Extracellular ATP triggers proteolysis and cytosolic Ca²⁺ rise in Plasmodium berghei and Plasmodium yoelii malaria parasites.

BACKGROUND: Plasmodium has a complex cell biology and it is essential to dissect the cell-signalling pathways underlying its survival within the host. METHODS: Using the fluorescence resonance energy transfer (FRET) peptide substrate Abz-AIKFFARQ-EDDnp and Fluo4/AM, the effects of extracellular ATP on triggering proteolysis and Ca²⁺ signalling in Plasmodium berghei and Plasmodium yoelii malaria parasites were investigated. RESULTS: The protease activity was blocked in the presence of the purinergic receptor blockers suramin (50 μM) and PPADS (50 μM) or the extracellular and intracellular calcium chelators EGTA (5 mM) and BAPTA/AM (25, 100, 200 and 500 μM), respectively for P. yoelii and P. berghei. Addition of ATP (50, 70, 200 and 250 μM) to isolated parasites previously loaded with Fluo4/AM in a Ca²⁺-containing medium led to an increase in cytosolic calcium. This rise was blocked by pre-incubating the parasites with either purinergic antagonists PPADS (50 μM), TNP-ATP (50 μM) or the purinergic blockers KN-62 (10 μM) and Ip5I (10 μM). Incubating P. berghei infected cells with KN-62 (200 μM) resulted in a changed profile of merozoite surface protein 1 (MSP1) processing as revealed by western blot assays. Moreover incubating P. berghei for 17 h with KN-62 (10 μM) led to an increase in rings forms (82% ± 4, n = 11) and a decrease in trophozoite forms (18% ± 4, n = 11). CONCLUSIONS: The data clearly show that purinergic signalling modulates P. berghei protease(s) activity and that MSP1 is one target in this pathway

Photoinduced Photosensitizer-Antibody Conjugates Kill HIV Env-Expressing Cells, Also Inactivating HIV.

HIV-infected cells persist for decades in patients administered with antiretroviral therapy (ART). Meanwhile, an alarming surge in drug-resistant HIV viruses has been occurring. Addressing these issues, we propose the application of photoimmunotherapy (PIT) against not only HIV Env-expressing cells but also HIV. Previously, we showed that a human anti-gp41 antibody (7B2) conjugated to cationic or anionic photosensitizers (PSs) could specifically target and kill the HIV Env-expressing cells. Here, our photolysis studies revealed that the binding of photoimmunoconjugates (PICs) on the membrane of HIV Env-expressing cells is sufficient to induce necrotic cell death due to physical damage to the membrane by singlet oxygen, which is independent of the type of PSs. This finding persuaded us to study the virus photoinactivation of PICs using two HIV-1 strains, X4 HIV-1 NL4-3 and JR-CSF virus. We observed that the PICs could destroy the viral strains, probably via physical damage on the HIV envelope. In conclusion, we report the application of PIT as a possible dual-tool for HIV immunotherapy and ART by killing HIV-expressing cells and cell-free HIV, respectively

POSITIVE AND NEGATIVE CHIRPING OF LASER-PULSES SHORTER THAN 100 FSEC IN A SATURABLE ABSORBER

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Transient Tribo-Dynamics of Thermo-Elastic Compliant High-Performance Piston Skirts

Advanced piston technology for motorsport applications is driven through development of lightweight pistons with preferentially compliant short partial skirts. The preferential compliance is achieved through structural stiffening, such that a greater entrainment wedge is achieved at the skirt’s bottom edge through thermo-elastic deformation, whilst better conforming contact geometry at the top of the skirt. In practice, the combination of some of these conditions is intended to improve the load-carrying capacity and reduce friction. The approach is fundamental to the underlying ethos of race and high-performance engine technology. Contact loads of the order of 5 kN and contact kinematics in the range 0–35 m/s result in harsh transient tribological conditions. Therefore, piston design requires detailed transient analysis, which integrates piston dynamics, thermo-elastic distortion and transient elastohydrodynamics. The paper provides such a detailed analysis as well as verification of the same using non-invasive ultrasonic-assisted lubricant film thickness measurement from a fired engine under normal operating conditions, an approach not hitherto reported in literature. Good agreement is noted between measured film thickness and predictions

Hsp21potentiates antifungal drug tolerance in Candida albicans

Peer reviewedPublisher PD

Quantifying Robotic Swarm Coverage

In the field of swarm robotics, the design and implementation of spatial density control laws has received much attention, with less emphasis being placed on performance evaluation. This work fills that gap by introducing an error metric that provides a quantitative measure of coverage for use with any control scheme. The proposed error metric is continuously sensitive to changes in the swarm distribution, unlike commonly used discretization methods. We analyze the theoretical and computational properties of the error metric and propose two benchmarks to which error metric values can be compared. The first uses the realizable extrema of the error metric to compute the relative error of an observed swarm distribution. We also show that the error metric extrema can be used to help choose the swarm size and effective radius of each robot required to achieve a desired level of coverage. The second benchmark compares the observed distribution of error metric values to the probability density function of the error metric when robot positions are randomly sampled from the target distribution. We demonstrate the utility of this benchmark in assessing the performance of stochastic control algorithms. We prove that the error metric obeys a central limit theorem, develop a streamlined method for performing computations, and place the standard statistical tests used here on a firm theoretical footing. We provide rigorous theoretical development, computational methodologies, numerical examples, and MATLAB code for both benchmarks.Comment: To appear in Springer series Lecture Notes in Electrical Engineering (LNEE). This book contribution is an extension of our ICINCO 2018 conference paper arXiv:1806.02488. 27 pages, 8 figures, 2 table

Effects of asenapine on depressive symptoms in patients with bipolar I disorder experiencing acute manic or mixed episodes: a post hoc analysis of two 3-week clinical trials

<p>Abstract</p> <p>Background</p> <p>Asenapine demonstrated superiority over placebo for mania in bipolar I disorder patients experiencing acute current manic or mixed episodes in 2 randomized, placebo-and olanzapine-controlled trials. We report the results of exploratory pooled post hoc analyses from these trials evaluating asenapine's effects on depressive symptoms in patients from these trials with significant baseline depressive symptoms.</p> <p>Methods</p> <p>In the original trials (A7501004 [NCT00159744], A7501005 [NCT00159796]), 977 patients were randomized to flexible-dose sublingual asenapine (10 mg twice daily on day 1; 5 or 10 mg twice daily thereafter), placebo, or oral olanzapine 5-20 mg once daily for 3 weeks. Three populations were defined using baseline depressive symptoms: (1) Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥20 (n = 132); (2) Clinical Global Impression for Bipolar Disorder-Depression (CGI-BP-D) scale severity score ≥4 (n = 170); (3) diagnosis of mixed episodes (n = 302) by investigative site screening. For each population, asenapine and olanzapine were independently compared with placebo using least squares mean change from baseline on depressive symptom measures.</p> <p>Results</p> <p>Decreases in MADRS total score were statistically greater with asenapine versus placebo at days 7 and 21 in all populations; differences between olanzapine and placebo were not significant. Decreases in CGI-BP-D score were significantly greater with asenapine versus placebo at day 7 in all categories and day 21 in population 1; CGI-BP-D score reductions were significantly greater with olanzapine versus placebo at day 21 in population 1 and day 7 in populations 2 and 3.</p> <p>Conclusions</p> <p>These post hoc analyses show that asenapine reduced depressive symptoms in bipolar I disorder patients experiencing acute manic or mixed episodes with clinically relevant depressive symptoms at baseline; olanzapine results appeared to be less consistent. Controlled studies of asenapine in patients with acute bipolar depression are necessary to confirm the generalizability of these findings.</p

Antigenic Complementarity in the Origins of Autoimmunity: A General Theory Illustrated With a Case Study of Idiopathic Thrombocytopenia Purpura

We describe a novel, testable theory of autoimmunity, outline novel predictions made by the theory, and illustrate its application to unravelling the possible causes of idiopathic thrombocytopenia purpura (ITP). Pairs of stereochemically complementary antigens induce complementary immune responses (antibody or T-cell) that create loss of regulation and civil war within the immune system itself. Antibodies attack antibodies creating circulating immune complexes; T-cells attack T-cells creating perivascular cuffing. This immunological civil war abrogates the self-nonself distinction. If at least one of the complementary antigens mimics a self antigen, then this unregulated immune response will target host tissues as well. Data demonstrating that complementary antigens are found in some animal models of autoimmunity and may be present in various human diseases, especially ITP, are reviewed. Specific mechanisms for preventing autoimmunity or suppressing existing autoimmunity are derived from the theory, and critical tests proposed. Finally, we argue that Koch's postulates are inadequate for establishing disease causation for multiple-antigen diseases and discuss the possibility that current research has failed to elucidate the causes of human autoimmune diseases because we are using the wrong criteria

The UK's Global Health Respiratory Network: Improving respiratory health of the world's poorest through research collaborations.

Respiratory disorders are responsible for considerable morbidity, health care utilisation, societal costs and approximately one in five deaths worldwide [1-4]. Yet, despite this substantial health and societal burden – which particularly affects the world’s poorest populations and as such is a major contributor to global health inequalities – respiratory disorders have historically not received the policy priority they warrant. For example, despite causing an estimated 1000 deaths per day, less than half of the world’s countries collect data on asthma prevalence (http://www.globalasthmareport.org/). This is true for both communicable and non-communicable respiratory disorders, many of which are either amenable to treatment or preventable

Selective enzymatic lipophilization of anthocyanin glucosides from blackcurrant (Ribes nigrum L.) skin extract and characterization of esterified anthocyanins

Anthocyanins (ANC) are hydrophilic and water-soluble polyphenolic plant pigments. The current barriers to successful application of ANC in food, cosmetic and pharmaceutical industries are predominantly related to performance, stability, formulation properties, and color. Enzymatic acylation of ANC could increase their stability without compromising bioactivity and chromatic features. Lipophilization of ANC-rich blackcurrant skin extract with Candida antarctica lipase B and octanoic acid was selective to cyanidin and delphinidin glucosides, but not the corresponding rutinosides. The reaction was chemo- and regioselective for acylation at the primary alcohol of the glucose moieties, greatly facilitating separation of the different glycoside derivatives