a simple, general, and exact formula for the rate. The predictions are in excellent agreement with experimental and computational investigations, and unambiguously explain the origin of the observed extreme nonlinearity. The results can also be applied to other systems modelled by an elastic string interacting with a periodic potential, such as Josephson junctions in superconductors.

The clinical manifestations of AIDS (acquired immune deficiency syndrome) often include neuropsychiatric and neurological deficits, including early memory loss and progressive dementia. HIV (human immunodeficiency virus), the aetiological agent of AIDS, is probably carried by infected macrophages in the central nervous system. The virus enters cells by binding its envelope glycoprotein gp120 to the CD4 antigen present on brain and immune cells. From the data reported in this paper, we now suggest that the neuronal deficits associated with HIV may not be entirely a result of infectivity, but that gp120 shed from HIV could directly produce the neuropathology as a result of its interference with endogenous neurotrophic substances. It is known that an analogue of a sequence contained in vasoactive intestinal peptide (VIP) occurs in all known sequenced gp120 isolates and that VIP is important for neuronal survival in cell culture. Here we show that purified gp120 from two diverse HIV isolates and a recombinant gp120 from a third isolate were all potent in specifically producing significant neuronal cell death in dissociated hippocampal cultures derived from fetal mice, and that this could be reduced by monoclonal antibodies against the murine CD4 antigen and completely antagonized by VIP.

Hemoglobin levels are believed to be regulated as per a set point model of regulation. This model of regulation, by which specific levels of a parameter are targeted and defended by physiological systems, implies a particular population correlation between the parameter and its controlling hormone. Empirical population correlations of other parameters and their controlling hormones, have denied the presence of such set point‐based regulation. To assess if hemoglobin is regulated according to a set point model we performed a systematic search of PubMed/MEDLINE and Web of Science identifying relevant reports published up to November 2018. Population hemoglobin/erythropoietin level correlations were retrieved, and these empirically derived correlations were compared with the positive correlation implied by a set point model of regulation. Authors of papers containing potentially suitable data were contacted with requests for further analyses, and a meta‐analysis was performed. Twelve correlations between hemoglobin and erythropoietin levels from eleven papers were analyzed. None of these correlations were significantly positive, three, restricted to the normal range of hemoglobin, were significantly negative. All but one of the other correlations showed a negative trend. New analyses of previously published data sets resulted in similar findings. In particular a new analysis of large data sets of males (n = 2417) and females (n = 2592) with normal range hemoglobin levels, revealed significantly negative correlations. A meta‐analysis of our results indicated that the data overall are not consistent with a positive relationship between hemoglobin and erythropoietin (P < 0.0001). Population data indicate that individuals do not have set point levels of hemoglobin. Though set points have long been regarded as integral components of homeostatic physiology evidence is accumulating casting doubt on the existence of such set points for some parameters. In this work we show that examination of the population correlations between haemoglobin and erythropoietin indicates that haemoglobin is yet another parameter, the regulation of which, is unlikely to be ordered about a set point level. This finding is relevant to understanding haemoglobin physiology but also has relevance to the understanding of homeostatic regulation in general.

The time evolution of many physical, chemical, and biological systems can be modelled by stochastic transitions between the minima of the potential energy surface describing the system of interest. We show that in cases where there are two (or more) possible pathways that the system can take, the time available for the transition to occur is crucially important. The well-known results of reaction rate theory for determining the rates of the transitions apply in the long-time limit. However, at short times, the system can instead choose to pass over higher energy barriers with much higher probability, as long as the distance to travel in phase space is shorter. We construct two simple models to illustrate this general phenomenon. We also present an extension of the gMAM algorithm of Vanden-Eijnden and Heymann [J. Chem. Phys. {\\bf 128}, 061103 (2008)] to determine the most likely path at both short and long times.

Turing (or double-diffusive) instabilities describe pattern formation in reaction-diffusion systems, and were proposed in 1952 as a potential mechanism behind pattern formation in nature, such as leopard spots and zebra stripes. Because the mechanism requires the reacting species to have significantly different diffusion rates, only a few liquid phase chemical reaction systems exhibiting the phenomenon have been discovered. In solids the situation is markedly different, since species such as impurities or other defects typically have diffusivities \\(\\propto\\!\\exp\\left( -E/k_{\\rm B} T\\right)\\), where \\(E\\) is the migration barrier and \\(T\\) is the temperature. This often leads to diffusion rates differing by several orders of magnitude. Here we use a simple, minimal model to show that an important class of emergent patterns in solids, namely void superlattices in irradiated metals, could also be explained by the Turing mechanism. Analytical results are confirmed by phase field simulations. The model (Cahn-Hilliard equations for interstitial and vacancy concentrations, coupled by creation and annihilation terms) is generic, and the mechanism could also be responsible for the patterns and structure observed in many solid state systems.

Objectives The sensitivities of the pituitary to thyroxine feedback, and the thyroid to thyrotropin stimulation determine the free thyroxine /thyrotropin feedback loop and can be described mathematically by two curves. It is not well understood how the two curves combine in a healthy population with normal thyroid function to express the individual balance points that are observed. This study was directed at this issue testing the possibilities of random combination and directed linkage between the two curves. Methods We reverse-engineered two sets of population data, on the assumption of independent combinations of thyroid and pituitary sensitivities, to obtain estimates of the curve describing thyroid sensitivity. Sensitivity studies were performed. Results No analysis resulted in a physiologically feasible estimate of the curve describing thyroid sensitivity. There was evidence of linkage of the two curves in terms of their combination throughout the normal range. Thyroid response curves reflecting a low free thyroxine response to thyrotropin tended to be combined in individuals with thyrotropin curves reflecting a high thyrotropin response to free thyroxine, and vice versa. Conclusions Thyroid and pituitary sensitivities are linked, being combined in individuals in a non-random directed pattern. Direct mutual interaction may contribute to this linkage. This linkage precludes the derivation of the curves describing these sensitivities from population data of the free thyroxine and thyrotropin relationship and complicates their derivation by physiological experimentation. This linkage and probable interaction may also bestow evolutionary advantage by minimising inter-individual variation in free thyroxine levels and by augmenting homeostasis.

Dislocation 'pile-ups' occur in crystals when a number of similar dislocations, gliding in a common slip plane, are driven by an applied stress towards an obstacle that they cannot overcome. In contrast to dislocation walls, pile-ups give rise to a long-range stress field, and their properties strongly influence the plastic behaviour of the crystal as a whole. In this paper, we apply the analytic model of a pile-up (due to Eshelby, Frank and Nabarro) to a cubic crystal. Full anisotropic elasticity is used, and the model is extended to predict the plastic displacement generated by a dislocation source during the formation of a pile-up. The results are applied to Fe close to the temperature of the α-γ phase transition, where the inclusion of anisotropy leads to a strikingly different prediction from that of the isotropic approximation.

IntroductionRespiratory tract infections (RTIs) are a leading cause of mortality and morbidity worldwide and one of the greatest causes of mortality in children under 5. Most people develop an acute RTI every year and these are the most common problems dealt with in primary care. RTI symptoms are similar but can be caused by a heterogeneous range of viral and bacterial pathogens.Antibiotics were prescribed in 68% of acute respiratory tract visits and of those, 80% were unnecessary (CDC guidelines, 2001), with acute infection likely to be self-limiting. Repeated and improper use of antibiotics is the primary cause of increasing resistance, decreasing efficacy of these essential drugs. The best way to control resistance is to decrease antibiotic misuse by implementing rapid and accurate diagnosis, facilitating appropriate treatment.A multiplex approach for detection of respiratory pathogens allows comprehensive screening, which is more effective in terms of time and resources compared to traditional methods thus allowing severely infected patients to be treated quickly and appropriately. This study reports the assessment of clinical samples using a respiratory multiplex array in a biochip platform for simultaneous detection of 22 clinically relevant bacterial and viral respiratory pathogens within a single patient sample (Table 1) and comparison against routine diagnostic approaches.Abstract P24 Table 1Respiratory pathogens detected with the Respiratory Multiplex ArrayAdenovirusInfluenza ABocavirusInfluenza BCoronavirus 229ERSV ACoronavirus OC43RSV BEnterovirusC. pneumoniaeMetapneumovirusM. pneumoniaeRhinovirusL. pneumophilaParainfluenza 1H. influenzaParainfluenza 2Strep. pneumoniaeParainfluenza 3Staph. aureusMethodsResidual clinical respiratory samples (n=502) were analysed using a Respiratory Multiplex Array applied to the Evidence Investigator analyser. This technology couples highly stringent multiplex PCR to biochip array technology. Results obtained were compared against routine diagnostic methods and % agreement determined.ResultsA high level of agreement was found between TaqMan based real-time assay and the Respiratory Multiplex Array. In a considerable number of samples, additional pathogens, previously unreported were detected with the Respiratory Multiplex Array. Sample re-testing confirmed that all were positive for the additional pathogens.ConclusionsThese results highlight the relevance of multiplexing for detection of co-infections, enhancing patient care. The British Lung Foundation estimate respiratory illness costs NHS pound sterling 6.6billion, so there is also potential for significant cost reductions should a system be implemented that allows for rapid and accurate detection of all causative agents of infection to ensure correct treatment.