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Background: Informed consent (IC) is essential in defending the autonomy of potential participants in clinical research. Despite the advances in research ethics, particularly in IC, the different guidelines and codes have not been fully implemented. Several studies have presented consent deficiencies that have resulted in unethical practices or poor understanding of the IC. Main body: This article reviews the evolution of IC, from its philosophical origins and initial use in the Ottoman Empire (16th century) to its use in clinical research today. It also presents the vision of the European project i-CONSENT (Grant Agreement number: 741856), whose main purpose is to improve the understanding of ICs in research and identifies the key components of a new paradigm to develop patient-centred ICs. Conclusions: In many cases, the IC has served to protect the investigator or sponsor from complaints. Different ethical guidelines have sought to make the IC a more useful tool, with little success. Today's IC is mainly a bureaucratic and legal process that fails to consider the patient's point of view. In this context, the Guidelines for Tailoring the Informed Consent Process in Clinical Studies provide alternatives to the current IC process, focusing on the patient's opinions and making them part of the process, thereby improving clinical research quality.
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The use of waste to capture CO2 has been on the rise, to reduce costs and to improve the environmental footprint. Here, a flue gas desulfurization (FGD) gypsum waste is proposed, which allows us to obtain a CaCO3-based solid, which should be recycled. The CO2 capture stage has primarily been carried out via the direct carbonation method or at high temperature. However, a high energy penalty and/or long reaction times make it unattractive from an industrial perspective. To avoid this, herein an indirect method is proposed, based on first capturing the CO2 with NaOH and later using an aqueous carbonation stage. This allows us to capture CO2 at a near-ambient temperature, improving reaction times and avoiding the energy penalty. The parameters studied were Ca2+/CO32- ratio, L/S ratio and temperature. Each of them has been optimized, with 1.25, 100 mL/g and 25 °C being the optimal values, respectively, reaching an efficiency of 72.52%. Furthermore, the utilization of the produced CaCO3 as a building material has been analyzed. The density, superficial hardness and the compressive strength of a material composed of 10 wt% of CaCO3 and 90 wt% of commercial gypsum, with a water/solid ratio of 0.5, is measured. When the waste is added, the density and the mechanical properties decreased, although the compressive strength and superficial hardness are higher than the requirements for gypsum panels. Thus, this work is promising for the carbonation of FGD-gypsum, which involves its chemical transformation into calcium carbonate through reacting it with the CO2 of flue gasses and recycling the generated wastes in construction materials.
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Cervical cancer constitutes a significant health burden for women worldwide despite being preventable by vaccination and screening. Advanced stages of the disease are associated with a poor prognosis, and treatment approaches have seen little change over several decades, resulting in an overall survival rate of no more than 17 months. Additionally, there are limited options for second-line treatment. The urgent need for innovative and effective therapies to improve the outlook for this group of patients, along with an enhanced understanding of the interactions between the disease and the host's immune system, has propelled immunotherapy into a rapidly advancing field with notable achievements. Among various immunotherapeutic approaches, immune checkpoint inhibitors emerge as the most advanced treatment option. Clinical trials assessing these inhibitors as single agents or in combination with chemotherapy show promising results. As immunotherapy begins to redefine standards of care for metastatic, recurrent, or persistent cervical cancer, this review addresses recent advances and current recommendations for its management in both first and second-line treatment. The goal is to provide insights into the evolving landscape of cervical cancer treatment, specifically focusing on immunotherapeutic interventions.
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Aim: Rose Bengal photodynamic antimicrobial therapy (RB-PDAT) has poor corneal penetration, limiting its efficacy against acanthamoeba keratitis (AK). Iontophoresis enhances corneal permeation of charged molecules, piquing interest in its effects on RB in ex vivo human corneas.Methods: Five donor whole globes each underwent iontophoresis with RB, soaking in RB, or were soaked in normal saline (controls). RB penetration and corneal thickness was assessed using confocal microscopy.Results: Iontophoresis increased RB penetration compared with soaking (177 ± 9.5 µm vs. 100 ± 5.7 µm, p < 0.001), with no significant differences in corneal thickness between groups (460 ± 87 µm vs. 407 ± 69 µm, p = 0.432).Conclusion: Iontophoresis significantly improves RB penetration and its use in PDAT could offer a novel therapy for acanthamoeba keratitis. Further studies are needed to validate clinical efficacy.
The study aimed to improve a new treatment for eye infections known as photodynamic antimicrobial therapy. It investigated whether the use of electricity through a technique called iontophoresis could help a chemical called Rose Bengal go deeper into the eye in order to target more severe infections. The iontophoresis machine was custom built, with patient-contacting components 3D printed. The experiments were performed using donated human eye tissue and found that iontophoresis significantly improved the penetration depth of Rose Bengal as compared with the current technique of only soaking the eye in Rose Bengal.
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Queratitis por Acanthamoeba , Córnea , Iontoforesis , Rosa Bengala , Humanos , Rosa Bengala/administración & dosificación , Iontoforesis/métodos , Córnea/metabolismo , Córnea/efectos de los fármacos , Queratitis por Acanthamoeba/tratamiento farmacológico , Fotoquimioterapia/métodos , Microscopía ConfocalRESUMEN
As a flagship of the Europe's Beating Cancer Plan, the European Commission supports EU member states' efforts to strengthen and expand the routine vaccination of girls and boys against human papillomavirus (HPV). Populations across Europe have grown in diversity, and health systems must adapt to meet the specific needs of increasing diversity. Healthcare professionals (HCPs) must strive to communicate HPV vaccine information in a culturally sensitive manner and address specific concerns related to cultural beliefs, trust in health systems and perceived risks. The objectives of this exploratory study are to identify which themes are most frequently raised during the recommendation of vaccination to minors based on the characteristics of the population (religion, region of origin, gender, level of education and language proficiency) and to collect strategies to improve communication with a diverse population. A survey was distributed through various European public health institutions to HCPs in the region and their networks. The survey included multi-response questions (themes addressed during vaccination recommendation based on population characteristics) and open-ended questions (own qualitative comments and strategies). The most common issues that arise during vaccine recommendation are a lack of knowledge, followed by misinformation. Differences were detected according to the population characteristics. Suggested strategies to improve HPV vaccine recommendation focused on the following aspects: affordability; sexuality and gender; communication platforms; multilingualism; quality of care; school collaboration. HCPs report differences according to the characteristics of the population receiving the recommendation. Personalisation of the recommendations would help to optimise the decision-making process for some groups.
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Cervical cancer (CC) remains among the most frequent cancers worldwide despite advances in screening and the development of vaccines against human papillomavirus (HPV), involved in virtually all cases of CC. In mid-income countries, a substantial proportion of the cases are diagnosed in advanced stages, and around 40% of them are diagnosed in women under 49 years, just below the global median age. This suggests that members of this age group share common risk factors, such as chronic inflammation. In this work, we studied samples from 46 patients below 45 years old, searching for a miRNA profile regulating cancer pathways. We found 615 differentially expressed miRNAs between tumor samples and healthy tissues. Through bioinformatic analysis, we found that several of them targeted elements of the JAK/STAT pathway and other inflammation-related pathways. We validated the interactions of miR-30a and miR-34c with JAK1 and STAT3, respectively, through dual-luciferase and expression assays in cervical carcinoma-derived cell lines. Finally, through knockdown experiments, we observed that these miRNAs decreased viability and promoted proliferation in HeLa cells. This work contributes to understanding the mechanisms through which HPV regulates inflammation, in addition to its canonical oncogenic function, and brings attention to the JAK/STAT signaling pathway as a possible diagnostic marker for CC patients younger than 45 years. To our knowledge to date, there has been no previous description of a panel of miRNAs or even ncRNAs in young women with locally advanced cervical cancer.
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Regulación Neoplásica de la Expresión Génica , Inflamación , MicroARNs , Factor de Transcripción STAT3 , Transducción de Señal , Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología , MicroARNs/genética , MicroARNs/metabolismo , Transducción de Señal/genética , Adulto , Inflamación/genética , Inflamación/patología , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Células HeLa , Janus Quinasa 1/metabolismo , Janus Quinasa 1/genética , Proliferación Celular/genética , Línea Celular Tumoral , Persona de Mediana EdadRESUMEN
PURPOSE: To report two cases of bilateral blepharokeratoconjunctivitis associated with hidradenitis suppurativa (HS). METHODS: Case report and literature review. The clinical courses of two patients with HS, including ocular presentation and medical management, are described. RESULTS: Two female patients aged 18 and 23-years-old with severe HS presented with bilateral blepharokeratoconjunctivitis. Shared slit lamp findings included bilateral corneal neovascularization and inferior corneal thinning. Systemic immunosuppression was needed in the first case, which resulted in improvement in the patient's ophthalmic and dermatological findings. CONCLUSION: We report two cases of bilateral blepharokeratoconjunctivitis in two patients with severe HS. To our knowledge, this association has not previously been described in the literature. Clinicians should be aware of this association given its potentially visually devastating manifestations and the need for early therapeutic interventions.
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The development of specific antiviral therapies targeting SARS-CoV-2 remains fundamental because of the continued high incidence of COVID-19 and limited accessibility to antivirals in some countries. In this context, dark chemical matter (DCM), a set of drug-like compounds with outstanding selectivity profiles that have never shown bioactivity despite being extensively assayed, appears to be an excellent starting point for drug development. Accordingly, in this study, we performed a high-throughput screening to identify inhibitors of the SARS-CoV-2 main protease (Mpro) using DCM compounds as ligands. Multiple receptors and two different docking scoring functions were employed to identify the best molecular docking poses. The selected structures were subjected to extensive conventional and Gaussian accelerated molecular dynamics. From the results, four compounds with the best molecular behavior and binding energy were selected for experimental testing, one of which presented inhibitory activity with a Ki value of 48 ± 5 µM. Through virtual screening, we identified a significant starting point for drug development, shedding new light on DCM compounds.
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Antivirales , Proteasas 3C de Coronavirus , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Inhibidores de Proteasas , SARS-CoV-2 , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/enzimología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/química , Proteasas 3C de Coronavirus/metabolismo , Antivirales/farmacología , Antivirales/química , Humanos , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/química , COVID-19/virología , Descubrimiento de Drogas/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Evaluación Preclínica de Medicamentos/métodos , Unión Proteica , LigandosRESUMEN
BACKGROUND: In Mexico, this pioneering research was undertaken to assess the accessibility of timely diagnosis of Dyads [Children and adolescents with Attention Deficit Hyperactivity Disorder (ADHD) and their primary caregivers] at specialized mental health services. The study was conducted in two phases. The first phase involved designing an "Access Pathway" aimed to identify barriers and facilitators for ADHD diagnosis; several barriers, with only the teacher being identified as a facilitator. In the second phase, the study aimed to determine the time taken for dyads, to obtain a timely diagnosis at each stage of the Access Pathway. As well as identify any disparities based on gender and socioeconomic factors that might affect the age at which children can access a timely diagnosis. METHOD: In a retrospective cohort study, 177 dyads participated. To collect data, the Acceda Survey was used, based on the robust Conceptual Model Levesque, 2013. The survey consisted of 48 questions that were both dichotomous and polytomous allowing the creation of an Access Pathway that included five stages: the age of perception, the age of search, the age of first contact with a mental health professional, the age of arrival at the host hospital, and the age of diagnosis. The data was meticulously analyzed using a comprehensive descriptive approach and a nonparametric multivariate approach by sex, followed by post-hoc Mann-Whitney's U tests. Demographic factors were evaluated using univariable and multivariable Cox regression analyses. RESULTS: 71% of dyads experienced a late, significantly late, or highly late diagnosis of ADHD. Girls were detected one year later than boys. Both boys and girls took a year to seek specialized mental health care and an additional year to receive a formal specialized diagnosis. Children with more siblings had longer delays in diagnosis, while caregivers with formal employment were found to help obtain timely diagnoses. CONCLUSIONS: Our findings suggest starting the Access Pathway where signs and symptoms of ADHD are detected, particularly at school, to prevent children from suffering consequences. Mental health school-based service models have been successfully tested in other latitudes, making them a viable option to shorten the time to obtain a timely diagnosis.
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Trastorno por Déficit de Atención con Hiperactividad , Diagnóstico Precoz , Accesibilidad a los Servicios de Salud , Servicios de Salud Mental , Humanos , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Niño , Masculino , Femenino , México/epidemiología , Adolescente , Estudios Retrospectivos , Servicios de Salud Mental/estadística & datos numéricos , Factores SocioeconómicosRESUMEN
Background: The aim of the present study was to describe the presence of co-infection by Toxoplasma gondii and Neospora caninum in goats reared in extensive systems from Mexico. Materials and Methods: A cross-sectional study was conducted to determine the frequency of T. gondii and N. caninum, by detecting antibodies to each parasite by mean commercial ELISA kits. A total of 176 blood samples were randomly collected from mature females reared in extensive system herds from 20 municipalities of state of Guanajuato, Mexico. Results: The general seroprevalence was 23.9 and 21.0% for T. gondii and N. caninum, respectively, while co-infection rate was 3.6%. For geographic and environmental variables, no differences were observed among T. gondii and coinfection; however, it was observed that altitude, annual precipitation, annual average temperature, and rainy period showed significant differences with N. caninum seropositive goats. Conclusion: The seroprevalence of both parasites was appreciated in most of the studied herds. The present study is the first report of T. gondii and N. caninum co-infection in goats from extensive herds in Mexico.
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Coccidiosis , Coinfección , Enfermedades de las Cabras , Cabras , Neospora , Toxoplasma , Toxoplasmosis Animal , Animales , Coccidiosis/veterinaria , Coccidiosis/epidemiología , Coccidiosis/parasitología , México/epidemiología , Toxoplasma/inmunología , Enfermedades de las Cabras/epidemiología , Enfermedades de las Cabras/parasitología , Toxoplasmosis Animal/epidemiología , Toxoplasmosis Animal/parasitología , Coinfección/epidemiología , Coinfección/veterinaria , Coinfección/parasitología , Estudios Seroepidemiológicos , Femenino , Estudios Transversales , Anticuerpos Antiprotozoarios/sangreRESUMEN
Importance: Evaluation of the microbiological diagnostic profile of multidrug-resistant Pseudomonas aeruginosa keratitis and potential management with rose bengal-photodynamic antimicrobial therapy (RB-PDAT) is important. Objective: To document the disease progression of carbapenemase-resistant P aeruginosa keratitis after an artificial tear contamination outbreak. Design, Setting, and Participants: This retrospective observation case series included 9 patients 40 years or older who presented at Bascom Palmer Eye Institute and had positive test results for multidrug-resistant P aeruginosa keratitis between January 1, 2022, and October 31, 2023. Main Outcomes and Measures: Evaluation of type III secretion phenotype, carbapenemase-resistance genes blaGES and blaVIM susceptibility to antibiotics, and in vitro and in vivo outcomes of RB-PDAT against multidrug-resistant P aeruginosa keratitis. Results: Among the 9 patients included in the analysis (5 women and 4 men; mean [SD] age, 73.4 [14.0] years), all samples tested positive for exoU and carbapenemase-resistant blaVIM and blaGES genes. Additionally, isolates were resistant to carbapenems as indicated by minimum inhibitory concentration testing. In vitro efficacy of RB-PDAT indicated its potential application for treating recalcitrant cases. These cases highlight the rapid progression and challenging management of multidrug-resistant P aeruginosa. Two patients were treated with RB-PDAT as an adjuvant to antibiotic therapy and had improved visual outcomes. Conclusions and Relevance: This case series highlights the concerning progression in resistance and virulence of P aeruginosa and emphasizes the need to explore alternative therapies like RB-PDAT that have broad coverage and no known antibiotic resistance. The findings support further investigation into the potential effects of RB-PDAT for other multidrug-resistant microbes.
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Carbapenémicos , Infecciones Bacterianas del Ojo , Pruebas de Sensibilidad Microbiana , Infecciones por Pseudomonas , Pseudomonas aeruginosa , Humanos , Femenino , Masculino , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/aislamiento & purificación , Pseudomonas aeruginosa/genética , Estudios Retrospectivos , Anciano , Infecciones Bacterianas del Ojo/microbiología , Infecciones Bacterianas del Ojo/tratamiento farmacológico , Infecciones Bacterianas del Ojo/diagnóstico , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Infecciones por Pseudomonas/diagnóstico , Persona de Mediana Edad , Carbapenémicos/uso terapéutico , Carbapenémicos/farmacología , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Anciano de 80 o más Años , Resultado del Tratamiento , Farmacorresistencia Bacteriana Múltiple , Proteínas Bacterianas/genéticaRESUMEN
Background: Negative dysphotopsias (ND) are visual aberrations associated with in-the-bag optic intraocular lens (IOL) placement, causing arc-shaped or linear shadows. Reverse optic capture (ROC) is employed to prevent ND, yet it poses the risk of posterior capsular opacification (PCO) which usually develops within 2-5 years post-surgery due to the lens epithelial cells (LECs) proliferation and migration onto the posterior capsule. This can lead to a cloudy or hazy appearance in the visual field. Early identification of posterior capsular opacities is crucial to ensure timely intervention and minimize visual impairment. Cases Presentations: Two cases of acute and rapidly progressive PCO following cataract extraction (CE) and IOL placement using the ROC technique to prevent ND are reported at the Bascom Palmer Eye Institute. At the two-week postoperative follow-up, both patients reported a significant progressive decrease in vision in the treated eye, and severe posterior capsular opacities were observed. A diagnosis of PCO was confirmed, and successful visual rehabilitation was achieved through the performance of ND:YAG laser capsulotomy without complications. This case series represents the first reported instances of patients developing PCO within two weeks of CE and IOL placement using the ROC technique. Conclusions: This case series sheds light on the occurrence of posterior capsular opacities shortly after CE and IOL placement using the ROC technique. It highlights the importance of preoperative patient education, postoperative monitoring, and prompt management of potential complications in cataract surgery.
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SARS-CoV-2 must bind its principal receptor, ACE2, on the target cell to initiate infection. This interaction is largely driven by the receptor binding domain (RBD) of the viral Spike (S) protein. Accordingly, antiviral compounds that can block RBD/ACE2 interactions can constitute promising antiviral agents. To identify such molecules, we performed a virtual screening of the Selleck FDA approved drugs and the Selleck database of Natural Products using a multistep computational procedure. An initial set of candidates was identified from an ensemble docking process using representative structures determined from the analysis of four 3 µ s molecular dynamics trajectories of the RBD/ACE2 complex. Two procedures were used to construct an initial set of candidates including a standard and a pharmacophore guided docking procedure. The initial set was subsequently subjected to a multistep sieving process to reduce the number of candidates to be tested experimentally, using increasingly demanding computational procedures, including the calculation of the binding free energy computed using the MMPBSA and MMGBSA methods. After the sieving process, a final list of 10 candidates was proposed, compounds which were subsequently purchased and tested ex-vivo. The results identified estradiol cypionate and telmisartan as inhibitors of SARS-CoV-2 entry into cells. Our findings demonstrate that the methodology presented here enables the discovery of inhibitors targeting viruses for which high-resolution structures are available.
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COVID-19 , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Humanos , Simulación del Acoplamiento Molecular , Reposicionamiento de Medicamentos/métodos , Enzima Convertidora de Angiotensina 2 , Simulación de Dinámica Molecular , Unión ProteicaRESUMEN
Bombesin is an endogenous peptide involved in a wide spectrum of physiological activities ranging from satiety, control of circadian rhythm and thermoregulation in the central nervous system, to stimulation of gastrointestinal hormone release, activation of macrophages and effects on development in peripheral tissues. Actions of the peptide are mediated through the two high affinity G-protein coupled receptors BB1R and BB2R. Under pathophysiological conditions, these receptors are overexpressed in many different types of tumors, such as prostate cancer, breast cancer, small and non-small cell lung cancer and pancreatic cancer. This observation has been used for designing cell markers, but it has not been yet exploited for therapeutical purposes. Despite the enormous biological interest of the peptide, little is known about the stereochemical features that contribute to their activity. On the one hand, mutagenesis studies identified a few receptor residues important for high bombesin affinity and on the other, a few studies focused on the relevance of diverse residues of the peptide for receptor activation. Models of the peptide bound to BB1R and BB2R can be helpful to improve our understanding of the stereochemical features granting bombesin activity. Accordingly, the present study describes the computational process followed to construct such models by means of Steered Molecular Dynamics, using models of the peptide and its receptors. Present results provide new insights into the structure-activity relationships of bombesin and its receptors, as well as render an explanation for the differential binding affinity observed towards BB1R and BB2R. Finally, these models can be further exploited to help for designing novel small molecule peptidomimetics with improved pharmacokinetics profile.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Masculino , Humanos , Bombesina/química , Bombesina/metabolismo , Receptores de Bombesina/metabolismo , PéptidosRESUMEN
PURPOSE: The aim of this study was to describe a combined surgical approach for ocular surface and visual rehabilitation in patients with limbal stem cell deficiency, corneal scarring, and cataract. We aimed to introduce this combined approach as an alternative to a staged approach and to describe the intraoperative use of a diamond ophthalmic burr (DOB) and optical coherence tomography (OCT) to achieve and confirm a smooth graft-host interface during the anterior lamellar keratoplasty (ALK) portion of the procedure. METHODS: The quintuple procedure described herein consists of a modified ALK, cataract extraction, intraocular lens implantation, simple limbal epithelial transplantation, and temporal tarsorrhaphy. Intraoperative OCT and DOB were used to guide the creation of the stromal bed during the ALK. The procedure was performed in a patient with limbal stem cell deficiency and corneal scarring after a chemical ocular burn. RESULTS: The tarsorrhaphy was removed at 3 months postoperatively once complete corneal epithelialization was observed. The best-corrected visual acuity improved from light perception preoperatively to 20/30 at 16 months postoperatively with the use of scleral contact lenses. At this postoperative time point, the cornea was clear and compact, and the ocular surface was stable. CONCLUSIONS: The quintuple procedure allowed for visual and ocular surface rehabilitation in cases in which follow-up for a staged approach was not possible. Intraoperative OCT allowed for real-time visualization and dissection of the stromal bed, whereas the use of the DOB helped achieve a smooth stromal surface for an optimal graft-host interface.
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Enfermedades de la Córnea , Lesiones de la Cornea , Trasplante de Córnea , Deficiencia de Células Madre Limbares , Humanos , Cicatriz/cirugía , Agudeza Visual , Córnea/cirugía , Lesiones de la Cornea/cirugía , Proteínas Tirosina Quinasas Receptoras , Trasplante de Córnea/métodos , Enfermedades de la Córnea/cirugíaRESUMEN
This research analyses how different cement mortars behave in terms of their physical and mechanical properties. Several components were necessary to make seven mixes of mortars, such as Portland cement, standard sand, and solid waste from a factory of sodium silicate, in addition to graphene oxide. Furthermore, graphene oxide (GO) was selected to reduce the micropores and increase the nanopores in the cement mortar. Hence, some tests were carried out to determine their density, humidity content, water absorption capacity, open void porosity, the alkali-silica reaction, as well as flexural and mechanical strength and acid resistance. Thus, standard-sand-manufactured mortars' mechanical properties were proved to be slightly better than those manufactured with recycled waste; the mortars with this recycled aggregate presented problems of alkali-silica reaction. In addition, GO (in a ratio GO/cement = 0.0003) performed as a filler, improving the mechanical properties (30%), alkali-silica (80%), and acid resistance.
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Mutants of Ras are oncogenic drivers of a large number of human tumors. Despite being recognized as an attractive target for the treatment of cancer, the high affinity for its substrate tagged the protein as undruggable for a few years. The identification of cryptic pockets on the protein surface gave the opportunity to identify molecules capable of acting as allosteric modulators. Several molecules were disclosed in recent years, with sotorasib and adagrasib already approved for clinical use. The present study makes use of computational methods to characterize eight prospective allosteric pockets (P1-P8) in K-Ras, four of which (P1-P4) were previously characterized in the literature. The present study also describes the results of a virtual screening study focused on the discovery of hit compounds, binders of the P4 site that can be considered as peptidomimetics of a fragment of the SOS αI helix, a guanine exchange factor of Ras. After a detailed description of the computational procedure followed, we disclose five hit compounds, prospective binders of the P4 allosteric site that exhibit an inhibitory capability higher than 30% in a cell proliferation assay at 50 µM.
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Neoplasias , Proteínas , Humanos , Sitio Alostérico , Estudios Prospectivos , Neoplasias/tratamiento farmacológicoRESUMEN
Antimicrobial resistance (AMR) represents a serious threat to global health. The development of new drugs to combat infections caused by bacteria resistant to multiple or even all available antibiotics is urgent. Most antibiotics used up to date have been identified from soil microorganisms. The marine environment represents an alternative source with great potential for the identification of microorganisms that produce bioactive molecules, including antibiotics. In this study, we analyzed the antibacterial activity of a collection of 82 bacterial strains isolated from marine water and sediment samples collected from the Southwestern Gulf of Mexico. Eight of the marine isolates inhibited the growth of different pathogenic bacteria, seven of which were identified as presumptive Pseudomonas aeruginosa. Interestingly, genome sequencing and phylogenetic analysis revealed that the remaining marine isolate showing antibacterial activity is a novel Pseudomonas species that we denominated Pseudomonas sp. GOM7, which was not pathogenic in the Galleria mellonella infection model in the conditions tested. Notably, Pseudomonas sp. GOM7 inhibited the growth of multidrug and methicillin-resistant strains of the priority pathogen Staphylococcus aureus. Our results show that the anti-S. aureus compound(s) produced by Pseudomonas sp. GOM7 can be extracted from the culture supernatant of this bacterium with the organic solvent ethyl acetate. Annotation of the Pseudomonas sp. GOM7 genome revealed the presence of several biosynthetic gene clusters predicted to code for possible antimicrobial compounds. Our results further highlight the potential of bacteria from the Gulf of Mexico as a source of novel antimicrobials.
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Staphylococcus aureus Resistente a Meticilina , Staphylococcus aureus , Staphylococcus aureus/genética , Pseudomonas/genética , Staphylococcus aureus Resistente a Meticilina/genética , Filogenia , Antibacterianos/farmacología , Pseudomonas aeruginosa/genética , Bacterias , Genómica , Pruebas de Sensibilidad MicrobianaRESUMEN
Despite the universal vaccination program, there are still regions and territories with a high prevalence of Hepatitis B Virus infection (HBV), such as the Amazon basin, where several indigenous communities live. Additionally, Hepatitis Delta Virus (HDV) is a defective that requires the hepatitis B surface antigen (HBsAg) for the assembly and release of de novo viral particles. Therefore, hepatitis D could be the result of HBV/HDV coinfection or HDV superinfection in individuals with chronic hepatitis B. Among the high prevalence HDV populations are indigenous communities of America. This study aims to describe and characterize the frequency of HBV and HDV infection, viral genotypes and HBV immune escape mutants in indigenous populations from different regions of Colombia. The diagnosis of hepatitis B and hepatitis D was confirmed by serological markers. Moreover, the HBV and HDV genome were amplified by PCR and RT-PCR, respectively, and, subsequently, the phylogenetic analysis was performed. We characterized 47 cases of chronic hepatitis B, 1 case of reactivation and 2 cases of occult hepatitis B infection (OBI). Furthermore, a high prevalence of HDV infection was identified in the study population (29.33%, 22/75) and the circulation of several HBV genotypes and subgenotypes (F1b, F3, F4, and D). Interestingly, this is the first report of the HDV genotype I circulation in this country. These findings demonstrated that HBV and HDV infections are still public health problems in indigenous communities in Colombia.
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The general assumption that the survival patterns of tropical and southern temperate birds are similar lacks empirical data from higher latitudes. Regional comparisons of New World species are rare, and this assumption has been based on data from African studies. Here, we estimate the survival rates of 88 tropical and southern temperate bird populations (69 species) from eight localities in South America to evaluate the hypothesis that the survival of these populations is homogeneous at the regional scale. We estimated survival based on the Cormack-Jolly-Seber model and compared values from different environments. The survival estimates ranged from 0.30 to 0.80 (0.56 ± 0.12). Apparent survival did not differ significantly between low-latitude tropical environments (03°S) and the other sites from high-latitudes (between 22° and 34°S). Despite a predicted positive trend, body size was not significantly related to survival among passerines. On the other hand, phylogenetic relationships explained more than a third of the variation in bird survival. Based on the largest available database on South American bird species, our findings support the hypothesis that bird survival is homogeneous, at the regional scale, along the southern hemisphere. In particular, we reinforce the hypothesis that climatic variation has a limited influence on bird survival in the southern hemisphere.