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Benzotriazoles (BTRs) and bisphenols (BPs), categorized as contaminants of emerging concern (CECs), pose significant risks to human health and ecosystems due to their endocrine-disrupting properties and environmental persistence. This study investigates the occurrence and behavior of nine BTRs and ten BPs in wastewater generated in a large-scale meat processing plant, evaluating the effectiveness of a modern mechanical-biological industrial on-site treatment plant in removing these contaminants, and based on the concentration levels from eleven sampling points at different stages of the treatment process. The method used to determine these micropollutants' concentration was ultrasound-assisted emulsification-microextraction for analytes isolation and gas chromatography-mass spectrometry for detection (USAEME-GC/MS). The results indicate that the rigorous quality control processes in the meat processing facility effectively limit the presence of these micropollutants, especially concerning BPs, which are absent or below detection limits in raw wastewater. While the concentrations of some of these micropollutants increased at different points in the treatment process, these values were relatively low, typically below one microgram per liter. Among the compounds analyzed, the only one present after completing the treatment was 5Cl-BTR (maximum concentration: 3007 ng/L), and these contamination levels are around seven times lower than the reference value associated with non-cancer health risk for drinking water. This study contributes to understanding these CECs in industrial wastewater and highlights the importance of effective treatment systems for environmental protection.
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Cattle ticks are a significant health concern in tropical livestock production due to their hematophagous behavior and potential as vectors for human and animal pathogens. In this study, we investigated the tick population present in dairy cattle production, calves, and grazing areas of livestock systems in the northwestern Colombian Amazon. Identification was based on taxonomic keys and molecular markers. Phylogenetic relationships were established using mitochondrial COX1 and 16S genes. Population structure analysis was performed considering age, racial type (B. indicus vs. B. taurus), and the influence of environmental factors and the geomorphological landscape on tick population dynamics. Our findings revealed the presence of a single tick species, with a unique haplotype identified for each mitochondrial gene assessed. Phylogenetic analysis classified the found species within Clade A of the Rhipicephalus microplus complex. Ticks were more prevalent during periods of low rainfall and high temperature, and B. taurus cows exhibited the highest tick abundance. Thus, these results provide insights into the population characteristics and distribution of the tick species present in dairy cattle production systems in the northwestern part of the Colombian Amazon. This information is fundamental for developing targeted strategies based on seasonal variation and host characteristics to mitigate tick infestation severity in the region.
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The contamination of marine and freshwater environments by nanoplastics is considered a global threat for aquatic biota. Taking into account the most recent concentration range estimates reported globally and recognizing a knowledge gap in polystyrene nanoplastics (PS-NPs) ecotoxicology, the present work investigated the harmful effects of 20 nm and 80 nm PS-NPs, at increasing biological complexity, on the rainbow trout Oncorhynchus mykiss RTG-2 and gilthead seabream Sparus aurata SAF-1 cell lines. Twenty nm PS-NPs exerted a greater cytotoxicity than 80 nm ones and SAF-1 were approximately 4-fold more vulnerable to PS-NPs than RTG-2. The engagement of PS-NPs with plasma membranes was accompanied by discernible uptake patterns and morphological alterations along with a nuclear translocation already within a 30-min exposure. Cells were structurally damaged only by the 20 nm PS-NPs in a time-dependent manner as indicated by distinctive features of the execution phase of the apoptotic cell death mechanism such as cell shrinkage, plasma membrane blebbing, translocation of phosphatidylserine to the outer leaflet of the cell membrane and DNA fragmentation. At last, functional analyses unveiled marked transcriptional impairment at both sublethal and lethal doses of 20 nm PS-NPs, with the latter impacting the "Steroid biosynthesis", "TGF-beta signaling pathway", "ECM-receptor interaction", "Focal adhesion", "Regulation of actin cytoskeleton" and "Protein processing in endoplasmic reticulum" pathways. Overall, a distinct ecotoxicological hazard of PS-NPs at environmentally relevant concentrations was thoroughly characterized on two piscine cell lines. The effects were demonstrated to depend on size, exposure time and model, emphasizing the need for a comparative evaluation of endpoints between freshwater and marine ecosystems.
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Poliestirenos , Contaminantes Químicos del Agua , Animales , Contaminantes Químicos del Agua/toxicidad , Poliestirenos/toxicidad , Agua Dulce , Transcriptoma/efectos de los fármacos , Oncorhynchus mykiss/fisiología , Dorada/fisiología , Línea Celular , Ecotoxicología , Agua de Mar/química , Nanopartículas/toxicidadRESUMEN
The thymus is a sophisticated primary lymphoid organ in jawed vertebrates, but knowledge on teleost thymus remains scarce. In this study, for the first time in the European sea bass, laser capture microdissection was leveraged to collect two thymic regions based on histological features, namely the cortex and the medulla. The two regions were then processed by RNAseq and in-depth functional transcriptome analyses with the aim of revealing differential gene expression patterns and gene sets enrichments, ultimately unraveling unique microenvironments imperative for the development of functional T cells. The sea bass cortex emerged as a hub of T cell commitment, somatic recombination, chromatin remodeling, cell cycle regulation, and presentation of self antigens from autophagy-, proteasome- or proteases-processed proteins. The cortex therefore accommodated extensive thymocyte proliferation and differentiation up to the checkpoint of positive selection. The medulla instead appeared as the center stage in autoimmune regulation by negative selection and deletion of autoreactive T cells, central tolerance mechanisms and extracellular matrix organization. Region-specific canonical markers of T and non-T lineage cells as well as signals for migration to/from, and trafficking within, the thymus were identified, shedding light on the highly coordinated and exquisitely complex bi-directional interactions among thymocytes and stromal components. Markers ascribable to thymic nurse cells and poorly characterized post-aire mTEC populations were found in the cortex and medulla, respectively. An in-depth data mining also exposed previously un-annotated genomic resources with differential signatures. Overall, our findings contribute to a broader understanding of the relationship between regional organization and function in the European sea bass thymus, and provide essential insights into the molecular mechanisms underlying T-cell mediated adaptive immune responses in teleosts.
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Lubina , Glándulas Endocrinas , Animales , Timo , Linfocitos T , Perfilación de la Expresión GénicaRESUMEN
INTRODUCTION: Tumor lysis syndrome (TLS) occurs frequently during induction therapy for acute lymphoblastic leukemia (ALL). Patients are categorized into intermediate or high risk based on lactate dehydrogenase (LDH) value and white blood cell (WBC) count according to an expert panel, although no effort has been made to analyze TLS in ALL and its potential consequences. METHODS: We retrospectively analyzed TLS, variables associated with its occurrence and its impact in overall survival and mortality during induction in a cohort of ALL patients in their first induction regimen. RESULTS: A total of 138 patients were included. 52.9% were male and median age at diagnosis was 34 years. Most of them were treated with Hyper-CVAD (39.1%) or a modified CALGB 10403 regimen (37.7%). TLS was identified in 42 patients (30.4%), and half of them fulfilled criteria for clinical TLS (C-TLS). Median overall survival (OS) was the lowest in C-TLS patients. An LDH 3 times greater its upper normal limit (ULN) value and a WBC count equal or greater than 50â109/l were associated with TLS development, and being male, hyperuricemia and an LDH 3 times greater its ULN value were associated with C-TLS development. C-TLS and AKI were associated with excess mortality during induction. CONCLUSION: TLS was identified in almost a third of ALL patients during induction therapy. Different thresholds for LDH value and WBC count as well as other variables that could identify patients at risk to developing this complication, which is associated with shorter OS. C-TLS confers a higher risk for mortality during induction.
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Research on coronavirus disease 2019 vaccination in immune-deficient/disordered people (IDP) has focused on cancer and organ transplantation populations. In a prospective cohort of 195 IDP and 35 healthy volunteers (HV), antispike immunoglobulin G (IgG) was detected in 88% of IDP after dose 2, increasing to 93% by 6 months after dose 3. Despite high seroconversion, median IgG levels for IDP never surpassed one-third that of HV. IgG binding to Omicron BA.1 was lowest among variants. Angiotensin-converting enzyme 2 pseudo-neutralization only modestly correlated with antispike IgG concentration. IgG levels were not significantly altered by receipt of different messenger RNA-based vaccines, immunomodulating treatments, and prior severe acute respiratory syndrome coronavirus 2 infections. While our data show that three doses of coronavirus disease 2019 vaccinations induce antispike IgG in most IDP, additional doses are needed to increase protection. Because of the notably reduced IgG response to Omicron BA.1, the efficacy of additional vaccinations, including bivalent vaccines, should be studied in this population.
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COVID-19 , Inmunoglobulina G , Humanos , Vacunas contra la COVID-19 , Estudios Prospectivos , COVID-19/prevención & control , InmunidadRESUMEN
The NK-lysin antimicrobial peptide, first identified in mammals, possesses both antibacterial and cytotoxic activity against cancer cell lines. Homologue peptides isolated from different fish species have been examined for their functional characteristics in the last few years. In this study, a NK-lysin transcript was identified in silico from the head kidney transcriptome of the Antarctic teleost Trematomus bernacchii. The corresponding amino acid sequence, slightly longer than NK-lysins of other fish species, contains six cysteine residues that in mammalian counterparts form three disulphide bridges. Real time-PCR analysis indicated its predominant expression in T. bernacchii immune-related organs and tissues, with greatest mRNA abundance detected in gills and spleen. Instead of focusing on the full T. bernacchii derived NK-lysin mature molecule, we selected a 27 amino acid residue peptide (named NKL-WT), corresponding to the potent antibiotic NK-2 sequence found in human NK-lysin. Moreover, we designed a mutant peptide (named NKL-MUT) in which two alanine residues substitute the two cysteines found in the NKL-WT. The two peptides were obtained by solid phase organic synthesis to investigate their functional features. NKL-WT and NKL-MUT displayed antibacterial activity against the human pathogenic bacterium Enterococcus faecalis and the ESKAPE pathogen Acinetobacter baumannii, respectively. Moreover, at the determined Minimum Inhibitory Concentration and Minimum Bactericidal Concentration values against these pathogens, both peptides showed high selectivity as they did not exhibit any haemolytic activity on erythrocytes or cytotoxic activity against mammalian primary cell lines. Finally, the NKL-MUT selectively triggers the killing of the melanoma cell line B16F10 by means of a pro-apoptotic pathway at a concentration range in which no effects were found in normal mammalian cell lines. In conclusion, the two peptides could be considered as promising candidates in the fight against antibiotic resistance and tumour proliferative action, and also be used as innovative adjuvants, either to decrease chemotherapy side effects or to enhance anticancer drug activity.
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Proteínas de Peces , Perciformes , Humanos , Animales , Regiones Antárticas , Proteínas de Peces/genética , Proteínas de Peces/química , Péptidos , Antibacterianos/farmacología , Perciformes/genética , Perciformes/metabolismo , Proteolípidos/genética , Proteolípidos/química , Peces/metabolismo , Mamíferos/metabolismoRESUMEN
The COVID-19 pandemic has escalated the risk of SARS-CoV-2 transmission in the dental practice, especially as droplet-aerosol particles are generated by high-speed instruments. This has heightened awareness of other orally transmitted viruses, including influenza and herpes simplex virus 1 (HSV1), which are capable of threatening life and impairing health. While current disinfection procedures commonly use surface wipe-downs to reduce viral transmission, they are not fully effective. Consequently, this provides the opportunity for a spectrum of emitted viruses to reside airborne for hours and upon surfaces for days. The objective of this study was to develop an experimental platform to identify a safe and effective virucide with the ability to rapidly destroy oral viruses transported within droplets and aerosols. Our test method employed mixing viruses and virucides in a fine-mist bottle atomizer to mimic the generation of oral droplet-aerosols. The results revealed that human betacoronavirus OC43 (related to SARS-CoV-2), human influenza virus (H1N1), and HSV1 from atomizer-produced droplet-aerosols were each fully destroyed by only 100 ppm of hypochlorous acid (HOCl) within 30 s, which was the shortest time point of exposure to the virucide. Importantly, 100 ppm HOCl introduced into the oral cavity is known to be safe for humans. In conclusion, this frontline approach establishes the potential of using 100 ppm HOCl in waterlines to continuously irrigate the oral cavity during dental procedures to expeditiously destroy harmful viruses transmitted within aerosols and droplets to protect practitioners, staff, and other patients.
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COVID-19 , Subtipo H1N1 del Virus de la Influenza A , Gripe Humana , Humanos , COVID-19/prevención & control , Gripe Humana/prevención & control , SARS-CoV-2 , Ácido Hipocloroso , Pandemias/prevención & control , Aerosoles y Gotitas RespiratoriasRESUMEN
TMPRSS13 is a member of the type II transmembrane serine protease (TTSP) family. Here we characterize a novel post-translational mechanism important for TMPRSS13 function: proteolytic cleavage within the extracellular TMPRSS13 stem region located between the transmembrane domain and the first site of N-linked glycosylation at asparagine (N)-250 in the scavenger receptor cysteine rich (SRCR) domain. Importantly, the catalytic competence of TMPRSS13 is essential for stem region cleavage, suggesting an autonomous mechanism of action. Site-directed mutagenesis of the 10 basic amino acids (four arginine and six lysine residues) in this region abrogated zymogen activation and catalytic activity of TMPRSS13, as well as phosphorylation, cell surface expression, and shedding. Mutation analysis of individual arginine residues identified R223, a residue located between the low-density lipoprotein receptor class A domain and the SRCR domain, as important for stem region cleavage. Mutation of R223 causes a reduction in the aforementioned functional processing steps of TMPRSS13. These data provide further insight into the roles of different post-translational modifications as regulators of the function and localization of TMPRSS13. Additionally, the data suggest the presence of complex interconnected regulatory mechanisms that may serve to ensure the proper levels of cell-surface and pericellular TMPRSS13-mediated proteolysis under homeostatic conditions.
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Proteínas de la Membrana , Procesamiento Proteico-Postraduccional , Arginina/metabolismo , Precursores Enzimáticos/metabolismo , Proteínas de la Membrana/metabolismo , ProteolisisRESUMEN
This study aimed to identify and quantify benzotriazoles (BTRs) emissions from road traffic and paved areas in an urban environment. Heterocyclic organic compounds BTRs are an emerging threat, under-recognized and under-analyzed in most environmental and water legislation. They are hazardous, potentially mutagenic, and carcinogenic micropollutants, not susceptible to effective biodegradation, and they move easily through the trophic chain, contaminating the environment and water resources. Traffic activities are a common source of BTR emissions in the urban environment, directly polluting human habitats through the different routes and numerous vehicles circulating in the cities. Using twelve heterogeneous locations scattered over a metropolitan area in Poland as a case study, this research analyzed the presence of BTRs in water samples from runoff produced from rainwater and snowmelt. 1H-BTR, 4Me-BTR, 5Me-BTR and 5Cl-BTR were detected in the tested runoff water. 5Cl-BTR was present in all samples and in the highest concentrations reaching 47,000 ng/L. Risk quotients calculated on the basis of the determined concentrations indicate that the highest environmental risk is associated with the presence of 5Cl-BTR and the sum of 4Me-BTR and 5Me-BTR, and the most sensitive organisms are bacteria and invertebrates. The results indicate that it is possible to associate the occurrence of these contaminants with the type of cover, traffic intensity, and vehicle type.
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Triazoles , Agua , Monitoreo del Ambiente , Humanos , Polonia , Medición de Riesgo , Triazoles/análisisRESUMEN
TMPRSS13, a member of the type II transmembrane serine protease (TTSP) family, harbors four N-linked glycosylation sites in its extracellular domain. Two of the glycosylated residues are located in the scavenger receptor cysteine-rich (SRCR) protein domain, while the remaining two sites are in the catalytic serine protease (SP) domain. In this study, we examined the role of N-linked glycosylation in the proteolytic activity, autoactivation, and cellular localization of TMPRSS13. Individual and combinatory site-directed mutagenesis of the glycosylated asparagine residues indicated that glycosylation of the SP domain is critical for TMPRSS13 autoactivation and catalytic activity toward one of its protein substrates, the prostasin zymogen. Additionally, SP domain glycosylation-deficient TMPRSS13 displayed impaired trafficking of TMPRSS13 to the cell surface, which correlated with increased retention in the endoplasmic reticulum. Importantly, we showed that N-linked glycosylation was a critical determinant for subsequent phosphorylation of endogenous TMPRSS13. Taken together, we conclude that glycosylation plays an important role in regulating TMPRSS13 activation and activity, phosphorylation, and cell surface localization.
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Membrana Celular/enzimología , Precursores Enzimáticos/metabolismo , Proteínas de la Membrana/metabolismo , Procesamiento Proteico-Postraduccional , Proteolisis , Serina Endopeptidasas/metabolismo , Animales , Células COS , Membrana Celular/genética , Chlorocebus aethiops , Precursores Enzimáticos/genética , Células HEK293 , Humanos , Proteínas de la Membrana/genética , Dominios Proteicos , Transporte de Proteínas/genética , Serina Endopeptidasas/genéticaRESUMEN
Soil enzymes mediate key processes and functions of the soils, such as organic matter decomposition and nutrient cycling in both natural and agricultural ecosystems. Here, we studied the activity of five extracellular soil enzymes involved in the C, N, and P-mineralizing process in both litter and surface soil layer of rainforest in the northwest region of the Colombian Amazon and the response of those soil enzymes to land use change. The experimental study design included six study sites for comparing long-term pasture systems to native forest and regeneration practices after pasture, within the main landscapes of the region, mountain and hill landscapes separately. Results showed considerable enzymatic activity in the litter layer of the forest, highlighting the vital role of this compartment in the nutrient cycling of low fertility soils from tropical regions. With the land use transition to pastures, changes in soil enzymatic activities were driven by the management of pastures, with SOC and N losses and reduced absolute activity of soil enzymes in long-term pastures under continuous grazing (25 years). However, the enzyme activities expressed per unit of SOC did not show changes in C and N-acquiring enzymes, suggesting a higher mineralization potential in pastures. Enzymatic stoichiometry analysis indicated a microbial P limitation that could lead to a high catabolic activity with a potential increase in the use of SOC by microbial communities in the search for P, thus affecting soil C sequestration, soil quality and the provision of soil-related ecosystem services.
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Acetilglucosaminidasa/análisis , Fosfatasa Ácida/análisis , Agricultura/métodos , Celulosa 1,4-beta-Celobiosidasa/análisis , Glucosidasas/análisis , Bosque Lluvioso , Suelo/química , Xilosidasas/análisis , Carbono/análisis , Colombia , Conservación de los Recursos Naturales , Microbiota , Nitrógeno/análisis , Fósforo/análisis , Microbiología del Suelo , Clima TropicalRESUMEN
The salivary glands of insects play a key role in the replication cycle and vectoring of viral pathogens. Consequently, Musca domestica (L.) (Diptera: Muscidae) and the Salivary Gland Hypertrophy Virus (MdSGHV) serve as a model to study insect vectoring of viruses. A better understanding of the structural changes of the salivary glands by the virus will help obtain a better picture of the pathological impact the virus has on adult flies. The salivary glands are a primary route for viruses to enter a new host. As such, studying the viral effect on the salivary glands is particularly important and can provide insights for the development of strategies to control the transmission of vector-borne diseases, such as dengue, malaria, Zika, and chikungunya virus. Using scanning and transmission electron microscopic techniques, researchers have shown the effects of infection by MdSGHV on the salivary glands; however, the exact location where the infection was found is unclear. For this reason, this study did a close examination of the effects of the hypertrophy virus on the salivary glands to locate the specific sites of infection. Here, we report that hypertrophy is present mainly in the secretory region, while other regions appeared unaffected. Moreover, there is a disruption of the cuticular, chitinous lining that separates the secretory cells from the lumen of the internal duct, and the disturbance of this lining makes it possible for the virus to enter the lumen. Thus, we report that the chitinous lining acts as an exit barrier of the salivary gland.
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Moscas Domésticas/virología , Virus de Insectos/patogenicidad , Glándulas Salivales/patología , Animales , Muscidae/virología , Glándulas Salivales/ultraestructura , Glándulas Salivales/virologíaRESUMEN
DNA polymerases play vital roles in the maintenance and replication of genomic DNA by synthesizing new nucleotide polymers using nucleoside triphosphates as substrates. Deoxynucleoside triphosphates (dNTPs) are the canonical substrates for DNA polymerases; however, some bacterial polymerases have been demonstrated to insert deoxynucleoside diphosphates (dNDPs), which lack a third phosphate group, the γ-phosphate. Whether eukaryotic polymerases can efficiently incorporate dNDPs has not been investigated, and much about the chemical or structural role played by the γ-phosphate of dNTPs remains unknown. Using the model mammalian polymerase (Pol) ß, we examine how Pol ß incorporates a substrate lacking a γ-phosphate [deoxyguanosine diphosphate (dGDP)] utilizing kinetic and crystallographic approaches. Using single-turnover kinetics, we determined dGDP insertion across a templating dC by Pol ß to be drastically impaired when compared to dGTP insertion. We found the most significant impairment in the apparent insertion rate (kpol), which was reduced 32000-fold compared to that of dGTP insertion. X-ray crystal structures revealed similar enzyme-substrate contacts for both dGDP and dGTP. These findings suggest the insertion efficiency of dGDP is greatly decreased due to impairments in polymerase chemistry. This work is the first instance of a mammalian polymerase inserting a diphosphate nucleotide and provides insight into the nature of polymerase mechanisms by highlighting how these enzymes have evolved to use triphosphate nucleotide substrates.
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ADN Polimerasa beta/química , Nucleótidos de Desoxiguanina/química , ADN/química , ADN Polimerasa beta/metabolismo , ADN Polimerasa Dirigida por ADN/metabolismo , Nucleótidos de Desoxiguanina/metabolismo , Desoxiguanosina/química , Difosfatos/química , Humanos , Cinética , Especificidad por SustratoRESUMEN
Carotenoids are lipophilic plastidial isoprenoids highly valued as nutrients and natural pigments. A correct balance of chlorophylls and carotenoids is required for photosynthesis and therefore highly regulated, making carotenoid enrichment of green tissues challenging. Here we show that leaf carotenoid levels can be boosted through engineering their biosynthesis outside the chloroplast. Transient expression experiments in Nicotiana benthamiana leaves indicated that high extraplastidial production of carotenoids requires an enhanced supply of their isoprenoid precursors in the cytosol, which was achieved using a deregulated form of the main rate-determining enzyme of the mevalonic acid (MVA) pathway. Constructs encoding bacterial enzymes were used to convert these MVA-derived precursors into carotenoid biosynthetic intermediates that do not normally accumulate in leaves, such as phytoene and lycopene. Cytosolic versions of these enzymes produced extraplastidial carotenoids at levels similar to those of total endogenous (i.e. chloroplast) carotenoids. Strategies to enhance the development of endomembrane structures and lipid bodies as potential extraplastidial carotenoid storage systems were not successful to further increase carotenoid contents. Phytoene was found to be more bioaccessible when accumulated outside plastids, whereas lycopene formed cytosolic crystalloids very similar to those found in the chromoplasts of ripe tomatoes. This extraplastidial production of phytoene and lycopene led to an increased antioxidant capacity of leaves. Finally, we demonstrate that our system can be adapted for the biofortification of leafy vegetables such as lettuce.
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Biofortificación , Carotenoides , Cloroplastos , Hojas de la Planta , PlastidiosRESUMEN
In this review, we summarize and discuss the trends and supporting findings in scientific literature on the gut mucosa immune role in European sea bass (Dicentrarchus labrax L.). Overall, the purpose is to provide an updated overview of the gastrointestinal tract functional regionalization and defence barriers. A description of the available information regarding immune cells found in two immunologically-relevant intestinal compartments, namely epithelium and lamina propria, is provided. Attention has been also paid to mucosal immunoglobulins and to the latest research investigating gut microbiota and dietary manipulation impacts. Finally, we review oral vaccination strategies, as a safe method for sea bass vaccine delivery.
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Inmunidad Adaptativa , Lubina/inmunología , Tracto Gastrointestinal/inmunología , Inmunidad Innata , AnimalesRESUMEN
Breast cancer progression is accompanied by increased expression of extracellular and cell-surface proteases capable of degrading the extracellular matrix as well as cleaving and activating downstream targets. The type II transmembrane serine proteases (TTSPs) are a family of cell-surface proteases that play critical roles in numerous types of cancers. Therefore, the aim of this study was to identify novel and uncharacterized TTSPs with differential expression in breast cancer and to determine their potential roles in progression. Systematic in silico data analysis followed by immunohistochemical validation identified increased expression of the TTSP family member, TMPRSS13 (transmembrane protease, serine 13), in invasive ductal carcinoma patient tissue samples compared to normal breast tissue. To test whether loss of TMPRSS13 impacts tumor progression, TMPRSS13 was genetically ablated in the oncogene-induced transgenic MMTV-PymT tumor model. TMPRSS13 deficiency resulted in a significant decrease in overall tumor burden and growth rate, as well as a delayed formation of detectable mammary tumors, thus suggesting a causal relationship between TMPRSS13 expression and the progression of breast cancer. Complementary studies using human breast cancer cell culture models revealed that siRNA-mediated silencing of TMPRSS13 expression decreases proliferation, induces apoptosis, and attenuates invasion. Importantly, targeting TMPRSS13 expression renders aggressive triple-negative breast cancer cell lines highly responsive to chemotherapy. At the molecular level, knockdown of TMPRSS13 in breast cancer cells led to increased protein levels of the tumor-suppressive protease prostasin. TMPRSS13/prostasin co-immunoprecipitation and prostasin zymogen activation experiments identified prostasin as a potential novel target for TMPRSS13. Regulation of prostasin levels may be a mechanism that contributes to the pro-oncogenic properties of TMPRSS13 in breast cancer. TMPRSS13 represents a novel candidate for targeted therapy in combination with standard of care chemotherapy agents in patients with hormone receptor-negative breast cancer or in patients with tumors refractory to endocrine therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma Ductal de Mama/patología , Neoplasias Mamarias Experimentales/patología , Proteínas de la Membrana/metabolismo , Serina Endopeptidasas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/genética , Mama/patología , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/genética , Línea Celular Tumoral , Supervivencia Celular/genética , Conjuntos de Datos como Asunto , Progresión de la Enfermedad , Resistencia a Antineoplásicos/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Glándulas Mamarias Animales/patología , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/genética , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Serina Endopeptidasas/genética , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genéticaRESUMEN
Cancer progression is often accompanied by increased levels of extracellular proteases capable of remodeling the extracellular matrix and promoting pro-cancerous signaling pathways by activating growth factors and receptors. The type II transmembrane serine protease (TTSP) family encompasses several proteases that play critical roles in cancer progression; however, the expression or function of the TTSP TMPRSS13 in carcinogenesis has not been examined. In the present study, we found TMPRSS13 to be differentially expressed at both the transcript and protein levels in human colorectal cancer (CRC). Immunohistochemical analyses revealed consistent high expression of TMPRSS13 protein on the cancer cell surface in CRC patient samples; in contrast, the majority of normal colon samples displayed no detectable expression. On a functional level, TMPRSS13 silencing in CRC cell lines increased apoptosis and impaired invasive potential. Importantly, transgenic overexpression of TMPRSS13 in CRC cell lines increased tolerance to apoptosis-inducing agents, including paclitaxel and HA14-1. Conversely, TMPRSS13 silencing rendered CRC cells more sensitive to these agents. Together, our findings suggest that TMPRSS13 plays an important role in CRC cell survival and in promoting resistance to drug-induced apoptosis; we also identify TMPRSS13 as a potential new target for monotherapy or combination therapy with established chemotherapeutics to improve treatment outcomes in CRC patients.
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Antineoplásicos/farmacología , Apoptosis , Neoplasias Colorrectales/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Serina Endopeptidasas/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Humanos , Proteínas de la Membrana/genética , Invasividad Neoplásica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Serina Endopeptidasas/genética , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
This method article proposes the establishment of a feasibility space as an objective to be achieved during the development of new technologies to convert energy from renewable resources. The feasibility space can also be a reference when designing an energy system based on renewable resources. The feasibility space is a set of parameter values for the design stage that define the economic and technical feasibility of an energy system or a new technology, which must be satisfied when the energy system comes into operation or when the new technology for converting power goes into operation. The study of possible feasibility spaces allows characterizing energy systems or new technologies as attractive investments, or on the other hand, as unfeasible ventures.-The method proposes to establish a goal to achieve during the development of technologies for energy conversion.-The method provides a benchmark for both the stages of design and development of generation systems and new technologies.-The feasibility space constitutes a planning tool for power systems based on renewable resources of any size.