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In stressed cells, apoptosis ensues when Bcl-2 family members Bax or Bak oligomerize and permeabilize the mitochondrial outer membrane. Certain BH3-only relatives can directly activate them to mediate this pivotal, poorly understood step. To clarify the conformational changes that induce Bax oligomerization, we determined crystal structures of BaxΔC21 treated with detergents and BH3 peptides. The peptides bound the Bax canonical surface groove but, unlike their complexes with prosurvival relatives, dissociated Bax into two domains. The structures define the sequence signature of activator BH3 domains and reveal how they can activate Bax via its groove by favoring release of its BH3 domain. Furthermore, Bax helices α2-α5 alone adopted a symmetric homodimer structure, supporting the proposal that two Bax molecules insert their BH3 domain into each other's surface groove to nucleate oligomerization. A planar lipophilic surface on this homodimer may engage the membrane. Our results thus define critical Bax transitions toward apoptosis.
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Apoptose , Cristalografia por Raios X , Proteína X Associada a bcl-2/química , Sequência de Aminoácidos , Animais , Citocromos c/metabolismo , Dimerização , Embrião de Mamíferos/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Lipossomos/metabolismo , Fígado/metabolismo , Camundongos , Mitocôndrias/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Conformação Proteica , Estrutura Terciária de Proteína , Alinhamento de Sequência , Proteína X Associada a bcl-2/metabolismoRESUMO
BAK and BAX execute intrinsic apoptosis by permeabilising the mitochondrial outer membrane. Their activity is regulated through interactions with pro-survival BCL-2 family proteins and with non-BCL-2 proteins including the mitochondrial channel protein VDAC2. VDAC2 is important for bringing both BAK and BAX to mitochondria where they execute their apoptotic function. Despite this important function in apoptosis, while interactions with pro-survival family members are well characterised and have culminated in the development of drugs that target these interfaces to induce cancer cell apoptosis, the interaction between BAK and VDAC2 remains largely undefined. Deep scanning mutagenesis coupled with cysteine linkage identified key residues in the interaction between BAK and VDAC2. Obstructive labelling of specific residues in the BH3 domain or hydrophobic groove of BAK disrupted this interaction. Conversely, mutating specific residues in a cytosol-exposed region of VDAC2 stabilised the interaction with BAK and inhibited BAK apoptotic activity. Thus, this VDAC2-BAK interaction site can potentially be targeted to either inhibit BAK-mediated apoptosis in scenarios where excessive apoptosis contributes to disease or to promote BAK-mediated apoptosis for cancer therapy.
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Apoptose , Canal de Ânion 2 Dependente de Voltagem , Proteína Killer-Antagonista Homóloga a bcl-2 , Canal de Ânion 2 Dependente de Voltagem/metabolismo , Canal de Ânion 2 Dependente de Voltagem/genética , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Humanos , Ligação Proteica , Mitocôndrias/metabolismo , Animais , Células HEK293RESUMO
ABSTRACT: Rituximab (RTX) and other monoclonal antibodies (mAbs) that bind directly to malignant cells are of great clinical value but are not effective for all patients. A major mechanism of action of RTX is antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells. Prior in vitro studies in our laboratory demonstrated that T cells contribute to maintaining the viability and cytotoxic potential of NK cells activated by anti-CD20-coated target B cells. Here, we conducted studies using a novel mouse model and clinical correlative analysis to assess whether T-cell help contribute to RTX-mediated NK-cell ADCC in the tumor microenvironment (TME) in vivo. A humanized mouse model was developed using Raji lymphoma cells and normal donor peripheral blood mononuclear cells that allows for control of T-cell numbers in the lymphoma TME. In this model, NK-cell viability and CD16 and CD25 expression dropped after RTX in the absence of T cells but increased in the presence of T cells. RTX therapy was more effective when T cells were present and was ineffective when NK cells were depleted. In patients with indolent lymphoma, fine needle aspirates were obtained before and â¼1 week after treatment with a RTX-containing regimen. There was a strong correlation between CD4+ T cells as well as total T cells in the pretherapy TME and an increase in NK-cell CD16 and CD25 expression after RTX. We conclude that T-cell help in the TME enhances RTX-mediated NK-cell viability and ADCC.
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Citotoxicidade Celular Dependente de Anticorpos , Células Matadoras Naturais , Rituximab , Microambiente Tumoral , Rituximab/farmacologia , Rituximab/uso terapêutico , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Animais , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Humanos , Camundongos , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Linhagem Celular Tumoral , Camundongos SCID , Linfoma/imunologia , Linfoma/tratamento farmacológico , Linfoma/patologia , Linfoma/terapia , FemininoRESUMO
Terpenoids constitute the largest class of plant primary and secondary metabolites with a broad range of biological and ecological functions. They are synthesized from isopentenyl diphosphate and dimethylallyl diphosphate, which in plastids are condensed by geranylgeranyl diphosphate synthases (GGPPSs) to produce GGPP (C20) for diterpene biosynthesis and by geranyl diphosphate synthases (GPPSs) to form GPP (C10) for monoterpene production. Depending on the plant species, unlike homomeric GGPPSs, GPPSs exist as homo- and heteromers, the latter of which contain catalytically inactive GGPPS-homologous small subunits (SSUs) that can interact with GGPPSs. By combining phylogenetic analysis with functional characterization of GGPPS homologs from a wide range of photosynthetic organisms, we investigated how different GPPS architectures have evolved within the GGPPS protein family. Our results reveal that GGPPS gene family expansion and functional divergence began early in nonvascular plants, and that independent parallel evolutionary processes gave rise to homomeric and heteromeric GPPSs. By site-directed mutagenesis and molecular dynamics simulations, we also discovered that Leu-Val/Val-Ala pairs of amino acid residues were pivotal in the functional divergence of homomeric GPPSs and GGPPSs. Overall, our study elucidated an evolutionary path for the formation of GPPSs with different architectures from GGPPSs and uncovered the molecular mechanisms involved in this differentiation.
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Dimetilaliltranstransferase , Diterpenos , Farnesiltranstransferase/genética , Farnesiltranstransferase/metabolismo , Filogenia , Dimetilaliltranstransferase/genética , Dimetilaliltranstransferase/metabolismo , Diterpenos/metabolismoRESUMO
Potassium channels embedded in cell membranes employ gates to regulate K+ current. While a specific constriction in the permeation pathway has historically been implicated in gating, recent reports suggest that the signature ion selectivity filter located in the outer membrane leaflet may be equally important. Inwardly rectifying K+ channels also control the directionality of flow, using intracellular polyamines to stem ion efflux by a valve-like action. This study presents crystallographic evidence of interdependent gates in the conduction pathway and reveals the mechanism of polyamine block. Reorientation of the intracellular domains, concomitant with activation, instigates polyamine release from intracellular binding sites to block the permeation pathway. Conformational adjustments of the slide helices, achieved by rotation of the cytoplasmic assembly relative to the pore, are directly correlated to the ion configuration in the selectivity filter. Ion redistribution occurs irrespective of the constriction, suggesting a more expansive role of the selectivity filter in gating than previously appreciated.
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Proteínas de Bactérias/química , Magnetospirillum/química , Receptores KIR/química , Sequência de Aminoácidos , Proteínas de Bactérias/isolamento & purificação , Sítios de Ligação , Cristalografia por Raios X , Escherichia coli/genética , Modelos Moleculares , Dados de Sequência Molecular , Fosfolipídeos/química , Poliaminas/química , Conformação Proteica , Receptores KIR/isolamento & purificação , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Alinhamento de SequênciaRESUMO
Certain BH3-only proteins transiently bind and activate Bak and Bax, initiating their oligomerization and the permeabilization of the mitochondrial outer membrane, a pivotal step in the mitochondrial pathway to apoptosis. Here we describe the first crystal structures of an activator BH3 peptide bound to Bak and illustrate their use in the design of BH3 derivatives capable of inhibiting human Bak on mitochondria. These BH3 derivatives compete for the activation site at the canonical groove, are the first engineered inhibitors of Bak activation, and support the role of key conformational transitions associated with Bak activation.
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Apoptose/efeitos dos fármacos , Proteína 11 Semelhante a Bcl-2 , Mitocôndrias , Peptídeos , Proteína Killer-Antagonista Homóloga a bcl-2 , Animais , Proteína 11 Semelhante a Bcl-2/química , Proteína 11 Semelhante a Bcl-2/farmacologia , Linhagem Celular Transformada , Humanos , Camundongos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Peptídeos/química , Peptídeos/farmacologia , Ligação Proteica , Relação Estrutura-Atividade , Proteína Killer-Antagonista Homóloga a bcl-2/química , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismoRESUMO
The most recent Sudan virus (SUDV) outbreak in Uganda was first detected in September 2022 and resulted in 164 laboratory-confirmed cases and 77 deaths. There are no approved vaccines against SUDV. Here, we investigated the protective efficacy of ChAdOx1-biEBOV in cynomolgus macaques using a prime or a prime-boost regimen. ChAdOx1-biEBOV is a replication-deficient simian adenovirus vector encoding SUDV and Ebola virus (EBOV) glycoproteins (GPs). Intramuscular vaccination induced SUDV and EBOV GP-specific IgG responses and neutralizing antibodies. Upon challenge with SUDV, vaccinated animals showed signs of disease like those observed in control animals, and no difference in survival outcomes were measured among all three groups. Viral load in blood samples and in tissue samples obtained after necropsy were not significantly different between groups. Overall, this study highlights the importance of evaluating vaccines in multiple animal models and demonstrates the importance of understanding protective efficacy in both animal models and human hosts.
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Synthetic chemists have developed robust methods to synthesize discrete molecules, linear and branched polymers, and disordered cross-linked networks. However, two-dimensional polymers (2DPs) prepared from designed monomers have been long missing from these capabilities, both as objects of chemical synthesis and in nature. Recently, new polymerization strategies and characterization methods have enabled the unambiguous realization of covalently linked macromolecular sheets. Here we review 2DPs and 2D polymerization methods. Three predominant 2D polymerization strategies have emerged to date, which produce 2DPs either as monolayers or multilayer assemblies. We discuss the fundamental understanding and scope of each of these approaches, including: the bond-forming reactions used, the synthetic diversity of 2DPs prepared, their multilayer stacking behaviors, nanoscale and mesoscale structures, and macroscale morphologies. Additionally, we describe the analytical tools currently available to characterize 2DPs in their various isolated forms. Finally, we review emergent 2DP properties and the potential applications of planar macromolecules. Throughout, we highlight achievements in 2D polymerization and identify opportunities for continued study.
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Polímeros , Substâncias Macromoleculares/química , Polimerização , Polímeros/químicaRESUMO
Pulmonary infections elicit a combination of tissue-resident and circulating T cell responses. Understanding the contribution of these anatomically distinct cellular pools in protective immune responses is critical for vaccine development. Francisella tularensis is a highly virulent bacterium capable of causing lethal systemic disease following pulmonary infection for which there is no currently licensed vaccine. Although T cells are required for survival of F. tularensis infection, the relative contribution of tissue-resident and circulating T cells is not completely understood, hampering design of effective, long-lasting vaccines directed against this bacterium. We have previously shown that resident T cells were not sufficient to protect against F. tularensis, suggesting circulating cells may serve a critical role in host defense. To elucidate the role of circulating T cells, we used a model of vaccination and challenge of parabiotic mice. Intranasally infected naive mice conjoined to immune animals had increased numbers of circulating memory T cells and similar splenic bacterial burdens as vaccinated-vaccinated pairs. However, bacterial loads in the lungs of naive parabionts were significantly greater than those observed in vaccinated-vaccinated pairs, but despite early control of F. tularensis replication, all naive-vaccinated pairs succumbed to infection. Together, these data define the specific roles of circulating and resident T cells in defense against infection that is initiated in the pulmonary compartment but ultimately causes disseminated disease. These data also provide evidence for employing vaccination strategies that elicit both pools of T cells for immunity against F. tularensis and may be a common theme for other disseminating bacterial infections.
Assuntos
Vacinas Bacterianas/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Francisella tularensis/imunologia , Células T de Memória/imunologia , Animais , Anticorpos Antibacterianos/sangue , Carga Bacteriana/imunologia , Feminino , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/metabolismo , Pneumopatias/imunologia , Pneumopatias/microbiologia , Pneumopatias/patologia , Camundongos , Camundongos Endogâmicos C57BL , Tularemia/imunologia , Tularemia/patologia , VacinaçãoRESUMO
Due to the myriad interactions between prosurvival and proapoptotic members of the Bcl-2 family of proteins, establishing the mechanisms that regulate the intrinsic apoptotic pathway has proven challenging. Mechanistic insights have primarily been gleaned from in vitro studies because genetic approaches in mammals that produce unambiguous data are difficult to design. Here we describe a mutation in mouse and human Bak that specifically disrupts its interaction with the prosurvival protein Bcl-xL Substitution of Glu75 in mBak (hBAK Q77) for leucine does not affect the three-dimensional structure of Bak or killing activity but reduces its affinity for Bcl-xL via loss of a single hydrogen bond. Using this mutant, we investigated the requirement for physical restraint of Bak by Bcl-xL in apoptotic regulation. In vitro, Bak(Q75L) cells were significantly more sensitive to various apoptotic stimuli. In vivo, loss of Bcl-xL binding to Bak led to significant defects in T-cell and blood platelet survival. Thus, we provide the first definitive in vivo evidence that prosurvival proteins maintain cellular viability by interacting with and inhibiting Bak.
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Apoptose/genética , Plaquetas/citologia , Linfócitos T/citologia , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína bcl-X/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Linhagem Celular , Sobrevivência Celular/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Ligação Proteica , Conformação Proteica , Domínios Proteicos/genética , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2/genéticaRESUMO
Although it is well established that density dependence drives changes in organismal abundance over time, relatively little is known about how density dependence affects variation in abundance over space. We tested the hypothesis that spatial trade-offs between food and safety can change the drivers of population distribution, caused by opposing patterns of density-dependent habitat selection (DDHS) that are predicted by the multidimensional ideal free distribution. We addressed this using winter aerial survey data of northern Yellowstone elk (Cervus canadensis) spanning four decades. Supporting our hypothesis, we found positive DDHS for food (herbaceous biomass) and negative DDHS for safety (openness and roughness), such that the primary driver of habitat selection switched from food to safety as elk density decreased from 9.3 to 2.0 elk/km2 . Our results demonstrate how population density can drive landscape-level shifts in population distribution, confounding habitat selection inference and prediction and potentially affecting community-level interactions.
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Cervos , Lobos , Animais , Ecossistema , Densidade Demográfica , Comportamento Predatório , Estações do Ano , Parques Recreativos , Noroeste dos Estados UnidosRESUMO
Quantum entanglement-based imaging promises significantly increased resolution by extending the spatial separation of optical collection apertures used in very-long-baseline interferometry for astronomy and geodesy. We report a tabletop entanglement-based interferometric imaging technique that utilizes two entangled field modes serving as a phase reference between two apertures. The spatial distribution of a simulated thermal light source is determined by interfering light collected at each aperture with one of the entangled fields and performing joint measurements. This experiment demonstrates the ability of entanglement to implement interferometric imaging.
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OBJECTIVES: Bronchiolitis is the most common cause for nonelective infant hospitalization in the United States with increasing utilization of high-flow nasal cannula (HFNC). We standardized initiation and weaning of HFNC for bronchiolitis and quantified the impact on outcomes. Our specific aim was to reduce hospital and ICU length of stay (LOS) by 10% between two bronchiolitis seasons after implementation. DESIGN: A quality improvement (QI) project using statistical process control methodology. SETTING: Tertiary-care children's hospital with 24 PICU and 48 acute care pediatric beds. PATIENTS: Children less than 24 months old with bronchiolitis without other respiratory diagnoses or underlying cardiac, respiratory, or neuromuscular disorders between December 2017 and November 2018 (baseline), and December 2018 and February 2020 (postintervention). INTERVENTIONS: Interventions included development of an HFNC protocol with initiation and weaning guidelines, modification of protocol and respiratory assessment classification, education, and QI rounds with a focus on efficient HFNC weaning, transfer, and/or discharge. MEASUREMENTS AND MAIN RESULTS: A total of 223 children were included (96 baseline and 127 postintervention). The primary outcome metric, average LOS per patient, decreased from 4.0 to 2.8 days, and the average ICU LOS per patient decreased from 2.8 to 1.9 days. The secondary outcome metric, average HFNC treatment hours per patient, decreased from 44.0 to 36.3 hours. The primary and secondary outcomes met criteria for special cause variation. Balancing measures included ICU readmission rates, 30-day readmission rates, and adverse events, which were not different between the two periods. CONCLUSIONS: A standardized protocol for HFNC management for patients with bronchiolitis was associated with decreased hospital and ICU LOS, less time on HFNC, and no difference in readmissions or adverse events.
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Bronquiolite , Cânula , Lactente , Criança , Humanos , Pré-Escolar , Melhoria de Qualidade , Desmame , Unidades de Terapia Intensiva Pediátrica , Bronquiolite/terapia , OxigenoterapiaRESUMO
Determining neuroendocrine tumor (NET) primary sites is pivotal for patient care as pancreatic NETs (pNETs) and small bowel NETs (sbNETs) have distinct treatment approaches. The diagnostic power and prioritization of fluorescence in situ hybridization (FISH) assay biomarkers for establishing primary sites has not been thoroughly investigated using machine learning (ML) techniques. We trained ML models on FISH assay metrics from 85 sbNET and 59 pNET samples for primary site prediction. Exploring multiple methods for imputing missing data, the impute-by-median dataset coupled with a support vector machine model achieved the highest classification accuracy of 93.1% on a held-out test set, with the top importance variables originating from the ERBB2 FISH probe. Due to the greater interpretability of decision tree (DT) models, we fit DT models to ten dataset splits, achieving optimal performance with k-nearest neighbor (KNN) imputed data and a transformation to single categorical biomarker probe variables, with a mean accuracy of 81.4%, on held-out test sets. ERBB2 and MET variables ranked as top-performing features in 9 of 10 DT models and the full dataset model. These findings offer probabilistic guidance for FISH testing, emphasizing the prioritization of the ERBB2, SMAD4, and CDKN2A FISH probes in diagnosing NET primary sites.
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Neoplasias Intestinais , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia , Hibridização in Situ Fluorescente , Neoplasias Intestinais/patologia , Neoplasias Pancreáticas/patologia , Aprendizado de MáquinaRESUMO
BACKGROUND: Understanding smoking behaviors in hospital patients who smoke may improve inpatient cessation treatments. This study aimed to describe smoking-related behaviors, past-quit attempts, and self-reported difficulties experienced in quitting among those who enrolled in a smoking cessation trial of varenicline. METHODS: Baseline data were obtained from adult hospitalized smokers (average ≥ 10 cigarettes/day in 4-weeks prior to hospitalization) who enrolled in a randomized, placebo-controlled trial of varenicline ± nicotine lozenges at five Australian public hospitals. A logistic regression model tested the association between participant characteristics and quitting in the previous 12 months. RESULTS: Participants' (n = 320; 57% male, 52.5 ± 12.1 years old) motivation and confidence in quitting were high. A total of 120 participants (37.5%) had attempted quitting in the previous 12-months. Prior hospitalization (P = .008) and employment status (P = .015) were significantly associated with past quit attempts. No statistically significant differences were noted in the reason for hospitalization or the level of nicotine dependence between participants who attempted quitting in the previous 12 months and their counterparts. Smoking cessation pharmacotherapy was used by 55% of those attempting to quit; nicotine replacement therapy (65.2%) and varenicline (16.7%) most common. Stress or anxiety, urges to smoke and a lack of motivation were the difficulties experienced in past quit attempts. CONCLUSIONS: Those who had a prior hospitalization and were unemployed had significantly greater odds of reporting past quit attempts. Further research is needed to investigate the degree of adherence among inpatient smokers with the smoke-free hospital policies and the frequency of NRT provision and uptake on admission.
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Abandono do Hábito de Fumar , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Vareniclina/uso terapêutico , Fumantes , Motivação , Dispositivos para o Abandono do Uso de Tabaco , Austrália/epidemiologia , Fumar/epidemiologia , HospitaisRESUMO
Insulin is a mainstay of therapy for diabetes mellitus, yet its thermal stability complicates global transportation and storage. Cold-chain transport, coupled with optimized formulation and materials, prevents to some degree nucleation of amyloid and hence inactivation of hormonal activity. These issues hence motivate the design of analogs with increased stability, with a promising approach being single-chain insulins (SCIs), whose C domains (foreshortened relative to proinsulin) resemble those of the single-chain growth factors (IGFs). We have previously demonstrated that optimized SCIs can exhibit native-like hormonal activity with enhanced thermal stability and marked resistance to fibrillation. Here, we describe the crystal structure of an ultrastable SCI (C-domain length 6; sequence EEGPRR) bound to modules of the insulin receptor (IR) ectodomain (N-terminal α-subunit domains L1-CR and C-terminal αCT peptide; "microreceptor" [µIR]). The structure of the SCI-µIR complex, stabilized by an Fv module, was determined using diffraction data to a resolution of 2.6 Å. Remarkably, the αCT peptide (IR-A isoform) "threads" through a gap between the flexible C domain and the insulin core. To explore such threading, we undertook molecular dynamics simulations to 1) compare threaded with unthreaded binding modes and 2) evaluate effects of C-domain length on these alternate modes. The simulations (employing both conventional and enhanced sampling simulations) provide evidence that very short linkers (C-domain length of -1) would limit gap opening in the SCI and so impair threading. We envisage that analogous threading occurs in the intact SCI-IR complex-rationalizing why minimal C-domain lengths block complete activity-and might be exploited to design novel receptor-isoform-specific analogs.
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Insulina , Receptor de Insulina , Receptor de Insulina/metabolismo , Insulina/metabolismo , Modelos Moleculares , Ligação Proteica , Peptídeos/químicaRESUMO
Apoptosis, the intrinsic programmed cell death process, is mediated by the Bcl-2 family members Bak and Bax. Activation via formation of symmetric core dimers and oligomerization on the mitochondrial outer membrane (MOM) leads to permeabilization and cell death. Although this process is linked to the MOM, the role of the membrane in facilitating such pores is poorly understood. We recently described Bak core domain dimers, revealing lipid binding sites and an initial role of lipids in oligomerization. Here we describe simulations that identified localized clustering and interaction of triacylglycerides (TAGs) with a minimized Bak dimer construct. Coalescence of TAGs occurred beneath this Bak dimer, mitigating dimer-induced local membrane thinning and curvature in representative coarse-grain MOM and model membrane systems. Furthermore, the effects observed as a result of coarse-grain TAG cluster formation was concentration dependent, scaling from low physiological MOM concentrations to those found in other organelles. We find that increasing the TAG concentration in liposomes mimicking the MOM decreased the ability of activated Bak to permeabilize these liposomes. These results suggest that the presence of TAGs within a Bak-lipid membrane preserves membrane integrity and is associated with reduced membrane stress, suggesting a possible role of TAGs in Bak-mediated apoptosis.
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Lipossomos , Proteína Killer-Antagonista Homóloga a bcl-2 , Apoptose , Lipídeos , Lipossomos/metabolismo , Membranas Mitocondriais/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2/análise , Proteína Killer-Antagonista Homóloga a bcl-2/química , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
PURPOSE: Despite recommendations from national organizations supporting the use of lymph node assessment (LNA) among patients with ductal carcinoma in situ (DCIS) at time of mastectomy, variation in practice patterns across the United States has been observed. However, few studies have evaluated LNA differences and rurality. METHODS: Data from the SEER Patterns of Care studies were used to identify women who underwent mastectomy for newly diagnosed DCIS during 2000, 2005, 2010, and 2015. Weighted multivariate logistic regression was used to evaluate the association between rural-urban residence and the use of LNA. A subgroup analysis was performed comparing the use of axillary lymph node dissection (ALND) versus sentinel lymph node biopsy (SLNB). RESULTS: Of the 504 patients included in the analysis, approximately 81% underwent LNA at time of mastectomy with lower rates of use observed among rural patients (66%) versus urban patients (82%). In multivariate analysis, LNA increased over time (p < 0.0001), and rural patients were less likely to receive LNA compared to urban patients [adjusted odds ratio (aOR) = 0.19; 95% confidence interval (CI) 0.06-0.66]. However, the likelihood of undergoing ALND relative to SLNB was lower among rural compared to urban patients (aOR = 0.16; 95% CI 0.03-0.73). CONCLUSIONS: Over time, the use of LNA with mastectomy has increased among DCIS patients. However, significant rural-urban differences in the use and type of LNA persist. The findings of this study highlight the importance of continued research aimed at examining the impact of rurality on the receipt of high-quality cancer care.
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Neoplasias da Mama , Carcinoma Intraductal não Infiltrante , Axila , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/cirurgia , Carcinoma Intraductal não Infiltrante/epidemiologia , Carcinoma Intraductal não Infiltrante/cirurgia , Feminino , Humanos , Excisão de Linfonodo , Linfonodos/cirurgia , Mastectomia , Biópsia de Linfonodo Sentinela , Estados Unidos/epidemiologiaRESUMO
Entanglement is a unique property of quantum systems and an essential resource for many quantum technologies. The ability to transfer or swap entanglement between systems is an important protocol in quantum information science. Entanglement swapping between photons forms the basis of distributed quantum networks. Here an experiment demonstrating entanglement swapping from two independent multimode time-frequency entangled sources is presented, resulting in multiple heralded frequency-mode Bell states. Entanglement in the heralded states is verified by measuring conditional anticorrelated joint spectra and quantum beating in two-photon interference. Our experiment heralds up to five orthogonal Bell pairs within the same setup, and this number is ultimately limited only by the entanglement of the initial sources.
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Assessing genetic differentiation among natural populations can aid understanding of dispersal patterns and connectivity among habitats. Several molecular markers have become increasingly popular in determining population genetic structure for this purpose. Here, we compared the resolution of mitochondrial cytochrome c oxidase subunit I (COI) and nuclear single nucleotide polymorphism (SNP) markers for detecting population structure among stream insects at small spatial scales. Individuals of three endemic taxa-Coloburiscus humeralis (Ephemeroptera), Zelandobius confusus (Plecoptera), and Hydropsyche fimbriata (Trichoptera)-were collected from forested streams that flow across open pasture in the North Island of New Zealand. Both COI and SNP data indicated limited population structure across the study area, and small differences observed among these species were likely related to their putative dispersal abilities. For example, fine-scale genetic differentiation between and among neighbouring stream populations for H. fimbriata suggests that gene flow, and hence dispersal, may be more limited for this species relative to the others. Based on the generally similar results provided by both types of markers, we suggest that either COI or SNP markers can provide suitable initial estimates of fine-scale population genetic differentiation in stream insects.