Acidic microenvironment plays a key role in human melanoma progression through a sustained exosome mediated transfer of clinically relevant metastatic molecules

Background: Microenvironment cues involved in melanoma progression are largely unknown. Melanoma is highly influenced in its aggressive phenotype by the changes it determinates in its microenvironment, such as pH decrease, in turn influencing cancer cell invasiveness, progression and tissue remodelling through an abundant secretion of exosomes, dictating cancer strategy to the whole host. A role of exosomes in driving melanoma progression under microenvironmental acidity was never described. Methods: We studied four differently staged human melanoma lines, reflecting melanoma progression, under microenvironmental acidic pHs pressure ranging between pH 6.0-6.7. To estimate exosome secretion as a function of tumor stage and environmental pH, we applied a technique to generate native fluorescent exosomes characterized by vesicles integrity, size, density, markers expression, and quantifiable by direct FACS analysis. Functional roles of exosomes were tested in migration and invasion tests. Then we performed a comparative proteomic analysis of acid versus control exosomes to elucidate a specific signature involved in melanoma progression. Results: We found that metastatic melanoma secretes a higher exosome amount than primary melanoma, and that acidic pH increases exosome secretion when melanoma is in an intermediate stage, i.e. metastatic non-invasive. We were thus able to show that acidic pH influences the intercellular cross-talk mediated by exosomes. In fact when exposed to exosomes produced in an acidic medium, pH naïve melanoma cells acquire migratory and invasive capacities likely due to transfer of metastatic exosomal proteins, favoring cell motility and angiogenesis. A Prognoscan-based meta-analysis study of proteins enriched in acidic exosomes, identified 11 genes (HRAS, GANAB, CFL2, HSP90B1, HSP90AB1, GSN, HSPA1L, NRAS, HSPA5, TIMP3, HYOU1), significantly correlating with poor prognosis, whose high expression was in part confirmed in bioptic samples of lymph node metastases. Conclusions: A crucial step of melanoma progression does occur at melanoma intermediate -stage, when extracellular acidic pH induces an abundant release and intra-tumoral uptake of exosomes. Such exosomes are endowed with pro-invasive molecules of clinical relevance, which may provide a signature of melanoma advancement

Enhancing the sustainability performance of Agri-Food Supply Chains by implementing Industry 4.0

[EN] In order to enhance the sustainability in the supply chain, its members should define and pursue common objectives in the three dimensions of the sustainability (economic, environmental and social). The Agri-Food Supply Chain (AFSC) is a network of different members such as farmers (producers), processors and distributors (wholesales, retailers.), etc.. In order to achieve the performance objectives of the AFSC, Industry 4.0 technologies can be implemented. The aim of this paper is to present a classification of these technologies according to two criteria: objective to be achieved (environmental or social) specified in the main issues to be covered in each objective and member of the AFSC supply chain where it is implemented. In this work, we focus on technologies that deal with environmental and social sustainability because economic sustainability will depend on the specific characteristics of the business (a supply chain using a specific Industry 4.0 technology may be profitable while others do not).This work has been funded by the Project GV/2017/065 "Development of a decision support tool for the management and improvement of sustainability in supply chains" funded by the Regional Government of Valencia. Authors also acknowledge the Project 691249, RUC-APS: Enhancing and implementing Knowledge based ICT solutions within high Risk and Uncertain Conditions for Agriculture Production Systems.Pérez Perales, D.; Verdecho Sáez, MJ.; Alarcón Valero, F. (2019). Enhancing the sustainability performance of Agri-Food Supply Chains by implementing Industry 4.0. 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How Do Humans Control Physiological Strain during Strenuous Endurance Exercise?

Background: Methodology/principal Findings: Conclusions/significance: Distance running performance is a viable model of human locomotion.To evaluate the physiologic strain during competitions ranging from 5-100 km, we evaluated heart rate (HR) records of competitive runners (n = 211). We found evidence that: 1) physiologic strain (% of maximum HR (%HRmax)) increased in proportional manner relative to distance completed, and was regulated by variations in running pace; 2) the %HRmax achieved decreased with relative distance; 3) slower runners had similar %HRmax response within a racing distance compared to faster runners, and despite differences in pace, the profile of %HRmax during a race was very similar in runners of differing ability; and 4) in cases where there was a discontinuity in the running performance, there was evidence that physiologic effort was maintained for some time even after the pace had decreased.The overall results suggest that athletes are actively regulating their relative physiologic strain during competition, although there is evidence of poor regulation in the case of competitive failures.2.308 SJR (2008) Q1, 60/1774 Medicine (miscellaneous), 19/144 Biochemistry, genetics and molecular biology (miscellaneous), 15/175 Agricultural and biological sciences (miscellaneous)UE

Scanning Electrochemical Microscopy. Theory of the Feedback Mode

The steady-state current that flows between the scanning tlp (a disk ultramicroelectrode imbedded in an Insulating sheath) and a planar sample substrate in a scannlng electrochemical microscope (SECM) operating in the feedback mode is calculated by the finite element method with an exponentlaily expandlng grld, for both conductlve and Insulating samples. For conductlve substrates the tip current, representing, for example, the oxidatkn reactlon of R to 0, is enhanced by flow of R generated at the substrate to the tlp and is a functlon of tiphubstrate distance, d , but not the radius of the lnsuiatlng sheath. For insulating substrates, the tlp current Is decreased by blockage of the diffusion of R to the tip by the substrate and depends upon d and the Insulating sheath radius. The theoretical results are compared to experimental studies

Why Are There So Few Rickettsia conorii conorii-Infected Rhipicephalus sanguineus Ticks in the Wild?

The bacterium Rickettsia conorii conorii is the etiological agent of Mediterranean spotted fever (MSF), which is a life-threatening infectious disease that is transmitted by Rhipicephalus sanguineus, the brown dog tick. Rh. sanguineus-R. conorii conorii relationships in the wild are still poorly understood one century after the discovery of the disease. In this study, we collected naturally infected ticks from the houses of people afflicted by MSF in Algeria. Colonies of both infected and non-infected ticks were maintained in our laboratory, and we studied the effect of temperature variations on the infected and non-infected ticks. We did not observe any major differences between the biological life cycle of the infected and non-infected ticks held at 25°C. However, a comparatively higher mortality relative to the control group was noticed when R. conorii conorii-infected engorged nymphs and adults were exposed to a low temperature (4°C) or high temperature (37°C) for one month and transferred to 25°C. R. conorii conorii-infected Rh. sanguineus may maintain and serve as reservoirs for the Rickettsia if they are not exposed to cold temperatures. New populations of ticks might become infected with Rickettsiae when feeding on a bacteremic animal reservoir

Acidic Extracellular pH Promotes Activation of Integrin αvβ3

Acidic extracellular pH is characteristic of the cell microenvironment in several important physiological and pathological contexts. Although it is well established that acidic extracellular pH can have profound effects on processes such as cell adhesion and migration, the underlying molecular mechanisms are largely unknown. Integrin receptors physically connect cells to the extracellular matrix, and are thus likely to modulate cell responses to extracellular conditions. Here, we examine the role of acidic extracellular pH in regulating activation of integrin [alpha]v[beta]3. Through computational molecular dynamics simulations, we find that acidic extracellular pH promotes opening of the [alpha]v[beta]3 headpiece, indicating that acidic pH can thereby facilitate integrin activation. This prediction is consistent with our flow cytometry and atomic force microscope-mediated force spectroscopy assays of integrin [alpha]v[beta]3 on live cells, which both demonstrate that acidic pH promotes activation at the intact cell surface. Finally, quantification of cell morphology and migration measurements shows that acidic extracellular pH affects cell behavior in a manner that is consistent with increased integrin activation. Taken together, these computational and experimental results suggest a new and complementary mechanism of integrin activation regulation, with associated implications for cell adhesion and migration in regions of altered pH that are relevant to wound healing and cancer.National Institute of Biomedical Imaging and Bioengineering (U.S.) (Award Number T32EB006348)Massachusetts Institute of Technology (Collamore-Rogers Fellowship)National Institutes of Health (U.S.) (NIH Cell Migration Consortium Grant U54-GM069668)National Science Foundation (U.S.) (CAREER Award)Singapore-MIT Alliance for Research and Technology (BioSystem and Micromechanics (BioSyM) Interdisciplinary Research Group

Cytostatic potential of novel agents that inhibit the regulation of intracellular pH

Cells within the acidic extracellular environment of solid tumours maintain their intracellular pH (pHi) through the activity of membrane-based ion exchange mechanisms including the Na+/H+ antiport and the Na+-dependent Cl−/HCO3− exchanger. Inhibition of these regulatory mechanisms has been proposed as an approach to tumour therapy. Previously available inhibitors of these exchangers were toxic (e.g. 4,4-diisothiocyanstilbene-2,2-disulphonic acid), and/or non-specific (e.g. 5-N-ethyl-N-isopropyl amiloride). Using two human (MCF7, MDA-MB231) and one murine (EMT6) breast cancer cell lines, we evaluated the influence of two new agents, cariporide (an inhibitor of the Na+/H+ antiport) and S3705 (an inhibitor of the Na+-dependent Cl−/HCO3− exchanger) on the regulation of intracellular pH (pHi). The cytotoxicity of the two agents was assessed by using clonogenic assays. Our results suggest that cariporide has similar efficacy and potency to 5-N-ethyl-N-isopropyl amiloride for inhibition of Na+/H+ exchange while S3705 is more potent and efficient than 4,4-diisothiocyanstilbene-2,2-disulphonic acid in inhibiting Na+-dependent Cl−/HCO3− exchange. The agents inhibited the growth of tumour cells when they were incubated at low pHe (7.0–6.8), but were non-toxic to cells grown at doses that inhibited the regulation of pHi. Our results indicate that cariporide and S3705 are selective cytostatic agents under in vitro conditions that reflect the slightly acidic microenvironment found in solid tumours

HIV-1 co-receptor usage:influence on mother-to-child transmission and pediatric infection

Viral CCR5 usage is not a predictive marker of mother to child transmission (MTCT) of HIV-1. CXCR4-using viral variants are little represented in pregnant women, have an increased although not significant risk of transmission and can be eventually also detected in the neonates. Genetic polymorphisms are more frequently of relevance in the child than in the mother. However, specific tissues as the placenta or the intestine, which are involved in the prevalent routes of infection in MTCT, may play an important role of selective barriers