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The design of efficient electrocatalysts is limited by scaling relationships governing trade-offs between thermodynamic and kinetic performance metrics. This â³iron lawâ³ of electrocatalysis arises from synthetic design strategies, where structural alterations to a catalyst must balance nucleophilic versus electrophilic character. Efforts to circumvent this fundamental impasse have focused on bioinspired applications of extended coordination spheres and charged sites proximal to a catalytic center. Herein, we report evidence for breaking a molecular scaling relationship involving electrocatalysis of the oxygen reduction reaction (ORR) by leveraging ligand design. We achieve this using a binuclear catalyst (a diiron porphyrin), featuring a macrocyclic ligand with extended electronic conjugation. This ligand motif delocalizes electrons across the molecular scaffold, improving the catalyst's nucleophilic and electrophilic character. As a result, our binuclear catalyst exhibits low overpotential and high catalytic turnover frequency, breaking the traditional trade-off between these two metrics.
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Nature offers inspiration for developing technologies that integrate the capture, conversion, and storage of solar energy. In this review article, we highlight principles of natural photosynthesis and artificial photosynthesis, drawing comparisons between solar energy transduction in biology and emerging solar-to-fuel technologies. Key features of the biological approach include use of earth-abundant elements and molecular interfaces for driving photoinduced charge separation reactions that power chemical transformations at global scales. For the artificial systems described in this review, emphasis is placed on advancements involving hybrid photocathodes that power fuel-forming reactions using molecular catalysts interfaced with visible-light-absorbing semiconductors.
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Fotosíntesis , Energía Solar , Catálisis , Luz , SemiconductoresRESUMEN
The main coronavirus disease 2019 (COVID-19) vaccine formulations used today are mainly based on the wild-type severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein as an antigen. However, new virus variants capable of escaping neutralization activity of serum antibodies elicited in vaccinated individuals have emerged. The Omicron (B.1.1.529) variant caused epidemics in regions of the world in which most of the population has been vaccinated. In this study, we aimed to understand what determines individual's susceptibility to Omicron in a scenario of extensive vaccination. For that purpose, we collected nasopharynx swab (n = 286) and blood samples (n = 239) from flu-like symptomatic patients, as well as their vaccination history against COVID-19. We computed the data regarding vaccine history, COVID-19 diagnosis, COVID-19 serology, and viral genome sequencing to evaluate their impact on the number of infections. As main results, we showed that vaccination in general did not reduce the number of individuals infected by Omicron, even with an increased immune response found among vaccinated, noninfected individuals. Nonetheless, we found that individuals who received the third vaccine dose showed significantly reduced susceptibility to Omicron infections. A relevant evidence that support this finding was the higher virus neutralization capacity of serum samples of most patients who received the third vaccine dose. In summary, this study shows that boosting immune responses after a third vaccine dose reduces susceptibility to COVID-19 caused by the Omicron variant. Results presented in this study are useful for future formulations of COVID-19 vaccination policies.
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Vacunas contra la COVID-19 , COVID-19 , Humanos , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19/prevención & control , Prueba de COVID-19 , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/inmunología , SARS-CoV-2 , Glicoproteína de la Espiga del CoronavirusRESUMEN
BACKGROUND: Acute Respiratory Distress Syndrome (ARDS) due tocoronavirus disease (COVID-19) infection has a unique phenotype generating a growing need to determine the existing differences that can alter existing evidence-based management strategies for ARDS. RESEARCH QUESTION: What differences does the clinical profile of patients with ARDS due to COVID 19 and Non-COVID 19 have? STUDY DESIGN AND METHODS: We conducted a comparative, observational, retrospective study in the Intensive Care Unit (ICU)of a third-level hospital in Mexico City, from March 2020 through March 2022. Clinical, echocardiographic, and laboratory variables were compared between patients with ARDS due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and those due to other etiologies. RESULTS: We enrolled 140 patients with a diagnosis of ARDS. The study group of COVID-19 etiology were younger males, higher body mass index, progressed to organ dysfunction, required more frequently renal replacement therapy, and higher SOFA score. There was no difference in rates of right ventricular dysfunction. INTERPRETATION: COVID-19 ARDS exhibit much greater severity that led to higher admission and mortality rates, whilst being younger and less comorbid.
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COVID-19 , Síndrome de Dificultad Respiratoria , Humanos , Masculino , México , Síndrome de Dificultad Respiratoria/terapia , Estudios Retrospectivos , SARS-CoV-2 , Atención Terciaria de Salud , FemeninoRESUMEN
BACKGROUND: Evaluation of the venous system has long been underestimated as an important component of the circulatory system. As systemic venous pressure increases, the perfusion pressure to the tissues is compromised. During initial resuscitation in cardiac surgery, excessive fluid administration is associated with increased morbidity and mortality. METHODS: We conducted a cross-sectional study of 60 consecutive adult patients who underwent cardiac surgery and in whom it was possible to obtain the venous excess ultrasound (VExUS) grading system and mean systemic filling pressure (Pmsf) in the postoperative period upon admission, at 24 and 48 h. We then determined the correlation between VExUS grading and Pmsf. RESULTS: On admission, patients with VExUS grading 0 predominated, with a progressive increase in venous congestion and an increase in Pmsf over the course of the first 48 h. There was a strong positive correlation between VExUS grading and the invasive measurement of Pmsf at 24 and 48 h after arrival. The presence of grade 2 or grade 3 venous congestion in the postoperative period poses an increased risk of developing acute kidney injury. CONCLUSION: The VExUS grading system indicates a high degree of systemic venous congestion in the first 48 h of the postoperative period after cardiac surgery and correlates with the Pmsf, which is the best surrogate of stressed circulatory volume.
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Procedimientos Quirúrgicos Cardíacos , Sistema Cardiovascular , Hiperemia , Humanos , Estudios TransversalesRESUMEN
Congenitally corrected transposition of the great arteries is a rare clinical entity, which usually presents during adulthood with associated defects; atrioventricular block, heart failure, systemic valve failure, and arrhythmias usually complicate the clinical course. Even rarer is associated hypertrophic cardiomyopathy, which complicates the disease course and clinical decision-making. Herein, we present a patient with this condition who underwent heart transplantation, with adequate clinical resolution.
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Cardiomiopatía Hipertrófica , Insuficiencia Cardíaca , Transposición de los Grandes Vasos , Humanos , Adulto , Transposición Congénitamente Corregida de las Grandes Arterias/complicaciones , Transposición de los Grandes Vasos/complicaciones , Transposición de los Grandes Vasos/diagnóstico por imagen , Transposición de los Grandes Vasos/cirugía , Ventrículos Cardíacos/diagnóstico por imagen , Insuficiencia Cardíaca/complicaciones , Cardiomiopatía Hipertrófica/complicaciones , Cardiomiopatía Hipertrófica/diagnóstico por imagenRESUMEN
Expanding proton-coupled electron transfer to multiproton translocations (MPCET) provides a bioinspired mechanism to transport protons away from the redox site. This expansion has been accomplished by separating the initial phenolic proton donor from the pyridine-based terminal proton acceptor by a Grotthuss-type proton wire made up of concatenated benzimidazoles that form a hydrogen-bonded network. However, it was found that the midpoint potential of the phenol oxidation that launched the Grotthuss-type proton translocations is a function of the number of benzimidazoles in the hydrogen-bonded network; it becomes less positive (i.e., a weaker oxidant) as the number of bridging benzimidazoles increases. Herein, we report a strategy to maintain the high redox potential necessary for oxidative processes relevant to artificial photosynthesis, e.g., water oxidation and long-range MPCET processes for managing protons. The integrated structural and functional roles of the benzimidazole-based bridge provide sites for substitution of the benzimidazoles with electron-withdrawing groups (e.g., trifluoromethyl groups). Such substitution increases the midpoint potential of the phenoxyl radical/phenol couple so that proton translocations over â¼11 Å become thermodynamically comparable to that of an unsubstituted system where one proton is transferred over â¼2.5 Å. The extended, substituted system maintains the hydrogen-bonded network; infrared spectroelectrochemistry confirms reversible proton translocations from the phenol to the pyridyl terminal proton acceptor upon oxidation and reduction. Theory supports the change in driving force with added electron-withdrawing groups and provides insight into the role of electron density and electrostatic potential in MPCET processes associated with these Grotthuss-type proton translocations.
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Fenoles , Protones , Bencimidazoles/química , Transporte de Electrón , Hidrógeno/química , Oxidación-Reducción , Fenol/química , Fenoles/químicaRESUMEN
Photoelectrosynthetic materials provide a bioinspired approach for using the power of the sun to produce fuels and other value-added chemical products. However, there remains an incomplete understanding of the operating principles governing their performance and thereby effective methods for their assembly. Herein we report the application of metalloporphyrins, several of which are known to catalyze the hydrogen evolution reaction, in forming surface coatings to assemble hybrid photoelectrosynthetic materials featuring an underlying gallium phosphide (GaP) semiconductor as a light capture and conversion component. The metalloporphyrin reagents used in this work contain a 4-vinylphenyl surface-attachment group at the ß-position of the porphyrin ring and a first-row transition metal ion (Fe, Co, Ni, Cu, or Zn) coordinated at the core of the macrocycle. In addition to describing the synthesis, optical, and electrochemical properties of the homogeneous porphyrin complexes, we also report on the photoelectrochemistry of the heterogeneous metalloporphyrin-modified GaP semiconductor electrodes. These hybrid, heterogeneous-homogeneous electrodes are prepared via UV-induced grafting of the homogeneous metalloporphyrin reagents onto the heterogeneous gallium phosphide surfaces. Three-electrode voltammetry measurements performed under controlled lighting conditions enable determination of the open-circuit photovoltages, fill factors, and overall current-voltage responses associated with these composite materials, setting the stage for better understanding charge-transfer and carrier-recombination kinetics at semiconductor|catalyst|liquid interfaces.
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Galio , Metaloporfirinas , Catálisis , Metaloporfirinas/química , Fosfinas , SemiconductoresRESUMEN
A large proportion of the world's population harbors latent HSV type 1 (HSV-1). Cross-talk between antiviral CD8+ T cells and HSV-1 appear to control latency/reactivation cycles. We found that compared with healthy asymptomatic individuals, in symptomatic (SYMP) patients, the CD8+ T cells with the same HLA-A*0201-restricted HSV-1 epitope specificities expressed multiple genes and proteins associated to major T cell exhaustion pathways and were dysfunctional. Blockade of immune checkpoints with anti-LAG-3 and anti-PD-1 antagonist mAbs synergistically restored the frequency and function of antiviral CD8+ T cells, both 1) ex vivo, in SYMP individuals and SYMP HLA-A*0201 transgenic mice; and 2) in vivo in HSV-1-infected SYMP HLA-A*0201 transgenic mice. This was associated with a significant reduction in virus reactivation and recurrent ocular herpetic disease. These findings confirm antiviral CD8+ T cell exhaustion during SYMP herpes infection and pave the way to targeting immune checkpoints to combat recurrent ocular herpes.
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Linfocitos T CD8-positivos/inmunología , Ojo/inmunología , Herpes Simple/inmunología , Herpesvirus Humano 1/fisiología , Adulto , Animales , Anticuerpos Bloqueadores/metabolismo , Enfermedades Asintomáticas , Células Cultivadas , Progresión de la Enfermedad , Ojo/virología , Femenino , Antígeno HLA-A2/metabolismo , Interacciones Huésped-Patógeno , Humanos , Masculino , Ratones Transgénicos , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Activación Viral , Latencia del Virus , Adulto JovenRESUMEN
BACKGROUND: Acute kidney injury (AKI) in patients with COVID-19 can be caused by multiple mechanisms. Renal resistive index (RRI) is a noninvasive instrument to evaluate kidney hemodynamics, and it is obtained by analysis of intrarenal arterial waves using Doppler ultrasound. This study aimed to determine the role of RRI in predicting AKI and adverse outcomes in critically ill patients with COVID-19. METHODS: This cross-sectional study included 65 patients with confirmed SARS-CoV-2 pneumonia admitted to the critical care unit from April 1, 2020, to June 20, 2020. Informed consent was obtained from all individual participants included in the study. Cardiac, pulmonary, and kidney ultrasonographic evaluations were performed in a protocolized way. RESULTS: In this cohort, 65 patients were included, mean age was 53.4 years, 79% were male, and 35% were diabetic. Thirty-four percent of patients developed AKI, 12% required RRT, and 35% died. Of the patients who developed AKI, 68% had RRI ≥ 0.7. Also, 75% of the patients who required RRT had RRI ≥ 0.7. In the adjusted Cox model, the RRI ≥ 0.7 was associated with higher mortality (HR 2.86, 95% CI: 1.19-6.82, p = 0.01). CONCLUSIONS: Critical care ultrasonography is a noninvasive, reproducible, and accurate bedside method that has proven its usefulness. An elevated RRI may have a role in predicting AKI, RRT initiation, and mortality in patients with severe SARS-CoV-2 pneumonia.
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Lesión Renal Aguda , COVID-19 , Lesión Renal Aguda/etiología , COVID-19/complicaciones , COVID-19/diagnóstico por imagen , Enfermedad Crítica , Estudios Transversales , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , SARS-CoV-2RESUMEN
BACKGROUND: Coronavirus disease 2019 (COVID-19) frequently involves cardiovascular manifestations such as right ventricular (RV) dysfunction and alterations in pulmonary hemodynamics. We evaluated the application of the critical care ultrasonography ORACLE protocol to identify the most frequent alterations and their influence on adverse outcomes, especially those involving the RV (dilatation and dysfunction). METHODS: This cross-sectional study included 204 adult patients with confirmed COVID-19 admitted at three centers. Echocardiography and lung ultrasound images were acquired on admission using the ORACLE ultrasonography algorithm. RESULTS: Two-hundred and four consecutive patients were evaluated: 22 (11.9%) demonstrated a fractional shortening of < 35%; 33 (17.1%) a tricuspid annular plane systolic excursion (TAPSE) of < 17 mm; 26 (13.5%) a tricuspid peak systolic S wave tissue Doppler velocity of < 9.5 cm/sec; 69 (37.5%) a RV basal diameter of > 41 mm; 119 (58.3%) a pulmonary artery systolic pressure (PASP) of > 35 mm Hg; and 14 (11%) a TAPSE/PASP ratio of < .31. The in-hospital mortality rate was 37.6% (n = 71). Multiple logistic regression modeling showed that PASP > 35 mm Hg, RV FS of < 35%, TAPSE < 17 mm, RV S wave < 9.5, and TAPSE/PASP ratio < .31 mm/mm Hg were associated with this outcome. PASP and the TAPSE/PASP ratio had the lowest feasibility of being obtained among the investigators (62.2%). CONCLUSION: The presence of RV dysfunction, pulmonary hypertension, and alteration of the RV-arterial coupling conveys an increased risk of in-hospital mortality in patients presenting with COVID-19 upon admission; therefore, searching for these alterations should be routine. These parameters can be obtained quickly and safely with the ORACLE protocol.
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COVID-19 , Disfunción Ventricular Derecha , Adulto , Estudios Transversales , Ecocardiografía Doppler , Mortalidad Hospitalaria , Humanos , Arteria Pulmonar/diagnóstico por imagen , SARS-CoV-2 , Disfunción Ventricular Derecha/diagnóstico por imagen , Función Ventricular DerechaRESUMEN
INTRODUCTION: Lung ultrasound (LUS) implementation in patients with COVID-19 can help to establish the degree of pulmonary involvement, evaluate treatment response and estimate in-hospital outcome. OBJECTIVE: To evaluate the application of a LUS protocol in patients with COVID-19 infection to predict in-hospital mortality. METHODS: The study was carried out from April 1 to August 1, 2020 in patients with COVID-19 infection admitted to the Intensive Care Unit. Lung evaluation was carried out by physicians trained in critical care ultrasonography. RESULTS: Most patients were males, median age was 56 years, and 59 % required mechanical ventilation. In-hospital mortality was 39.4 %, and in those with a LUS score ≥ 19, mortality was higher (50 %). The multiple logistic regression model showed that a LUS score ≥ 19 was significantly associated with mortality (hazard ratio = 2.55, p = 0.01). CONCLUSIONS: LUS is a safe and fast clinical tool that can be applied at bedside in patients with COVID-19 infection to establish the degree of parenchymal involvement and predict mortality.
INTRODUCCIÓN: La implementación del ultrasonido pulmonar (LUS) en los pacientes con COVID-19 puede ayudar a establecer el grado de afectación pulmonar, evaluar la respuesta al tratamiento y estimar el desenlace intrahospitalario. OBJETIVO: Evaluar la aplicación de un protocolo LUS en pacientes con infección por COVID-19 para predecir mortalidad intrahospitalaria. MÉTODOS: El estudio se realizó del 1 de abril al 1 de agosto de 2020 en pacientes con infección por COVID-19, ingresados en la Unidad de Terapia Intensiva. Se realizó evaluación pulmonar por médicos entrenados en ultrasonografía crítica. RESULTADOS: La mayoría de los pacientes fue del sexo masculino, la edad mediana fue de 56 años y 59 % requirió ventilación mecánica. La mortalidad intrahospitalaria fue de 39.4 % y en aquellos con puntuación de LUS ≥ 19, de 50 %. El modelo de regresión logística múltiple mostró que la puntuación de LUS ≥ 19 se asoció significativamente a mortalidad (cociente de riesgo = 2.55, p = 0.01). CONCLUSIONES: El LUS es una herramienta clínica segura y rápida que puede realizarse al lado de la cama de los pacientes con infección por COVID-19, para establecer el grado de afectación parenquimatosa y predecir la mortalidad.
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COVID-19/complicaciones , Mortalidad Hospitalaria , Unidades de Cuidados Intensivos , Pulmón/diagnóstico por imagen , Ultrasonografía , Anciano , COVID-19/mortalidad , Cuidados Críticos , Femenino , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Pruebas en el Punto de Atención , Respiración Artificial/estadística & datos numéricosRESUMEN
BACKGROUND: Coronavirus disease 2019 (COVID-19) is characterized by severe lung involvement and hemodynamic alterations. Critical care ultrasonography is vital because it provides real time information for diagnosis and treatment. Suggested protocols for image acquisition and measurements have not yet been evaluated. METHODS: This cross-sectional study was conducted at two centers from 1 April 2020 to 30 May 2020 in adult patients with confirmed COVID-19 infection admitted to the critical care unit. Cardiac and pulmonary evaluations were performed using the ORACLE protocol, specifically designed for this study, to ensure a structured process of image acquisition and limit staff exposure to the infection. RESULTS: Eighty-two consecutively admitted patients were evaluated. Most of the patients were males, with a median age of 56 years, and the most frequent comorbidities were hypertension and type 2 diabetes, and 25% of the patients had severe acute respiratory distress syndrome. The most frequent ultrasonographic findings were elevated pulmonary artery systolic pressure (69.5%), E/e' ratio > 14 (29.3%), and right ventricular dilatation (28%) and dysfunction (26.8%). A high rate of fluid responsiveness (82.9%) was observed. The median score (19 points) on pulmonary ultrasound did not reveal any variation between the groups. Elevated pulmonary artery systolic pressure was associated with higher in-hospital mortality. CONCLUSION: The ORACLE protocol was a feasible, rapid, and safe bedside tool for hemodynamic and respiratory evaluation of patients with COVID-19. Further studies should be performed on the alteration in pulmonary hemodynamics and right ventricular function and its relationship with outcomes.
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COVID-19/complicaciones , COVID-19/fisiopatología , Cuidados Críticos/métodos , Cardiopatías/diagnóstico por imagen , Enfermedades Pulmonares/diagnóstico por imagen , Ultrasonografía/métodos , Anciano , Protocolos Clínicos , Estudios Transversales , Estudios de Factibilidad , Femenino , Corazón/diagnóstico por imagen , Corazón/fisiopatología , Cardiopatías/etiología , Cardiopatías/fisiopatología , Hemodinámica/fisiología , Humanos , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/fisiopatología , Masculino , Persona de Mediana Edad , Pandemias , Sistemas de Atención de Punto , Ultrasonografía/instrumentaciónRESUMEN
Different therapeutic strategies have been investigated to target and eliminate HIV-1-infected cells by using armed antibodies specific to viral proteins, with varying degrees of success. Herein, we propose a new strategy by combining photodynamic therapy (PDT) with HIV Env-targeted immunotherapy, and refer to it as HIV photoimmunotherapy (PIT). A human anti-gp41 antibody (7B2) was conjugated to two photosensitizers (PSs) with different charges through different linking strategies; "Click" conjugation by using an azide-bearing porphyrin attached via a disulfide bridge linker with a drug-to-antibody ratio (DAR) of exactly 4, and "Lysine" conjugation by using phthalocyanine IRDye 700DX dye with average DARs of 2.1, 3.0 and 4.4. These photo-immunoconjugates (PICs) were compared via biochemical and immunological characterizations regarding the dosimetry, solubility, and cell targeting. Photo-induced cytotoxicity of the PICs were compared using assays for apoptosis, reactive oxygen species (ROS), photo-cytotoxicity, and confocal microscopy. Targeted phototoxicity seems to be primarily dependent on the binding of PS-antibody to the HIV antigen on the cell membrane, whilst being independent of the PS type. This is the first report of the application of PIT for HIV immunotherapy by killing HIV Env-expressing cells.
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Aniones , Fármacos Anti-VIH/farmacología , Cationes , Inmunoconjugados/farmacología , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Aniones/química , Fármacos Anti-VIH/química , Anticuerpos Monoclonales , Apoptosis/efectos de los fármacos , Cationes/química , Línea Celular Tumoral , Células Cultivadas , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , VIH/efectos de los fármacos , VIH/genética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Humanos , Inmunoconjugados/química , Fármacos Fotosensibilizantes/química , Especies Reactivas de Oxígeno/metabolismo , Replicación Viral/efectos de los fármacos , Productos del Gen env del Virus de la Inmunodeficiencia Humana/antagonistas & inhibidores , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen env del Virus de la Inmunodeficiencia Humana/metabolismoRESUMEN
We report on the interplay between light absorption, charge transfer, and catalytic activity at molecular-catalyst-modified semiconductor liquid junctions. Factors limiting the overall photoelectrosynthetic transformations are presented in terms of distinct regions of experimental polarization curves, where each region is related to the fraction of surface-immobilized catalysts present in their activated form under varying intensities of simulated solar illumination. The kinetics associated with these regions are described using steady-state or pre-equilibrium approximations yielding rate laws similar in form to those applied in studies involving classic enzymatic reactions and Michaelis-Menten-type kinetic analysis. However, in the case of photoelectrosynthetic constructs, both photons and electrons serve as reagents for producing activated catalysts. This work forges a link between kinetic models describing biological assemblies and emerging molecular-based technologies for solar energy conversion, providing a conceptual framework for extracting kinetic benchmarking parameters currently not possible to establish.
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Cervical cancer is a major cause of death in females worldwide. While survival rates have historically improved, there remains a continuous need to identify novel molecules that are effective against this disease. Here, we show that enoxacin, a drug most commonly used to treat a broad array of bacterial infections, is able to inhibit growth of the cervical cancer cells. Furthermore, our data show that epigallocatechin gallate (EGCG), a plant bioactive compound abundant in green tea, and known for its antioxidant effects, similarly functions as an antiproliferative agent. Most importantly, we provide evidence that EGCG functions synergistically against cancer cell proliferation in combined treatment with enoxacin. These data collectively suggest that enoxacin and EGCG may be useful treatment options for cases of cervical cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proliferación Celular/efectos de los fármacos , Neoplasias del Cuello Uterino/tratamiento farmacológico , Catequina/agonistas , Catequina/análogos & derivados , Catequina/farmacología , Enoxacino/agonistas , Enoxacino/farmacología , Femenino , Células HeLa , Humanos , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patologíaRESUMEN
Chlamydia trachomatis entry into host cells is mediated by pathogen-directed remodeling of the actin cytoskeleton. The chlamydial type III secreted effector, translocated actin recruiting phosphoprotein (Tarp), has been implicated in the recruitment of actin to the site of internalization. Tarp harbors G-actin binding and proline rich domains required for Tarp-mediated actin nucleation as well as unique F-actin binding domains implicated in the formation of actin bundles. Little is known about the mechanical properties of actin bundles generated by Tarp or the mechanism by which Tarp mediates actin bundle formation. In order to characterize the actin bundles and elucidate the role of different Tarp domains in the bundling process, purified Tarp effectors and Tarp truncation mutants were analyzed using Total Internal Reflection Fluorescence (TIRF) microscopy. Our data indicate that Tarp mediated actin bundling is independent of actin nucleation and the F-actin binding domains are sufficient to bundle actin filaments. Additionally, Tarp-mediated actin bundles demonstrate distinct bending stiffness compared to those crosslinked by the well characterized actin bundling proteins fascin and alpha-actinin, suggesting Tarp may employ a novel actin bundling strategy. The capacity of the Tarp effector to generate novel actin bundles likely contributes to chlamydia's efficient mechanism of entry into human cells.
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Actinas/metabolismo , Fenómenos Biofísicos , Chlamydia trachomatis/metabolismo , Fosfoproteínas/metabolismo , Fluorescencia , Fosfoproteínas/química , Dominios ProteicosAsunto(s)
COVID-19/complicaciones , Electrocardiografía , Cardiomiopatía de Takotsubo/complicaciones , Cardiomiopatía de Takotsubo/diagnóstico , COVID-19/fisiopatología , Diagnóstico Diferencial , Ecocardiografía , Femenino , Hemodinámica , Humanos , Persona de Mediana Edad , SARS-CoV-2 , Cardiomiopatía de Takotsubo/fisiopatologíaRESUMEN
Response to breast cancer chemoprevention can depend upon host genetic makeup and initiating events leading up to preneoplasia. Increased expression of aromatase and estrogen receptor (ER) is found in conjunction with breast cancer. To investigate response or resistance to endocrine therapy, mice with targeted overexpression of Esr1 or CYP19A1 to mammary epithelial cells were employed, representing two direct pathophysiological interventions in estrogen pathway signaling. Both Esr1 and CYP19A1 overexpressing mice responded to letrozole with reduced hyperplastic alveolar nodule prevalence and decreased mammary epithelial cell proliferation. CYP19A1 overexpressing mice were tamoxifen sensitive but Esr1 overexpressing mice were tamoxifen resistant. Increased ER expression occurred with tamoxifen resistance but no consistent changes in progesterone receptor, pSTAT3, pSTAT5, cyclin D1 or cyclin E levels in association with response or resistance were found. RNA-sequencing (RNA-seq) was employed to seek a transcriptome predictive of tamoxifen resistance using these models and a second tamoxifen-resistant model, BRCA1 deficient/Trp53 haploinsufficient mice. Sixty-eight genes associated with immune system processing were upregulated in tamoxifen-resistant Esr1- and Brca1-deficient mice, whereas genes related to aromatic compound metabolic process were upregulated in tamoxifen-sensitive CYP19A1 mice. Interferon regulatory factor 7 was identified as a key transcription factor regulating these 68 immune processing genes. Two loci encoding novel transcripts with high homology to human immunoglobulin lambda-like polypeptide 1 were uniquely upregulated in the tamoxifen-resistant models. Letrozole proved to be a successful alternative to tamoxifen. Further study of transcriptional changes associated with tamoxifen resistance including immune-related genes could expand our mechanistic understanding and lead to biomarkers predictive of escape or response to endocrine therapies.
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Aromatasa/metabolismo , Receptor alfa de Estrógeno/metabolismo , Fenómenos del Sistema Inmunológico/genética , Neoplasias Mamarias Animales/tratamiento farmacológico , Nitrilos/farmacología , Lesiones Precancerosas/tratamiento farmacológico , Tamoxifeno/farmacología , Triazoles/farmacología , Animales , Antineoplásicos Hormonales/farmacología , Inhibidores de la Aromatasa/farmacología , Proteína BRCA1/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/inmunología , Biomarcadores de Tumor/metabolismo , Resistencia a Antineoplásicos/genética , Femenino , Citometría de Flujo , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Técnicas para Inmunoenzimas , Letrozol , Neoplasias Mamarias Animales/genética , Neoplasias Mamarias Animales/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Lesiones Precancerosas/genética , Lesiones Precancerosas/metabolismo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Sugarcane is the source of sugar in all tropical and subtropical countries and is becoming increasingly important for bio-based fuels. However, its large (10 Gb), polyploid, complex genome has hindered genome based breeding efforts. Here we release the largest and most diverse set of sugarcane genome sequences to date, as part of an on-going initiative to provide a sugarcane genomic information resource, with the ultimate goal of producing a gold standard genome. RESULTS: Three hundred and seventeen chiefly euchromatic BACs were sequenced. A reference set of one thousand four hundred manually-annotated protein-coding genes was generated. A small RNA collection and a RNA-seq library were used to explore expression patterns and the sRNA landscape. In the sucrose and starch metabolism pathway, 16 non-redundant enzyme-encoding genes were identified. One of the sucrose pathway genes, sucrose-6-phosphate phosphohydrolase, is duplicated in sugarcane and sorghum, but not in rice and maize. A diversity analysis of the s6pp duplication region revealed haplotype-structured sequence composition. Examination of hom(e)ologous loci indicate both sequence structural and sRNA landscape variation. A synteny analysis shows that the sugarcane genome has expanded relative to the sorghum genome, largely due to the presence of transposable elements and uncharacterized intergenic and intronic sequences. CONCLUSION: This release of sugarcane genomic sequences will advance our understanding of sugarcane genetics and contribute to the development of molecular tools for breeding purposes and gene discovery.