RESUMEN
CSL proteins [named after the homologs CBF1 (RBP-Jκ in mice), Suppressor of Hairless and LAG-1] are conserved transcription factors found in animals and fungi. In the fission yeast Schizosaccharomyces pombe, they regulate various cellular processes, including cell cycle progression, lipid metabolism and cell adhesion. CSL proteins bind to DNA through their N-terminal Rel-like domain and central ß-trefoil domain. Here, we investigated the importance of DNA binding for CSL protein functions in fission yeast. We created CSL protein mutants with disrupted DNA binding and found that the vast majority of CSL protein functions depend on intact DNA binding. Specifically, DNA binding is crucial for the regulation of cell adhesion, lipid metabolism, cell cycle progression, long non-coding RNA expression and genome integrity maintenance. Interestingly, perturbed lipid metabolism leads to chromatin structure changes, potentially linking lipid metabolism to the diverse phenotypes associated with CSL protein functions. Our study highlights the critical role of DNA binding for CSL protein functions in fission yeast.
Asunto(s)
Proteínas de Ciclo Celular , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Factores de Transcripción , Schizosaccharomyces/metabolismo , Schizosaccharomyces/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , Proteínas de Schizosaccharomyces pombe/genética , Unión Proteica , Metabolismo de los Lípidos/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Ciclo Celular/genética , Regulación Fúngica de la Expresión Génica , ADN de Hongos/metabolismo , ADN de Hongos/genéticaRESUMEN
BACKGROUND: In kidney damage, molecular changes can be used as early damage kidney biomarkers, such as Kidney Injury Molecule-1 and Neutrophil gelatinase-associated lipocalin. These biomarkers are associated with toxic metal exposure or disturbed homeostasis of trace elements, which might lead to serious health hazards. This study aimed to evaluate the relationship between exposure to trace elements and early damage kidney biomarkers in a pediatric population. METHODS: In Tlaxcala, a cross-sectional study was conducted on 914 healthy individuals. The participants underwent a medical review and a socio-environmental questionnaire. Five early damage kidney biomarkers were determined in the urine with Luminex, and molybdenum, copper, selenium, nickel, and iodine were measured with ICP-Mass. RESULTS: The eGFR showed a median of 103.75 mL/min/1.73 m2. The median levels for molybdenum, copper, selenium, nickel, and iodine were 24.73 ng/mL, 73.35 ng/mL, 4.78 ng/mL, 83.68 ng/mL, and 361.83 ng/mL, respectively. Except for molybdenum and nickel, the other trace elements had significant associations with the eGFR and the early kidney damage biomarkers. Additionally, we report the association of different exposure scenarios with renal parameters. DISCUSSION: and Conclusions. Among the explored metals, exposure to Cu and iodine impairs renal function. In contrast, Se may manifest as a beneficial metal. Interactions of Mo-Se and Mo-Iodine seem to alter the expression of NGAL; Mo-Cu for CLU; Mo-Cu, Mo-Se, and Mo-iodine for Cys-C and a-1MG; and Mo-Cu and Mo-iodine for KIM-1; were noticed. Our study could suggest that trace element interactions were associated with early kidney damage biomarkers.
Asunto(s)
Biomarcadores , Exposición a Riesgos Ambientales , Oligoelementos , Humanos , Biomarcadores/orina , Biomarcadores/metabolismo , Niño , Masculino , Femenino , Oligoelementos/análisis , Oligoelementos/orina , Exposición a Riesgos Ambientales/efectos adversos , Estudios Transversales , Adolescente , Lipocalina 2/orina , Tasa de Filtración Glomerular , Cobre/orina , Cobre/análisis , Selenio/orina , Selenio/análisis , Enfermedades Renales/inducido químicamente , Enfermedades Renales/orina , Enfermedades Renales/metabolismo , Riñón/metabolismo , Preescolar , Níquel/orinaRESUMEN
BACKGROUND: In vitro embryo production is a highly demanded reproductive technology in horses, which requires the recovery (in vivo or post-mortem) and in vitro maturation (IVM) of oocytes. Oocytes subjected to IVM exhibit poor developmental competence compared to their in vivo counterparts, being this related to a suboptimal composition of commercial maturation media. The objective of this work was to study the effect of different concentrations of secretome obtained from equine preovulatory follicular fluid (FF) on cumulus-oocyte complexes (COCs) during IVM. COCs retrieved in vivo by ovum pick up (OPU) or post-mortem from a slaughterhouse (SLA) were subjected to IVM in the presence or absence of secretome (Control: 0 µg/ml, S20: 20 µg/ml or S40: 40 µg/ml). After IVM, the metabolome of the medium used for oocyte maturation prior (Pre-IVM) and after IVM (Post-IVM), COCs mRNA expression, and oocyte meiotic competence were analysed. RESULTS: IVM leads to lactic acid production and an acetic acid consumption in COCs obtained from OPU and SLA. However, glucose consumption after IVM was higher in COCs from OPU when S40 was added (Control Pre-IVM vs. S40 Post-IVM: 117.24 ± 7.72 vs. 82.69 ± 4.24; Mean µM ± SEM; p < 0.05), while this was not observed in COCs from SLA. Likewise, secretome enhanced uptake of threonine (Control Pre-IVM vs. S20 Post-IVM vs. S40 Post-IVM: 4.93 ± 0.33 vs. 3.04 ± 0.25 vs. 2.84 ± 0.27; Mean µM ± SEM; p < 0.05) in COCs recovered by OPU. Regarding the relative mRNA expression of candidate genes related to metabolism, Lactate dehydrogenase A (LDHA) expression was significantly downregulated when secretome was added during IVM at 20-40 µg/ml in OPU-derived COCs (Control vs. S20 vs. S40: 1.77 ± 0.14 vs. 1 ± 0.25 vs. 1.23 ± 0.14; fold change ± SEM; p < 0.05), but not in SLA COCs. CONCLUSIONS: The addition of secretome during in vitro maturation (IVM) affects the gene expression of LDHA, glucose metabolism, and amino acid turnover in equine cumulus-oocyte complexes (COCs), with diverging outcomes observed between COCs retrieved using ovum pick up (OPU) and slaughterhouse-derived COCs (SLA).
Asunto(s)
Medios de Cultivo , Células del Cúmulo , Líquido Folicular , Técnicas de Maduración In Vitro de los Oocitos , Oocitos , Animales , Caballos , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Líquido Folicular/metabolismo , Líquido Folicular/química , Técnicas de Maduración In Vitro de los Oocitos/veterinaria , Células del Cúmulo/metabolismo , Células del Cúmulo/efectos de los fármacos , Femenino , Medios de Cultivo/farmacología , Secretoma/metabolismoRESUMEN
Streptococcus pneumoniae is a major cause of disease and death that develops resistance to multiple antibiotics. DNA topoisomerase I (TopoI) is a novel pneumococcal drug target. TopoI is the sole type-I pneumococcal topoisomerase that regulates supercoiling homeostasis in this bacterium. In this study, a direct in vitro interaction between TopoI and RNA polymerase (RNAP) was detected by surface plasmon resonance. To understand the interplay between transcription and supercoiling regulation in vivo, genome-wide association of RNAP and TopoI was studied by ChIP-Seq. RNAP and TopoI were enriched at the promoters of 435 and 356 genes, respectively. Higher levels of expression were consistently measured in those genes whose promoters recruit both RNAP and TopoI, in contrast with those enriched in only one of them. Both enzymes occupied a narrow region close to the ATG codon. In addition, RNAP displayed a regular distribution throughout the coding regions. Likewise, the summits of peaks called with MACS tool, mapped around the ATG codon in both cases. However, RNAP showed a broader distribution towards ATG-downstream positions. Remarkably, inhibition of RNAP with rifampicin prevented the localization of TopoI at promoters and, vice versa, inhibition of TopoI with seconeolitsine prevented the binding of RNAP to promoters. This indicates a functional interplay between RNAP and TopoI. To determine the molecular factors responsible for RNAP and TopoI co-recruitment, we looked for DNA sequence motifs. We identified a motif corresponding to a -10-extended promoter for TopoI and for RNAP. Furthermore, RNAP was preferentially recruited to genes co-directionally oriented with replication, while TopoI was more abundant in head-on genes. TopoI was located in the intergenic regions of divergent genes pairs, near the promoter of the head-on gene of the pair. These results suggest a role for TopoI in the formation/stability of the RNAP-DNA complex at the promoter and during transcript elongation.
Asunto(s)
ADN-Topoisomerasas de Tipo I/genética , ARN Polimerasas Dirigidas por ADN/genética , Infecciones Neumocócicas/genética , Streptococcus pneumoniae/genética , Transcripción Genética/efectos de los fármacos , Farmacorresistencia Bacteriana/genética , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Genoma Bacteriano/genética , Motivos de Nucleótidos/efectos de los fármacos , Infecciones Neumocócicas/tratamiento farmacológico , Infecciones Neumocócicas/microbiología , Regiones Promotoras Genéticas/genética , Rifampin/farmacología , Streptococcus pneumoniae/patogenicidad , Resonancia por Plasmón de SuperficieRESUMEN
The rise of antimicrobial resistance poses a significant global health threat, necessitating urgent efforts to identify novel antimicrobial agents. In this study, we undertook a thorough screening of soil-derived bacterial isolates to identify candidates showing antimicrobial activity against Gram-positive bacteria. A highly active antagonistic isolate was initially identified as Bacillus altitudinis ECC22, being further subjected to whole genome sequencing. A bioinformatic analysis of the B. altitudinis ECC22 genome revealed the presence of two gene clusters responsible for synthesizing two circular bacteriocins: pumilarin and a novel circular bacteriocin named altitudin A, alongside a closticin 574-like bacteriocin (CLB) structural gene. The synthesis and antimicrobial activity of the bacteriocins, pumilarin and altitudin A, were evaluated and validated using an in vitro cell-free protein synthesis (IV-CFPS) protocol coupled to a split-intein-mediated ligation procedure, as well as through their in vivo production by recombinant E. coli cells. However, the IV-CFPS of CLB showed no antimicrobial activity against the bacterial indicators tested. The purification of the bacteriocins produced by B. altitudinis ECC22, and their evaluation by MALDI-TOF MS analysis and LC-MS/MS-derived targeted proteomics identification combined with massive peptide analysis, confirmed the production and circular conformation of pumilarin and altitudin A. Both bacteriocins exhibited a spectrum of activity primarily directed against other Bacillus spp. strains. Structural three-dimensional predictions revealed that pumilarin and altitudin A may adopt a circular conformation with five- and four-α-helices, respectively.
Asunto(s)
Bacillus , Bacteriocinas , Bacteriocinas/genética , Bacteriocinas/farmacología , Antibacterianos/química , Cromatografía Liquida , Escherichia coli/metabolismo , Espectrometría de Masas en Tándem , Bacillus/metabolismoRESUMEN
The topology of DNA duplexes changes during replication and also after deproteinization in vitro. Here we describe these changes and then discuss for the first time how the distribution of superhelical stress affects the DNA topology of replication intermediates, taking into account the progression of replication forks. The high processivity of Topo IV to relax the left-handed (+) supercoiling that transiently accumulates ahead of the forks is not essential, since DNA gyrase and swiveling of the forks cooperate with Topo IV to accomplish this task in vivo. We conclude that despite Topo IV has a lower processivity to unlink the right-handed (+) crossings of pre-catenanes and fully replicated catenanes, this is indeed its main role in vivo. This would explain why in the absence of Topo IV replication goes-on, but fully replicated sister duplexes remain heavily catenated.
Asunto(s)
Replicación del ADN , Topoisomerasa de ADN IV , ADN/genética , Topoisomerasa de ADN IV/genética , Topoisomerasa de ADN IV/metabolismo , Conformación de Ácido NucleicoRESUMEN
To explore the existing literature on the effect of Interprofessional Education (IPE) on the work environment of health professionals. The research question was systematized according to the PCC (Population, Concept, and Context) format. A scoping review was performed. A search of multiple bibliographic databases identified 407 papers, of which 21 met the inclusion criteria. The populations of the 21 studies reviewed were composed of professionals in the fields of medicine, nursing, psychology, occupational therapy, physiotherapy, and social work, among others. The study contexts were both academic and nonacademic hospitals, mental health institutions, and community settings, and the topics examined were organizational climate, organizational culture, organizational attachment and job satisfaction. The findings from the reviewed studies showed positive effects of IPE interventions on organizational climate and culture, but the results on job satisfaction and organizational attachment were mixed (i.e., positive and no effects following IPE interventions). Research on IPE is worth more attention as IPE could be an effective alternative for the fulfillment of the Quadruple Aim and achieving the third of the United Nations Sustainable Development Goals, aimed at improving health and well-being. It seems critical for IPE to be positioned as a trend in global health, aiming at boosting human health resources as one of its building blocks and calling the attention of health decision-makers.
RESUMEN
Topoisomerase I (TopoI) in Streptococcus pneumoniae, encoded by topA, is a suitable target for drug development. Seconeolitsine (SCN) is a new antibiotic that specifically blocks this enzyme. We obtained the topARA mutant, which encodes an enzyme less active than the wild type (topAWT) and more resistant to SCN inhibition. Likely due to the essentiality of TopoI, we were unable to replace the topAWT allele by the mutant topARA version. We compared the in vivo activity of TopoIRA and TopoIWT using regulated overexpression strains, whose genes were either under the control of a moderately (PZn) or a highly active promoter (PMal). Overproduction of TopoIRA impaired growth, increased SCN resistance and, in the presence of the gyrase inhibitor novobiocin (NOV), caused lower relaxation than TopoIWT. Differential transcriptomes were observed when the topAWT and topARA expression levels were increased about 5-fold. However, higher increases (10-15 times), produced a similar transcriptome, affecting about 52% of the genome, and correlating with a high DNA relaxation level with most responsive genes locating in topological domains. These results confirmed that TopoI is indeed the target of SCN in S. pneumoniae and show the important role of TopoI in global transcription, supporting its suitability as an antibiotic target.
Asunto(s)
ADN-Topoisomerasas de Tipo I , Transcriptoma , ADN-Topoisomerasas de Tipo I/genética , ADN-Topoisomerasas de Tipo I/metabolismo , Streptococcus pneumoniae/genética , Girasa de ADN/genética , Girasa de ADN/metabolismo , Antibacterianos/farmacologíaRESUMEN
Recently, the food industry and the animal farming field have been working on different strategies to reduce the use of antibiotics in animal production. The use of probiotic producers of antimicrobial peptides (bacteriocins) is considered to be a potential solution to control bacterial infections and to reduce the use of antibiotics in animal production. In this study, Ligilactobacillus salivarius P1CEA3, isolated from the gastrointestinal tract (GIT) of pigs, was selected for its antagonistic activity against Gram-positive pathogens of relevance in swine production. Whole genome sequencing (WGS) of L. salivarius P1ACE3 revealed the existence of two gene clusters involved in bacteriocin production, one with genes encoding the class II bacteriocins salivaricin B (SalB) and Abp118, and a second cluster encoding a putative nisin variant. Colony MALDI-TOF MS determinations and a targeted proteomics combined with massive peptide analysis (LC-MS/MS) of the antimicrobial peptides encoded by L. salivarius P1CEA3 confirmed the production of a 3347 Da novel nisin variant, termed nisin S, but not the production of the bacteriocins SalB and Abp118, in the supernatants of the producer strain. This is the first report of a nisin variant encoded and produced by L. salivarius, a bacterial species specially recognized for its safety and probiotic potential.
Asunto(s)
Bacteriocinas , Ligilactobacillus salivarius , Nisina , Porcinos , Animales , Nisina/genética , Nisina/farmacología , Cromatografía Liquida , Espectrometría de Masas en Tándem , Bacteriocinas/genética , Bacteriocinas/farmacología , Antibacterianos/farmacología , Péptidos AntimicrobianosRESUMEN
The DNA topoisomerases gyrase and topoisomerase I as well as the nucleoid-associated protein HU maintain supercoiling levels in Streptococcus pneumoniae, a main human pathogen. Here, we characterized, for the first time, a topoisomerase I regulator protein (StaR). In the presence of sub-inhibitory novobiocin concentrations, which inhibit gyrase activity, higher doubling times were observed in a strain lacking staR, and in two strains in which StaR was over-expressed either under the control of the ZnSO4-inducible PZn promoter (strain ΔstaRPZnstaR) or of the maltose-inducible PMal promoter (strain ΔstaRpLS1ROMstaR). These results suggest that StaR has a direct role in novobiocin susceptibility and that the StaR level needs to be maintained within a narrow range. Treatment of ΔstaRPZnstaR with inhibitory novobiocin concentrations resulted in a change of the negative DNA supercoiling density (σ) in vivo, which was higher in the absence of StaR (σ = -0.049) than when StaR was overproduced (σ = -0.045). We have located this protein in the nucleoid by using super-resolution confocal microscopy. Through in vitro activity assays, we demonstrated that StaR stimulates TopoI relaxation activity, while it has no effect on gyrase activity. Interaction between TopoI and StaR was detected both in vitro and in vivo by co-immunoprecipitation. No alteration of the transcriptome was associated with StaR amount variation. The results suggest that StaR is a new streptococcal nucleoid-associated protein that activates topoisomerase I activity by direct protein-protein interaction.
Asunto(s)
ADN-Topoisomerasas de Tipo I , Streptococcus pneumoniae , Humanos , ADN-Topoisomerasas de Tipo I/genética , ADN-Topoisomerasas de Tipo I/metabolismo , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/metabolismo , Novobiocina/farmacología , ADN Bacteriano/genética , Girasa de ADN/genética , Girasa de ADN/metabolismoRESUMEN
The coronavirus pandemic has brought about global change in travel behavior. Transit ridership volumes have dropped to record lows. Concerning environmental, health, and social consequences lie in store if transit networks are not able to regain a substantial portion of pre-pandemic users. Transit providers have implemented several interventions aimed at both slowing the spread of the virus and retaining riders as travel restrictions lift. While the effectiveness of these measures has been evaluated with respect to spread rate reduction, little consideration has been given to their impact on riders' feelings of worry regarding virus contraction. By deploying a photo-simulation approach in a randomized control trial, this study finds that level of compliance with safety measures and the conditions of transit spaces themselves significantly impact riders' levels of worry. Given these findings, a series of recommendations are made regarding compliance practices that are expected to lessen rider worry regarding the risks of COVID-19 infection.
RESUMEN
During replication, the topology of DNA changes continuously in response to well-known activities of DNA helicases, polymerases, and topoisomerases. However, replisomes do not always progress at a constant speed and can slow-down and even stall at precise sites. The way these changes in the rate of replisome progression affect DNA topology is not yet well understood. The interplay of DNA topology and replication in several cases where progression of replication forks reacts differently to changes in DNA topology ahead is discussed here. It is proposed, there are at least two types of replication fork barriers: those that behave also as topological barriers and those that do not. Two-Dimensional (2D) agarose gel electrophoresis is the method of choice to distinguish between these two different types of replication fork barriers.
Asunto(s)
Replicación del ADN , ADN , ADN/genética , ADN Helicasas/metabolismoRESUMEN
Presynaptic neurotransmitter release is strictly regulated by SNARE proteins, Ca2+ and a number of Ca2+ sensors including synaptotagmins (Syts) and Double C2 domain proteins (Doc2s). More than seventy years after the original description of spontaneous release, the mechanism that regulates this process is still poorly understood. Syt-1, Syt7 and Doc2 proteins contribute predominantly, but not exclusively, to synchronous, asynchronous and spontaneous phases of release. The proteins share a conserved tandem C2 domain architecture, but are functionally diverse in their subcellular location, Ca2+-binding properties and protein interactions. In absence of Syt-1, Doc2a and -b, neurons still exhibit spontaneous vesicle fusion which remains Ca2+-sensitive, suggesting the existence of additional sensors. Here, we selected Doc2c, rabphilin-3a and Syt-7 as three potential Ca2+ sensors for their sequence homology with Syt-1 and Doc2b. We genetically ablated each candidate gene in absence of Doc2a and -b and investigated spontaneous and evoked release in glutamatergic hippocampal neurons, cultured either in networks or on microglial islands (autapses). The removal of Doc2c had no effect on spontaneous or evoked release. Syt-7 removal also did not affect spontaneous release, although it altered short-term plasticity by accentuating short-term depression. The removal of rabphilin caused an increased spontaneous release frequency in network cultures, an effect that was not observed in autapses. Taken together, we conclude that Doc2c and Syt-7 do not affect spontaneous release of glutamate in hippocampal neurons, while our results suggest a possible regulatory role of rabphilin-3a in neuronal networks. These findings importantly narrow down the repertoire of synaptic Ca2+ sensors that may be implicated in the spontaneous release of glutamate.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/fisiología , Proteínas de Unión al Calcio/fisiología , Calcio/metabolismo , Hipocampo/metabolismo , Proteínas del Tejido Nervioso/fisiología , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Sinaptotagmina I/fisiología , Proteínas de Transporte Vesicular/fisiología , Potenciales de Acción , Proteínas Adaptadoras Transductoras de Señales/química , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Proteínas Adaptadoras Transductoras de Señales/genética , Secuencia de Aminoácidos , Animales , Proteínas de Unión al Calcio/química , Proteínas de Unión al Calcio/deficiencia , Proteínas de Unión al Calcio/genética , Células Cultivadas , Secuencia Conservada , Ácido Glutámico/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Potenciales Postsinápticos Miniatura/fisiología , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Técnicas de Placa-Clamp , Dominios Proteicos , Proteínas Recombinantes/metabolismo , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Sinaptotagmina I/química , Sinaptotagmina I/deficiencia , Sinaptotagmina I/genética , Proteínas de Transporte Vesicular/química , Proteínas de Transporte Vesicular/deficiencia , Proteínas de Transporte Vesicular/genética , Rabfilina-3ARESUMEN
The high impact of air quality on environmental and human health justifies the increasing research activity regarding its measurement, modelling, forecasting and anomaly detection. Raw data offered by sensors usually makes the mentioned time series disciplines difficult. This is why the application of techniques to improve time series processing is a challenge. In this work, Singular Spectral Analysis (SSA) is applied to air quality analysis from real recorded data as part of the Help Responder research project. Authors evaluate the benefits of working with SSA processed data instead of raw data for modelling and estimation of the resulting time series. However, what is more relevant is the proposal to detect indoor air quality anomalies based on the analysis of the time derivative SSA signal when the time derivative of the noisy original data is useless. A dual methodology, evaluating level and dynamics of the SSA signal variation, contributes to identifying risk situations derived from air quality degradation.
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Contaminantes Atmosféricos , Contaminación del Aire Interior , Contaminación del Aire , Contaminantes Atmosféricos/análisis , Contaminación del Aire/análisis , Contaminación del Aire Interior/análisis , Monitoreo del Ambiente/métodos , Predicción , HumanosRESUMEN
Clinical data suggest that cardiosphere-derived cells (CDCs) could modify post-infarction scar and ventricular remodeling and reduce the incidence of ventricular tachycardia (VT). This paper assesses the effect of CDCs on VT substrate in a pig model of postinfarction monomorphic VT. We studied the effect of CDCs on the electrophysiological properties and histological structure of dense scar and heterogeneous tissue (HT). Optical mapping and histological evaluation were performed 16 weeks after the induction of a myocardial infarction by transient occlusion of the left anterior descending (LAD) artery in 21 pigs. Four weeks after LAD occlusion, pigs were randomized to receive intracoronary plus trans-myocardial CDCs (IC+TM group, n: 10) or to a control group. Optical mapping (OM) showed an action potential duration (APD) gradient between HT and normal tissue in both groups. CDCs increased conduction velocity (53 ± 5 vs. 45 ± 6 cm/s, p < 0.01), prolonged APD (280 ± 30 ms vs. 220 ± 40 ms, p < 0.01) and decreased APD dispersion in the HT. During OM, a VT was induced in one and seven of the IC+TM and control hearts (p = 0.03), respectively; five of these VTs had their critical isthmus located in intra-scar HT found adjacent to the coronary arteries. Histological evaluation of HT revealed less fibrosis (p < 0.01), lower density of myofibroblasts (p = 0.001), and higher density of connexin-43 in the IC+TM group. Scar and left ventricular volumes did not show differences between groups. Allogeneic CDCs early after myocardial infarction can modify the structure and electrophysiology of post-infarction scar. These findings pave the way for novel therapeutic properties of CDCs.
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Infarto del Miocardio , Taquicardia Ventricular , Animales , Cicatriz/patología , Corazón , Infarto del Miocardio/patología , Miocardio/patología , Células Madre/patología , Porcinos , Taquicardia Ventricular/patologíaRESUMEN
High-risk human papillomavirus type 16/18 (HPV16/18) genotyping is unable to accurately discriminate nonprogressive infections from those that will progress to cervical cancer. Our study aimed to assesses if additional testing either with liquid-based cytology (LBC) or the putative progression markers p16/Ki-67 and HPV16/18 E6 oncoprotein (E6) can improve the efficiency of HPV16/18 genotyping for triaging high-risk HPV (hrHPV)-positive women through better cancer risk stratification. Women attending colposcopy after positive HPV16/18 genotyping results within the Forwarding Research for Improved Detection and Access for Cervical Cancer Screening and Triage (FRIDA) hrHPV-based screening study in Tlaxcala, Mexico, underwent further testing with LBC, p16/Ki-67 dual-stained (DS) cytology and E6. We calculated measures of test performance for detecting histologically confirmed cervical intraepithelial neoplasia grade 2 or higher (CIN2+) and grade 3 or higher (CIN3+). A number of 475 (64.3%) of 739 HPV16/18-positive women had complete results for all tests. Triage positivity rates were 14.1%, 18.5% and 24.4%, for LBC, E6 and DS, respectively. Compared with LBC, DS had higher sensitivity (24.4% vs 60.0%) although lower specificity (87.0% vs 79.3%) for CIN3+ (P < .001), whereas E6 had a sensitivity of 37.8% and a specificity of 83.5%. No invasive cancer was missed by DS or E6, but 75% were in normal cytology. DS test was associated with nearly 75% reduction of colposcopy referrals compared with the direct referral of all HPV16/18-positive women, giving the least number of colposcopies (n = 4.3) per CIN3+ detected. We show that adjunctive testing of HPV16/18-positive women with DS may greatly reduce unnecessary colposcopy referrals within HPV-based screening employing HPV16/18 genotyping while retaining acceptable sensitivity for CIN2+ and CIN3+.
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Detección Precoz del Cáncer/métodos , Papillomavirus Humano 16/metabolismo , Papillomavirus Humano 18/metabolismo , Antígeno Ki-67/metabolismo , Proteínas Oncogénicas/metabolismo , Infecciones por Papillomavirus/virología , Adulto , Femenino , HumanosRESUMEN
CK11 is a rainbow trout (Oncorhynchus mykiss) CC chemokine phylogenetically related to both mammalian CCL27 and CCL28 chemokines, strongly transcribed in skin and gills in homeostasis, for which an immune role had not been reported to date. In the current study, we have demonstrated that CK11 is not chemotactic for unstimulated leukocyte populations from central immune organs or mucosal tissues but instead exerts a potent antimicrobial activity against a wide range of rainbow trout pathogens. Our results show that CK11 strongly inhibits the growth of different rainbow trout Gram-positive and Gram-negative bacteria, namely Lactococcus garvieae, Aeromonas salmonicida subsp. salmonicida, and Yersinia ruckeri and a parasitic ciliate Ichthyophthirius multifiliis Similarly to mammalian chemokines and antimicrobial peptides, CK11 exerted its antimicrobial activity, rapidly inducing membrane permeability in the target pathogens. Further transcriptional studies confirmed the regulation of CK11 transcription in response to exposure to some of these pathogens in specific conditions. Altogether, our studies related to phylogenetic relations, tissue distribution, and biological activity point to CK11 as a potential common ancestor of mammalian CCL27 and CCL28. To our knowledge, this study constitutes the first report of a fish chemokine with antimicrobial activity, thus establishing a novel role for teleost chemokines in antimicrobial immunity that supports an evolutionary relationship between chemokines and antimicrobial peptides.
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Quimiocinas CC/inmunología , Bacterias Gramnegativas/inmunología , Bacterias Grampositivas/inmunología , Oncorhynchus mykiss/inmunología , Aeromonas salmonicida , Animales , Quimiocina CCL27/genética , Quimiocinas CC/genética , Quimiocinas CC/aislamiento & purificación , Quimiotaxis , Perfilación de la Expresión Génica , Branquias/inmunología , Filogenia , Piel/inmunología , Yersinia ruckeriRESUMEN
Due to helical structure of DNA, massive amounts of positive supercoils are constantly introduced ahead of each replication fork. Positive supercoiling inhibits progression of replication forks but various mechanisms evolved that permit very efficient relaxation of that positive supercoiling. Some of these mechanisms lead to interesting topological situations where DNA supercoiling, catenation and knotting coexist and influence each other in DNA molecules being replicated. Here, we first review fundamental aspects of DNA supercoiling, catenation and knotting when these qualitatively different topological states do not coexist in the same circular DNA but also when they are present at the same time in replicating DNA molecules. We also review differences between eukaryotic and prokaryotic cellular strategies that permit relaxation of positive supercoiling arising ahead of the replication forks. We end our review by discussing very recent studies giving a long-sought answer to the question of how slow DNA topoisomerases capable of relaxing just a few positive supercoils per second can counteract the introduction of hundreds of positive supercoils per second ahead of advancing replication forks.
Asunto(s)
Replicación del ADN , ADN Encadenado/química , ADN Circular/química , ADN Superhelicoidal/química , ADN/química , Conformación de Ácido Nucleico , ADN/genética , Células Eucariotas/metabolismo , Modelos Moleculares , Células Procariotas/metabolismoRESUMEN
We demonstrate efficient pulse-energy extraction from a partly quenched erbium-doped aluminosilicate fiber amplifier. This has a high erbium concentration that allows for short devices with reduced nonlinear distortions but also results in partial quenching and thus significant unsaturable absorption, even though the fiber is still able to amplify. Although the quenching degrades the average-power efficiency, the pulse energy remains high, and our results point to an increasingly promising outcome for short pulses. Furthermore, unlike unquenched fibers, the conversion efficiency improves at low repetition rates, which we attribute to smaller relative energy loss to quenched ions at higher pulse energy. A short (2.6 m) cladding-pumped partly quenched Er-doped fiber with 95-dB/m 1530-nm peak absorption and saturation energy estimated to 85 µJ reached 0.8 mJ of output energy when seeded by 0.2-µs, 23-µJ pulses. Thus, according to our results, pulses can be amplified to high energy in short highly Er-doped fibers designed to reduce nonlinear distortions at the expense of average-power efficiency.
RESUMEN
OBJECTIVE: To assess the relationship between labor quality of life (LQL) and organizational workers performance (OWP) from seven public hospitals, analyzing the influence of the personnel management (PM) as mediator of this relationship. MATERIALS AND METHODS: A cross-sectional study was conducted in 866 professionals and managers of public hospitals from Tlaxcala and Mexico City. The LQL was assessed with a validated questionnaire, OWP with 34 indicators, and PM with an instrument designed for this study. RESULTS: Mean scores of LQL, were significantly lower among workers from Tlaxcala. Participants who perceived an adequate PM, they increased at 2.7 times their likelihood of having highest LQL, and participants categorized in the high LQL presented 69% higher likelihood of having an adequate OWP. CONCLUSIONS: The appropriate PM was associated with greater LQL, showing to be a mediator variable between the positive relationship of CVL and the OWP.
OBJETIVO: Evaluar la relación entre calidad de vida laboral (CVL) y el desempeño organizacional (DO) de trabajadores de siete hospitales públicos, a partir del análisis de la influencia de la gestión directiva (GD) como mediadora de esta relación. MATERIAL Y MÉTODOS: Se realizó un estudio transversal en 866 profesionales y directivos de hospitales públicos de Tlaxcala y de la Ciudad de México. La CVL fue medida con un instrumento validado, el DO con 34 indicadores y la GD con un instrumento diseñado para este estudio. RESULTADOS: Los puntajes de gestión directiva, CVL, DO y GD fueron sig- nificativamente menores en los trabajadores de Tlaxcala. Los participantes que percibieron adecuada GD incrementaron 2.7 veces más la probabilidad de percibir elevada CVL y los participantes categorizados en elevada CVL presentaron 69% mayor probabilidad de tener adecuado DO. CONCLUSIONES: La adecuada GD se asoció con una mejor CVL, lo que mostró ser una variable mediadora de la relación positiva entre CVL y DO.