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1.
Cell ; 156(3): 549-62, 2014 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-24485460

RESUMEN

Vascular permeability is frequently associated with inflammation and is triggered by a cohort of secreted permeability factors such as vascular endothelial growth factor (VEGF). Here, we show that the physiological vascular permeability that precedes implantation is directly controlled by progesterone receptor (PR) and is independent of VEGF. Global or endothelial-specific deletion of PR blocks physiological vascular permeability in the uterus, whereas misexpression of PR in the endothelium of other organs results in ectopic vascular leakage. Integration of an endothelial genome-wide transcriptional profile with chromatin immunoprecipitation sequencing revealed that PR induces an NR4A1 (Nur77/TR3)-dependent transcriptional program that broadly regulates vascular permeability in response to progesterone. Silencing of NR4A1 blocks PR-mediated permeability responses, indicating a direct link between PR and NR4A1. This program triggers concurrent suppression of several junctional proteins and leads to an effective, timely, and venous-specific regulation of vascular barrier function that is critical for embryo implantation.


Asunto(s)
Permeabilidad Capilar , Endotelio Vascular/metabolismo , Útero/metabolismo , Animales , Endometrio/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , Ratones , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética
2.
Opt Express ; 32(4): 6494-6506, 2024 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-38439350

RESUMEN

We study the generation of spin-orbit (SO) modes via four-wave mixing (FWM)-based parametric amplification. SO modes carry quantized total angular momentum (TAM), and we show that FWM processes that generate new signals conserve TAM. This is a generalization of prior research which operated in a regime where FWM processes conserved spin and orbital angular momenta independently. We calculate the growth rates of new modes for both degenerate and nondegenerate pump configurations. Our theory is validated against numerical simulations for the cases where the generated signals are in the same SO mode(s) as the pump(s). We also calculate the growth rates of signals in SO modes other than the pumps.

3.
Opt Express ; 31(2): 2316-2329, 2023 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-36785248

RESUMEN

Quantum measurements that use the entangled photons' polarization to encode quantum information require calibration and alignment of the measurement bases between spatially separate observers. Because of the changing birefringence in optical fibers arising from temperature fluctuations or external mechanical vibrations, the polarization state at the end of a fiber channel is unpredictable and time-varying. Polarization tracking and stabilization methods originally developed for classical optical communications cannot be applied to polarization-entangled photons, where the separately detected photons are statistically unpolarized, yet quantum mechanically correlated. We report here a fast method for automatic alignment and dynamic tracking of the polarization measurement bases between spatially separated detectors. The system uses the Nelder-Mead simplex method to minimize the observed coincidence rate between non-locally measured entangled photon pairs, without relying on classical wavelength-multiplexed pilot tones or temporally interleaved polarized photons. Alignment and control is demonstrated in a 7.1 km deployed fiber loop as well as in a controlled drifting scenario.

4.
Conserv Biol ; : e14221, 2023 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-37937455

RESUMEN

Reliable maps of species distributions are fundamental for biodiversity research and conservation. The International Union for Conservation of Nature (IUCN) range maps are widely recognized as authoritative representations of species' geographic limits, yet they might not always align with actual occurrence data. In recent area of habitat (AOH) maps, areas that are not habitat have been removed from IUCN ranges to reduce commission errors, but their concordance with actual species occurrence also remains untested. We tested concordance between occurrences recorded in camera trap surveys and predicted occurrences from the IUCN and AOH maps for 510 medium- to large-bodied mammalian species in 80 camera trap sampling areas. Across all areas, cameras detected only 39% of species expected to occur based on IUCN ranges and AOH maps; 85% of the IUCN only mismatches occurred within 200 km of range edges. Only 4% of species occurrences were detected by cameras outside IUCN ranges. The probability of mismatches between cameras and the IUCN range was significantly higher for smaller-bodied mammals and habitat specialists in the Neotropics and Indomalaya and in areas with shorter canopy forests. Our findings suggest that range and AOH maps rarely underrepresent areas where species occur, but they may more often overrepresent ranges by including areas where a species may be absent, particularly at range edges. We suggest that combining range maps with data from ground-based biodiversity sensors, such as camera traps, provides a richer knowledge base for conservation mapping and planning.


Combinación de censos con fototrampas y mapas de extensión de la UICN para incrementar el conocimiento sobre la distribución de las especies Resumen Los mapas confiables de la distribución de las especies son fundamentales para la investigación y conservación de la biodiversidad. Los mapas de distribución de la Unión Internacional para la Conservación de la Naturaleza (UICN) están reconocidos como representaciones de autoridad de los límites geográficos de las especies, aunque no siempre se alinean con los datos actuales de su presencia. En los mapas recientes de área de hábitat (ADH), las áreas que no son hábitat han sido eliminadas de la distribución de la UICN para reducir los errores de comisión, pero su concordancia con la presencia actual de las especies tampoco ha sido analizada. Analizamos la concordancia entre la presencia registrada por los censos de fototrampas y pronosticamos la presencia a partir de los mapas de la UICN y de ADH de 510 especies de mamíferos de talla mediana a grande en 80 áreas de muestreo de fototrampas. Las cámaras detectaron sólo el 39% de las especies esperadas con base en la distribución de la UICN y los mapas de ADH en todas las áreas; el 85% de las disparidades con la UICN ocurrieron dentro de los 200 km a partir del borde de la distribución. Sólo el 4% de la presencia de las especies fue detectada por las cámaras ubicadas fuera de la distribución de la UICN. La probabilidad de disparidad entre las cámaras y la UICN fue significativamente mayor para los mamíferos de talla pequeña y para los especialistas de hábitat en las regiones Neotropical e Indomalaya y en áreas con doseles forestales más bajos. Nuestros hallazgos sugieren que los mapas de distribución y ADH pocas veces subrepresentan las áreas con presencia de las especies, pero con frecuencia pueden sobrerrepresentar la distribución al incluir áreas en donde las especies pueden estar ausentes, en particular los bordes de la distribución. Sugerimos que la combinación de los mapas de distribución con los sensores de biodiversidad en tierra, como las fototrampas, proporciona una base más rica de conocimiento para el mapeo y la planeación de la conservación.

5.
Br J Anaesth ; 130(1): e137-e147, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36109206

RESUMEN

BACKGROUND: PROcedure SPECific Postoperative Pain ManagemenT (PROSPECT) guidelines recommend erector spinae plane (ESP) block or paravertebral block (PVB) for postoperative analgesia after video-assisted thoracoscopic surgery (VATS). However, there are few trials comparing the effectiveness of these techniques on patient-centric outcomes, and none evaluating chronic postsurgical pain (CPSP). Furthermore, there are no available trials comparing ultrasound-guided ESP with surgically placed PVB in this patient cohort. METHODS: We conducted a two-centre, prospective, randomised, double-blind, controlled trial, comparing anaesthesiologist-administered, ultrasound-guided ESP catheter with surgeon-administered, video-assisted PVB catheter analgesia among 80 adult patients undergoing VATS. Participants received a 20 ml bolus of levobupivacaine 0.375% followed by infusion of levobupivacaine 0.15% (10-15 ml h-1) for 48 h. Primary outcome was Quality of Recovery-15 score (QoR-15) at 24 h. Secondary outcomes included QoR-15 at 48 h, peak inspiratory flow (ml s-1) at 24 h and 48 h, area under the pain verbal response score vs time curve (AUC), opioid consumption, Comprehensive Complication Index, length of stay, and CPSP at 3 months after surgery. RESULTS: Median (25-75%) QoR-15 at 24 h was higher in ESP (n=37) compared with PVB (n=37): 118 (106-134) vs 110 (89-121) (P=0.03) and at 48 h: 131 (121-139) vs 120 (111-133) (P=0.03). There were no differences in peak inspiratory flow, AUC, Comprehensive Complication Index, length of hospital stay, and opioid consumption. Incidence of CPSP at 3 months was 12 (34%) for ESP and 11 (31%) for PVB (P=0.7). CONCLUSIONS: Compared with video-assisted, surgeon-placed paravertebral catheter, erector spinae catheter improved overall QoR-15 scores at 24 h and 48 h but without differences in pain or opioid consumption after minimally invasive thoracic surgery. CLINICAL TRIAL REGISTRATION: NCT04729712.


Asunto(s)
Bloqueo Nervioso , Cirugía Torácica , Adulto , Humanos , Levobupivacaína , Analgésicos Opioides/uso terapéutico , Estudios Prospectivos , Bloqueo Nervioso/métodos , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/prevención & control , Dolor Postoperatorio/etiología , Cirugía Torácica Asistida por Video/métodos
6.
Biom J ; 65(7): e2200203, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37085745

RESUMEN

Recently, the use of mobile technologies in ecological momentary assessments (EMAs) and interventions has made it easier to collect data suitable for intraindividual variability studies in the medical field. Nevertheless, especially when self-reports are used during the data collection process, there are difficulties in balancing data quality and the burden placed on the subject. In this paper, we address this problem for a specific EMA setting that aims to submit a demanding task to subjects at high/low values of a self-reported variable. We adopt a dynamic approach inspired by control chart methods and design optimization techniques to obtain an EMA triggering mechanism for data collection that considers both the individual variability of the self-reported variable and of the adherence. We test the algorithm in both a simulation setting and with real, large-scale data from a tinnitus longitudinal study. A Wilcoxon signed rank test shows that the algorithm tends to have both a higher F1 score and utility than a random schedule and a rule-based algorithm with static thresholds, which are the current state-of-the-art approaches. In conclusion, the algorithm is proven effective in balancing data quality and the burden placed on the participants, especially in studies where data collection is impacted by adherence.


Asunto(s)
Evaluación Ecológica Momentánea , Humanos , Estudios Longitudinales , Recolección de Datos
7.
PLoS Pathog ; 16(4): e1008438, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32353066

RESUMEN

One of the defining characteristics of the B cell receptor (BCR) is the extensive diversity in the repertoire of immunoglobulin genes that make up the BCR, resulting in broad range of specificity. Gammaherpesviruses are B lymphotropic viruses that establish life-long infection in B cells, and although the B cell receptor plays a central role in B cell biology, very little is known about the immunoglobulin repertoire of gammaherpesvirus infected cells. To begin to characterize the Ig genes expressed by murine gammaherpesvirus 68 (MHV68) infected cells, we utilized single cell sorting to sequence and clone the Ig variable regions of infected germinal center (GC) B cells and plasma cells. We show that MHV68 infection is biased towards cells that express the Igλ light chain along with a single heavy chain variable gene, IGHV10-1*01. This population arises through clonal expansion but is not viral antigen specific. Furthermore, we show that class-switching in MHV68 infected cells differs from that of uninfected cells. Fewer infected GC B cells are class-switched compared to uninfected GC B cells, while more infected plasma cells are class-switched compared to uninfected plasma cells. Additionally, although they are germinal center derived, the majority of class switched plasma cells display no somatic hypermutation regardless of infection status. Taken together, these data indicate that selection of infected B cells with a specific BCR, as well as virus mediated manipulation of class switching and somatic hypermutation, are critical aspects in establishing life-long gammaherpesvirus infection.


Asunto(s)
Linfocitos B/inmunología , Gammaherpesvirinae/fisiología , Infecciones por Herpesviridae/veterinaria , Cadenas Pesadas de Inmunoglobulina/inmunología , Región Variable de Inmunoglobulina/inmunología , Cadenas lambda de Inmunoglobulina/inmunología , Enfermedades de los Roedores/inmunología , Animales , Linfocitos B/virología , Femenino , Gammaherpesvirinae/genética , Centro Germinal/inmunología , Centro Germinal/virología , Infecciones por Herpesviridae/genética , Infecciones por Herpesviridae/inmunología , Infecciones por Herpesviridae/virología , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Cadenas lambda de Inmunoglobulina/genética , Ratones , Ratones Endogámicos C57BL , Células Plasmáticas/inmunología , Células Plasmáticas/virología , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/inmunología , Enfermedades de los Roedores/genética , Enfermedades de los Roedores/virología
8.
Opt Express ; 30(11): 18481-18495, 2022 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-36221648

RESUMEN

We experimentally demonstrate that when two spin-orbit coupled orbital angular momentum (OAM) modes of opposite topological charge co-propagate in the Kerr nonlinear regime in a hollow ring-core optical fiber, the vectorial mode superposition exhibits a unique power-dependent rotation effect. This effect is analogous to nonlinear polarization rotation in single-mode fibers, however, the added spatial dimension produces a visually observable rotation of the spatial pattern emerging from the fiber when imaged through a linear polarizer. A dielectric metasurface q-plate was designed and fabricated to excite the desired mode combination in a hollow ring-core fiber that supports stable propagation of OAM modes. The observed spatial patterns show strong agreement with numerical simulations of the vector coupled nonlinear Schrödinger equations. These results constitute the first measurements of what can be described as the spin-orbit coupled generalization of the nonlinear polarization rotation effect.

9.
Opt Express ; 30(22): 39431-39444, 2022 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-36298896

RESUMEN

Single photon detectors have dark count rates that depend strongly on the bias level for detector operation. In the case of weak light sources such as novel lasers or single-photon emitters, the rate of counts due to the light source can be comparable to that of the detector dark counts. In such cases, a characterization of the statistical properties of the dark counts is necessary. The dark counts are often assumed to follow a Poisson process that is statistically independent of the incident photon counts. This assumption must be validated for specific types of photodetectors. In this work, we focus on single-photon avalanche photodiodes (SPADs) made for 1550 nm. For the InGaAs detectors used, we find the measured distributions often differ significantly from Poisson due to the presence of dead time and afterpulsing with the difference increasing with the bias level used for obtaining higher quantum efficiencies. We find that when the dead time is increased to remove the effects of afterpulsing, it is necessary to correct the measured distributions for the effects of the dead time. To this end, we apply an iterative algorithm to remove dead time effects from the probability distribution for dark counts as well as for the case where light from an external weak laser source (known to be Poisson) is detected together with the dark counts. We believe this to be the first instance of the comprehensive application of this algorithm to real data and find that the dead time corrected probability distributions are Poisson distributions in both cases. We additionally use the Grassberger-Procaccia algorithm to estimate the entropy production rates of the dark count processes, which provides a single metric that characterizes the temporal correlations between dark counts as well as the shape of the distribution. We have thus developed a systematic procedure for taking data with 1550 nm SPADs and obtaining accurate photocount statistics to examine novel light sources.

10.
Philos Trans A Math Phys Eng Sci ; 380(2214): 20210120, 2022 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-34802273

RESUMEN

We describe the population-based susceptible-exposed-infected-removed (SEIR) model developed by the Irish Epidemiological Modelling Advisory Group (IEMAG), which advises the Irish government on COVID-19 responses. The model assumes a time-varying effective contact rate (equivalently, a time-varying reproduction number) to model the effect of non-pharmaceutical interventions. A crucial technical challenge in applying such models is their accurate calibration to observed data, e.g. to the daily number of confirmed new cases, as the history of the disease strongly affects predictions of future scenarios. We demonstrate an approach based on inversion of the SEIR equations in conjunction with statistical modelling and spline-fitting of the data to produce a robust methodology for calibration of a wide class of models of this type. This article is part of the theme issue 'Data science approaches to infectious disease surveillance'.


Asunto(s)
COVID-19 , Susceptibilidad a Enfermedades , Humanos , Modelos Estadísticos , SARS-CoV-2
11.
BMC Pulm Med ; 22(1): 418, 2022 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-36376851

RESUMEN

BACKGROUND: Although asthma does not appear to be a risk factor for severe coronavirus disease 2019 (COVID-19), outcomes could vary for patients with different asthma subtypes. The objective of this analysis was to compare COVID-19 outcomes in real-world cohorts in the United States among patients with asthma, with or without evidence of allergy. METHODS: In a retrospective analysis of the COVID-19 Optum electronic health record dataset (February 20, 2020-January 28, 2021), patients diagnosed with COVID-19 with a history of moderate-to-severe asthma were divided into 2 cohorts: those with evidence of allergic asthma and those without (nonallergic asthma). After 1:1 propensity score matching, in which covariates were balanced and potential bias was removed, COVID-19 outcomes were compared between cohorts. RESULTS: From a COVID-19 population of 591,198 patients, 1595 patients with allergic asthma and 8204 patients with nonallergic asthma were identified. After propensity score matching (n = 1578 per cohort), risk of death from any cause after COVID-19 diagnosis was significantly lower for patients with allergic vs nonallergic asthma (hazard ratio, 0.48; 95% CI 0.28-0.83; P = 0.0087), and a smaller proportion of patients with allergic vs nonallergic asthma was hospitalized within - 7 to + 30 days of COVID-19 diagnosis (13.8% [n = 217] vs 18.3% [n = 289]; P = 0.0005). Among hospitalized patients, there were no significant differences between patients with allergic or nonallergic asthma in need for intensive care unit admission, respiratory support, or COVID-19 treatment. CONCLUSIONS: Asthma subtype may influence outcomes after COVID-19; patients with allergic asthma are at lower risk for hospitalization/death than those with nonallergic asthma.


Asunto(s)
Asma , COVID-19 , Hipersensibilidad , Humanos , COVID-19/epidemiología , Prueba de COVID-19 , Estudios Retrospectivos , Asma/complicaciones , Asma/epidemiología , Asma/diagnóstico , Hipersensibilidad/complicaciones , Hipersensibilidad/epidemiología , Tratamiento Farmacológico de COVID-19
12.
Neonatal Netw ; 41(2): 94-99, 2022 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-35260426

RESUMEN

AIMS: (a) Quantify frequency of patient moves within a NICU with single patient and semi-private rooms (SPR). (b) Compare staff and parent perceptions of these moves. METHODS: A hospital administrative database was evaluated to quantify the frequency of moves. A Room Change Questionnaire was devised to evaluate perceptions from NICU families and staff. RESULTS: Most families reported experiencing at least 1 patient move (92 percent), with the majority reporting at least 3 moves (58 percent). Staff perceived moves as negative significantly more than parents (p < .01), and overreported negative family perceptions (p < .01). Overall, moves did not bother families (52 percent); however, most families who moved 3 or more times reported at least 1 negative perception (63 percent). CONCLUSION: SFRs increase the number of patient moves. NICU staff's perception is significantly more negative than family's perception; however, most families who were moved frequently reported at least 1 negative perception.


Asunto(s)
Unidades de Cuidado Intensivo Neonatal , Transferencia de Pacientes , Humanos , Recién Nacido , Padres , Habitaciones de Pacientes , Encuestas y Cuestionarios
13.
J Appl Biomech ; 38(1): 39-46, 2022 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-35061998

RESUMEN

Investigating all forces exerted on the patient's body during high-velocity, low-amplitude spinal manipulative therapy (SMT) remains fundamental to elucidate how these may contribute to SMT's effects. Previous conflicting findings preclude our understanding of the relationship between SMT forces acting at the clinician-patient and patient-table interfaces. This study aimed to quantify forces at the clinician-participant and participant-table interfaces during thoracic SMT in asymptnomatic adults. An experienced clinician provided a posterior to anterior SMT centered to T7 transverse processes using predetermined force-time characteristics to 40 asymptomatic volunteers (20 females; average age = 27.2 [4.9] y). Forces at the clinician-participant interface were recorded by triaxial load cells; whereas, forces at the participant-table interface were recorded by the force-sensing table technology. Preload force, total peak force, time to peak, and loading rate at each interface were analyzed descriptively. Total peak vertical forces at the clinician-participant interface averaged 532 (71) N while total peak forces at the participant-table interface averaged 658 (33) N. Forces at the participant-table interface were, on average, 1.27 (0.25) times larger than the ones at the clinician-participant interface. Larger forces at the participant-table interface compared with the ones at the clinician-participant interface during thoracic SMT are consistent with mathematical models developed to investigate thoracic impact simulating a dynamic force-deflection response.


Asunto(s)
Manipulación Espinal , Adulto , Fenómenos Biomecánicos , Femenino , Humanos , Vértebras Torácicas
14.
Glob Chang Biol ; 27(16): 3718-3731, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33887083

RESUMEN

Human activity and land use change impact every landscape on Earth, driving declines in many animal species while benefiting others. Species ecological and life history traits may predict success in human-dominated landscapes such that only species with "winning" combinations of traits will persist in disturbed environments. However, this link between species traits and successful coexistence with humans remains obscured by the complexity of anthropogenic disturbances and variability among study systems. We compiled detection data for 24 mammal species from 61 populations across North America to quantify the effects of (1) the direct presence of people and (2) the human footprint (landscape modification) on mammal occurrence and activity levels. Thirty-three percent of mammal species exhibited a net negative response (i.e., reduced occurrence or activity) to increasing human presence and/or footprint across populations, whereas 58% of species were positively associated with increasing disturbance. However, apparent benefits of human presence and footprint tended to decrease or disappear at higher disturbance levels, indicative of thresholds in mammal species' capacity to tolerate disturbance or exploit human-dominated landscapes. Species ecological and life history traits were strong predictors of their responses to human footprint, with increasing footprint favoring smaller, less carnivorous, faster-reproducing species. The positive and negative effects of human presence were distributed more randomly with respect to species trait values, with apparent winners and losers across a range of body sizes and dietary guilds. Differential responses by some species to human presence and human footprint highlight the importance of considering these two forms of human disturbance separately when estimating anthropogenic impacts on wildlife. Our approach provides insights into the complex mechanisms through which human activities shape mammal communities globally, revealing the drivers of the loss of larger predators in human-modified landscapes.


Asunto(s)
Animales Salvajes , Rasgos de la Historia de Vida , Animales , Ecosistema , Actividades Humanas , Humanos , Mamíferos , América del Norte
15.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-34299009

RESUMEN

As many jurisdictions consider relaxing cannabis legislation and usage is increasing in North America and other parts of the world, there is a need to explore the possible genetic differences underlying the subjective effects of cannabis. This pilot study investigated specific genetic variations within the cannabinoid receptor 1 (CNR1) gene for association with the subjective effects of smoked cannabis. Data were obtained from a double-blinded, placebo-controlled clinical trial studying the impact of cannabis intoxication on driving performance. Participants randomized to the active cannabis group who consented to secondary genetic analysis (n = 52) were genotyped at the CNR1 rs1049353 and rs2023239 polymorphic areas. Maximum value and area under the curve (AUC) analyses were performed on subjective measures data. Analysis of subjective effects by genotype uncovered a global trend towards greater subjective effects for rs1049353 T-allele- and rs2023239 C-allele-carrying subjects. However, significant differences attributed to allelic identity were only documented for a subset of subjective effects. Our findings suggest that rs1049353 and rs2023239 minor allele carriers experience augmented subjective effects during acute cannabis intoxication.


Asunto(s)
Afecto/efectos de los fármacos , Cannabinoides/farmacología , Cannabis/química , Fumar Marihuana/genética , Receptor Cannabinoide CB1/genética , Adulto , Alelos , Área Bajo la Curva , Cannabinoides/administración & dosificación , Cannabinoides/sangre , Femenino , Genotipo , Humanos , Masculino , Fumar Marihuana/psicología , Proyectos Piloto , Polimorfismo de Nucleótido Simple
16.
Stat Methods Appt ; 30(5): 1365-1398, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34840548

RESUMEN

We propose a weighted stochastic block model (WSBM) which extends the stochastic block model to the important case in which edges are weighted. We address the parameter estimation of the WSBM by use of maximum likelihood and variational approaches, and establish the consistency of these estimators. The problem of choosing the number of classes in a WSBM is addressed. The proposed model is applied to simulated data and an illustrative data set.

17.
Mol Pharmacol ; 98(3): 267-279, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32817462

RESUMEN

Human cytochrome P450 (P450) CYP2B6 undergoes nitric oxide (NO)-dependent proteasomal degradation in response to the NO donor dipropylenetriamine NONOate (DPTA) and biologic NO in HeLa and HuH7 cell lines. CYP2B6 is also downregulated by NO in primary human hepatocytes. We hypothesized that NO or derivative reactive nitrogen species may generate adducts of tyrosine and/or cysteine residues, causing CYP2B6 downregulation, and selected Tyr and Cys residues for mutation based on predicted solvent accessibility. CYP2B6V5-Y317A, -Y380A, and -Y190A mutant proteins expressed in HuH7 cells were less sensitive than wild-type (WT) enzyme to degradation evoked by DPTA, suggesting that these tyrosines are targets for NO-dependent downregulation. The Y317A or Y380A mutants did not show increases in high molecular mass (HMM) species after treatment with DPTA or bortezomib + DPTA, in contrast to the WT enzyme. Carbon monoxide-releasing molecule 2 treatment caused rapid suppression of 2B6 enzyme activity, significant HMM species generation, and ubiquitination of CYP2B6 protein but did not stimulate CYP2B6 degradation. The CYP2B6 inhibitor 4-(4-chlorophenyl)imidazole blocked NO-dependent CYP2B6 degradation, suggesting that NO access to the active site is important. Molecular dynamics simulations predicted that tyrosine nitrations of CYP2B6 would cause significant destabilizing perturbations of secondary structure and remove correlated motions likely required for enzyme function. We propose that cumulative nitrations of Y190, Y317, and Y380 by reactive nitrogen species cause destabilization of CYP2B6, which may act synergistically with heme nitrosylation to target the enzyme for degradation. SIGNIFICANCE STATEMENT: This work provides novel insight into the mechanisms by which nitric oxide, which is produced in hepatocytes in response to inflammation, triggers the ubiquitin-dependent proteasomal degradation of the cytochrome P450 (P450) enzyme CYP2B6. Our data demonstrate that both nitration of specific tyrosine residues and interaction of nitric oxide (NO) with the P450 heme are necessary for NO to trigger ubiquitination and protein degradation.


Asunto(s)
Citocromo P-450 CYP2B6/química , Citocromo P-450 CYP2B6/metabolismo , Donantes de Óxido Nítrico/farmacología , Tirosina/química , Línea Celular , Citocromo P-450 CYP2B6/genética , Regulación hacia Abajo , Células HeLa , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Cultivo Primario de Células , Proteolisis
18.
Ann Surg ; 272(5): 807-813, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32925254

RESUMEN

OBJECTIVE: Utilizing a standardized dataset based on a newly developed list of 27 univocally defined complications, this study analyzed data to assess the incidence and grading of complications and evaluate outcomes associated with gastrectomy for cancer in Europe. SUMMARY BACKGROUND DATA: The absence of a standardized system for recording gastrectomy-associated complications makes it difficult to compare results from different hospitals and countries. METHODS: Using a secure online platform (www.gastrodata.org), referral centers for gastric cancer in 11 European countries belonging to the Gastrectomy Complications Consensus Group recorded clinical, oncological, and surgical data, and outcome measures at hospital discharge and at 30 and 90 days postoperatively. This retrospective observational study included all consecutive resections over a 2-year period. RESULTS: A total of 1349 gastrectomies performed between January 2017 and December 2018 were entered into the database. Neoadjuvant chemotherapy was administered to 577 patients (42.8%). Total (46.1%) and subtotal (46.4%) gastrectomy were the predominant resections. D2 or D2+ lymphadenectomy was performed in almost 80% of operations. The overall complications' incidence was 29.8%; 402 patients developed 625 complications, with the most frequent being nonsurgical infections (23%), anastomotic leak (9.8%), other postoperative abnormal fluid from drainage and/or abdominal collections (9.3%), pleural effusion (8.3%), postoperative bleeding (5.6%), and other major complications requiring invasive treatment (5.6%). The median Clavien-Dindo score and Comprehensive Complications Index were IIIa and 26.2, respectively. In-hospital, 30-day, and 90-day mortality were 3.2%, 3.6%, and 4.5%, respectively. CONCLUSIONS: The use of a standardized platform to collect European data on perioperative complications revealed that gastrectomy for gastric cancer is still associated with heavy morbidity and mortality. Actions are needed to limit the incidence of, and to effectively treat, the most frequent and most lethal complications.


Asunto(s)
Gastrectomía , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/patología , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía , Adulto , Anciano , Europa (Continente)/epidemiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Sistema de Registros , Estudios Retrospectivos
19.
Opt Express ; 28(23): 34111-34122, 2020 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-33182888

RESUMEN

The property of self-imaging combined with the polarization birefringence of the angled multimode waveguide is used to design a silicon nitride (SiN) polarization splitter (PS) at λ ∼ 1550 nm. The demonstrated PS on a 450 nm thick SiN device layer (with 2.5 µm cladding oxide) has a footprint of 80 µm×13 µm and exhibits nearly wavelength independent performance over the C+L bands. Also, the device can be configured as a polarization combiner (PC) in reverse direction with similar bandwidth and performance. The measured crosstalk (CT) and insertion loss (IL) are respectively <-18 dB (<-20 dB) and ∼0.7 dB (∼0.8 dB) for TE (TM) polarization over the measurement wavelength range of 1525 nm ≤λ ≤ 1625 nm. The measured device parameter variations suggest some tolerance to fabrication variations. Such a device is a good candidate for a photonics integrated chip (PIC) foundry-compatible, SiN PS.

20.
Opt Express ; 28(22): 33528-33537, 2020 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-33115013

RESUMEN

The plasmon resonance of a structure is primarily dictated by its optical properties and geometry, which can be modified to enable hot-carrier photodetectors with superior performance. Recently, metal alloys have played a prominent role in tuning the resonance of plasmonic structures through chemical composition engineering. However, it has been unclear how alloying modifies the time dynamics of the generated hot-carriers. In this work, we elucidate the role of chemical composition on the relaxation time of hot-carriers for the archetypal AuxAg1-x thin film system. Through time-resolved optical spectroscopy measurements in the visible wavelength range, we measure composition-dependent relaxation times that vary up to 8× for constant pump fluency. Surprisingly, we find that the addition of 2% of Ag into Au films can increase the hot-carrier lifetime by approximately 35% under fixed fluence, as a result of a decrease in optical loss. Further, the relaxation time is found to be inversely proportional to the imaginary part of the permittivity. Our results indicate that alloying is a promising approach to effectively control hot-carrier relaxation time in metals.

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