Differential Effects of Buffer pH On Ca\u3csup\u3e2+\u3c/sup\u3e-Induced ROS Emission with Inhibited Mitochondrial Complexes I and III

Excessive mitochondrial reactive oxygen species (ROS) emission is a critical component in the etiology of ischemic injury. Complex I and complex III of the electron transport chain are considered the primary sources of ROS emission during cardiac ischemia and reperfusion (IR) injury. Several factors modulate ischemic ROS emission, such as an increase in extra-matrix Ca2+, a decrease in extra-matrix pH, and a change in substrate utilization. Here we examined the combined effects of these factors on ROS emission from respiratory complexes I and III under conditions of simulated IR injury. Guinea pig heart mitochondria were suspended in experimental buffer at a given pH and incubated with or without CaCl2. Mitochondria were then treated with either pyruvate, a complex I substrate, followed by rotenone, a complex I inhibitor, or succinate, a complex II substrate, followed by antimycin A, a complex III inhibitor. H2O2 release rate and matrix volume were compared with and without adding CaCl2 and at pH 7.15, 6.9, or 6.5 with pyruvate + rotenone or succinate + antimycin A to simulate conditions that may occur during in vivo cardiac IR injury. We found a large increase in H2O2 release with high [CaCl2] and pyruvate + rotenone at pH 6.9, but not at pHs 7.15 or 6.5. Large increases in H2O2 release rate also occurred at each pH with high [CaCl2] and succinate + antimycin A, with the highest levels observed at pH 7.15. The increases in H2O2 release were associated with significant mitochondrial swelling, and both H2O2 release and swelling were abolished by cyclosporine A, a desensitizer of the mitochondrial permeability transition pore (mPTP). These results indicate that ROS production by complex I and by complex III is differently affected by buffer pH and Ca2+ loading with mPTP opening. The study suggests that changes in the levels of cytosolic Ca2+ and pH during IR alter the relative amounts of ROS produced at mitochondrial respiratory complex I and complex III

Parasite diversity and ecology in a model species, the guppy (Poecilia reticulata) in Trinidad

The guppy (Poecilia reticulata) is a model species in ecology and evolution. Many studies have examined effects of predators on guppy behaviour, reproduction, survival strategies, feeding and other life-history traits, but few have studied variation in their parasite diversity. We surveyed parasites of 18 Trinidadian populations of guppy, to provide insight on the geographical mosaic of parasite variability, which may act as a source of natural selection acting on guppies. We found 21 parasite species, including five new records for Trinidad. Spatial variation in parasite diversity was significantly higher than that of piscine predators, and significant variation in parasite richness among individuals and populations was correlated with: (i) host size, (ii) snail species richness, and (iii) the distance between populations. Differences in parasite species richness are likely to play an important, yet underestimated role in the biology of this model species of vertebrate ecology and evolution

Hydrophilic titanium surface‐induced macrophage modulation promotes pro‐osteogenic signalling

Objectives: As biomaterial‐induced modulation of mediators of the immune response may be a potential therapeutic approach to enhance wound healing events, the aim of this study was to delineate the effects of titanium surface modification on macrophage phenotype and function. Material and methods: Rodent bone marrow‐derived macrophages were polarized into M1 and M2 phenotypes and cultured on micro‐rough (SLA) and hydrophilic modified SLA (modSLA) titanium discs. Macrophage phenotype and cytokine secretion were subsequently assessed by immunostaining and ELISA, respectively. Osteoblast gene expression in response to culture in the M1 and M2 macrophage conditioned media was also evaluated over 7 days by RT‐PCR. Results: M1 macrophage culture on the modSLA surface promoted an M2‐like phenotype as demonstrated by marked CD163 protein expression, Arg1 gene expression and the secretion of cytokines that significantly upregulated in osteoblasts the expression of genes associated with the TGF‐ß/BMP signalling pathway and osteogenesis. In comparison, M2 macrophage culture on SLA surface promoted an inflammatory phenotype and cytokine profile that was not conducive for osteogenic gene expression. Conclusions: Macrophages are able to alter or switch their phenotype according to the signals received from the biomaterial surface. A hydrophilic micro‐rough titanium surface topography elicits a macrophage phenotype associated with reduced inflammation and enhanced pro‐osteogenic signalling

Long-term cleaning patterns of the sharknose goby (Elacatinus evelynae)

Cleaning interactions, which involve a cleaner removing ectoparasites and other material from the body of a heterospecific (client), are iconic symbiotic interactions observed on coral reefs worldwide. These small cleaners play a disproportionately large role in the structuring and function of coral reefs, influencing species interaction networks, client health and biodiversity. Cleaning patterns, however, are likely to be context-dependent and highly heterogeneous, and although we have some understanding about their spatial variation, longer-term temporal changes in cleaning interactions have remained understudied. Given that coral reefs are globally threatened and are currently experiencing large shifts in their biodiversity, it is vital that we determine which clients are consistently most important for maintaining cleaning. Using a long-term, 8-yr data set (2010–17) on the cleaning behaviour of the predominant Caribbean cleaner, the sharknose goby (Elacatinus evelynae), we investigated whether cleaner fish from the same reef show consistent patterns in their interactions with client species over time. Here we conclusively show that cleaning behaviour is highly plastic, as no single species or family was cleaned consistently more than others, in terms of cleaning frequency and duration, across all years. Only 40% of the species were cleaned more than others, and we also observed ca. one-third of species experience inconsistent cleaning patterns across years. Our study thus quantifies how dynamic cleaner–client relationships are on the same reef across years and highlights the importance of long-term data

Immune evasion in cancer: mechanistic basis and therapeutic strategies

Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through “equilibrium” and “senescence” before re- emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, deregulated metabolism etc. In this review, we will discuss the advances made towards understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection

Effect of Food on the Steady-State Pharmacokinetics of Tenofovir and Emtricitabine plus Efavirenz in Ugandan Adults

We investigated the effect of food on the steady-state pharmacokinetics of a proprietary fixed-dose combination (FDC) tablet containing tenofovir disoproxil fumarate (TDF)/emtricitabine/efavirenz. Fifteen Ugandan HIV-1 patients at steady-state dosing with TDF/emtricitabine/efavirenz were admitted for 24-hour intensive pharmacokinetic sampling after dosing in the fasting state. Blood sampling was repeated seven days later with TDF/emtricitabine/efavirenz administered with food (19 g fat). Drug concentrations in plasma were determined by liquid chromatography and tandem mass spectrometry. Geometric mean ratios (GMRs) and confidence intervals (CIs) of parameters were calculated (reference, fasting). For efavirenz, GMRs (90% CIs) for Cmax, AUC0−24, and C24 were 1.47 (1.24–1.75), 1.13 (1.03–1.23), and 1.01 (0.91–1.11), respectively. Corresponding GMRs were 1.04 (0.84–1.27), 1.19 (1.10–1.29), and 0.99 (0.82–1.19) for tenofovir, 0.83 (0.76–0.92), 0.87 (0.78–0.97), and 0.91 (0.73–1.14) for emtricitabine. Stable patients may take the FDC without meal restrictions. The FDC should be taken without food by patients experiencing central nervous system toxicities

Getting into hot water:sick guppies frequent warmer thermal conditions

Ectotherms depend on the environmental temperature for thermoregulation and exploit thermal regimes that optimise physiological functioning. They may also frequent warmer conditions to up-regulate their immune response against parasite infection and/or impede parasite development. This adaptive response, known as ‘behavioural fever’, has been documented in various taxa including insects, reptiles and fish, but only in response to endoparasite infections. Here, a choice chamber experiment was used to investigate the thermal preferences of a tropical freshwater fish, the Trinidadian guppy (Poecilia reticulata), when infected with a common helminth ectoparasite Gyrodactylus turnbulli, in female-only and mixed-sex shoals. The temperature tolerance of G. turnbulli was also investigated by monitoring parasite population trajectories on guppies maintained at a continuous 18, 24 or 32 °C. Regardless of shoal composition, infected fish frequented the 32 °C choice chamber more often than when uninfected, significantly increasing their mean temperature preference. Parasites maintained continuously at 32 °C decreased to extinction within 3 days, whereas mean parasite abundance increased on hosts incubated at 18 and 24 °C. We show for the first time that gyrodactylid-infected fish have a preference for warmer waters and speculate that sick fish exploit the upper thermal tolerances of their parasites to self medicate

Parental awareness regarding pediatric antibiotic use in Madinah, Saudi Arabia

Purpose: To determine the level of awareness of antibiotic use in children in Madinah, Saudi Arabia, and to identify factors associated with parental decisions regarding it. Methods: Using a multiple-choice-question-based questionnaire survey, 1256 forms were distributed to visitors of major shopping malls in Madinah City to obtain socio-demographic and antibiotics knowledgebased data from October 2017 to January 2018. Differences in scores between and within groups on knowledge of parents about antibiotics were determined. Results: Most participants (67 %) had good basic knowledge of antibiotics: 69 and 40 % of respondents were aware of their side effects and antibacterial resistance, respectively. Participants in high age groups (> 46 years old) have a significantly higher mean knowledge score (55.4 ± 20.1, p < 0.05) than those in younger groups. Educational status increased the mean knowledge score by approximately 60 %, with the most educated group having a mean score of 61.2 ± 16.4 (p < 0.05). Conclusion: These results reveal the importance of awareness campaigns on antibiotic use and the role of healthcare professionals in the education of patients and parents on correct use of antibiotics, as well as the significance of antibacterial resistance. Keywords: Antibiotics misuse, Pediatrics, Patient education, Antibacterial resistanc

Immunogenetic novelty confers a selective advantage in host–pathogen coevolution

The major histocompatibility complex (MHC) is crucial to the adaptive immune response of vertebrates and is among the most polymorphic gene families known. Its high diversity is usually attributed to selection imposed by fast-evolving pathogens. Pathogens are thought to evolve to escape recognition by common immune alleles, and, hence, novel MHC alleles, introduced through mutation, recombination, or gene flow, are predicted to give hosts superior resistance. Although this theoretical prediction underpins host–pathogen “Red Queen” coevolution, it has not been demonstrated in the context of natural MHC diversity. Here, we experimentally tested whether novel MHC variants (both alleles and functional “supertypes”) increased resistance of guppies (Poecilia reticulata) to a common ectoparasite (Gyrodactylus turnbulli). We used exposure-controlled infection trials with wild-sourced parasites, and Gyrodactylus-naïve host fish that were F2 descendants of crossed wild populations. Hosts carrying MHC variants (alleles or supertypes) that were new to a given parasite population experienced a 35–37% reduction in infection intensity, but the number of MHC variants carried by an individual, analogous to heterozygosity in single-locus systems, was not a significant predictor. Our results provide direct evidence of novel MHC variant advantage, confirming a fundamental mechanism underpinning the exceptional polymorphism of this gene family and highlighting the role of immunogenetic novelty in host–pathogen coevolution