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1.
Nat Mater ; 2024 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-39060470

RESUMEN

Helicity in solids often arises from the precise ordering of cooperative intra- and intermolecular interactions unique to natural, organic or molecular systems. This exclusivity limited the realization of helicity and its ensuing properties in dense inorganic solids. Here we report that Ga atoms in GaSeI, a representative III-VI-VII one-dimensional (1D) van der Waals crystal, manifest the rare Boerdijk-Coxeter helix motif. This motif is a non-repeating geometric pattern characterized by 1D face-sharing tetrahedra whose adjacent vertices are rotated by an irrational angle. Using InSeI and GaSeI, we show that the modularity of 1D van der Waals lattices accommodates the systematic twisting of a periodic tetrahelix with a 41 screw axis in InSeI to an infinitely extending Boerdijk-Coxeter helix in GaSeI. GaSeI crystals are non-centrosymmetric, optically active and exfoliable to a single chain. These results present a materials platform towards understanding the origin and physical manifestation of aperiodic helicity in low-dimensional solids.

2.
J Transl Med ; 22(1): 524, 2024 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-38822345

RESUMEN

BACKGROUND: Olfactory neuroblastoma is a rare malignancy of the anterior skull base typically treated with surgery and adjuvant radiation. Although outcomes are fair for low-grade disease, patients with high-grade, recurrent, or metastatic disease oftentimes respond poorly to standard treatment methods. We hypothesized that an in-depth evaluation of the olfactory neuroblastoma tumor immune microenvironment would identify mechanisms of immune evasion in high-grade olfactory neuroblastoma as well as rational targetable mechanisms for future translational immunotherapeutic approaches. METHODS: Multispectral immunofluorescence and RNAScope evaluation of the tumor immune microenvironment was performed on forty-seven clinically annotated olfactory neuroblastoma samples. A retrospective chart review was performed and clinical correlations assessed. RESULTS: A significant T cell infiltration was noted in olfactory neuroblastoma samples with a stromal predilection, presence of myeloid-derived suppressor cells, and sparse natural killer cells. A striking decrease was observed in MHC-I expression in high-grade olfactory neuroblastoma compared to low-grade disease, representing a mechanism of immune evasion in high-grade disease. Mechanistically, the immune effector stromal predilection appears driven by low tumor cell MHC class II (HLA-DR), CXCL9, and CXCL10 expression as those tumors with increased tumor cell expression of each of these mediators correlated with significant increases in T cell infiltration. CONCLUSION: These data suggest that immunotherapeutic strategies that augment tumor cell expression of MHC class II, CXCL9, and CXCL10 may improve parenchymal trafficking of immune effector cells in olfactory neuroblastoma and augment immunotherapeutic responses.


Asunto(s)
Quimiocina CXCL10 , Quimiocina CXCL9 , Estesioneuroblastoma Olfatorio , Antígenos HLA-DR , Inmunoterapia , Microambiente Tumoral , Humanos , Estesioneuroblastoma Olfatorio/terapia , Estesioneuroblastoma Olfatorio/patología , Estesioneuroblastoma Olfatorio/inmunología , Quimiocina CXCL10/metabolismo , Inmunoterapia/métodos , Femenino , Masculino , Persona de Mediana Edad , Quimiocina CXCL9/metabolismo , Microambiente Tumoral/inmunología , Antígenos HLA-DR/metabolismo , Anciano , Neoplasias Nasales/terapia , Neoplasias Nasales/patología , Neoplasias Nasales/inmunología , Adulto , Regulación Neoplásica de la Expresión Génica
3.
Am J Med Genet A ; 194(5): e63523, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38164622

RESUMEN

The FMR1 5' regulation gene region harbors a CGG trinucleotide repeat expansion (CGG-TRE) that causes Fragile X syndrome (FXS) when it expands to more than 200 repetitions. Ricaurte is a small village in southwestern Colombia, with an FXS prevalence of 1 in 38 men and 1 in 100 women (~100 times higher than the worldwide reported prevalence), defining Ricaurte as the largest FXS cluster in the world. In the present study, using next-generation sequencing of whole exome capture, we genotype 55 individuals from Ricaurte (49 with either full mutation or with premutation), four individuals from neighboring villages (with either the full mutation or with the premutation), and one unaffected woman, native of Ricaurte, who did not belong to any of the affected families. With advanced clustering and haplotype reconstruction, we modeled a common haplotype of 33 SNPs spanning 83,567,899 bp and harboring the FMR1 gene. This reconstructed haplotype was found in all the men from Ricaurte who carried the expansion, demonstrating that the genetic conglomerate of FXS in this population is due to a founder effect. The definition of this founder effect and its population outlining will allow a better prediction, follow-up, precise and personalized characterization of epidemiological parameters, better knowledge of the disease's natural history, and confident improvement of the clinical attention, life quality, and health interventions for this community.


Asunto(s)
Síndrome del Cromosoma X Frágil , Masculino , Humanos , Femenino , Síndrome del Cromosoma X Frágil/epidemiología , Síndrome del Cromosoma X Frágil/genética , Efecto Fundador , Epidemiología Molecular , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Expansión de Repetición de Trinucleótido , Mutación
4.
J Nucl Cardiol ; 37: 101854, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38606610

RESUMEN

BACKGROUND: Myocardial flow reserve (MFR) by positron emission tomography (PET) is a validated measure of cardiovascular risk. Elevated resting rate pressure product (RPP = heart rate x systolic blood pressure) can cause high resting myocardial blood flow (MBF), resulting in reduced MFR despite normal/near-normal peak stress MBF. When resting MBF is high, it is not known if RPP-corrected MFR (MFRcorrected) helps reclassify CV risk. We aimed to study this question in patients without obstructive coronary artery disease (CAD). METHODS: We retrospectively studied patients referred for rest/stress cardiac PET at our center from 2006 to 2020. Patients with abnormal perfusion (summed stress score >3) or prior coronary artery bypass grafting (CABG) were excluded. MFRcorrected was defined as stress MBF/corrected rest MBF where corrected rest MBF = rest MBF x 10,000/RPP. The primary outcome was major cardiovascular events (MACE): cardiovascular death or myocardial infarction. Associations of MFR and MFRcorrected with MACE were assessed using unadjusted and adjusted Cox regression. RESULTS: 3276 patients were followed for a median of 7 (IQR 3-12) years. 1685 patients (51%) had MFR <2.0, and of those 366 (22%) had an MFR ≥2.0 after RPP correction. MFR <2.0 was associated with an increased absolute risk of MACE (HR 2.24 [1.79-2.81], P < 0.0001). Among patients with MFR <2.0, the risk of MACE was not statistically different between patients with an MFRcorrected ≥2.0 compared with those with MFRcorrected <2.0 (1.9% vs 2.3% MACE/year, HR 0.84 [0.63-1.13], P = 0.26) even after adjustment for confounders (P = 0.66). CONCLUSIONS: In patients without overt obstructive CAD and MFR< 2.0, there was no significant difference in cardiovascular risk between patients with discordant (≥2.0) and concordant (<2) MFR following RPP correction. This suggests that RPP-corrected MFR may not consistently provide accurate risk stratification in patients with normal perfusion and MFR <2.0. Stress MBF and uncorrected MFR should be reported to more reliably convey cardiovascular risk beyond perfusion results.


Asunto(s)
Enfermedad de la Arteria Coronaria , Reserva del Flujo Fraccional Miocárdico , Tomografía de Emisión de Positrones , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Pronóstico , Anciano , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/fisiopatología , Enfermedad de la Arteria Coronaria/complicaciones , Imagen de Perfusión Miocárdica , Circulación Coronaria
5.
J Nucl Cardiol ; : 101908, 2024 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-38996910

RESUMEN

BACKGROUND: The epidemiology of coronary artery disease (CAD) has shifted, with increasing prevalence of cardiometabolic disease and decreasing findings of obstructive CAD on myocardial perfusion imaging (MPI). Coronary microvascular dysfunction (CMD), defined as impaired myocardial flow reserve (MFR) by positron emission tomography (PET), has emerged as a key mediator of risk. We aimed to assess whether PET MFR provides additive value for risk stratification of cardiometabolic disease patients compared with single-photon emission computed tomography (SPECT) MPI. METHODS: We retrospectively followed patients referred for PET, exercise SPECT, or pharmacologic SPECT MPI with cardiometabolic disease (obesity, diabetes, or chronic kidney disease) and without known CAD. We compared rates and hazards of composite major adverse cardiovascular events (MACEs) (annualized cardiac mortality or acute myocardial infarction) among propensity-matched PET and SPECT patients using Poisson and Cox regression. Normal SPECT was defined as a total perfusion deficit (TPD) of <5%, reflecting the absence of obstructive CAD. Normal PET was defined as a TPD of <5% plus an MFR of ≥2.0. RESULTS: Among 21,544 patients referred from 2006 to 2020, cardiometabolic disease was highly prevalent (PET: 2308 [67%], SPECT: 9984 [55%]) and higher among patients referred to PET (P < 0.001). Obstructive CAD findings (TPD > 5%) were uncommon (PET: 21% and SPECT: 11%). Conversely, impaired MFR on PET (<2.0) was common (62%). In a propensity-matched analysis over a median 6.4-year follow-up, normal PET identified low-risk (0.9%/year MACE) patients, and abnormal PET identified high-risk (4.2%/year MACE) patients with cardiometabolic disease; conversely, those with normal pharmacologic SPECT remained moderate-risk (1.6%/year, P < 0.001 compared to normal PET). CONCLUSIONS: Cardiometabolic disease is common among patients referred for MPI and is associated with a heterogenous level of risk. Compared with pharmacologic SPECT, PET with MFR can detect nonobstructive CAD including CMD and can more accurately discriminate low-risk from higher-risk individuals.

6.
Transfus Med ; 34(2): 142-153, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38151257

RESUMEN

OBJECTIVE: The aim of this work was to evaluate the relationship of the maternal mortality ratio due to obstetric haemorrhage (MMROH) with the national blood donations, particularly O RhD negative (Oneg) before and during COVID-19 pandemic. BACKGROUND: The maternal mortality ratio is increasing in Colombia, yet little is known regarding the relationship between blood donations and maternal mortality due to obstetric haemorrhage. MATERIALS AND METHODS: A retrospective cross-sectional study between January 1, 2018, and December 31, 2021, was performed, to assess MMROH compared to the blood donations notified to the Colombian National Haemovigilance System, through non-parametric methods. Because a relationship between blood donations and MMROH was identified, the analysis was expanded from 2009 to 2017. RESULTS: In 2020, Colombia increased the MMROH by 32% compared to 2019 which coincided with the lockdown period to contain COVID-19. An inversed relationship (SumD2 = 631.0; rs = -0.7335; p 0.01) between blood donations, particularly Oneg (SumD2 = 652.0; rs = -0.7912; p 0.002) and MMROH was identified. For the years 2015-2019 and 2021, the annual mean MMROH was 8.5 ± 0.5 per 100 000 live births when the annual mean blood donations was 18.2 ± 0.4 donations per 1000 people and the Oneg was 1.0 ± 0.0 donations per 1000 people. In contrast, the years 2009-2014 and 2020 displayed an annual MMROH of 12.6 ± 0.8, when the annual collection of blood was 16.4 ± 0.8 donations and the Oneg was 0.9 ± 0.0, p < 0.001. CONCLUSION: There was an inverse relationship between blood donation, mainly Oneg, and maternal mortality from obstetric haemorrhage. However, we recognise these deaths could be related to other reasons, especially when they occurred in rural areas with limited access to medical services.


Asunto(s)
Mortalidad Materna , Pandemias , Embarazo , Femenino , Humanos , Colombia/epidemiología , Estudios Retrospectivos , Estudios Transversales , Hemorragia
7.
Nucleic Acids Res ; 50(3): 1256-1268, 2022 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-35104875

RESUMEN

DNA nanostructures are a promising tool to deliver molecular payloads to cells. DNA origami structures, where long single-stranded DNA is folded into a compact nanostructure, present an attractive approach to package genes; however, effective delivery of genetic material into cell nuclei has remained a critical challenge. Here, we describe the use of DNA nanostructures encoding an intact human gene and a fluorescent protein encoding gene as compact templates for gene integration by CRISPR-mediated homology-directed repair (HDR). Our design includes CRISPR-Cas9 ribonucleoprotein binding sites on DNA nanostructures to increase shuttling into the nucleus. We demonstrate efficient shuttling and genomic integration of DNA nanostructures using transfection and electroporation. These nanostructured templates display lower toxicity and higher insertion efficiency compared to unstructured double-stranded DNA templates in human primary cells. Furthermore, our study validates virus-like particles as an efficient method of DNA nanostructure delivery, opening the possibility of delivering nanostructures in vivo to specific cell types. Together, these results provide new approaches to gene delivery with DNA nanostructures and establish their use as HDR templates, exploiting both their design features and their ability to encode genetic information. This work also opens a door to translate other DNA nanodevice functions, such as biosensing, into cell nuclei.


Asunto(s)
Técnicas de Transferencia de Gen , Nanoestructuras , Transporte Activo de Núcleo Celular , Sistemas CRISPR-Cas , ADN/genética , Edición Génica/métodos , Genoma , Humanos
8.
J Behav Med ; 47(2): 295-307, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38127175

RESUMEN

BACKGROUND: Colorectal cancer (CRC) and liver cancer are two of the leading causes of cancer death in the United States and persistent disparities in CRC and liver cancer incidence and outcomes exist. Chronic hepatitis C virus (HCV) infection is one of the main contributors to liver cancer. Effective screening for both CRC and HCV exist and are recommended for individuals based upon age, regardless of gender or sex assigned at birth. Recommendations for both screening behaviors have been recently updated. However, screening rates for both CRC and HCV are suboptimal. Targeting adoption of multiple screening behaviors has the potential to reduce cancer mortality and disparities. OBJECTIVE: To examine psychosocial factors associated with completion of CRC and HCV screenings in order to inform a multi-behavioral educational intervention that pairs CRC and HCV screening information. METHODS: A cross-sectional survey was conducted with participants (N = 50) recruited at two community health centers in Florida (United States). Kruskal-Wallis and Fisher's exact tests were used to examine associations between completion of both CRC and HCV screening, CRC and HCV knowledge, Preventive Health Model constructs (e.g., salience and coherence, response efficacy, social influence), and sociodemographic variables. RESULTS: Most participants were White (84%), female (56%), insured (80%), and reported a household income of $25,000 or less (53%). 30% reported ever previously completing both CRC and HCV screenings. Prior completion of both screening behaviors was associated with higher educational attainment (p = .014), having health insurance (p = .022), being U.S.-born (p = .043), and higher salience and coherence scores for CRC (p = .040) and HCV (p = .004). CONCLUSIONS: Findings demonstrate limited uptake of both CRC and HCV screenings among adults born between 1945 and 1965. Uptake was associated with multiple sociodemographic factors and health beliefs related to salience and coherence. Salience and coherence are modifiable factors associated with completion of both screening tests, suggesting the importance of incorporating these health beliefs in a multi-behavioral cancer education intervention. Additionally, health providers could simultaneously recommend and order CRC and HCV screening to improve uptake among this age cohort.


Asunto(s)
Neoplasias Colorrectales , Hepatitis C Crónica , Neoplasias Hepáticas , Adulto , Recién Nacido , Humanos , Estados Unidos , Femenino , Estudios Transversales , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/psicología , Hepacivirus , Detección Precoz del Cáncer/psicología , Tamizaje Masivo , Centros Comunitarios de Salud
9.
Lett Appl Microbiol ; 77(5)2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38769598

RESUMEN

Porphyromonas gingivalis is a nonmotile, obligate anaerobic, Gram-negative bacterium known for its association with periodontal disease and its involvement in systemic diseases such as atherosclerosis, cardiovascular disease, colon cancer, and Alzheimer's disease. This bacterium produces several virulence factors, including capsules, fimbriae, lipopolysaccharides, proteolytic enzymes, and hemagglutinins. A comparative genomic analysis revealed the open pangenome of P. gingivalis and identified complete type IV secretion systems in strain KCOM2805 and almost complete type VI secretion systems in strains KCOM2798 and ATCC49417, which is a new discovery as previous studies did not find the proteins involved in secretion systems IV and VI. Conservation of some virulence factors between different strains was observed, regardless of their genetic diversity and origin. In addition, we performed for the first time a reconstruction analysis of the gene regulatory network, identifying transcription factors and proteins involved in the regulatory mechanisms of bacterial pathogenesis. In particular, QseB regulates the expression of hemagglutinin and arginine deaminase, while Rex may suppress the release of gingipain through interactions with PorV and the formatum/nitrate transporter. Our study highlights the central role of conserved virulence factors and regulatory pathways, particularly QseB and Rex, in P. gingivalis and provides insights into potential therapeutic targets.


Asunto(s)
Redes Reguladoras de Genes , Genoma Bacteriano , Redes y Vías Metabólicas , Porphyromonas gingivalis , Factores de Virulencia , Porphyromonas gingivalis/genética , Porphyromonas gingivalis/metabolismo , Porphyromonas gingivalis/patogenicidad , Factores de Virulencia/genética , Redes y Vías Metabólicas/genética , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Humanos , Regulación Bacteriana de la Expresión Génica
10.
Anal Bioanal Chem ; 415(29-30): 7085-7101, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37776351

RESUMEN

A robust and efficient extraction method was developed to detect a broad range of pollutants of emerging interest in three freshwater invasive species: American red crab (Prokambarus clarkii), Asian clam (Corbicula fluminea), and pumpkinseed fish (Lepomis gibbosus). One native species, "petxinot" clam (Anodonta cygnea), was also evaluated. Invasive species are often more resistant to contamination and could be used in biomonitoring studies to assess the effect of contaminants of emerging concern on aquatic ecosystems while preserving potentially threatened native species. So far, most extraction methods developed for this purpose have focused on analyzing fish and generally focus on a limited number of compounds, especially analyzing compounds from the same family. In this sense, we set out to optimize a method that would allow the simultaneous extraction of 87 PhACs, 11 flame retardants, 21 per- and poly-fluoroalkyl substances, and 54 pesticides. The optimized method is based on ultrasound-assisted solvent extraction. Two tests were performed during method development, one to choose the extraction solvent with the best recovery efficiencies and one to select the best clean-up. The analysis was performed by high-performance liquid chromatography coupled to high-resolution mass spectrometry. The method obtained recoveries between 40 and 120% and relative standard deviations of less than 25% for 85% of the analytes in the four validated matrices. Limits of quantification between 0.01 ng g-1 and 22 ng g-1 were obtained. Application of the method on real samples from the Albufera Natural Park of Valencia (Spain) confirmed the presence of contaminants of emerging concern in all samples, such as acetaminophen, hydrochlorothiazide, tramadol, PFOS, carbendazim, and fenthion. PFAS were the group of compounds with the highest mean concentrations. C. fluminea was the species with the highest detection frequency, and P. clarkii had the highest average concentrations, so its use is prioritized for biomonitoring studies.


Asunto(s)
Especies Introducidas , Espectrometría de Masas en Tándem , Animales , Espectrometría de Masas en Tándem/métodos , Ecosistema , Agua Dulce , Solventes/química , Extracción en Fase Sólida/métodos
11.
BMC Public Health ; 23(1): 216, 2023 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-36721121

RESUMEN

BACKGROUND: The Latinx population experiences some of the highest rates of chronic disease, including obesity and type II diabetes. Such conditions may be especially burdensome in rural Latinx communities that often face barriers to accessing disease prevention resources and public health programs. METHODS: Diverse stakeholders (i.e., patients, community members, system of healthcare clinics, community food bank) tailored an existing cookbook, based on the U.S. Department of Agriculture MyPlate healthy eating and dietary guidelines, for local ingredients, health literacy, and language for rural Latinx and Indigenous Latin Americans. The cookbook recipes were disseminated widely via virtual cooking demonstrations, food distribution events, and social media. Pre- and posttest surveys were used to assess changes in diabetes knowledge measured by the 24-item American Diabetes Association Diabetic Knowledge Questionnaire and confidence in dietary behavior change over time measured by 4 questions of the 17-item Mediterranean Diet Index. A mixed effects, repeated measures analysis was conducted with gender ID, age range and educational attainment included as covariates and assessment interval as the predictor (pretest vs posttest) and change in confidence about adhering to four specific components of the Mediterranean diet. Focus groups elicited information on participants' motivation and ability to use the recipes and eat healthy foods following the virtual cooking demonstration participation. RESULTS: A total of 20 virtual cooking demonstrations were conducted and 60 participants completed a pretest survey and 54 a posttest survey, a subsample (n = 19) participated in one of three focus groups. Most participants were female, identified as Latinx/Hispanic, were between the ages of 40-49, and spoke Spanish. 17% identified as Indigenous Latin American specifically as Purépecha, an indigenous group from Michoacán, Mexico. Survey and focus group findings indicated at posttest an increase in diabetes knowledge among participants with no prior diagnosis of chronic health conditions and more confidence in limiting sugary beverages and refined wheat pasta/white rice among indigenous participants. Focus group discussions explicated the quantitative findings. CONCLUSION: This study brought together patients and key stakeholders committed to addressing the social determinants of health and it mobilized the community to develop culturally vetted health education materials. The findings indicate the need for increased access to evidence-based nutrition education and to culturally appropriate food products that can be easily incorporated into daily food preparation.


Asunto(s)
Diabetes Mellitus Tipo 2 , Población Rural , Humanos , Femenino , Adulto , Persona de Mediana Edad , Masculino , Hispánicos o Latinos , Alimentos , Procesos Mentales
12.
Int J Mol Sci ; 24(2)2023 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-36674998

RESUMEN

Mitochondrial dysfunction is a key pathological event in many diseases. Its role in energy production, calcium homeostasis, apoptosis regulation, and reactive oxygen species (ROS) balance render mitochondria essential for cell survival and fitness. However, there are no effective treatments for most primary and secondary mitochondrial diseases to this day. Therefore, new therapeutic approaches, such as the modulation of the mitochondrial unfolded protein response (mtUPR), are being explored. mtUPRs englobe several compensatory processes related to proteostasis and antioxidant system mechanisms. mtUPR activation, through an overcompensation for mild intracellular stress, promotes cell homeostasis and improves lifespan and disease alterations in biological models of mitochondrial dysfunction in age-related diseases, cardiopathies, metabolic disorders, and primary mitochondrial diseases. Although mtUPR activation is a promising therapeutic option for many pathological conditions, its activation could promote tumor progression in cancer patients, and its overactivation could lead to non-desired side effects, such as the increased heteroplasmy of mitochondrial DNA mutations. In this review, we present the most recent data about mtUPR modulation as a therapeutic approach, its role in diseases, and its potential negative consequences in specific pathological situations.


Asunto(s)
Enfermedades Mitocondriales , Humanos , Enfermedades Mitocondriales/tratamiento farmacológico , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Longevidad , Respuesta de Proteína Desplegada
13.
Int J Mol Sci ; 24(19)2023 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-37834028

RESUMEN

Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic disorders frequently associated with iron accumulation in the basal nuclei of the brain. Among NBIA subtypes, ß-propeller protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45. The aim of this study was to demonstrate the autophagic defects and secondary pathological consequences in cellular models derived from two patients harboring WDR45 mutations. Both protein and mRNA expression levels of WDR45 were decreased in patient-derived fibroblasts. In addition, the increase of LC3B upon treatments with autophagy inducers or inhibitors was lower in mutant cells compared to control cells, suggesting decreased autophagosome formation and impaired autophagic flux. A transmission electron microscopy (TEM) analysis showed mitochondrial vacuolization associated with the accumulation of lipofuscin-like aggregates containing undegraded material. Autophagy dysregulation was also associated with iron accumulation and lipid peroxidation. In addition, mutant fibroblasts showed altered mitochondrial bioenergetics. Antioxidants such as pantothenate, vitamin E and α-lipoic prevented lipid peroxidation and iron accumulation. However, antioxidants were not able to correct the expression levels of WDR45, neither the autophagy defect nor cell bioenergetics. Our study demonstrated that WDR45 mutations in BPAN cellular models impaired autophagy, iron metabolism and cell bioenergetics. Antioxidants partially improved cell physiopathology; however, autophagy and cell bioenergetics remained affected.


Asunto(s)
Antioxidantes , Proteínas Portadoras , Humanos , Antioxidantes/farmacología , Antioxidantes/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Peroxidación de Lípido , Autofagia/genética , Hierro/metabolismo
14.
Proc Biol Sci ; 289(1989): 20221838, 2022 12 21.
Artículo en Inglés | MEDLINE | ID: mdl-36541174

RESUMEN

Assembly processes are highly dynamic with biotic filters operating more intensely at local scales, yet the strength of biotic interactions can vary across time and latitude. Predation, for example, can be stronger at lower latitudes, while competition can intensify at later stages of assembly due to resource limitation. Since biotic filters act upon functional traits of organisms, we explored trait-mediated community assembly in diverse marine assemblages from four regions along the Pacific coast of North and Central America. Using predator exclusion experiments and two assembly stages, we tested the hypotheses that non-random trait patterns would emerge during late assembly at all regions due to competition and at lower latitude regions regardless of assembly stage due to predation. As expected, trait divergence occurred in late assembly but only at higher latitude regions, while in tropical Panama, relaxed predation caused trait divergence during late assembly. Moreover, colonizing trait strategies were common during early assembly while competitive strategies were favoured during late assembly at higher latitude regions. Predation-resistant traits were only favoured in Panama during both assembly stages. Our large-scale manipulative study demonstrates that different biotic interactions across time and latitude can have important consequences for trait assembly.


Asunto(s)
Ecosistema , Conducta Predatoria , Animales , América Central , Panamá
15.
Prev Med ; 158: 107021, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35305995

RESUMEN

One of the largest disparities in cancer mortality in the United States occurs with colorectal cancer (CRC). The objectives of this multilevel two-arm intervention trial were to compare the efficacy of two interventions to promote CRC screening (CRCS) with fecal immunochemical test (FIT) and examine sociodemographic and psychosocial predictors of FIT screening. Individuals ages 50-75 (n = 326) who were not up-to-date with CRCS, could understand English or Spanish, and were at average CRC risk were recruited from two federally qualified health centers (FQHCs) in Florida. Prior to intervention, CRCS rates in the FQHCs were 27.1% and 32.9%, respectively. Study enrollment occurred April 2018-November 2019. System-level intervention components included leveraging electronic medical record (EMR) systems and delivering patient reminders. Participants were randomized to C-CARES (education+FIT) or C-CARES Plus (C-CARES+personalized coaching [for those not completing FIT within 90 days]). Primary outcome was completed FIT returned <1 year. Primary outcome analyses were performed using logistic regression. 225 participants completed FIT (69.0% [95% CI: 64.0-74.0%]), with no significant difference in FIT uptake by intervention arm (67.3% C-CARES Plus vs. 70.8% C-CARES; p = .49). FIT uptake was significantly higher among patients who received intervention materials in Spanish (77.2%) compared to those who received materials in English (63.2%, p < .01). The personalized coaching in the C-CARES Plus arm did not appear to provide added benefit beyond the C-CARES intervention. Multilevel approaches that include EMR prompts, reminders, FIT access, and provision of low-literacy, language-concordant education can support efforts to improved community clinics' CRCS rates. Future efforts should focus on repeat FIT screening. Trial registration: The trial was registered at ClinicalTrials.gov (NCT03906110).


Asunto(s)
Neoplasias Colorrectales , Alfabetización , Anciano , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/prevención & control , Neoplasias Colorrectales/psicología , Detección Precoz del Cáncer , Florida , Humanos , Tamizaje Masivo , Persona de Mediana Edad , Sangre Oculta , Estados Unidos
16.
J Appl Microbiol ; 133(2): 422-435, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35352442

RESUMEN

AIM: The objective of this research was to screen fungal isolates originally isolated from cotton plants and measure their effects on the interactions between soybean and two aboveground pests (cabbage looper; Trichoplusia ni and soybean looper; Chrysodeixis includens) as well as a belowground pest (soybean cyst nematode; Heterodera glycines). METHODS AND RESULTS: For aboveground pests, we measured the leaf area consumed and larval weight. For our belowground pest tests, we measured shoot height, shoot fresh weight, root fresh weight and number of cysts. Out of the 50 fungal isolates tested, we tested 30 fungi in the interaction with cabbage looper, 36 for soybean looper, 41 for soybean cyst nematode. We tested 23 isolates against all pests and identified multiple isolates that significantly changed the response of pests on inoculated soybean plants versus controls. CONCLUSIONS: We identified three fungal isolates that significantly reduced both leaf area consumed aboveground by caterpillars and number of cysts produced belowground by nematodes. These isolates were an Epicoccum italicum, a Chaetomium undulatum and a Stemphylium majusculum. SIGNIFICANCE AND IMPACT OF STUDY: Overall, this study provides important insights into plant-fungal interactions and their effect on both above- and belowground pests. This study also highlights an important first step towards harnessing the potential of microbial inoculates as a tool for integrated pest management in soybeans.


Asunto(s)
Quistes , Fabaceae , Mariposas Nocturnas , Tylenchoidea , Animales , Hongos , Glycine max
17.
Neurosurg Focus ; 52(5): E5, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35535826

RESUMEN

OBJECTIVE: The objective of this paper was to describe the volumetric natural history of meningiomas in patients with neurofibromatosis type 2 (NF2). METHODS: The authors performed a retrospective descriptive study by reviewing NF2 patients with meningiomas at their institution between 2000 and 2019. Demographic data were collected from the electronic medical records. Tumor volume was collected using volumetric segmentation software. Imaging characteristics including peritumoral brain edema (PTBE) and tumor calcification were collected for each patient from their first to most recent MRI at the authors' institution. An increase of 15% or more per year from original tumor size was used as the cutoff to define growth. RESULTS: A total of 137 meningiomas from 48 patients were included in the analysis. The average number of tumors per person was 2.9. Ninety-nine (72.3%) tumors were in female patients. The median length of follow-up from first imaging to last imaging was 32 months (IQR 10.9, 68.3 months). Most tumors were located in the cerebral convexity (24.8%), followed by the falcine region (18.2%) and spine (10.2%). The median tumor growth was 0.12 cm3/yr (IQR 0.03, 0.52 cm3/yr). At the time of first imaging, 21.9% of tumors had calcifications, while 13.9% of meningiomas had PTBE. Of 137 tumors, 52 showed growth. Characteristics associated with tumor growth included PTBE (OR 9.12, 95% CI 1.48-56.4), tumor volume (per cm3) at first imaging (OR 0.91, 95% CI 0.83-0.99), and 10-year increased age at first imaging (OR 0.57, 95% CI 0.43-0.74). PTBE had the shortest median time to growth at 9.2 months. CONCLUSIONS: Although the majority of NF2-associated meningiomas do not grow in the short term, a wide range of growth patterns can be seen. Younger age at first imaging and presence of PTBE are associated with growth. Patients with these characteristics likely benefit from closer follow-up.


Asunto(s)
Edema Encefálico , Neoplasias Meníngeas , Meningioma , Neurofibromatosis 2 , Femenino , Humanos , Imagen por Resonancia Magnética , Neoplasias Meníngeas/complicaciones , Neoplasias Meníngeas/diagnóstico por imagen , Neoplasias Meníngeas/patología , Meningioma/complicaciones , Meningioma/diagnóstico por imagen , Meningioma/patología , Neurofibromatosis 2/complicaciones , Neurofibromatosis 2/diagnóstico por imagen , Neurofibromatosis 2/patología , Estudios Retrospectivos
18.
J Neurooncol ; 151(2): 307-312, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33398533

RESUMEN

PURPOSE: Clear cell meningioma (CCM) is a rare WHO grade II meningioma variant, characterized by aggressive features and a high tumor recurrence rate. In this study, we compared overall and progression-free survivals between CCMs and other WHO grade II meningiomas. METHODS: A retrospective institutional database review was performed to identify all patients who underwent surgical resection of a WHO grade II meningioma between 1997 and 2019. Overall survival and progression-free survival were compared between patients with clear cell meningiomas and patients with other WHO grade II meningiomas. Multivariable Cox proportional-hazards analysis was used to identify independent predictors of tumor recurrence and survival. RESULTS: We included a total of 214 patients in this study (43 CCMs, 171 other WHO grade II meningiomas). Patients with CCMs had significantly shorter progression-free (p = 0.001) and overall (p = 0.026) survivals than patients with other grade II meningiomas. In multivariable analysis, clear cell histology was a significant and powerful independent predictor of tumor recurrence (HR 1.93; 95% CI 1.14-3.26) when controlling for tumor location, extent of resection, and adjuvant radiation. In multivariable analysis, clear cell histology correlated with increased mortality (HR 1.96, 95% CI 0.97-3.94), though this was not statistically significant. CONCLUSION: This is the first study to compare overall and progression-free survivals between CCMs and other WHO grade II meningiomas. Clear cell histology predicts a higher risk of tumor recurrence and mortality than other grade II histologies. Future studies may help to understand the impact of these findings and the treatment implications.


Asunto(s)
Neoplasias Meníngeas/mortalidad , Meningioma/mortalidad , Procedimientos Neuroquirúrgicos/mortalidad , Radioterapia Adyuvante/mortalidad , Terapia Combinada , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Neoplasias Meníngeas/patología , Neoplasias Meníngeas/terapia , Meningioma/patología , Meningioma/terapia , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Organización Mundial de la Salud
19.
J Neurooncol ; 151(2): 173-179, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33205354

RESUMEN

PURPOSE: WHO grade II meningiomas behave aggressively, with recurrence rates as high as 60%. Although complete resection in low-grade meningiomas is associated with a relatively low recurrence rate, the impact of complete resection for WHO grade II meningiomas is less clear. We studied the association of extent of resection with overall and progression-free survivals in patients with WHO grade II meningiomas. METHODS: A retrospective database review was performed to identify all patients who underwent surgical resection for intracranial WHO grade II meningiomas at our institution between 1995 and 2019. Kaplan-Meier analysis was used to compare overall and progression-free survivals between patients who underwent gross total resection (GTR) and those who underwent subtotal resection (STR). Multivariable Cox proportional-hazards analysis was used to identify independent predictors of tumor recurrence and mortality. RESULTS: Of 214 patients who underwent surgical resection for WHO grade II meningiomas (median follow-up 53.4 months), 158 had GTR and 56 had STR. In Kaplan-Meier analysis, patients who underwent GTR had significantly longer progression-free (p = 0.002) and overall (p = 0.006) survivals than those who underwent STR. In multivariable Cox proportional-hazards analysis, GTR independently predicted prolonged progression-free (HR 0.57, p = 0.038) and overall (HR 0.44, p = 0.017) survivals when controlling for age, tumor location, and adjuvant radiation. CONCLUSIONS: Extent of resection independently predicts progression-free and overall survivals in patients with WHO grade II meningiomas. In an era of increasing support for adjuvant treatment modalities in the management of meningiomas, our data support maximal safe resection as the primary goal in treatment of these patients.


Asunto(s)
Márgenes de Escisión , Neoplasias Meníngeas/mortalidad , Meningioma/mortalidad , Procedimientos Neuroquirúrgicos/mortalidad , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Neoplasias Meníngeas/patología , Neoplasias Meníngeas/cirugía , Meningioma/patología , Meningioma/cirugía , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Organización Mundial de la Salud
20.
Philos Trans A Math Phys Eng Sci ; 379(2209): 20200346, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34510929

RESUMEN

The hydrodeoxygenation (HDO) of acetophenone was evaluated in liquid phase and gas phase over monometallic Pt/SiO2, Co/SiO2 and bimetallic Pt-Co/SiO2 catalysts. The influence of reaction time and loading of the catalyst were analysed by following the conversion and products selectivity. Phenylethanol, cyclohexylethanone and cyclohexylethanol are the main products of reaction using the Pt/SiO2 catalyst. By contrast, ethylbenzene and phenylethanol are the only products formed on the Co/SiO2 and Pt-Co/SiO2 catalysts. The bimetallic catalyst is more stable as a function of time and more active towards the HDO process than the monometallic systems. The presence of an organic solvent showed only minor changes in product yields with no effect on the product speciation. Periodic density functional theory analysis indicates a stronger interaction between the carbonyl group of acetophenone with Co than with Pt sites of the mono and bimetallic systems, indicating a key activity of oxophilic sites towards improved selectivity to deoxygenated products. This article is part of the theme issue 'Bio-derived and bioinspired sustainable advanced materials for emerging technologies (part 2)'.

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