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1.
Mol Cell ; 83(16): 2911-2924.e16, 2023 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-37506699

RESUMEN

During eukaryotic DNA replication, Pol α-primase generates primers at replication origins to start leading-strand synthesis and every few hundred nucleotides during discontinuous lagging-strand replication. How Pol α-primase is targeted to replication forks to prime DNA synthesis is not fully understood. Here, by determining cryoelectron microscopy (cryo-EM) structures of budding yeast and human replisomes containing Pol α-primase, we reveal a conserved mechanism for the coordination of priming by the replisome. Pol α-primase binds directly to the leading edge of the CMG (CDC45-MCM-GINS) replicative helicase via a complex interaction network. The non-catalytic PRIM2/Pri2 subunit forms two interfaces with CMG that are critical for in vitro DNA replication and yeast cell growth. These interactions position the primase catalytic subunit PRIM1/Pri1 directly above the exit channel for lagging-strand template single-stranded DNA (ssDNA), revealing why priming occurs efficiently only on the lagging-strand template and elucidating a mechanism for Pol α-primase to overcome competition from RPA to initiate primer synthesis.


Asunto(s)
ADN Primasa , Replicación del ADN , Humanos , ADN Primasa/genética , ADN Primasa/metabolismo , Microscopía por Crioelectrón , ADN Helicasas/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , ADN de Cadena Simple/metabolismo
2.
Cell ; 162(1): 59-71, 2015 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-26095252

RESUMEN

eIF4E, the major cap-binding protein, has long been considered limiting for translating the mammalian genome. However, the eIF4E dose requirement at an organismal level remains unexplored. By generating an Eif4e haploinsufficient mouse, we found that a 50% reduction in eIF4E expression, while compatible with normal development and global protein synthesis, significantly impeded cellular transformation. Genome-wide translational profiling uncovered a translational program induced by oncogenic transformation and revealed a critical role for the dose of eIF4E, specifically in translating a network of mRNAs enriched for a unique 5' UTR signature. In particular, we demonstrate that the dose of eIF4E is essential for translating mRNAs that regulate reactive oxygen species, fueling transformation and cancer cell survival in vivo. Our findings indicate eIF4E is maintained at levels in excess for normal development that are hijacked by cancer cells to drive a translational program supporting tumorigenesis.


Asunto(s)
Transformación Celular Neoplásica , Embrión de Mamíferos/metabolismo , Factor 4E Eucariótico de Iniciación/genética , Factor 4E Eucariótico de Iniciación/metabolismo , Dosificación de Gen , Regiones no Traducidas 5' , Animales , Carcinogénesis , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Biosíntesis de Proteínas , Especies Reactivas de Oxígeno/metabolismo
3.
Nature ; 600(7890): 743-747, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34700328

RESUMEN

Replisome disassembly is the final step of eukaryotic DNA replication and is triggered by ubiquitylation of the CDC45-MCM-GINS (CMG) replicative helicase1-3. Despite being driven by evolutionarily diverse E3 ubiquitin ligases in different eukaryotes (SCFDia2 in budding yeast1, CUL2LRR1 in metazoa4-7), replisome disassembly is governed by a common regulatory principle, in which ubiquitylation of CMG is suppressed before replication termination, to prevent replication fork collapse. Recent evidence suggests that this suppression is mediated by replication fork DNA8-10. However, it is unknown how SCFDia2 and CUL2LRR1 discriminate terminated from elongating replisomes, to selectively ubiquitylate CMG only after termination. Here we used cryo-electron microscopy to solve high-resolution structures of budding yeast and human replisome-E3 ligase assemblies. Our structures show that the leucine-rich repeat domains of Dia2 and LRR1 are structurally distinct, but bind to a common site on CMG, including the MCM3 and MCM5 zinc-finger domains. The LRR-MCM interaction is essential for replisome disassembly and, crucially, is occluded by the excluded DNA strand at replication forks, establishing the structural basis for the suppression of CMG ubiquitylation before termination. Our results elucidate a conserved mechanism for the regulation of replisome disassembly in eukaryotes, and reveal a previously unanticipated role for DNA in preserving replisome integrity.


Asunto(s)
Replicación del ADN , Eucariontes , Microscopía por Crioelectrón , ADN/metabolismo , ADN Helicasas/metabolismo , Eucariontes/genética , Humanos , Ubiquitina-Proteína Ligasas/metabolismo
4.
Immunol Rev ; 318(1): 110-137, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37565407

RESUMEN

Cancer patients treated with immune checkpoint inhibitors (ICIs) are susceptible to a broad and variable array of immune-related adverse events (irAEs). With increasing clinical use of ICIs, defining the mechanism for irAE development is more critical than ever. However, it currently remains challenging to predict when these irAEs occur and which organ may be affected, and for many of the more severe irAEs, inaccessibility to the tissue site hampers mechanistic insight. This lack of understanding of irAE development in the clinical setting emphasizes the need for greater use of preclinical models that allow for improved prediction of biomarkers for ICI-initiated irAEs or that validate treatment options that inhibit irAEs without hampering the anti-tumor immune response. Here, we discuss the utility of preclinical models, ranging from exploring databases to in vivo animal models, focusing on where they are most useful and where they could be improved.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Neoplasias , Animales , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias/tratamiento farmacológico , Neoplasias/etiología , Inmunoterapia/efectos adversos , Biomarcadores
5.
Traffic ; 25(1): e12925, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38272448

RESUMEN

Ceroid lipofuscinosis neuronal 5 (CLN5) and cathepsin D (CTSD) are soluble lysosomal enzymes that also localize extracellularly. In humans, homozygous mutations in CLN5 and CTSD cause CLN5 disease and CLN10 disease, respectively, which are two subtypes of neuronal ceroid lipofuscinosis (commonly known as Batten disease). The mechanisms regulating the intracellular trafficking of CLN5 and CTSD and their release from cells are not well understood. Here, we used the social amoeba Dictyostelium discoideum as a model system to examine the pathways and cellular components that regulate the intracellular trafficking and release of the D. discoideum homologs of human CLN5 (Cln5) and CTSD (CtsD). We show that both Cln5 and CtsD contain signal peptides for secretion that facilitate their release from cells. Like Cln5, extracellular CtsD is glycosylated. In addition, Cln5 release is regulated by the amount of extracellular CtsD. Autophagy induction promotes the release of Cln5, and to a lesser extent CtsD. Release of Cln5 requires the autophagy proteins Atg1, Atg5, and Atg9, as well as autophagosomal-lysosomal fusion. Atg1 and Atg5 are required for the release of CtsD. Together, these data support a model where Cln5 and CtsD are actively released from cells via their signal peptides for secretion and pathways linked to autophagy. The release of Cln5 and CtsD from cells also requires microfilaments and the D. discoideum homologs of human AP-3 complex mu subunit, the lysosomal-trafficking regulator LYST, mucopilin-1, and the Wiskott-Aldrich syndrome-associated protein WASH, which all regulate lysosomal exocytosis in this model organism. These findings suggest that lysosomal exocytosis also facilitates the release of Cln5 and CtsD from cells. In addition, we report the roles of ABC transporters, microtubules, osmotic stress, and the putative D. discoideum homologs of human sortilin and cation-independent mannose-6-phosphate receptor in regulating the intracellular/extracellular distribution of Cln5 and CtsD. In total, this study identifies the cellular mechanisms regulating the release of Cln5 and CtsD from D. discoideum cells and provides insight into how altered trafficking of CLN5 and CTSD causes disease in humans.


Asunto(s)
Dictyostelium , Lipofuscinosis Ceroideas Neuronales , Humanos , Lipofuscinosis Ceroideas Neuronales/genética , Lipofuscinosis Ceroideas Neuronales/metabolismo , Catepsina D/metabolismo , Dictyostelium/metabolismo , Señales de Clasificación de Proteína , Proteínas de Membrana de los Lisosomas/genética
6.
EMBO J ; 40(23): e108819, 2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-34694004

RESUMEN

The human replisome is an elaborate arrangement of molecular machines responsible for accurate chromosome replication. At its heart is the CDC45-MCM-GINS (CMG) helicase, which, in addition to unwinding the parental DNA duplex, arranges many proteins including the leading-strand polymerase Pol ε, together with TIMELESS-TIPIN, CLASPIN and AND-1 that have key and varied roles in maintaining smooth replisome progression. How these proteins are coordinated in the human replisome is poorly understood. We have determined a 3.2 Šcryo-EM structure of a human replisome comprising CMG, Pol ε, TIMELESS-TIPIN, CLASPIN and AND-1 bound to replication fork DNA. The structure permits a detailed understanding of how AND-1, TIMELESS-TIPIN and Pol ε engage CMG, reveals how CLASPIN binds to multiple replisome components and identifies the position of the Pol ε catalytic domain. Furthermore, the intricate network of contacts contributed by MCM subunits and TIMELESS-TIPIN with replication fork DNA suggests a mechanism for strand separation.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas del Citoesqueleto/metabolismo , ADN Polimerasa II/metabolismo , Replicación del ADN , Proteínas de Unión al ADN/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Proteínas Adaptadoras Transductoras de Señales/química , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/genética , Proteínas del Citoesqueleto/química , Proteínas del Citoesqueleto/genética , ADN Polimerasa II/química , ADN Polimerasa II/genética , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Humanos , Péptidos y Proteínas de Señalización Intracelular/química , Péptidos y Proteínas de Señalización Intracelular/genética , Modelos Moleculares , Proteínas de Unión a Poli-ADP-Ribosa/química , Proteínas de Unión a Poli-ADP-Ribosa/genética , Conformación Proteica
7.
J Cell Sci ; 136(9)2023 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-37070275

RESUMEN

Biochemical studies of human actin and its binding partners rely heavily on abundant and easily purified α-actin from skeletal muscle. Therefore, muscle actin has been used to evaluate and determine the activities of most actin regulatory proteins but there is an underlying concern that these proteins perform differently from actin present in non-muscle cells. To provide easily accessible and relatively abundant sources of human ß- or γ-actin (i.e. cytoplasmic actins), we developed Saccharomyces cerevisiae strains that express each as their sole source of actin. Both ß- or γ-actin purified in this system polymerize and interact with various binding partners, including profilin, mDia1 (formin), fascin and thymosin-ß4 (Tß4). Notably, Tß4 and profilin bind to ß- or γ-actin with higher affinity than to α-actin, emphasizing the value of testing actin ligands with specific actin isoforms. These reagents will make specific isoforms of actin more accessible for future studies on actin regulation.


Asunto(s)
Actinas , Saccharomycetales , Humanos , Actinas/metabolismo , Profilinas/metabolismo , Saccharomycetales/metabolismo , Isoformas de Proteínas , Forminas , Saccharomyces cerevisiae/metabolismo
8.
Am J Physiol Renal Physiol ; 326(5): F802-F813, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38545652

RESUMEN

Men are likely at greater risk for heat-induced acute kidney injury compared with women, possibly due to differences in vascular control. We tested the hypothesis that the renal vasoconstrictor and vasodilator responses will be greater in younger women compared with men during passive heat stress. Twenty-five healthy adults [12 women (early follicular phase) and 13 men] completed two experimental visits, heat stress or normothermic time-control, assigned in a block-randomized crossover design. During heat stress, participants wore a water-perfused suit perfused with 50°C water. Core temperature was increased by ∼0.8°C in the first hour before commencing a 2-min cold pressor test (CPT). Core temperature remained clamped and at 1-h post-CPT, subjects ingested a whey protein shake (1.2 g of protein/kg body wt), and measurements were taken pre-, 75 min, and 150 min post-protein. Beat-to-beat blood pressure (Penaz method) was measured and segmental artery vascular resistance (VR, Doppler ultrasound) was calculated as segmental artery blood velocity ÷ mean arterial pressure. CPT-induced increases in segmental artery VR did not differ between trials (trial effect: P = 0.142) nor between men (heat stress: 1.5 ± 1.0 mmHg/cm/s, normothermia: 1.4 ± 1.0 mmHg/cm/s) and women (heat stress: 1.4 ± 1.2 mmHg/cm/s, normothermia: 2.1 ± 1.1 mmHg/cm/s) (group effect: P = 0.429). Reductions in segmental artery VR following oral protein loading did not differ between trials (trial effect: P = 0.080) nor between men (heat stress: -0.6 ± 0.8 mmHg/cm/s, normothermia: -0.6 ± 0.6 mmHg/cm/s) and women (heat stress: -0.5 ± 0.5 mmHg/cm/s, normothermia: -1.1 ± 0.6 mmHg/cm/s) (group effect: P = 0.204). Renal vasoconstrictor responses to the cold pressor test and vasodilator responses following an oral protein load during heat stress or normothermia do not differ between younger men and younger women in the early follicular phase of the menstrual cycle.NEW & NOTEWORTHY The mechanisms underlying greater heat-induced acute kidney injury risk in men versus women remain unknown. This study examined renal vascular control, including both vasodilatory (oral protein load) and vasoconstrictor (cold presser test) responses, during normothermia and heat stress and compared these responses between men and women. The results indicated that in both conditions neither renal vasodilatory nor vasoconstrictor responses differ between younger men and younger women.


Asunto(s)
Respuesta al Choque Térmico , Vasodilatación , Humanos , Femenino , Masculino , Adulto , Adulto Joven , Respuesta al Choque Térmico/fisiología , Estudios Cruzados , Factores Sexuales , Resistencia Vascular , Riñón/irrigación sanguínea , Vasoconstricción , Circulación Renal , Arteria Renal , Trastornos de Estrés por Calor/fisiopatología , Presión Sanguínea/fisiología , Factores de Edad
9.
Int J Cancer ; 2024 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-39001563

RESUMEN

Despite advancements in treating cutaneous melanoma, patients with acral and mucosal (A/M) melanomas still have limited therapeutic options and poor prognoses. We analyzed 156 melanomas (101 cutaneous, 28 acral, and 27 mucosal) using the Foundation One cancer-gene specific clinical testing platform and identified new, potentially targetable genomic alterations (GAs) in specific anatomic sites of A/M melanomas. Using novel pre-clinical models of A/M melanoma, we demonstrate that several GAs and corresponding oncogenic pathways associated with cutaneous melanomas are similarly targetable in A/M melanomas. Other alterations, including MYC and CRKL amplifications, were unique to A/M melanomas and susceptible to indirect targeting using the BRD4 inhibitor JQ1 or Src/ABL inhibitor dasatinib, respectively. We further identified new, actionable A/M-specific alterations, including an inactivating NF2 fusion in a mucosal melanoma responsive to dasatinib in vivo. Our study highlights new molecular differences between cutaneous and A/M melanomas, and across different anatomic sites within A/M, which may change clinical testing and treatment paradigms for these rare melanomas.

10.
Ann Surg ; 279(4): 657-664, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-37389897

RESUMEN

OBJECTIVE: The aim of this study was to compare infectious complications in pancreatoduodenectomy (PD) patients with biliary stents treated with short, medium, or long durations of prophylactic antibiotics. BACKGROUND: Pre-existing biliary stents have historically been associated with higher infection risk after PD. Patients are administered prophylactic antibiotics, but the optimal duration remains unknown. METHODS: This single-institution retrospective cohort study included consecutive PD patients from October 2016 to April 2022. Antibiotics were continued past the operative dose per surgeon discretion. Infection rates were compared by short (≤24 h), medium (>24 but ≤96 h), and long (>96 h) duration antibiotics. Multivariable regression analysis was performed to evaluate associations with a primary composite outcome of wound infection, organ-space infection, sepsis, or cholangitis. RESULTS: Among 542 PD patients, 310 patients (57%) had biliary stents. The composite outcome occurred in 28% (34/122) short, 25% (27/108) medium, and 29% (23/80) long-duration ( P =0.824) antibiotic patients. There were no differences in other infection rates or mortality. On multivariable analysis, antibiotic duration was not associated with infection rate. Only postoperative pancreatic fistula (odds ratio 33.1, P <0.001) and male sex (odds ratio 1.9, P =0.028) were associated with the composite outcome. CONCLUSIONS: Among 310 PD patients with biliary stents, long-duration prophylactic antibiotics were associated with similar composite infection rates to short and medium durations but were used almost twice as often in high-risk patients. These findings may represent an opportunity to de-escalate antibiotic coverage and promote risk-stratified antibiotic stewardship in stented patients by aligning antibiotic duration with risk-stratified pancreatectomy clinical pathways.


Asunto(s)
Sistema Biliar , Pancreaticoduodenectomía , Humanos , Masculino , Pancreaticoduodenectomía/efectos adversos , Estudios Retrospectivos , Antibacterianos/uso terapéutico , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/tratamiento farmacológico , Profilaxis Antibiótica , Stents/efectos adversos
11.
J Vasc Surg ; 80(1): 260-267.e2, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38493897

RESUMEN

OBJECTIVE: Gender disparities in surgical training and assessment are described in the general surgery literature. Assessment disparities have not been explored in vascular surgery. We sought to investigate gender disparities in operative assessment in a national cohort of vascular surgery integrated residents (VIRs) and fellows (VSFs). METHODS: Operative performance and autonomy ratings from the Society for Improving Medical Professional Learning (SIMPL) application database were collected for all vascular surgery participating institutions from 2018 to 2023. Logistic generalized linear mixed models were conducted to examine the association of faculty and trainee gender on faculty and self-assessment of autonomy and performance. Data were adjusted for post-graduate year and case complexity. Random effects were included to account for clustering effects due to participant, program, and procedure. RESULTS: One hundred three trainees (n = 63 VIRs; n = 40 VSFs; 63.1% men) and 99 faculty (73.7% men) from 17 institutions (n = 12 VIR and n = 13 VSF programs) contributed 4951 total assessments (44.4% by faculty, 55.6% by trainees) across 235 unique procedures. Faculty and trainee gender were not associated with faculty ratings of performance (faculty gender: odds ratio [OR], 0.78; 95% confidence interval [CI], 0.27-2.29; trainee gender: OR, 1.80; 95% CI, 0.76-0.43) or autonomy (faculty gender: OR, 0.99; 95% CI, 0.41-2.39; trainee gender: OR, 1.23; 95% CI, 0.62-2.45) of trainees. All trainees self-assessed at lower performance and autonomy ratings as compared with faculty assessments. However, women trainees rated themselves significantly lower than men for both autonomy (OR, 0.57; 95% CI, 0.43-0.74) and performance (OR, 0.40; 95% CI, 0.30-0.54). CONCLUSIONS: Although gender was not associated with differences in faculty assessment of performance or autonomy among vascular surgery trainees, women trainees perceive themselves as performing with lower competency and less autonomy than their male colleagues. These findings suggest utility for exploring gender differences in real-time feedback delivered to and received by trainees and targeted interventions to align trainee self-perception with actual operative performance and autonomy to optimize surgical skill acquisition.


Asunto(s)
Competencia Clínica , Educación de Postgrado en Medicina , Internado y Residencia , Autonomía Profesional , Cirujanos , Procedimientos Quirúrgicos Vasculares , Humanos , Femenino , Masculino , Procedimientos Quirúrgicos Vasculares/educación , Cirujanos/educación , Cirujanos/psicología , Factores Sexuales , Médicos Mujeres , Estados Unidos , Sexismo , Docentes Médicos , Adulto
12.
Phys Chem Chem Phys ; 2024 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-39405048

RESUMEN

Nitrogen-containing polycyclic aromatic hydrocarbons (NPAHs) are important molecules for astrochemistry and prebiotic chemistry, as their occurrence spans from interstellar molecular clouds to planetary systems. Their formation has been previously explored in gas phase experiments, but the role of solid-state chemical reactions in their formation under cryogenic conditions remains elusive. Here, we explore the formation of NPAHs through vacuum ultraviolet (VUV) irradiation of pyridine:acetylene ices in amorphous and co-crystalline phases, with the aim to simulate conditions relevant to the interstellar medium and Titan's atmosphere. Our results show that the synthesis of ethynylpyridines from VUV-irradiated pyridine:acetylene amorphous ices is achievable at 18 K. In the co-crystal phase, photolysis at 110 K leads to the formation of NPAHs such as quinolizinium+ and precursors, reflecting a dynamical system under our conditions. In contrast, irradiation at 90 K under stable conditions did not produce volatile photoproducts. These results suggest that such chemical processes can occur in Titan's atmosphere and potentially in its stratosphere, where the co-condensation of these molecules can form composite ices. Concurrently, the formation of stable co-crystals can influence the depletion rates of pyridine, which suggests that these structures can be preserved and potentially delivered to Titan's surface. Our findings provide insights into the molecular diversity and chemical evolution of organic matter on Titan, crucial for future space exploration missions, such as the Dragonfly mission, which may uncover higher-order organics derived from pyridine precursors on Titan's surface.

13.
J Phycol ; 60(1): 15-25, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-37948315

RESUMEN

The relative frequency of sexual versus asexual reproduction governs the distribution of genetic diversity within and among populations. Most studies on the consequences of reproductive variation focus on the mating system (i.e., selfing vs. outcrossing) of diploid-dominant taxa (e.g., angiosperms), often ignoring asexual reproduction. Although reproductive systems are hypothesized to be correlated with life-cycle types, variation in the relative rates of sexual and asexual reproduction remains poorly characterized across eukaryotes. This is particularly true among the three major lineages of macroalgae (green, brown, and red). The Rhodophyta are particularly interesting, as many taxa have complex haploid-diploid life cycles that influence genetic structure. Though most marine reds have separate sexes, we show that freshwater red macroalgae exhibit patterns of switching between monoicy and dioicy in sister taxa that rival those recently shown in brown macroalgae and in angiosperms. We advocate for the investigation of reproductive system evolution using freshwater reds, as this will expand the life-cycle types for which these data exist, enabling comparative analyses broadly across eukaryotes. Unlike their marine cousins, species in the Batrachospermales have macroscopic gametophytes attached to filamentous, often microscopic sporophytes. While asexual reproduction through monospores may occur in all freshwater reds, the Compsopogonales are thought to be exclusively asexual. Understanding the evolutionary consequences of selfing and asexual reproduction will aid in our understanding of the evolutionary ecology of all algae and of eukaryotic evolution generally.


Asunto(s)
Algas Marinas , Algas Marinas/genética , Reproducción , Reproducción Asexuada , Agua Dulce , Genitales
14.
Environ Res ; 248: 118223, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38286254

RESUMEN

Dust is a sink for flame retardants, which are added to a myriad of consumer products in residential spaces. Organophosphate esters (OPEs) and brominated flame retardants (BFRs) are two classes of flame retardants that are frequently used in consumer products and consequently found in dust. In this present work, a novel solvent-limited microextraction technique, which we detailed in a companion study, was applied for the determination of four OPEs and two BFRs with limits of quantitation at the ng/g level by gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry from n = 47 air filter dust samples collected from forced air HVAC systems. Levels of the BFRs, including tetrabromobisphenol-A and its derivative tribromobisphenol-A, were found at levels <4 µg/g and not frequently detected. Conversely, all four OPEs were detected in all air filter dust samples. Total OPE load was dominated by tris(2,4-di-tert-butylphenyl) phosphate, T24DtBPP, a novel OPE not widely examined in the literature. Comparison of individual and total OPE concentrations to residential characteristics revealed statistically significant relationships to location of the home and dominant flooring type. Overall, this study motivates future work in examining the whole house exposome using air filter dust as a passive sampling regime with more examination of T24DtBPP loads within other indoor spaces.


Asunto(s)
Filtros de Aire , Contaminación del Aire Interior , Exposoma , Retardadores de Llama , Retardadores de Llama/análisis , Polvo/análisis , Organofosfatos/análisis , Contaminación del Aire Interior/análisis , Monitoreo del Ambiente , Ésteres/análisis
15.
Artículo en Inglés | MEDLINE | ID: mdl-39299513

RESUMEN

STUDY OBJECTIVE: Ob/Gyn resident experience with robotic gynecologic surgery has been evaluated at time of graduation, but no specific surgical procedures were identified to differentiate the experiences of residents at each level. This study proposes to determine which factors are correlated with more hands-on robotic surgery experience and resident satisfaction. DESIGN: An IRB-approved, 15-question survey was distributed electronically. 98 responses were received for a rate of 44%. Linear regression and ANOVA statistical analysis were performed. SETTING: Current residents at eight Ob/gyn residency programs in the US were surveyed. PATIENTS: N/A INTERVENTIONS: Survey administration MEASUREMENT AND MAIN RESULTS: The majority of respondents were satisfied (48%) or had neutral feelings (20%) with regard to their robotic surgery experience. All respondents reported experience with uterine manipulation or bedside assisting by PGY2. Earliest experience performing hysterectomy was most common in PGY2 or PGY3. Seventy-six percent of PGY3 or PGY4 residents report operating on the console for some or all major robotic surgeries, with 69% having participated in greater than 20 robotic surgery cases during residency. Only exposure to MIGS faculty is significantly associated with high robotic surgery experience (p=.022). Overall satisfaction with robotic surgery experience increased significantly with higher level of participation (p<.0001), particularly operating at the console during some or most of the surgery; longitudinal experiences with hysterectomy, myomectomy, and salpingectomy/oophorectomy (p<.05); but not with solely bedside assisting or vaginal cuff closure. Factors limiting robotic console experience included case time constraints, lack of first assists, case complexity, and attending comfort. CONCLUSIONS: Ob/Gyn resident satisfaction with training is significantly related to level and duration of robotic surgery participation. MIGS faculty contribute to more resident experience, and limiting factors include time constraints, case complexity and lack of first assists. These results can provide a framework for structuring resident training in robotic surgery.

16.
J Trauma Stress ; 2024 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-38959155

RESUMEN

Despite the widespread use and perceived efficacy of cannabidiol (CBD) as an anxiolytic, few controlled studies have evaluated the effects of CBD on anxiety-relevant indications, and only one has done so in the context of trauma-related symptoms. The current study was designed to address this gap in the literature. Participants were 42 trauma-exposed individuals (Mage = 23.12 years, SDage = 6.61) who endorsed elevated stress. They were randomly assigned to take 300 mg of oral CBD or placebo daily for 1 week. Acute (i.e., following an initial 300 mg dose) and repeated (i.e., following 1 week of daily 300 mg dosing) effects of CBD were evaluated in relation to indicators of anxious arousal (i.e., anxiety, distress, heart rate) in response to idiographic trauma script presentation. The results of the current study suggest that relative to placebo, 300 mg CBD did not significantly reduce anxiety, B = 13.37, t(37) = 1.71, p = .096, d = 0.09, Bayes factor (BF10) = 0.54; distress, B = 15.20, t(37) = 1.31, p = .197, d = 0.07, BF10 = 0.51; or heart rate, B = -1.09, t(36) = -0.32, p = .755, d = 0.02, BF10 = 0.29, evoked by idiographic trauma script presentation in the context of acute or repeated administration. These data suggest that CBD may not effectively reduce trauma-relevant emotional arousal; however, more work is needed to confidently assert such claims due to the small sample size. The current study extends the groundwork for additional studies in this important area.

17.
Artículo en Inglés | MEDLINE | ID: mdl-39393986

RESUMEN

OBJECTIVES: Evaluate the correlation of non-invasive echocardiographic estimates of right ventricular systolic pressure with measurements on cardiac catheterization in children with pulmonary hypertension. DESIGN: Retrospective chart review. SETTING: Quaternary academic children's hospital. PARTICIPANTS: Patients younger than 18 years with a diagnosis of pulmonary hypertension and confirmatory cardiac catheterization from 2015 to 2018. MEASUREMENTS AND MAIN RESULTS: We analyzed the correlation between measures of right ventricular systolic pressure using nonparametric Spearman rho (ρ) with statistical significance set at p < 0.05. RESULTS: Children (N = 111) with biventricular circulation, strictly defined pulmonary hypertension, and adequate tricuspid regurgitation on echocardiogram to estimate right ventricular systolic pressure using the modified Bernoulli equation. Median age and weight were 4.3 years and 14.4 kg. Median right ventricular systolic pressure estimated by tricuspid regurgitant velocity on echocardiography was 55 mmHg (IQR 45-75 mmHg) plus right atrial pressure. On cardiac catheterization, median right ventricular systolic pressure was 57 mmHg (IQR 46-75 mmHg). Echocardiographic estimates of right ventricular systolic pressure were moderately well correlated with right ventricular systolic pressure directly measured on catheterization (ρ = 0.44, 95% CI 0.27-0.6, p < 0.001) with a median difference of 4 mmHg (IQR -10 to 17). Subgroup analysis revealed that echocardiography and catheterization measurements correlated well in children with suprasystemic right ventricular pressure on cardiac catheterization (ρ = 0.75, 95% CI 0.51-0.99, p < 0.001) although catheterization measurements were a median of 26 mmHg (IQR 12-31) higher than echocardiographic estimates in this subgroup. CONCLUSIONS: In children with pulmonary hypertension, echocardiographic estimates of right ventricular pressure correlated moderately well with gold standard measurements by cardiac catheterization with stronger correlation in children with suprasystemic right ventricular pressures. This is reassuring for clinicians who must rely on echocardiography for risk stratification before anesthetizing children with pulmonary hypertension.

18.
Subst Use Misuse ; 59(11): 1604-1612, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38946130

RESUMEN

INTRODUCTION: Cannabidiol (CBD) shows promise for a variety of indications, including anxiety. Prior survey work indicates anxiety ranks as a top reason for which people use cannabidiol (CBD), but no work has evaluated individuals using CBD specifically for anxiety. METHOD: The current study evaluated CBD product use patterns and perceptions within a sample of 81 participants (Mage = 32.63, SDage = 12.99) who reported using CBD products for anxiety-related concerns within the past 30 days. RESULTS: Family and friends, followed by popular and scientific literature, were the most common sources informing participants' decision to use CBD products to target anxiety. On average, participants reported using CBD products daily for at least a year and indicated it was very effective in targeting anxiety-related symptoms. The top three ranked symptoms improved by CBD products were subjective anxiety, difficulty falling asleep, and irritability. These findings were despite the fact that the most frequent dosing levels (∼50mg) were well below those empirically observed to yield anxiolytic effects. Most participants denied side effects, adding to the literature supporting CBD products' safety and tolerability. Finally, participants were generally poorly informed about the nature of CBD products (e.g., distinction from THC), suggesting a need for consumer education. CONCLUSION: Collectively, the current study extends prior survey work suggesting powerful expectancies about CBD products, particularly in terms of anxiety reduction, including among those using it to target anxiety-related symptoms. Findings also highlight the importance of addressing the gap between scientific and consumer knowledge.


Asunto(s)
Ansiedad , Cannabidiol , Humanos , Cannabidiol/uso terapéutico , Femenino , Adulto , Masculino , Ansiedad/tratamiento farmacológico , Persona de Mediana Edad , Adulto Joven , Ansiolíticos/uso terapéutico
19.
J Neurophysiol ; 129(6): 1293-1309, 2023 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-37099016

RESUMEN

When stopping a closing door or catching an object, humans process the motion of inertial objects and apply reactive limb force over short period to interact with them. One way in which the visual system processes motion is through extraretinal signals associated with smooth pursuit eye movements (SPEMs). We conducted three experiments to investigate how SPEMs contribute to anticipatory and reactive hand force modulation when interacting with a virtual object moving in the horizontal plane. We hypothesized that SPEM signals are critical for timing motor responses, anticipatory control of hand force, and task performance. Participants held a robotic manipulandum and attempted to stop an approaching simulated object by applying a force impulse (area under force-time curve) that matched the object's virtual momentum upon contact. We manipulated the object's momentum by varying either its virtual mass or its speed under free gaze or constrained gaze conditions. We examined gaze variables, the timing of hand motor responses, anticipatory force control, and overall task performance. Our results show that when participants were fixated at a designated location instead of following objects with SPEM, anticipatory modulation of hand force before contact decreased. However, constraining gaze by asking participants to fixate did not seem to affect the timing of the motor response or the task performance. Together, these results suggest that SPEMs may be important for anticipatory control of hand force before contact and may also play a critical role in anticipatory stabilization of limb posture when humans interact with moving objects.NEW & NOTEWORTHY We show for the first time that smooth pursuit eye movements (SPEMs) play a role in the modulation of anticipatory control of hand force to stabilize posture against contact forces. SPEMs are critical for tracking moving objects, facilitate processing motion of moving objects, and are impacted during aging and in many neurological disorders, such as Alzheimer's disease and multiple sclerosis. These results provide a novel basis to probe how changes in SPEMs could contribute to deficient limb motor control in older adults and patients with neurological disorders.


Asunto(s)
Percepción de Movimiento , Enfermedades del Sistema Nervioso , Humanos , Anciano , Seguimiento Ocular Uniforme , Movimientos Oculares , Desempeño Psicomotor/fisiología , Mano/fisiología , Percepción de Movimiento/fisiología
20.
Br J Haematol ; 202(5): 937-941, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37287128

RESUMEN

Patients with sickle cell disease (SCD) are considered to be immunocompromised, yet data on the antibody response to SARS-CoV-2 vaccination in SCD is limited. We investigated anti-SARS-CoV-2 IgG titres and overall neutralizing activity in 201 adults with SCD and demographically matched non-SCD controls. Unexpectedly, patients with SCD generate a more robust and durable COVID-19 vaccine IgG response compared to matched controls, though the neutralizing activity remained similar across both cohorts. These findings suggest that patients with SCD achieve a similar antibody response following COVID-19 vaccination compared to the general population, with implications for optimal vaccination strategies for patients with SCD.


Asunto(s)
Anemia de Células Falciformes , COVID-19 , Adulto , Humanos , Vacunas contra la COVID-19 , COVID-19/prevención & control , SARS-CoV-2 , Vacunación , Inmunoglobulina G , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/terapia , Anticuerpos Antivirales , Inmunidad , Anticuerpos Neutralizantes
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