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JOURNAL/nrgr/04.03/01300535-202504000-00033/figure1/v/2024-07-06T104127Z/r/image-tiff Behavioral recovery using (viable) peripheral nerve allografts to repair ablation-type (segmental-loss) peripheral nerve injuries is delayed or poor due to slow and inaccurate axonal regeneration. Furthermore, such peripheral nerve allografts undergo immunological rejection by the host immune system. In contrast, peripheral nerve injuries repaired by polyethylene glycol fusion of peripheral nerve allografts exhibit excellent behavioral recovery within weeks, reduced immune responses, and many axons do not undergo Wallerian degeneration. The relative contribution of neurorrhaphy and polyethylene glycol-fusion of axons versus the effects of polyethylene glycol per se was unknown prior to this study. We hypothesized that polyethylene glycol might have some immune-protective effects, but polyethylene glycol-fusion was necessary to prevent Wallerian degeneration and functional/behavioral recovery. We examined how polyethylene glycol solutions per se affect functional and behavioral recovery and peripheral nerve allograft morphological and immunological responses in the absence of polyethylene glycol-induced axonal fusion. Ablation-type sciatic nerve injuries in outbred Sprague-Dawley rats were repaired according to a modified protocol using the same solutions as polyethylene glycol-fused peripheral nerve allografts, but peripheral nerve allografts were loose-sutured (loose-sutured polyethylene glycol) with an intentional gap of 1-2 mm to prevent fusion by polyethylene glycol of peripheral nerve allograft axons with host axons. Similar to negative control peripheral nerve allografts not treated by polyethylene glycol and in contrast to polyethylene glycol-fused peripheral nerve allografts, animals with loose-sutured polyethylene glycol peripheral nerve allografts exhibited Wallerian degeneration for all axons and myelin degeneration by 7 days postoperatively and did not recover sciatic-mediated behavioral functions by 42 days postoperatively. Other morphological signs of rejection, such as collapsed Schwann cell basal lamina tubes, were absent in polyethylene glycol-fused peripheral nerve allografts but commonly observed in negative control and loose-sutured polyethylene glycol peripheral nerve allografts at 21 days postoperatively. Loose-sutured polyethylene glycol peripheral nerve allografts had more pro-inflammatory and less anti-inflammatory macrophages than negative control peripheral nerve allografts. While T cell counts were similarly high in loose-sutured-polyethylene glycol and negative control peripheral nerve allografts, loose-sutured polyethylene glycol peripheral nerve allografts expressed some cytokines/chemokines important for T cell activation at much lower levels at 14 days postoperatively. MHCI expression was elevated in loose-sutured polyethylene glycol peripheral nerve allografts, but MHCII expression was modestly lower compared to negative control at 21 days postoperatively. We conclude that, while polyethylene glycol per se reduces some immune responses of peripheral nerve allografts, successful polyethylene glycol-fusion repair of some axons is necessary to prevent Wallerian degeneration of those axons and immune rejection of peripheral nerve allografts, and produce recovery of sensory/motor functions and voluntary behaviors. Translation of polyethylene glycol-fusion technologies would produce a paradigm shift from the current clinical practice of waiting days to months to repair ablation peripheral nerve injuries.
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The Platte River/High Plains Aquifer (PR/HPA) region is characterized by cropland, pastures, and grasslands that are faced with changing climatic conditions and agricultural intensification. The PR/HPA Long-Term Agroecosystem Research (LTAR) site is located in Eastern Nebraska with the goal of improving resilience, sustainability, and profitability of agroecosystems through enhancing ecosystem services and environmental quality, developing strategies for efficient agricultural production, and mitigating and adapting to climate change. To meet this goal, a common experiment and five ancillary experiments have been developed to evaluate prevailing regional practices in grain crop production systems compared to alternative practices in rainfed and irrigated systems. These experiments reflect different geographic regions and cropping systems within PR/HPA. The common experiment is at a plot scale under sub-drip irrigation. The prevailing practice is a corn-soybean rotation with a fixed N fertilizer rate. The alternative practice is a corn-winter wheat-relay cropped soybean rotation with temporally variable N rates using fertigation. There is also an auxiliary alternative practice, a corn-soybean rotation with temporally variable N rates using fertigation with fall manure application after soybean harvest. This document describes the regional characteristics, cropland LTAR experiments, stakeholder engagement, and future plans for the PR/HPA cropland experiments.
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Insects are the major pollination vectors for angiosperms, and insects native to a given habitat can play an irreplaceable ecological role in food webs and plant reproduction. With precipitous declines in insect species over the last decades, it is urgent to document insect assemblages in native plant communities to support conservation efforts. Identifying pollinators and their pollination activity is challenging; however, emerging technological methods are providing new monitoring capabilities. In this study, we compare the accuracy of two different methods of monitoring to assess the flower-visiting insect assemblage and likely pollinators of Encinitas baccharis (Baccharis vanessae): focal observations and video recordings from camera traps. B. vanessae is a rare, endemic species found in Coastal Sage Scrub communities in San Diego County. This federally listed species is threatened by habitat loss and fragmentation, which may also be affecting the availability of its insect pollinators. Results indicate that B. vanessae supports and is supported by a variety of flower-visiting insect groups. The diversity of insect visitors at male and female plants were similar across all diversity measurements. The insect vectors identified were as expected given B. vanessae pollination syndrome. This syndrome also aligns with wind as a pollination vector, providing evidence of ambophily. While focal observations underreported insect activity by approximately half, the proportions of common diurnal visitors were similar with both methods. Camera traps were unable to provide sufficient detail to discern visually similar groups, but were able to record nocturnal insect activity, which was dominated by moths (Lepidoptera, 82%). While collection protocol in this study did not record the time an insect spent interacting with a flower, we anecdotally observed moths spent notably longer periods in contact with flowers than most diurnal insects. This study has implications for effective monitoring and conservation of endangered plant species and their affiliated pollinators.
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OBJECTIVE: Health literacy is the ability to find, understand, and use information and services to inform health-related decisions and actions. Inadequate health literacy is associated with health disparities, poor health outcomes, and increased emergency department (ED) visits and hospitalizations. Children with medical complexity (CMC) have high rates of acute health care utilization. We examined the association of parental health literacy with acute care utilization and costs in CMC. METHODS: This cross-sectional study included parents of CMC receiving primary care at a free-standing children's hospital. We measured parental health literacy using the Single Item Literacy Screener, which measures the assistance needed to read health care materials. Our main predictor was parental health literacy, categorized as adequate versus inadequate. In a sensitivity analysis, we categorized health literacy as never needing assistance versus needing any assistance. Main outcomes were annual ED visits, hospitalizations, and associated costs. RESULTS: Of the 236 parents of CMC, 5.5% had inadequate health literacy. Health literacy was not associated with acute care utilization or associated costs. In our sensitivity analysis, CMC whose parents need any assistance to read health care materials had 188% higher ED costs (adjusted rate ratio 2.88 [95% confidence interval: 1.63-5.07]) and 126% higher hospitalization costs (adjusted rate ratio 2.26 [95% confidence interval: 1.49-3.44]), compared with CMC whose parents never need assistance. CONCLUSIONS: Inadequate parental health literacy was not associated with acute care utilization. However, CMC of parents needing any assistance to read health materials had higher ED and hospitalization costs. Further multicenter studies are needed.
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Servicio de Urgencia en Hospital , Alfabetización en Salud , Padres , Humanos , Alfabetización en Salud/estadística & datos numéricos , Estudios Transversales , Padres/psicología , Femenino , Masculino , Servicio de Urgencia en Hospital/estadística & datos numéricos , Niño , Hospitalización/estadística & datos numéricos , Preescolar , Adulto , Hospitales Pediátricos , Aceptación de la Atención de Salud/estadística & datos numéricos , AdolescenteRESUMEN
Splenic artery embolization (SAE) has become a favored alternative to splenectomy, offering a less invasive intervention for injured spleens while preserving spleen function. However, our understanding of the role that hemodynamics plays during embolization remains limited. In this study, we utilized patient-specific computational fluid dynamics (CFD) simulations to study distal and proximal embolization strategies commonly used in SAE. Detailed 3D computer models were constructed considering the descending aorta, various major visceral arteries, and the iliac arteries. Subsequently, the blood flow and pressure associated with different coil placement locations in proximal embolization were studied considering the collateral vessels. Coil induced variations in pressure fields were quantified and compared to baseline. The coil induced flow stagnation was also quantified with particle residence time. Distal embolization was modeled with Lagrangian particle tracking and the effect of particle size, release location, and timing on embolization outcome was studied. Our findings highlight the crucial role of collateral vessels in maintaining blood supply to the spleen following proximal embolization. It was demonstrated that coil location can affect distal pressure and that strategic coil placement guided by patient-specific CFD simulations can further reduce this pressure as desired. Additionally, the results point to the critical roles that particle size, release timing, and location play in distal embolization. Our study provides an early attempt to use patient-specific computer modeling for optimizing embolization strategies and ultimately improving patient outcomes during SAE procedures.
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OBJECTIVES: We aimed to evaluate the effectiveness of alternating magnetic fields (AMF) combined with antibiotics in reducing Staphylococcus aureus biofilm on metal implants in a large animal model, compared to antibiotics alone. METHODS: Metal plates were inoculated with a clinical MRSA strain and then implanted into thirty-three ewes divided into three groups: positive control, linezolid only, and a combination of linezolid and AMF. Animals had either titanium or cobalt-chrome plates and were sacrificed at 5 or 21 days post-implantation. Blood and tissue samples were collected at various time points post-AMF treatment. RESULTS: In vivo efficacy studies demonstrated significant biofilm reduction on titanium and cobalt-chrome implants with AMF-linezolid combination treatment compared to controls. Significant bacterial reductions were also observed in surrounding tissues and bones. Cytokine analysis showed improved inflammatory responses with combination therapy, and histopathology confirmed reduced inflammation, necrosis, and bacterial presence, especially at 5 days post-implantation. CONCLUSIONS: This study demonstrates that combining AMF with antibiotics significantly reduces biofilm-associated infections on metal implants in a large animal model. Numerical simulations confirmed targeted heating, and in vivo results showed substantial bacterial load reduction and reduced inflammatory response. These findings support the potential of AMF as a non-invasive treatment for prosthetic joint infections.
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Antibacterianos , Biopelículas , Linezolid , Infecciones Relacionadas con Prótesis , Infecciones Estafilocócicas , Animales , Biopelículas/efectos de los fármacos , Linezolid/farmacología , Linezolid/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Ovinos , Femenino , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antibacterianos/administración & dosificación , Infecciones Relacionadas con Prótesis/microbiología , Infecciones Relacionadas con Prótesis/tratamiento farmacológico , Infecciones Relacionadas con Prótesis/prevención & control , Campos Magnéticos , Modelos Animales de Enfermedad , Prótesis e Implantes/microbiología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Oxazolidinonas/farmacología , Oxazolidinonas/uso terapéutico , Oxazolidinonas/administración & dosificaciónRESUMEN
Prior studies have suggested that immune thrombotic thrombocytopenic purpura (iTTP) may display seasonal variation; however, methodologic limitations and sample sizes have diminished the ability to perform a rigorous assessment. This 5-year retrospective study assessed the epidemiology of iTTP and determined whether it displays a seasonal pattern. Patients with both initial and relapsed iTTP (defined as a disintegrin and metalloprotease with thrombospondin type motifs 13 activity <10%) from 24 tertiary centers in Australia, Canada, France, Greece, Italy, Spain, and the US were included. Seasons were defined as: Northern Hemisphere-winter (December-February); spring (March-May); summer (June-August); autumn (September-November) and Southern Hemisphere-winter (June-August); spring (September-November); summer (December-February); autumn (March-May). Additional outcomes included the mean temperature in months with and without an iTTP episode at each site. A total of 583 patients experienced 719 iTTP episodes. The observed proportion of iTTP episodes during the winter was significantly greater than expected if equally distributed across seasons (28.5%, 205/719, 25.3%-31.9%; p = .03). Distance from the equator and mean temperature deviation both positively correlated with the proportion of iTTP episodes during winter. Acute iTTP episodes were associated with the winter season and colder temperatures, with a second peak during summer. Occurrence during winter was most pronounced at sites further from the equator and/or with greater annual temperature deviations. Understanding the etiologies underlying seasonal patterns of disease may assist in discovery and development of future preventative therapies and inform models for resource utilization.
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Estaciones del Año , Humanos , Femenino , Masculino , Estudios Retrospectivos , Adulto , Persona de Mediana Edad , Púrpura Trombocitopénica Trombótica/epidemiología , Anciano , Adolescente , Adulto Joven , Canadá/epidemiologíaRESUMEN
INTRODUCTION: The Control Network Neuromodulation to Enhance Cognitive Training in Complex Traumatic Brain Injury (CONNECT-TBI) study is an ongoing randomized, double-blinded, sham-controlled multisite clinical trial to determine the enhancing effects of noninvasive neuromodulation when paired with cognitive training in military participants (Veterans and active duty) with mild TBI. Attention Process Training-III (APT-III) was selected for its strong evidence base, manualized procedures, and computerized program. However, many aspects of APT-III that make it ideal for personalization make it less ideal for reliable implementation across participants, clinicians/technicians, and sites. The purpose of this feature article is to highlight APT-III procedures that require additional standardization for reliable administration across participants and sites. MATERIALS AND METHODS: Ten studies using APT-III were reviewed for methodology of APT-III administration. The manual was also scrutinized; aspects of administration that involved clinical decision-making, subjectivity, flexibility, and/or that were identified by the APT-III developers as areas in need of "empirical evaluation" were flagged by clinicians. Literature and manual review findings were presented to the team for discussion and solution-finding. The authors created and refined a standardized process that would allow participants to move through APT-III training, including task movement algorithms and new materials drafts. Refining of algorithms and drafts continued until there was a consensus from team members. RESULTS: Many gray areas were identified, but we will limit our reporting to focus on (1) dosage, (2) adaptation, (3) metacognitive strategy instruction, and (4) goal attainment scaling. We present APT-III manual details, literature review findings, and CONNECT-TBI decisions and materials for each of these areas of focus. CONCLUSIONS: We have highlighted some of the major gray areas of APT-III administration so that fellow researchers can understand the need to take similar steps in clinical trials using APT-III. We provide examples of our standardization process and resultant rules and materials. Our algorithm, based on prior studies using the APT-III and our own iterative adjustments, allows for adjustment of the difficulty and speed of the training tasks (but within certain parameters) in order to achieve the best balance between individualization and consistency across participants and sites. We provide an example of a workflow and reporting process for future studies.
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Atención , Humanos , Atención/fisiología , Método Doble Ciego , Lesiones Traumáticas del Encéfalo/terapiaRESUMEN
While the centrality of posttranscriptional modifications to RNA biology has long been acknowledged, the function of the vast majority of modified sites remains to be discovered. Illustrative of this, there is not yet a discrete biological role assigned for one of the most highly conserved modifications, 5-methyluridine at position 54 in tRNAs (m5U54). Here, we uncover contributions of m5U54 to both tRNA maturation and protein synthesis. Our mass spectrometry analyses demonstrate that cells lacking the enzyme that installs m5U in the T-loop (TrmA in Escherichia coli, Trm2 in Saccharomyces cerevisiae) exhibit altered tRNA modification patterns. Furthermore, m5U54-deficient tRNAs are desensitized to small molecules that prevent translocation in vitro. This finding is consistent with our observations that relative to wild-type cells, trm2Δ cell growth and transcriptome-wide gene expression are less perturbed by translocation inhibitors. Together our data suggest a model in which m5U54 acts as an important modulator of tRNA maturation and translocation of the ribosome during protein synthesis.
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Escherichia coli , ARN de Transferencia , Ribosomas , Saccharomyces cerevisiae , Uridina , ARN de Transferencia/metabolismo , ARN de Transferencia/genética , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Ribosomas/metabolismo , Uridina/metabolismo , Escherichia coli/metabolismo , Escherichia coli/genética , Procesamiento Postranscripcional del ARN , Biosíntesis de Proteínas , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , ARNt Metiltransferasas/metabolismo , ARNt Metiltransferasas/genéticaRESUMEN
Apicomplexan parasites balance proliferation, persistence, and spread in their metazoan hosts. AGC kinases, such as PKG, PKA, and the PDK1 ortholog SPARK, integrate environmental signals to toggle parasites between replicative and motile life stages. Recent studies have cataloged pathways downstream of apicomplexan PKG and PKA; however, less is known about the global integration of AGC kinase signaling cascades. Here, conditional genetics coupled to unbiased proteomics demonstrates that SPARK complexes with an elongin-like protein to regulate the stability of PKA and PKG in the model apicomplexan Toxoplasma gondii. Defects attributed to SPARK depletion develop after PKG and PKA are down-regulated. Parasites lacking SPARK differentiate into the chronic form of infection, which may arise from reduced activity of a coccidian-specific PKA ortholog. This work delineates the signaling topology of AGC kinases that together control transitions within the asexual cycle of this important family of parasites.
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Proteínas Protozoarias , Toxoplasma , Toxoplasma/genética , Toxoplasma/enzimología , Toxoplasma/fisiología , Toxoplasma/crecimiento & desarrollo , Proteínas Protozoarias/metabolismo , Proteínas Protozoarias/genética , Animales , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de GMP Cíclico/genética , Transducción de Señal , Reproducción AsexuadaRESUMEN
Background: The univoltine leaf beetle Psylliodesattenuata (Koch, 1803) is a pest of Cannabis and Humulus (Cannabaceae) and native to the Palaearctic Region, known from eastern Asia to western Europe. New information: First North American records are presented for P.attenuata from Canada: Ontario and Québec. Adult beetle feeding damage to hops Humuluslupulus L. (Cannabacaea) plants is recorded from Québec. Diagnostic information is presented to distinguish P.attenuata from other North American Chrysomelidae and a preliminary assessment of its potential to spread in North America is presented. While our climate analysis is limited by a lack of data, it appears P.attenuata is physiologically capable of persisting throughout the range of Humulus in North America.The United States of America and Canada are now known to be home to 71 or more species of adventive Chrysomelidae.
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In this study we have identified POLθ-S6K-p62 as a novel druggable regulator of radiation response in prostate cancer. Despite significant advances in delivery, radiotherapy continues to negatively affect treatment outcomes and quality of life due to resistance and late toxic effects to the surrounding normal tissues such as bladder and rectum. It is essential to develop new and effective strategies to achieve better control of tumor. We found that ribosomal protein S6K (RPS6KB1) is elevated in human prostate tumors, and contributes to resistance to radiation. As a downstream effector of mTOR signaling, S6K is known to be involved in growth regulation. However, the impact of S6K signaling on radiation response has not been fully explored. Here we show that loss of S6K led to formation of smaller tumors with less metastatic ability in mice. Mechanistically we found that S6K depletion reduced NFκB and SQSTM1 (p62) reporter activity and DNA polymerase θ (POLθ) that is involved in alternate end-joining repair. We further show that the natural compound berberine interacts with S6K in a in a hitherto unreported novel mode and that pharmacological inhibition of S6K with berberine reduces Polθ and downregulates p62 transcriptional activity via NFκB. Loss of S6K or pre-treatment with berberine improved response to radiation in prostate cancer cells and prevented radiation-mediated resurgence of PSA in animals implanted with prostate cancer cells. Notably, silencing POLQ in S6K overexpressing cells enhanced response to radiation suggesting S6K sensitizes prostate cancer cells to radiation via POLQ. Additionally, inhibition of autophagy with CQ potentiated growth inhibition induced by berberine plus radiation. These observations suggest that pharmacological inhibition of S6K with berberine not only downregulates NFκB/p62 signaling to disrupt autophagic flux but also decreases Polθ. Therefore, combination treatment with radiation and berberine inhibits autophagy and alternate end-joining DNA repair, two processes associated with radioresistance leading to increased radiation sensitivity.
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FN-kappa B , Neoplasias de la Próstata , Tolerancia a Radiación , Proteína Sequestosoma-1 , Transducción de Señal , Masculino , Animales , Humanos , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/tratamiento farmacológico , Proteína Sequestosoma-1/metabolismo , Proteína Sequestosoma-1/genética , FN-kappa B/metabolismo , FN-kappa B/genética , Transducción de Señal/efectos de los fármacos , Ratones , Tolerancia a Radiación/efectos de los fármacos , Línea Celular Tumoral , ADN Polimerasa Dirigida por ADN/genética , ADN Polimerasa Dirigida por ADN/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/genéticaRESUMEN
BACKGROUND AND AIMS: Dysregulated cholesterol metabolism is a hallmark of atherosclerotic cardiovascular diseases, yet our understanding of how endogenous cholesterol synthesis affects atherosclerosis is not clear. The energy sensor AMP-activated protein kinase (AMPK) phosphorylates and inhibits the rate-limiting enzyme in the mevalonate pathway HMG-CoA reductase (HMGCR). Recent work demonstrated that when AMPK-HMGCR signaling was compromised in an Apoe-/- model of hypercholesterolemia, atherosclerosis was exacerbated due to elevated hematopoietic stem and progenitor cell mobilization and myelopoiesis. We sought to validate the significance of the AMPK-HMGCR signaling axis in atherosclerosis using a non-germline hypercholesterolemia model with functional ApoE. METHODS: Male and female HMGCR S871A knock-in (KI) mice and wild-type (WT) littermate controls were made atherosclerotic by intravenous injection of a gain-of-function Pcsk9D374Y-adeno-associated virus followed by high-fat and high-cholesterol atherogenic western diet feeding for 16 weeks. RESULTS: AMPK activation suppressed endogenous cholesterol synthesis in primary bone marrow-derived macrophages from WT but not HMGCR KI mice, without changing other parameters of cholesterol regulation. Atherosclerotic plaque area was unchanged between WT and HMGCR KI mice, independent of sex. Correspondingly, there were no phenotypic differences observed in hematopoietic progenitors or differentiated immune cells in the bone marrow, blood, or spleen, and no significant changes in systemic markers of inflammation. When lethally irradiated female mice were transplanted with KI bone marrow, there was similar plaque content relative to WT. CONCLUSIONS: Given previous work, our study demonstrates the importance of preclinical atherosclerosis model comparison and brings into question the importance of AMPK-mediated control of cholesterol synthesis in atherosclerosis.
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Proteínas Quinasas Activadas por AMP , Aterosclerosis , Colesterol , Hidroximetilglutaril-CoA Reductasas , Proproteína Convertasa 9 , Animales , Femenino , Masculino , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Aterosclerosis/metabolismo , Aterosclerosis/patología , Aterosclerosis/genética , Aterosclerosis/enzimología , Células Cultivadas , Colesterol/biosíntesis , Colesterol/metabolismo , Colesterol/sangre , Modelos Animales de Enfermedad , Hidroximetilglutaril-CoA Reductasas/metabolismo , Hipercolesterolemia/metabolismo , Hipercolesterolemia/enzimología , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Placa Aterosclerótica , Proproteína Convertasa 9/metabolismo , Proproteína Convertasa 9/genética , Transducción de SeñalAsunto(s)
Ecocardiografía Doppler , Arteria Pulmonar , Insuficiencia de la Válvula Tricúspide , Humanos , Insuficiencia de la Válvula Tricúspide/fisiopatología , Insuficiencia de la Válvula Tricúspide/complicaciones , Insuficiencia de la Válvula Tricúspide/diagnóstico por imagen , Ecocardiografía Doppler/métodos , Arteria Pulmonar/diagnóstico por imagen , Arteria Pulmonar/fisiopatología , Femenino , Masculino , Índice de Severidad de la Enfermedad , Reproducibilidad de los Resultados , Persona de Mediana Edad , Sístole , Sensibilidad y Especificidad , AncianoRESUMEN
Metabolic programming underpins inflammation and liver macrophage activation in the setting of chronic liver disease. Here, we sought to identify the role of an important metabolic regulator, AMP-activated protein kinase (AMPK), specifically within myeloid cells during the progression of non-alcoholic steatohepatitis (NASH) and whether treatment with metformin, a firstline therapy for diabetes and activator of AMPK could stem disease progression. Male and female Prkaa1fl/fl/Prkaa2fl/fl (Flox) control and Flox-LysM-Cre+ (MacKO) mice were fed a low-fat control or a choline-deficient, amino acid defined 45% Kcal high-fat diet (CDAHFD) for 8 weeks, where metformin was introduced in the drinking water (50 or 250 mg/kg/day) for the last 4 weeks. Hepatic steatosis and fibrosis were dramatically increased in response to CDAHFD-feeding compared to low-fat control. While myeloid AMPK signaling had no effect on markers of hepatic steatosis or circulating markers, fibrosis as measured by total liver collagen was significantly elevated in livers from MacKO mice, independent of sex. Although treatment with 50 mg/kg/day metformin had no effect on any parameter, intervention with 250 mg/kg/day metformin completely ameliorated hepatic steatosis and fibrosis in both male and female mice. While the protective effect of metformin was associated with lower final body weight, and decreased expression of lipogenic and Col1a1 transcripts, it was independent of myeloid AMPK signaling. These results suggest that endogenous AMPK signaling in myeloid cells, both liver-resident and infiltrating, acts to restrict fibrogenesis during CDAHFD-induced NASH progression but is not the mechanism by which metformin improves markers of NASH.
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Proteínas Quinasas Activadas por AMP , Dieta Alta en Grasa , Metformina , Enfermedad del Hígado Graso no Alcohólico , Transducción de Señal , Animales , Metformina/farmacología , Metformina/uso terapéutico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/etiología , Ratones , Dieta Alta en Grasa/efectos adversos , Proteínas Quinasas Activadas por AMP/metabolismo , Masculino , Femenino , Transducción de Señal/efectos de los fármacos , Células Mieloides/metabolismo , Células Mieloides/efectos de los fármacos , Cirrosis Hepática/metabolismo , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Cirrosis Hepática/inducido químicamente , Ratones Endogámicos C57BL , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patologíaRESUMEN
Realizing topological superconductivity by integrating high-transition-temperature (TC) superconductors with topological insulators can open new paths for quantum computing applications. Here, a new approach is reported for increasing the superconducting transition temperature ( T C onset ) $( {T_{\mathrm{C}}^{{\mathrm{onset}}}} )$ by interfacing the unconventional superconductor Fe(Te,Se) with the topological insulator Bi-Te system in the low-Se doping regime, near where superconductivity vanishes in the bulk. The critical finding is that the T C onset $T_{\mathrm{C}}^{{\mathrm{onset}}}$ of Fe(Te,Se) increases from nominally non-superconducting to as high as 12.5 K when Bi2Te3 is replaced with the topological phase Bi4Te3. Interfacing Fe(Te,Se) with Bi4Te3 is also found to be critical for stabilizing superconductivity in monolayer films where T C onset $T_{\mathrm{C}}^{{\mathrm{onset}}}$ can be as high as 6 K. Measurements of the electronic and crystalline structure of the Bi4Te3 layer reveal that a large electron transfer, epitaxial strain, and novel chemical reduction processes are critical factors for the enhancement of superconductivity. This novel route for enhancing TC in an important epitaxial system provides new insight on the nature of interfacial superconductivity and a platform to identify and utilize new electronic phases.
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Stent migration is a rare but significant complication following endovascular procedures. Techniques for managing dislodged stents have included surgical, endovascular, and conservative approaches. This case details a patient who had a covered stent placed within the left renal vein which later migrated to the pulmonary artery causing damage to the tricuspid valve. The migrated stent was successfully removed using a percutaneous endovascular approach utilizing fluoroscopy and transesophageal echocardiogram guidance.
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Background: Thinner anterior hip capsules are associated with hip laxity, but there is little known about the impact of capsular thickness on the development of instability after primary hip arthroscopic surgery. Purpose: To investigate the relationship between hip capsular thickness as measured on preoperative magnetic resonance imaging (MRI) and the development of hip instability after hip arthroscopic surgery for femoroacetabular impingement. Study Design: Case-control study; Level of evidence, 3. Methods: We reviewed revision hip arthroscopic procedures performed between January 1, 2019, and May 1, 2021, at a single institution. Inclusion criteria were preoperative MRI/magnetic resonance arthrography, completion of the study traction protocol, and asymmetric distraction between the hips of ≥3 mm on examination under anesthesia. A comparison group of patients treated for femoroacetabular impingement with primary hip arthroscopic surgery who did not develop capsular instability were matched 1:1 to the patients with instability. Superolateral hip capsular thickness was measured on MRI before index surgery. Analysis was conducted using independent-samples t tests and multivariable linear regression. Results: A total of 44 patients were included, with 22 patients each in the instability and no-instability groups. The mean capsular thickness was lower in the patients with hip instability than in those without (1.9 ± 0.6 vs 3.4 ± 1.1 mm, respectively; P < .001). Decreased capsular thickness was significantly associated with hips with instability versus no-instability (ß = -1.468 [95% CI, -2.049 to -0.887]; P < .001). Conclusion: Thinner preoperative hip capsules in the region of the iliofemoral ligament were seen in patients who subsequently underwent revision arthroscopic surgery for hip instability compared to patients who underwent primary hip arthroscopic surgery without subsequent revision. Patients at a higher risk for the development of postoperative hip instability had a superolateral hip capsular thickness of <2 mm.
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Importance: Current interventions for posttraumatic stress disorder (PTSD) are efficacious, yet effectiveness may be limited by adverse effects and high withdrawal rates. Acupuncture is an emerging intervention with positive preliminary data for PTSD. Objective: To compare verum acupuncture with sham acupuncture (minimal needling) on clinical and physiological outcomes. Design, Setting, and Participants: This was a 2-arm, parallel-group, prospective blinded randomized clinical trial hypothesizing superiority of verum to sham acupuncture. The study was conducted at a single outpatient-based site, the Tibor Rubin VA Medical Center in Long Beach, California, with recruitment from April 2018 to May 2022, followed by a 15-week treatment period. Following exclusion for characteristics that are known PTSD treatment confounds, might affect biological assessment, indicate past nonadherence or treatment resistance, or indicate risk of harm, 93 treatment-seeking combat veterans with PTSD aged 18 to 55 years were allocated to group by adaptive randomization and 71 participants completed the intervention protocols. Interventions: Verum and sham were provided as 1-hour sessions, twice weekly, and participants were given 15 weeks to complete up to 24 sessions. Main Outcomes and Measures: The primary outcome was pretreatment to posttreatment change in PTSD symptom severity on the Clinician-Administered PTSD Scale-5 (CAPS-5). The secondary outcome was pretreatment to posttreatment change in fear-conditioned extinction, assessed by fear-potentiated startle response. Outcomes were assessed at pretreatment, midtreatment, and posttreatment. General linear models comparing within- and between-group were analyzed in both intention-to-treat (ITT) and treatment-completed models. Results: A total of 85 male and 8 female veterans (mean [SD] age, 39.2 [8.5] years) were randomized. There was a large treatment effect of verum (Cohen d, 1.17), a moderate effect of sham (d, 0.67), and a moderate between-group effect favoring verum (mean [SD] Δ, 7.1 [11.8]; t90 = 2.87, d, 0.63; P = .005) in the intention-to-treat analysis. The effect pattern was similar in the treatment-completed analysis: verum d, 1.53; sham d, 0.86; between-group mean (SD) Δ, 7.4 (11.7); t69 = 2.64; d, 0.63; P = .01). There was a significant pretreatment to posttreatment reduction of fear-potentiated startle during extinction (ie, better fear extinction) in the verum but not the sham group and a significant correlation (r = 0.31) between symptom reduction and fear extinction. Withdrawal rates were low. Conclusions and Relevance: The acupuncture intervention used in this study was clinically efficacious and favorably affected the psychobiology of PTSD in combat veterans. These data build on extant literature and suggest that clinical implementation of acupuncture for PTSD, along with further research about comparative efficacy, durability, and mechanisms of effects, is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02869646.