Membrane computing simulation of sexually transmitted bacterial infections in hotspots of individuals with various risk behaviors.

The epidemiology of sexually transmitted infections (STIs) is complex due to the coexistence of various pathogens, the variety of transmission modes derived from sexual orientations and behaviors at different ages and genders, and sexual contact hotspots resulting in network transmission. There is also a growing proportion of recreational drug users engaged in high-risk sexual activities, as well as pharmacological self-protection routines fostering non-condom practices. The frequency of asymptomatic patients makes it difficult to develop a comprehensive approach to STI epidemiology. Modeling approaches are required to deal with such complexity. Membrane computing is a natural computing methodology for the virtual reproduction of epidemics under the influence of deterministic and stochastic events with an unprecedented level of granularity. The application of the LOIMOS program to STI epidemiology illustrates the possibility of using it to shape appropriate interventions. Under the conditions of our basic landscape, including sexual hotspots of individuals with various risk behaviors, an increase in condom use reduces STIs in a larger proportion of heterosexuals than in same-gender sexual contacts and is much more efficient for reducing Neisseria gonorrhoeae than Chlamydia and lymphogranuloma venereum infections. Amelioration from diagnostic STI screening could be instrumental in reducing N. gonorrhoeae infections, particularly in men having sex with men (MSM), and Chlamydia trachomatis infections in the heterosexual population; however, screening was less effective in decreasing lymphogranuloma venereum infections in MSM. The influence of STI epidemiology of sexual contacts between different age groups (<35 and ≥35 years) and in bisexual populations was also submitted for simulation.IMPORTANCEThe epidemiology of sexually transmitted infections (STIs) is complex and significantly influences sexual and reproductive health worldwide. Gender, age, sexual orientation, sexual behavior (including recreational drug use and physical and pharmacological protection practices), the structure of sexual contact networks, and the limited application or efficiency of diagnostic screening procedures create variable landscapes in different countries. Modeling techniques are required to deal with such complexity. We propose the use of a simulation technology based on membrane computing, mimicking in silico STI epidemics under various local conditions with an unprecedented level of detail. This approach allows us to evaluate the relative weight of the various epidemic drivers in various populations at risk and the possible outcomes of interventions in particular epidemiological landscapes.

Simulating the efficacy of vaccines on the epidemiological dynamics of SARS-CoV-2 in a membrane computing model.

Membrane computing is a natural computing procedure inspired in the compartmental structure of living cells. This approach allows mimicking the complex structure of biological processes, and, when applied to transmissible diseases, can simulate a virtual 'epidemic' based on interactions between elements within the computational model according to established conditions. General and focused vaccination strategies for controlling SARS-Cov-2 epidemics have been simulated for 2.3 years from the emergence of the epidemic in a hypothetical town of 10320 inhabitants in a country with mean European demographics where COVID-19 is imported. The age and immunological-response groups of the hosts and their lifestyles were minutely examined. The duration of natural, acquired immunity influenced the results; the shorter the duration, the more endemic the process, resulting in higher mortality, particularly among elderly individuals. During epidemic valleys between waves, the proportion of infected patients belonging to symptomatic groups (mostly elderly) increased in the total population, a population that largely benefits from standard double vaccination, particularly with boosters. There was no clear difference when comparing booster shots provided at 4 or 6 months after standard double-dose vaccination. Vaccines even of moderate efficacy (short-term protection) were effective in decreasing the number of symptomatic cases. Generalized vaccination of the entire population (all ages) added little benefit to overall mortality rates, and this situation also applied for generalized lockdowns. Elderly-only vaccination and lockdowns, even without general interventions directed to reduce population transmission, is sufficient for dramatically reducing mortality.

Antioxidant Supplementation Modulates Neutrophil Inflammatory Response to Exercise-Induced Stress.

The aim of the present report was to evaluate the inflammatory response to a 2000-m running test considering neutrophil myeloperoxidase as an inflammatory marker, and to verify if supplements rich in antioxidants could modulate Post-test antioxidant and anti-inflammatory responses. To this end, a 21-day homogenization period was carried out with three groups: a control group, a supplemented group taking an almond beverage enriched with vitamins C and E and a third group consuming the same beverage but enriched with Lippia citriodora extract. At the end of this period, participants performed a 2000-m run, and blood samples were obtained the day before and immediately after the running test. Plasma and neutrophils were isolated. As a result, plasma creatine kinase and myoglobin increased, indicating Post-test muscle damage. Plasma oxidative markers were increased in all groups, except in the group supplemented with the almond beverage. Neutrophil antioxidant enzymes were significantly increased only in the control group, suggesting an antioxidant effect of the supplements provided in the other groups. Myeloperoxidase activity was significantly increased after the test in the control group, while increased enzyme levels were detected in plasma of the supplement groups. Therefore, antioxidant consumption seems to favour myeloperoxidase release. The connection of this observation with post-exercise recovery will require further investigation.

Adipose-derived mesenchymal stromal cells for the treatment of patients with severe SARS-CoV-2 pneumonia requiring mechanical ventilation. A proof of concept study.

BACKGROUND: Identification of effective treatments in severe cases of COVID-19 requiring mechanical ventilation represents an unmet medical need. Our aim was to determine whether the administration of adipose-tissue derived mesenchymal stromal cells (AT-MSC) is safe and potentially useful in these patients. METHODS: Thirteen COVID-19 adult patients under invasive mechanical ventilation who had received previous antiviral and/or anti-inflammatory treatments (including steroids, lopinavir/ritonavir, hydroxychloroquine and/or tocilizumab, among others) were treated with allogeneic AT-MSC. Ten patients received two doses, with the second dose administered a median of 3 days (interquartile range-IQR- 1 day) after the first one. Two patients received a single dose and another patient received 3 doses. Median number of cells per dose was 0.98 × 106 (IQR 0.50 × 106) AT-MSC/kg of recipient's body weight. Potential adverse effects related to cell infusion and clinical outcome were assessed. Additional parameters analyzed included changes in imaging, analytical and inflammatory parameters. FINDINGS: First dose of AT-MSC was administered at a median of 7 days (IQR 12 days) after mechanical ventilation. No adverse events were related to cell therapy. With a median follow-up of 16 days (IQR 9 days) after the first dose, clinical improvement was observed in nine patients (70%). Seven patients were extubated and discharged from ICU while four patients remained intubated (two with an improvement in their ventilatory and radiological parameters and two in stable condition). Two patients died (one due to massive gastrointestinal bleeding unrelated to MSC therapy). Treatment with AT-MSC was followed by a decrease in inflammatory parameters (reduction in C-reactive protein, IL-6, ferritin, LDH and d-dimer) as well as an increase in lymphocytes, particularly in those patients with clinical improvement. INTERPRETATION: Treatment with intravenous administration of AT-MSC in 13 severe COVID-19 pneumonia under mechanical ventilation in a small case series did not induce significant adverse events and was followed by clinical and biological improvement in most subjects. FUNDING: None.

Simulating the Influence of Conjugative-Plasmid Kinetic Values on the Multilevel Dynamics of Antimicrobial Resistance in a Membrane Computing Model.

Bacterial plasmids harboring antibiotic resistance genes are critical in the spread of antibiotic resistance. It is known that plasmids differ in their kinetic values, i.e., conjugation rate, segregation rate by copy number incompatibility with related plasmids, and rate of stochastic loss during replication. They also differ in cost to the cell in terms of reducing fitness and in the frequency of compensatory mutations compensating plasmid cost. However, we do not know how variation in these values influences the success of a plasmid and its resistance genes in complex ecosystems, such as the microbiota. Genes are in plasmids, plasmids are in cells, and cells are in bacterial populations and microbiotas, which are inside hosts, and hosts are in human communities at the hospital or the community under various levels of cross-colonization and antibiotic exposure. Differences in plasmid kinetics might have consequences on the global spread of antibiotic resistance. New membrane computing methods help to predict these consequences. In our simulation, conjugation frequency of at least 10-3 influences the dominance of a strain with a resistance plasmid. Coexistence of different antibiotic resistances occurs if host strains can maintain two copies of similar plasmids. Plasmid loss rates of 10-4 or 10-5 or plasmid fitness costs of ≥0.06 favor plasmids located in the most abundant species. The beneficial effect of compensatory mutations for plasmid fitness cost is proportional to this cost at high mutation frequencies (10-3 to 10-5). The results of this computational model clearly show how changes in plasmid kinetics can modify the entire population ecology of antibiotic resistance in the hospital setting.

Changes in metabolic and inflammatory parameters in a type 1 diabetic patient performing extreme activities / Cambios en parámetros metabólicos e inflamatorios en un paciente diabético tipo 1 realizando actividades extremas

Background: physical activity in type 1 diabetic patients allows a better control of glycaemia and glycosylated hemoglobin, helps to maintain a residual endocrine pancreatic mass and optimizes subsequent insulin requirements. These improvements might be due in part to increases in anti-inflammatory cytokines that could help to minimize β-cell destruction. However, type, intensity and frequency of exercise for type 1 diabetic patients remain to be established. Case report: we present the case of a 48-year-old man diagnosed with type 1 diabetes at the age of 23. He is a professional alpinist and recently was recruited in a program of the Yuri Gagarin Cosmonaut Training Center (Russia) to be the first diabetic astronaut. Metabolic and inflammatory responses were assessed after performing two extreme activities. Discussion: well programmed extreme activities accompanied by a correct dietetic intervention can reduce the adverse metabolic and inflammatory processes that appear due to exercise and diabetes

Introducción: la actividad física en pacientes diabéticos tipo 1 permite un mejor control de la glucemia y hemoglobina glucosilada, ayuda a mantener una masa residual de páncreas endocrino y optimiza las necesidades de insulina. Estas mejoras podrían ser debidas en parte al incremento en citocinas antiinflamatorias que ayudarían a minimizar la destrucción de células β. Sin embargo, el tipo, la intensidad y la frecuencia de ejercicio para pacientes diabéticos tipo 1 no han sido establecidos. Caso clínico: presentamos el caso de un varón de 48 años de edad diagnosticado de diabetes tipo 1 a los 23. Es alpinista profesional y recientemente ha sido reclutado por el Centro de Entrenamiento para Cosmonautas Yuri Gagarin (Rusia) para ser el primer astronauta diabético. Hemos comparado respuestas metabólicas e inflamatorias tras realizar dos actividades extremas. Discusión: actividades extremas bien programadas y con una correcta intervención dietética pueden reducir la descompensación metabólica e inflamatoria causada por la combinación actividad-enfermedad

Simulating Multilevel Dynamics of Antimicrobial Resistance in a Membrane Computing Model.

Membrane computing is a bio-inspired computing paradigm whose devices are the so-called membrane systems or P systems. The P system designed in this work reproduces complex biological landscapes in the computer world. It uses nested "membrane-surrounded entities" able to divide, propagate, and die; to be transferred into other membranes; to exchange informative material according to flexible rules; and to mutate and be selected by external agents. This allows the exploration of hierarchical interactive dynamics resulting from the probabilistic interaction of genes (phenotypes), clones, species, hosts, environments, and antibiotic challenges. Our model facilitates analysis of several aspects of the rules that govern the multilevel evolutionary biology of antibiotic resistance. We examined a number of selected landscapes where we predict the effects of different rates of patient flow from hospital to the community and vice versa, the cross-transmission rates between patients with bacterial propagules of different sizes, the proportion of patients treated with antibiotics, and the antibiotics and dosing found in the opening spaces in the microbiota where resistant phenotypes multiply. We also evaluated the selective strengths of some drugs and the influence of the time 0 resistance composition of the species and bacterial clones in the evolution of resistance phenotypes. In summary, we provide case studies analyzing the hierarchical dynamics of antibiotic resistance using a novel computing model with reciprocity within and between levels of biological organization, a type of approach that may be expanded in the multilevel analysis of complex microbial landscapes.IMPORTANCE The work that we present here represents the culmination of many years of investigation in looking for a suitable methodology to simulate the multihierarchical processes involved in antibiotic resistance. Everything started with our early appreciation of the different independent but embedded biological units that shape the biology, ecology, and evolution of antibiotic-resistant microorganisms. Genes, plasmids carrying these genes, cells hosting plasmids, populations of cells, microbial communities, and host's populations constitute a complex system where changes in one component might influence the other ones. How would it be possible to simulate such a complexity of antibiotic resistance as it occurs in the real world? Can the process be predicted, at least at the local level? A few years ago, and because of their structural resemblance to biological systems, we realized that membrane computing procedures could provide a suitable frame to approach these questions. Our manuscript describes the first application of this modeling methodology to the field of antibiotic resistance and offers a bunch of examples-just a limited number of them in comparison with the possible ones to illustrate its unprecedented explanatory power.

Effect of a 2000-m running test on antioxidant and cytokine response in plasma and circulating cells

Exercise intensity usually correlates with increased oxidative stress and enhanced cytokine production. However, it is unknown if all types of exercise that induce muscle damage can cause a parallel response in the oxidation balance and cytokine production. To this end, the effect of a 2000-m running test in a group of volunteers that regularly train in aerobic routines was studied. Different circulating parameters were measured, oxidative stress markers (protein carbonyls and malondialdehyde), antioxidant enzyme activity, and cytokine levels in plasma as well as in the main circulating cells of blood samples obtained in basal conditions and after test execution. As a result, the test caused muscle damage evidenced by an increase in circulating creatine kinase and myoglobin. This was accompanied by an increase in protein carbonyls in plasma and peripheral blood mononuclear cells. Activities of antioxidant enzymes (catalase, glutathione peroxidase and reductase, superoxide dismutase) were elevated in peripheral blood mononuclear cells, neutrophils, and erythrocytes after the test. Regarding cytokine production, interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-α exhibited no significant changes after the test. Results suggest that this short but intense running exercise (2000 m) can induce muscle damage and elicit a good balance between oxidant/antioxidant responses with no changes in the circulating concentration of pro-inflammatory cytokines

Effect of a 2000-m running test on antioxidant and cytokine response in plasma and circulating cells.

Exercise intensity usually correlates with increased oxidative stress and enhanced cytokine production. However, it is unknown if all types of exercise that induce muscle damage can cause a parallel response in the oxidation balance and cytokine production. To this end, the effect of a 2000-m running test in a group of volunteers that regularly train in aerobic routines was studied. Different circulating parameters were measured, oxidative stress markers (protein carbonyls and malondialdehyde), antioxidant enzyme activity, and cytokine levels in plasma as well as in the main circulating cells of blood samples obtained in basal conditions and after test execution. As a result, the test caused muscle damage evidenced by an increase in circulating creatine kinase and myoglobin. This was accompanied by an increase in protein carbonyls in plasma and peripheral blood mononuclear cells. Activities of antioxidant enzymes (catalase, glutathione peroxidase and reductase, superoxide dismutase) were elevated in peripheral blood mononuclear cells, neutrophils, and erythrocytes after the test. Regarding cytokine production, interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-α exhibited no significant changes after the test. Results suggest that this short but intense running exercise (2000 m) can induce muscle damage and elicit a good balance between oxidant/antioxidant responses with no changes in the circulating concentration of pro-inflammatory cytokines.

A membrane computing simulator of trans-hierarchical antibiotic resistance evolution dynamics in nested ecological compartments (ARES).

BACKGROUND: Antibiotic resistance is a major biomedical problem upon which public health systems demand solutions to construe the dynamics and epidemiological risk of resistant bacteria in anthropogenically-altered environments. The implementation of computable models with reciprocity within and between levels of biological organization (i.e. essential nesting) is central for studying antibiotic resistances. Antibiotic resistance is not just the result of antibiotic-driven selection but more properly the consequence of a complex hierarchy of processes shaping the ecology and evolution of the distinct subcellular, cellular and supra-cellular vehicles involved in the dissemination of resistance genes. Such a complex background motivated us to explore the P-system standards of membrane computing an innovative natural computing formalism that abstracts the notion of movement across membranes to simulate antibiotic resistance evolution processes across nested levels of micro- and macro-environmental organization in a given ecosystem. RESULTS: In this article, we introduce ARES (Antibiotic Resistance Evolution Simulator) a software device that simulates P-system model scenarios with five types of nested computing membranes oriented to emulate a hierarchy of eco-biological compartments, i.e. a) peripheral ecosystem; b) local environment; c) reservoir of supplies; d) animal host; and e) host's associated bacterial organisms (microbiome). Computational objects emulating molecular entities such as plasmids, antibiotic resistance genes, antimicrobials, and/or other substances can be introduced into this framework and may interact and evolve together with the membranes, according to a set of pre-established rules and specifications. ARES has been implemented as an online server and offers additional tools for storage and model editing and downstream analysis. CONCLUSIONS: The stochastic nature of the P-system model implemented in ARES explicitly links within and between host dynamics into a simulation, with feedback reciprocity among the different units of selection influenced by antibiotic exposure at various ecological levels. ARES offers the possibility of modeling predictive multilevel scenarios of antibiotic resistance evolution that can be interrogated, edited and re-simulated if necessary, with different parameters, until a correct model description of the process in the real world is convincingly approached. ARES can be accessed at http://gydb.org/ares.

GyDB mobilomics: LTR retroelements and integrase-related transposons of the pea aphid Acyrthosiphon pisum genome.

The Gypsy Database concerning Mobile Genetic Elements (release 2.0) is a wiki-style project devoted to the phylogenetic classification of LTR retroelements and their viral and host gene relatives characterized from distinct organisms. Furthermore, GyDB 2.0 is concerned with studying mobile elements within genomes. Therefore, an in-progress repository was created for databases with annotations of mobile genetic elements from particular genomes. This repository is called Mobilomics and the first uploaded database contains 549 LTR retroelements and related transposases which have been annotated from the genome of the Pea aphid Acyrthosiphon pisum. Mobilomics is accessible from the GyDB 2.0 project using the URL: http://gydb.org/index.php/Mobilomics.

The Gypsy Database (GyDB) of mobile genetic elements: release 2.0.

This article introduces the second release of the Gypsy Database of Mobile Genetic Elements (GyDB 2.0): a research project devoted to the evolutionary dynamics of viruses and transposable elements based on their phylogenetic classification (per lineage and protein domain). The Gypsy Database (GyDB) is a long-term project that is continuously progressing, and that owing to the high molecular diversity of mobile elements requires to be completed in several stages. GyDB 2.0 has been powered with a wiki to allow other researchers participate in the project. The current database stage and scope are long terminal repeats (LTR) retroelements and relatives. GyDB 2.0 is an update based on the analysis of Ty3/Gypsy, Retroviridae, Ty1/Copia and Bel/Pao LTR retroelements and the Caulimoviridae pararetroviruses of plants. Among other features, in terms of the aforementioned topics, this update adds: (i) a variety of descriptions and reviews distributed in multiple web pages; (ii) protein-based phylogenies, where phylogenetic levels are assigned to distinct classified elements; (iii) a collection of multiple alignments, lineage-specific hidden Markov models and consensus sequences, called GyDB collection; (iv) updated RefSeq databases and BLAST and HMM servers to facilitate sequence characterization of new LTR retroelement and caulimovirus queries; and (v) a bibliographic server. GyDB 2.0 is available at http://gydb.org.

T regulatory cells and HIV infection.

Several issues of HIV pathogenesis remain unsolved. Among them, the reason for uncontrolled viral replication in the majority of infected patients is one of the most investigated but still not completely understood. In the last four years a new player has been incorporated into the HIV field: T regulatory (Treg) cells. They are a subset of CD4+ T-cells whose main function is to maintain peripheral tolerance in order to avoid autoimmunity. However, their role in chronic viral and parasitic infections has also been recognized. Several papers have been published in the last years on the potential role of these cells on HIV disease pathogenesis. From the data available so far, two main, nonexclusive roles have been attributed to Treg cells in HIV: a detrimental effect mediated through the impairment of HIV-specific responses, and a beneficial effect by limiting immune activation. The topic is currently highly controversial for different reasons, one of the most important being the lack of standardized assays to measure levels and function of Treg cells.

Influence of human T cell lymphotropic virus type 2 coinfection on virological and immunological parameters in HIV type 1-infected patients.

BACKGROUND: Human T cell lymphotropic virus type 2 (HTLV-2) infection is not rare among injection drug users with human immunodeficiency virus (HIV) infection and may exert a protective role in the progression of HIV disease. METHODS: Immunological and virological parameters were compared in HIV-HTLV-2-coinfected patients and a control group of HIV-monoinfected subjects. All individuals were antiretroviral therapy naive. HIV-specific CD8+ T cell levels were measured using an interferon-gamma assay in response to 125 optimally defined HIV peptides divided into 5 pools. Immune activation was evaluated by measuring levels of CD38 in different CD4+ and CD8+ T cell subsets. In a subgroup of patients, the production of CCL4 in parallel with interferon-gamma was assessed in response to Gag peptides. RESULTS: Lower plasma HIV-RNA levels were found in HIV-HTLV-2-coinfected patients than in HIV-monoinfected patients, despite the 2 groups having similar CD4+ T cell counts. Coinfected patients also had significantly lower levels of CD38 expression in total CD8+ T cells and in its naive subset. CD8+ T cell levels specific for each pool of peptides were similar in both groups, but cells mainly contributing to HIV Gag-specific responses in coinfected patients were CCL4 positive and interferon-gamma negative, whereas for HIV-monoinfected subjects, the response was dominated by CCL4-positive and interferon-gamma-positive cells. CONCLUSIONS: HTLV-2 coinfection may exert a protective role on HIV disease progression by lowering HIV replication and immune activation. A predominance of CCL4 single positive HIV-specific CD8+ T cells in HIV-HTLV-2-coinfected patients could explain this effect.

Acute allergic reaction to an iron compound in a milk-allergic patient.

A child allergic to cow's milk developed a mild systemic allergic reaction after the first dose of Ferplex 40 (iron proteinsuccinylate). Skin tests and in vitro studies were performed in the child, in three cow's milk-allergic controls and in a non-allergic control. Milk, casein and iron proteinsuccinylate (Ferplex 40) were used for skin tests, specific immunoglobulin E (IgE) determination, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), immunoblotting and enzyme allergo sorbent test (EAST) inhibition. A review of the drug information sheet and contact with the manufacturer were also performed. Although proteinsuccinylate is indeed a succinylated casein (each dose containing about 575 mg of casein) there was no indication of the milk protein content in the prescribing information provided by the manufacturer. Skin tests and specific IgE were positive in the case and in all allergic controls, except for EAST to iron proteinsuccinylate in one control. In EAST, iron proteinsuccinylate in solid phase was 100% inhibited by casein and casein in solid phase was inhibited 74% by iron proteinsuccinylate. SDS-PAGE of iron proteinsuccinylate showed a broad 46 kDa band and a blur of aggregated material. On immunoblot, the patient's IgE reacted to this heavily aggregated material and in the native casein extract recognized a 35-kDa band. The allergenicity of succinylated casein (proteinsuccinylate) among milk-allergic children is demonstrated. The protein source used in drug-protein conjugates should always be indicated by the manufacturer (as it should be in foods) to avoid potential risks to allergic patients.

Occupational asthma to carmine in a butcher.

UNLABELLED: Hypersensitivity to carmine (E120) has been identified as a cause of food intolerance and occupational asthma. We present a case of occupational asthma following exposure to carmine in a manufacturer of sausages and review the literature. CASE REPORT: A 42-year-old non-atopic male presented with a 5-year history of rhinoconjunctivitis and asthma on occupational exposure to food additive dusts. Symptoms increased after work. The patient had been exposed for more than 20 years. METHODS: Skin prick tests were performed with a battery of common inhalant allergens and spices. Cochineal, carmine lake and additive mixes used by the patient were extracted and subsequently used for skin prick test, bronchial provocation and in vitro measurements (specific IgE, Western blot and chromatographic fractionation). RESULTS: Prick tests were positive to carmine and carmine-containing additives; carmine-specific IgE and bronchial challenge tests were also positive (PC20 = 0.0004 mg/ml and 1.6 kU/l). Western blot showed IgE binding to bands of about 30 kDa on cochineal extract and a diffuse pattern at 40-97 kDa on carmine. This result was confirmed by gel filtration chromatography and dot blot. Carmine completely inhibited IgE binding to cochineal extract. DISCUSSION: Carmine is a potential sensitizer in an occupational setting: 18 cases of occupational asthma have been described to date. Carmine allergens are poorly defined; in general, proteins from cochineal not removed by the extraction process are considered as the main allergens in carmine. Our results are consistent with this, but show that these proteins may be subject to chemical modification.

Inference of reversible tree languages.

In this paper, we study the notion of k-reversibility and k-testability when regular tree languages are involved. We present an inference algorithm for learning a k-testable tree language that runs in polynomial time with respect to the size of the sample used. We also study the tree language classes in relation to other well known ones, and some properties of these languages are proven.