Multiscale model for the effects of adaptive immunity suppression on the viral therapy of cancer

Oncolytic virotherapy - the use of viruses that specifically kill tumor cells - is an innovative and highly promising route for treating cancer. However, its therapeutic outcomes are mainly impaired by the host immune response to the viral infection. In the present work, we propose a multiscale mathematical model to study how the immune response interferes with the viral oncolytic activity. The model assumes that cytotoxic T cells can induce apoptosis in infected cancer cells and that free viruses can be inactivated by neutralizing antibodies or cleared at a constant rate by the innate immune response. Our simulations suggest that reprogramming the immune microenvironment in tumors could substantially enhance the oncolytic virotherapy in immune-competent hosts. Viable routes to such reprogramming are either in situ virus-mediated impairing of CD$8^+$ T cells motility or blockade of B and T lymphocytes recruitment. Our theoretical results can shed light on the design of viral vectors or new protocols with neat potential impacts on the clinical practice.Comment: 14 pages, 4 figure

A new species of Neotropical freshwater stingray of the genus Potamotrygon Garman, 1877 from the Río Madrede Díos, Peru (Chondrichthyes: Potamotrygonidae)

Potamotrygon tatianae sp. nov., is described from Río Madre de Díos, Peru, upper Rio Madeira basin. The new species is distinguished from all congeners by a unique combination of characters, including its dorsal color pattern formed by a relatively slender, highly convoluted, beige to dark brown vermicular pattern, a single row of dorsal tail spines, and a relatively longer tail posterior to caudal stings. Potamotrygon tatianae sp. nov., occurs sympatrically with other species of Potamotrygon (P. falkneri, P. orbignyi and P. motoro). From the similar species P. falkneri, P. tatianae sp. nov., is further distinguished by the absence of circular, reniform, and oval spots, by its proportionally much longer tail, by having dorsal tail spines in one irregular row, and by features of the ventral lateral-line canal, dermal denticles and neurocranium. From P. orbignyi, the new species is distinct by lacking a reticulate pattern on dorsal disc and by the presence of two angular cartilages. From P. motoro, P. tatianae sp. nov., is further separated by the lack of ocelli formed by strong black concentric rings, by the more flattened aspect of its head and disc, and by having smaller and more numerous teeth. The discovery of a new species that so closely resembles a congeneric form in color pattern, a feature highly variable within the latter, highlights the importance of examining large series of individuals and of detailed morphological analyses in revealing the potentially highly cryptic nature of the diversity within the family.Potamotrygon tatianae sp. nov., é descrita do Río Madre de Díos, Peru, alto da bacia do Río Madeira. Essa nova espécie é distinta de todas as espécies congenéricas por uma combinação única de caracteres, incluindo sua coloração dorsal formada por um padrão vermicular de cor bege a marrom escuro, relativamente delgado e altamente convoluto, uma única fileira mediana dorsal de espinhos sobre a cauda e uma cauda relativamente longa posteriormente aos ferrões caudais. Potamotrygon tatianae sp. nov., ocorre em simpatria com outras espécies de Potamotrygon (P. falkneri, P. orbignyi and P. motoro). Da espécie similar P. falkneri, P.tatianae sp. nov., é também distinguida pela ausência de manchas circulares, reniformes e ovais, por sua cauda proporcionalmente mais longa, por apresentar espinhos caudais em uma única fileira irregular e por caracteres dos canais ventrais da linha lateral, dentículos dérmicos e neurocrânio. De P. orbignyi, a nova espécie é distinguida pela ausência de um padrão reticulado no dorso do disco e pela presença de duas cartilagens angulares. De P. motoro, P. tatianae sp. nov., é separada pela ausência de ocelos formados por anéis negros concêntricos intensos, pelo aspecto mais achatado da cabeça e disco e pela presença de dentes menores e mais numerosos. A descoberta de uma espécie nova que é semelhante a uma outra espécie congenérica que possui um padrão de colorido dorsal semelhante, um caráter muito variável nesta espécie, ressalta a importância de examinar séries grandes de indivíduos e de análises morfológicas detalhadas para revelar a natureza potencialmente críptica da diversidade dentro da família

A Mechanism Linking Two Known Vulnerability Factors for Alcohol Abuse: Heightened Alcohol Stimulation and Low Striatal Dopamine D2 Receptors

Alcohol produces both stimulant and sedative effects in humans and rodents. In humans, alcohol abuse disorder is associated with a higher stimulant and lower sedative responses to alcohol. Here, we show that this association is conserved in mice and demonstrate a causal link with another liability factor: low expression of striatal dopamine D2 receptors (D2Rs). Using transgenic mouse lines, we find that the selective loss of D2Rs on striatal medium spiny neurons enhances sensitivity to ethanol stimulation and generates resilience to ethanol sedation. These mice also display higher preference and escalation of ethanol drinking, which continues despite adverse outcomes. We find that striatal D1R activation is required for ethanol stimulation and that this signaling is enhanced in mice with low striatal D2Rs. These data demonstrate a link between two vulnerability factors for alcohol abuse and offer evidence for a mechanism in which low striatal D2Rs trigger D1R hypersensitivity, ultimately leading to compulsive-like drinkingFil: Bocarsly, Miriam E.. National Institutes of Health; Estados UnidosFil: da Silva e Silva, Daniel. National Institutes of Health; Estados UnidosFil: Kolb, Vanessa. National Institutes of Health; Estados UnidosFil: Luderman, Kathryn D.. National Institutes of Health; Estados UnidosFil: Shashikiran, Sannidhi. National Institutes of Health; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Sibley, David R.. National Institutes of Health; Estados UnidosFil: Dobbs, Lauren K.. National Institutes of Health; Estados Unidos. University of Texas at Austin; Estados UnidosFil: Álvarez, Verónica Alicia. National Institutes of Health; Estados Unido

Overcoming inertia : drivers of the outsourcing process

Almost all managers have directly or indirectly been involved in the practice of outsourcing in recent years. But as they know, outsourcing is not straightforward. Outsourcing inertia, when companies are slow to adapt to changing circumstances that accommodate higher outsourcing levels, may undermine a firm’s performance. This article investigates the presence of outsourcing inertia and the factors that help managers overcome it. Using statistical evidence, we show that positive performance effects related to outsourcing can accumulate when circumstances change. This is then followed by rapid increases in outsourcing levels (i.e. outsourcing processes). We investigate what gives rise to these outsourcing processes through follow-up interviews with sourcing executives, which suggest five drivers behind outsourcing processes: managerial initiative (using outside experience); hierarchy (foreign headquarters); imitation (of competitors and of similar firms); outsider advice (from external institutions); knowledge sources (using external information). These five drivers all offer scope for managerial action. We tie them to academic literatures and suggest ways of investigating their presence and impact on the outsourcing process. Overall, we conclude that while economizing factors play a key role in explaining how much firms outsource, it is socializing factors that tend to drive outsourcing processes

Maximal lactate steady state in swimming tethered

This study investigated whether aerobic capacity (AC) in tethered swimming corresponds to maximal lactate steady state (MLSS) and its correlation with 30 min (V30) and 400m (V400) free swimming velocity. Twenty-five swimmers were submitted to an incremental tethered swimming test (ITS) with each stage lasting 3 minutes, initial load 20N, with 10N increments and a 30s interval to collect blood samples and lactatemia ([La-]). The abrupt increase in [La-] against force (F) corresponded to AC (ACBI). The points obtained for [La-] against force (N) were adjusted with an exponential curve model to determine AC corresponding to 3.5mmol.l-1 (AC3.5) and 4.0mmol.l-1 (AC4.0). Later swimmers performed maximum exercise for 30 minutes (V30) and 400m (V400) in free swimming. After one week, nine swimmers performed three random 30 minute tethered swimming exercises with 90%, 100%, and 110% intensity ACBI MLSS. Comparisons between ACs (AC3.5, AC4.0, and ACBI) were made by the one-way Anova test. Pearson correlation was used for possible correlations between ACs and between ACs and V30 and V400 (p0.91) and V400 (r\u3e0.63). We can conclude that ACBI corresponds to MLSS and both individually determined. AC and from the fixed lactate concentrations (3.5 and 4mM) can be used to predict mean 30 minute and 400m free swimming velocity

North African dust intrusions and increased risk of respiratory diseases in Southern Portugal

The study of dust intrusions in Portugal is still a subject on which little investigation has been made, especially in terms of their effects. Thus, this work aims to achieve two goals: firstly, to characterize the dust intrusions in the study area; and secondly, to evaluate the possible statistical association between the dust intrusion days and hospital admissions due to respiratory diseases. Dust intrusions in Portugal are prevalent during the summer season. During this season, the dust plumes tend to cover broader areas than in the other seasons and they have origin in the North African countries. In the study area for the period between 2005 and 2015, the relative risk of urgent hospitalizations due to respiratory diseases was 12.6% higher during dust intrusion days. In order to obtain this statistical association, a Distributed Lag Nonlinear Model was developed. With this work, we expect to help the development of further studies regarding North African dust intrusions in Portugal, more precisely their effects on human health.info:eu-repo/semantics/acceptedVersio

Antioxidant capacities of flavones and benefits in oxidative-stress related diseases

Flavonoids, a group of secondary metabolites widely distributed in the plant kingdom, have been acknowledged for their interesting medicinal properties. Among them, natural flavones, as well as some of their synthetic derivatives, have been shown to exhibit several biological activities, including antioxidant, anti-inflammatory, antitumor, anti-allergic, neuroprotective, cardioprotective and antimicrobial. The antioxidant properties of flavones allow them to demonstrate potential application as preventive and attenuating agents in oxidative stress, i.e., a biological condition that is closely associated to aging process and several diseases. Some flavones interfere in distinct oxidative-stress related events by directly reducing the levels of intracellular free radicals (hydroxyl, superoxide and nitric oxide) and/or of reactive species (e.g. hydrogen peroxide, peroxynitrite and hypochlorous acid) thus preventing their amplification and the consequent damage of other biomolecules such as lipids, proteins and DNA. Flavones can also hinder the activity of central free radical-producing enzymes, such as xanthine oxidase and nicotinamide adenine dinucleotide phosphate oxidase (NADPH-oxidase) or inducible nitric oxide synthase (iNOS) and can even modulate the intracellular levels of pro-oxidant and/or antioxidant enzymes. The evaluation of flavones antioxidant ability has been extensively determined in chemical or biological in vitro models, but in vivo therapy with individual flavones or with flavones-enriched extracts has also been reported. The present manuscript revises relevant studies focusing the preventive effects of flavones on stress-related diseases, namely the neurological and cardiovascular diseases, and diabetes and its associated complications