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The blood-brain barrier (BBB) is a selectively permeable barrier separating the periphery from the central nervous system (CNS). The BBB restricts the flow of most material into and out of the CNS, including many drugs that could be used as potent therapies. BBB permeability is modulated by several cells that are collectively called the neurovascular unit (NVU). The NVU consists of specialized CNS endothelial cells (ECs), pericytes, astrocytes, microglia, and neurons. CNS ECs maintain a complex "seal" via tight junctions, forming the BBB; breakdown of these tight junctions leads to BBB disruption. Pericytes control the vascular flow within capillaries and help maintain the basal lamina. Astrocytes control much of the flow of material that has moved beyond the CNS EC layer and can form a secondary barrier under inflammatory conditions. Microglia survey the border of the NVU for noxious material. Neuronal activity also plays a role in the maintenance of the BBB. Since astrocytes, pericytes, microglia, and neurons are all able to modulate the permeability of the BBB, understating the complex contributions of each member of the NVU will potentially uncover novel and effective methods for delivery of neurotherapies to the CNS.
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Células Endoteliales , Pericitos , Astrocitos/metabolismo , Barrera Hematoencefálica/fisiología , Sistema Nervioso Central , Células Endoteliales/fisiología , Humanos , Pericitos/metabolismoRESUMEN
Efficient and deterministic nonlinear phononic interactions could revolutionize classical and quantum information processing at radio frequencies in much the same way that nonlinear photonic interactions have at optical frequencies. Here we show that in the important class of phononic materials that are piezoelectric, deterministic nonlinear phononic interactions can be enhanced by orders of magnitude via the heterogeneous integration of high-mobility semiconductor materials. To this end, a lithium niobate and indium gallium arsenide heterostructure is utilized to produce the most efficient three- and four-wave phononic mixing to date, to the best of our knowledge. We then show that the conversion efficiency can be further enhanced by applying semiconductor bias fields that amplify the phonons. We present a theoretical model that accurately predicts the three-wave mixing efficiencies in this work and extrapolate that these nonlinearities can be enhanced far beyond what is demonstrated here by confining phonons to smaller dimensions in waveguides and optimizing the semiconductor material properties.
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This study investigated the real-world incidence rate of serotonin syndrome in patients receiving tedizolid and concomitant serotonergic agents. A retrospective cohort of 479 adult patients was assessed between January 2015 and July 2023. Overall, a rare rate of 0.4% (2/479) of possible serotonin syndrome with tedizolid was identified. Given that concomitant serotonergic agents were commonly used, further study is warranted to determine causality.
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BACKGROUND: Severe COVID-19 is uncommon, restricted to 19% of the total population. In response to the first virus wave (alpha variant of SARS-CoV-2), we investigated whether a biomarker indicated severity of disease and, in particular, if variable expression of angiotensin converting enzyme 2 (ACE2) in blood might clarify this difference in risk and of post COVID -19 conditions (PCC). METHODS: The IRB-approved study compared patients hospitalized with severe COVID-19 to healthy controls. Severe infection was defined requiring oxygen or increased oxygen need from baseline at admission with positive COVID-19 PCR. A single blood sample was obtained from patients within a day of admission. ACE2 RNA expression in blood cells was measured by an RT-PCR assay. Plasma ACE1 and ACE2 enzyme activities were quantified by fluorescent peptides. Plasma TIMP-1, PIIINP and MMP-9 antigens were quantified by ELISA. Data were entered into REDCap and analyzed using STATA v 14 and GraphPad Prism v 10. RESULTS: Forty-eight patients and 72 healthy controls were recruited during the pandemic. ACE2 RNA expression in peripheral blood mononuclear cells (PBMC) was rarely detected acutely during severe COVID-19 but common in controls (OR for undetected ACE2: 12.4 [95% CI: 2.62-76.1]). ACE2 RNA expression in PBMC did not determine plasma ACE1 and ACE2 activity, suggesting alternative cell-signaling pathways. Markers of fibrosis (TIMP-1 and PIIINP) and vasculopathy (MMP-9) were additionally elevated. ACE2 RNA expression during severe COVID-19 often responded within hours to convalescent plasma. Analogous to oncogenesis, we speculate that potent, persistent, cryptic processes following COVID-19 (the renin-angiotensin system (RAS), fibrosis and vasculopathy) initiate or promote post-COVID-19 conditions (PCC) in susceptible individuals. CONCLUSIONS: This work elucidates biological and temporal plausibility for ACE2, TIMP1, PIIINP and MMP-9 in the pathogenesis of PCC. Intersection of these independent systems is uncommon and may in part explain the rarity of PCC.
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Enzima Convertidora de Angiotensina 2 , COVID-19 , Leucocitos Mononucleares , SARS-CoV-2 , Humanos , COVID-19/sangre , Enzima Convertidora de Angiotensina 2/sangre , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/virología , Anciano , Adulto , Biomarcadores/sangre , Inhibidor Tisular de Metaloproteinasa-1/sangre , Inhibidor Tisular de Metaloproteinasa-1/genética , Metaloproteinasa 9 de la Matriz/sangre , Metaloproteinasa 9 de la Matriz/genética , Índice de Severidad de la Enfermedad , Estudios de Casos y Controles , Peptidil-Dipeptidasa A/sangre , Peptidil-Dipeptidasa A/genéticaRESUMEN
Palmoplantar pustulosis is a variant of psoriasis and a chronic skin disorder in which pruritic pustular eruptions appear on the palms and soles. It is thought to arise from a variety of genetic and environmental factors, is limited in prevalence, and has proven quite difficult to treat. The symptoms it inflicts on those affected are quite debilitating and the treatment landscape is constantly evolving, thus emphasizing the need for updates of the literature as time passes. Current treatments include topical agents, oral therapies, and phototherapy, amongst other treatments. In this systemic review, we explore newer literature from 2015 to 2022 on various treatment regimens for palmoplantar pustulosis. J Drugs Dermatol. 2024;23(8):626-631. doi:10.36849/JDD.doi:10.36849/7612R1.
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Fármacos Dermatológicos , Psoriasis , Humanos , Psoriasis/terapia , Psoriasis/diagnóstico , Psoriasis/tratamiento farmacológico , Fármacos Dermatológicos/uso terapéutico , Fármacos Dermatológicos/administración & dosificación , Fototerapia/métodos , Administración Oral , Administración Cutánea , Resultado del TratamientoRESUMEN
BACKGROUND: Children with medical complexity (CMC) have unique, and often unmet, housing needs that place them at risk for housing insecurity and poor health outcomes. Yet, little is known about how families with CMC discuss their housing needs with healthcare providers. We sought to understand: (1) how housing is currently discussed between CMC caregivers and healthcare providers, and (2) how CMC caregivers want such conversations to occur. METHODS: From August to November 2020, we conducted semi-structured interviews with parents/guardians of CMC (<26 years old) in Maryland as part of a larger study to understand their housing experience. Four questions on communication with providers about housing were developed a priori and included in this analysis. Qualitative content analysis was applied to interview transcripts. RESULTS: Among 31 completed interviews, most participants were female (90%), lived in single-family homes (68%) and were from a mix of neighbourhood types (urban 19%, suburban 58%, rural 22%). Their children ranged in age from 6 months to 22 years, had a mix of insurance types (public 65%, private 29%, both 6%) and nearly all required medical equipment or technology. Four themes emerged: (1) Current housing conversations are rare and superficial, (2) Ideal housing conversations would result in thoughtful care plans and concrete supports, (3) Frequency and initiation of housing conversations are best tailored to family preferences and (4) Value of housing conversations are limited by lack of provider knowledge and time. CONCLUSIONS: Conversations about housing needs for CMC happen in limited ways with healthcare providers, despite a desire on the part of their caregivers. Such conversations can give meaningful insights into the family's specific housing challenges, allowing providers to appropriately tailor care plans and referrals. Future work is needed to capture provider perspectives, design CMC-specific housing screeners and develop interdisciplinary referral strategies.
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Cuidadores , Vivienda , Niño , Humanos , Femenino , Adulto , Masculino , Personal de Salud , Comunicación , Cognición , Investigación CualitativaRESUMEN
OBJECTIVE: This study is an economic evaluation comparing virtual surgical planning (VSP) utilization to free hand mandibular reconstruction (FHR) for advanced oral cavity cancer, for which the cost effectiveness remains poorly understood. The proposed clinical benefits of VSP must be weighed against the additional upfront costs. METHODS: A Markov decision analysis model was created for VSP and FHR based on literature review and institutional data over a 35-year time horizon. Model parameters were derived and averaged from systematic review and institutional experience. VSP cost and surgical time saving was incorporated. We accounted for long-term risks including cancer recurrence and hardware failure/exposure. We calculated cost in US dollars and effectiveness in quality-adjusted-life-years (QALYs). A health care perspective was adopted, discounting costs and effectiveness at 3%/year. Deterministic and probabilistic sensitivity analyses tested model robustness. RESULTS: In the base case scenario, total VSP strategy cost was $49,498 with 8.37 QALYs gained while FHR cost was $42,478 with 8.27 QALY gained. An incremental cost-effectiveness ratio (ICER), or the difference in cost/difference in effectiveness, for VSP was calculated at $68,382/QALY gained. VSP strategy favorability was sensitive to variations of patient age at diagnosis and institutional VSP cost with one-way sensitivity analysis. VSP was less economically favorable for patients >75.5 years of age or for institutional VSP costs >$10,745. In a probabilistic sensitivity analysis, 55% of iterations demonstrated an ICER value below a $100,000/QALY threshold. CONCLUSIONS/RELEVANCE: VSP is economically favorable compared to FHR in patients requiring mandibular reconstruction for advanced oral cancer, but these results are sensitive to the patient's age at diagnosis and the institutional VSP cost. Our results do not suggest if one "should or should not" use VSP, rather, emphasizes the need for patient selection regarding which patients would most benefit from VSP when evaluating quality of life and long-term complications. Further studies are necessary to demonstrate improved long-term risk for hardware failure/exposure in VSP compared to FHR.
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Reconstrucción Mandibular , Años de Vida Ajustados por Calidad de Vida , Femenino , Humanos , Masculino , Análisis de Costo-Efectividad , Técnicas de Apoyo para la Decisión , Reconstrucción Mandibular/métodos , Reconstrucción Mandibular/economía , Cadenas de Markov , Neoplasias de la Boca/cirugía , Neoplasias de la Boca/economía , Cirugía Asistida por Computador/métodos , Cirugía Asistida por Computador/economía , Resultado del TratamientoRESUMEN
Background: Early detection of melanoma improves survival; however, patients face long wait times to receive dermatology care. Teledermatology (TD) is a promising tool to optimize access to care and has shown promise for the identification of malignancies but has not been well studied for melanoma. We evaluated the utility of TD as a triage tool to allow high-risk lesions of concern to be seen more expeditiously. Methods: Patient sociodemographic factors and histological characteristics of 836 melanomas biopsied between March 2020 and November 2022 in the University of Pittsburgh Medical Center health system were retrospectively evaluated, stratified by initial appointment type of TD versus in-person visit. Results: Patients first seeking care through teledermatology had shorter wait times to initial evaluation (p < 0.001) and eventual biopsy (p < 0.001), and these melanomas had higher Breslow thickness (p < 0.001), were more ulcerated (p = 0.002), invasive (p = 0.001), and of a more aggressive subtype (p = 0.007) than those initially evaluated in-person. TD was also utilized by a higher proportion of younger (p = 0.001) and non-white (p = 0.03) patients who identified their own lesion (p < 0.001). Conclusions: TD may be a strategy to improve melanoma outcomes by providing an accessible avenue of expedited care for high-risk lesions associated with worse clinical prognosticators of disease.
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Dermatología , Melanoma , Neoplasias Cutáneas , Telemedicina , Humanos , Melanoma/diagnóstico , Estudios Retrospectivos , Hospitales , Neoplasias Cutáneas/diagnósticoRESUMEN
Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS). Infiltrating inflammatory immune cells perpetuate demyelination and axonal damage in the CNS and significantly contribute to pathology and clinical deficits. While the cytokine interferon (IFN)γ is classically described as deleterious in acute CNS autoimmunity, we and others have shown astrocytic IFNγ signaling also has a neuroprotective role. Here, we performed RNA sequencing and ingenuity pathway analysis on IFNγ-treated astrocytes and found that PD-L1 was prominently expressed. Interestingly, PD-1/PD-L1 antagonism reduced apoptosis in leukocytes exposed to IFNγ-treated astrocytes in vitro. To further elucidate the role of astrocytic IFNγ signaling on the PD-1/PD-L1 axis in vivo, we induced the experimental autoimmune encephalomyelitis (EAE) model of MS in Aldh1l1-CreERT2, Ifngr1fl/fl mice. Mice with conditional astrocytic deletion of IFNγ receptor exhibited a reduction in PD-L1 expression which corresponded to increased infiltrating leukocytes, particularly from the myeloid lineage, and exacerbated clinical disease. PD-1 agonism reduced EAE severity and CNS-infiltrating leukocytes. Importantly, PD-1 is expressed by myeloid cells surrounding MS lesions. These data support that IFNγ signaling in astrocytes diminishes inflammation during chronic autoimmunity via upregulation of PD-L1, suggesting potential therapeutic benefit for MS patients.
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Antígeno B7-H1 , Encefalomielitis Autoinmune Experimental , Interferón gamma , Esclerosis Múltiple , Enfermedades Neurodegenerativas , Animales , Humanos , Ratones , Astrocitos/metabolismo , Autoinmunidad , Antígeno B7-H1/metabolismo , Sistema Nervioso Central/patología , Encefalomielitis Autoinmune Experimental/patología , Inflamación/metabolismo , Interferón gamma/metabolismo , Ratones Endogámicos C57BL , Esclerosis Múltiple/patología , Enfermedades Neurodegenerativas/metabolismo , Receptor de Muerte Celular Programada 1/metabolismoRESUMEN
GAPDH, a heme chaperone, has been previously implicated in the incorporation of heme into iNOS and soluble guanylyl cyclase (sGC). Since sGC is critical for myoglobin (Mb) heme-maturation, we investigated the role of GAPDH in the maturation of this globin, as well as hemoglobins α, ß, and γ. Utilizing cell culture systems, we found that overexpression of wild-type GAPDH increased, whereas GAPDH mutants H53A and K227A decreased, the heme content of Mb and Hbα and Hbß. Overexpression of wild-type GAPDH fully recovered the heme-maturation inhibition observed with the GAPDH mutants. Partial rescue was observed by overexpression of sGCß1 but not by overexpression of a sGCΔß1 deletion mutant, which is unable to bind the sGCα1 subunit required to form the active sGCα1ß1 complex. Wild type and mutant GAPDH was found to be associated in a complex with each of the globins and Hsp90. GAPDH at endogenous levels was found to be associated with Mb in differentiating C2C12 myoblasts, and with Hbγ or Hbα in differentiating HiDEP-1 erythroid progenitor cells. Knockdown of GAPDH in C2C12 cells suppressed Mb heme-maturation. GAPDH knockdown in K562 erythroleukemia cells suppressed Hbα and Hbγ heme-maturation as well as Hb dimerization. Globin heme incorporation was not only dependent on elevated sGCα1ß1 heterodimer formation, but also influenced by iron provision and magnitude of expression of GAPDH, d-aminolevulinic acid, and FLVCR1b. Together, our data support an important role for GAPDH in the maturation of myoglobin and γ, ß, and α hemoglobins.
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Gliceraldehído-3-Fosfato Deshidrogenasas/metabolismo , Hemo/metabolismo , Hemoglobinas/metabolismo , Chaperonas Moleculares/metabolismo , Mioglobina/metabolismo , Gliceraldehído-3-Fosfato Deshidrogenasas/genética , Células HEK293 , Hemo/genética , Hemoglobinas/genética , Humanos , Células K562 , Chaperonas Moleculares/genética , Mutación Missense , Mioglobina/genética , Sarcoglicanos/genética , Sarcoglicanos/metabolismoRESUMEN
Longer glucan chains tend to precipitate. Glycogen, by far the largest mammalian glucan and the largest molecule in the cytosol with up to 55 000 glucoses, does not, due to a highly regularly branched spherical structure that allows it to be perfused with cytosol. Aberrant construction of glycogen leads it to precipitate, accumulate into polyglucosan bodies that resemble plant starch amylopectin and cause disease. This pathology, amylopectinosis, is caused by mutations in a series of single genes whose functions are under active study toward understanding the mechanisms of proper glycogen construction. Concurrently, we are characterizing the physicochemical particularities of glycogen and polyglucosans associated with each gene. These genes include GBE1, EPM2A and EPM2B, which respectively encode the glycogen branching enzyme, the glycogen phosphatase laforin and the laforin-interacting E3 ubiquitin ligase malin, for which an unequivocal function is not yet known. Mutations in GBE1 cause a motor neuron disease (adult polyglucosan body disease), and mutations in EPM2A or EPM2B a fatal progressive myoclonus epilepsy (Lafora disease). RBCK1 deficiency causes an amylopectinosis with fatal skeletal and cardiac myopathy (polyglucosan body myopathy 1, OMIM# 615895). RBCK1 is a component of the linear ubiquitin chain assembly complex, with unique functions including generating linear ubiquitin chains and ubiquitinating hydroxyl (versus canonical amine) residues, including of glycogen. In a mouse model we now show (i) that the amylopectinosis of RBCK1 deficiency, like in adult polyglucosan body disease and Lafora disease, affects the brain; (ii) that RBCK1 deficiency glycogen, like in adult polyglucosan body disease and Lafora disease, has overlong branches; (iii) that unlike adult polyglucosan body disease but like Lafora disease, RBCK1 deficiency glycogen is hyperphosphorylated; and finally (iv) that unlike laforin-deficient Lafora disease but like malin-deficient Lafora disease, RBCK1 deficiency's glycogen hyperphosphorylation is limited to precipitated polyglucosans. In summary, the fundamental glycogen pathology of RBCK1 deficiency recapitulates that of malin-deficient Lafora disease. Additionally, we uncover sex and genetic background effects in RBCK1 deficiency on organ- and brain-region specific amylopectinoses, and in the brain on consequent neuroinflammation and behavioural deficits. Finally, we exploit the portion of the basic glycogen pathology that is common to adult polyglucosan body disease, both forms of Lafora disease and RBCK1 deficiency, namely overlong branches, to show that a unified approach based on downregulating glycogen synthase, the enzyme that elongates glycogen branches, can rescue all four diseases.
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Enfermedad del Almacenamiento de Glucógeno Tipo IV , Enfermedad de Lafora , Ubiquitina-Proteína Ligasas , Animales , Regulación hacia Abajo , Glucanos/metabolismo , Glucógeno/metabolismo , Enfermedad del Almacenamiento de Glucógeno , Glucógeno Sintasa/genética , Glucógeno Sintasa/metabolismo , Enfermedad de Lafora/genética , Enfermedad de Lafora/patología , Ratones , Epilepsias Mioclónicas Progresivas , Enfermedades del Sistema Nervioso , Proteínas Tirosina Fosfatasas no Receptoras/genética , Ubiquitina/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoAsunto(s)
Oximetría , Oxígeno , Pigmentación de la Piel , Artefactos , Oximetría/normas , Oxígeno/análisis , Reproducibilidad de los Resultados , HumanosRESUMEN
INTRODUCTION: Adipokines are associated with several pathological states including, metabolic syndrome, obesity, insulin resistance and type 2 diabetes. One of these adipokines, adiponectin is of particular interest as it has been shown to have numerous anti-inflammatory effects, However, the association between adiponectin and blood pressure remains inconclusive especially in the Latino adolescent with obesity. PURPOSE: To investigate the relationship between plasma adiponectin and blood pressure in Latino adolescents' boys with obesity and a with a family history of Type 2 diabetes. METHODS: Thirty two Latino adolescent males with obesity aged 14-17 years with a family history of type 2 diabetes underwent a frequently sampled glucose tolerance test (FSIVGTT) to measure insulin sensitivity. Body composition was assessed using dual energy x-ray absorptiometry. Obesity was defined as having a BMI percentile ≥95. Blood pressure was assessed using the Dinamap automated blood pressure monitor, and the average of three readings was used in the analysis. Fasting plasma adiponectin was determined using radioimmunoassay. RESULTS: There were moderate positive significant correlations for adiponectin and Systolic blood pressure(SBP) (rho = 0.436, p < 0.027) and Diastolic blood pressure(DBP) (rho = 0.41,p < 0.028). A multivariate liner regression showed that plasma adiponectin could significantly detect 19% of the variance in SBP (p = 0.017, and 33% for DBP (p = 0.017). In a simple linear regression adiponectin was not related to any of our variables (p < 0.05). CONCLUSION: In conclusion, adiponectin was positively and significantly correlated to blood pressure in Latino adolescent with obesity. Future studies should investigate this relationship in a large sample of Latino adolescent youth.
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Adiponectina , Presión Sanguínea , Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Obesidad Infantil , Adolescente , Humanos , Masculino , Adipoquinas , Adiponectina/sangre , Índice de Masa Corporal , Hispánicos o LatinosRESUMEN
Since the initial description of intraneural (IN) perineurioma in 1964, advances in the understanding of the clinical presentation, diagnostic imaging, pathologic features, and genetic underpinnings have changed how this pathology is managed. IN perineuriomas are rare, benign peripheral nerve sheath tumors, most frequently coming to clinical attention when patients present with painless, progressive weakness or sensory loss in adolescence or young adulthood. The gold standard of diagnosis has traditionally been with targeted tissue biopsy demonstrating "pseudo-onion bulb" formation with positive epithelial membrane antigen (EMA) staining. However, modern magnetic resonance imaging is allowing some patients to forgo biopsy. Recent genetic studies of IN perineuriomas have demonstrated common TRAF7 point mutations and rare NF2 mutations, which may present targets for diagnosis or therapy in the future. Current advances have allowed for us to provide improved patient counseling with informed understanding for various clinical scenarios. With the workup and diagnosis now clearly defined, the next frontier is for improving the lives of patients with IN perineuriomas through the interaction between restoration of functional deficits and advances in our understanding of the genetics of this entity.
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Neoplasias de los Nervios Craneales , Neoplasias de la Vaina del Nervio , Neoplasias del Sistema Nervioso Periférico , Adolescente , Humanos , Adulto Joven , Adulto , Neoplasias de la Vaina del Nervio/diagnóstico , Neoplasias de la Vaina del Nervio/genética , Neoplasias de la Vaina del Nervio/cirugía , Neoplasias del Sistema Nervioso Periférico/diagnóstico por imagen , Neoplasias del Sistema Nervioso Periférico/genética , Imagen por Resonancia Magnética , Mucina-1RESUMEN
AIM AND OBJECTIVE: To explore the perceptions of nursing students regarding the treatment of men in nursing during their clinical placement. BACKGROUND: Negative placement experiences of men who are nursing students is a risk factor for student attrition. Hence, exploring gender disparity in treatment during placement from both men and women studying nursing will contribute to improving student experience and reducing attrition. DESIGN: Survey capturing both quantitative and qualitative data. METHODS: Nursing students were surveyed between July and September 2021 across 16 Schools of Nursing in Australia. In addition to the Clinical Learning Environment Inventory (CLEI-19), an open-ended question explored if men received different treatment during clinical placement. RESULTS: Those who expressed difference in treatment of men were less satisfied with their clinical learning experience (p < .001). Of the 486 (39.6%) who responded to the open-ended question, 152 (31%) indicated a difference in the treatment of men, reporting that men received: (a) better (39%); (b) different, not exclusively better or worse (19%); and (c) worse (42%) treatment from either the clinical facilitator or ward staff. While both men and women perceived gender differences in the treatment of men during placement, men were more likely to report worse treatment. CONCLUSION: Despite the advances achieved in recruiting men in nursing, negative experiences during clinical placement are characterised by stereotypes, prejudice and discrimination, adversely impact retention. RELEVANCE TO CLINICAL PRACTICE: Nurse educators need to recognise specific support students require during placement regardless of gender. Our findings reinforce the adverse impacts of inequitable treatment on both men and women nursing students on learning, clinical performance, morale and ultimately on retention in the nursing workforce. Addressing gender stereotyping and discrimination in the undergraduate nursing program is an important step in promoting diversity and inclusivity in the nursing workforce.
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Bachillerato en Enfermería , Estudiantes de Enfermería , Masculino , Humanos , Femenino , Estudios Transversales , Aprendizaje , Australia , Encuestas y CuestionariosRESUMEN
BACKGROUND: The endoplasmic reticulum senses alterations to cellular homeostasis that activates the unfolded protein response (UPR). UPR proteins are known to aid in regulating glucose and lipid metabolism. CREB3 is a UPR-associated transcription factor whose potential role in regulating energy metabolism remains unclear. METHODS: Eight-week-old wild-type (WT) and Creb3+/- mice were placed on control and high-fat diets (HFD) for 8 weeks, and metabolic phenotypes characterized by weekly weighing, indirect calorimetry, body composition scans, glucose tolerance tests, plasma analysis, tissue lipid quantifications and gene/protein expression analysis. RESULTS: HFD weight gain in Creb3+/- males was reduced by 34% (p < 0.0001) and females by 39.5% (p = 0.014) from their WT counterparts. No differences were found in HFD food intake or total fecal lipids between genotypes. Creb3+/- mice had increased energy expenditure and respiratory exchange ratios (p = 0.002) relative to WT. Creb3+/- mice had significant reductions in absolute fat and lean tissue, while Creb3+/- females had significant reductions in body fat% and increased lean% composition (p < 0.0001) compared to WT females. Creb3+/- mice were protected from HFD-induced basal hyperglycemia (males p < 0.0001; females p = 0.0181). Creb3+/- males resisted HFD-induced hepatic lipid accumulation (p = 0.025) and glucose intolerance compared to WT (p < 0.0001) while Creb3+/- females were protected from lipid accumulation in skeletal muscle (p = 0.001). Despite the metabolic differences of Creb3+/- mice on HFD, lipid plasma profiles did not significantly differ from WT. Fasted Creb3+/- mice additionally revealed upregulation of hepatic energy expenditure and gluconeogenic genes such as Pgc-1a and Gr (glucocorticoid receptor) (p < 0.05), respectively. CONCLUSIONS: Reduced expression of CREB3 increased energy expenditure and the respiratory exchange ratio, and protected mice from HFD-induced weight gain, basal hyperglycemia, and sex-specific tissue lipid accumulation. We postulate that CREB3 is a novel key regulator of diet-induced obesity and energy metabolism that warrants further investigation as a potential therapeutic target in metabolic disorders.
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Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Dieta Alta en Grasa , Metabolismo Energético , Obesidad , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Dieta Alta en Grasa/efectos adversos , Metabolismo Energético/genética , Femenino , Intolerancia a la Glucosa/genética , Metabolismo de los Lípidos , Lípidos , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/genética , Obesidad/metabolismo , Factores de Transcripción/metabolismo , Aumento de PesoRESUMEN
Despite the increasing numbers of women students in medical schools, focused attention on their perceptions about medical school and the medical profession remain underexamined. These perceptions are important to understand, particularly since women students are likely burdened with a host of gender norms related to work, family, and their future roles as physicians. Early experiences in medical school offer important insights into the larger student experience and are tied to academic outcomes and feelings of belonging. To examine early experiences of women medical students, this qualitative study used sensemaking theory to describe the current context and "story" of ideal worker norms. Critical qualitative interviews of 38 women students were performed during their first 2 months of medical school and explored both how the students perceived and experienced ideal worker norms, and how they made sense of the "story" of ideal worker norms. The participants described ways they encountered gendering and ideal worker norms through displays of nurturing behaviour, expectations to balance a future family, and whether they looked or acted the part of a doctor. This article highlights the challenges women medical students are already aware they will face, the opportunities they look forward to, and the strengths they anticipate leaning on to navigate their profession. Results from this study have implications for women medical students' learning experiences and transitions into medical school and for faculty, staff, and scholars concerned with challenging gendering norms that shape medical education.
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Educación Médica , Médicos , Estudiantes de Medicina , Femenino , Humanos , Investigación Cualitativa , Facultades de MedicinaRESUMEN
Livestock have contributed significantly to advances in biomedicine and offer unique advantages over rodent models. The human is the ideal biomedical model; however, ethical reasons limit the testing of hypotheses and treatments in humans. Rodent models are frequently used as alternatives to humans due to size, low cost, and ease of genetic manipulation, and have contributed tremendously to our understanding of human health and disease. However, the use of rodents in translational research pose challenges for researchers due to physiological differences to humans. The use of livestock species as biomedical models can address these challenges as livestock have several similarities to human anatomy, physiology, genetics, and metabolism and their larger size permits collection of more frequent and often larger samples. Additionally, recent advances in genetics in livestock species allow for studies in genomics, proteomics, and metabolomics, which have the added benefit of applications to both humans in biomedical research and livestock in improving production. In this review, we provide an overview of scientific findings using livestock and benefits of each model to the livestock industry and to biomedical research.
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Investigación Biomédica , Ganado , Animales , Genómica , Metabolómica , Investigación Biomédica TraslacionalRESUMEN
In this chapter, we describe the process of obtaining medical imaging data and its storage protocol. The authors also explain in a step-by-step approach how to extract and prepare the medical imaging data for machine learning algorithms. And finally, the process of building and assessing a convolutional neural network for medical imaging data is illustrated.
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Aprendizaje Automático , Redes Neurales de la Computación , Algoritmos , NeuroimagenRESUMEN
High-risk human papillomaviruses (HR-HPVs) promote cervical cancer as well as a subset of anogenital and head and neck cancers. Due to their limited coding capacity, HPVs hijack the host cell's DNA replication and repair machineries to replicate their own genomes. How this host-pathogen interaction contributes to genomic instability is unknown. Here, we report that HPV-infected cancer cells express high levels of RNF168, an E3 ubiquitin ligase that is critical for proper DNA repair following DNA double-strand breaks, and accumulate high numbers of 53BP1 nuclear bodies, a marker of genomic instability induced by replication stress. We describe a mechanism by which HPV E7 subverts the function of RNF168 at DNA double-strand breaks, providing a rationale for increased homology-directed recombination in E6/E7-expressing cervical cancer cells. By targeting a new regulatory domain of RNF168, E7 binds directly to the E3 ligase without affecting its enzymatic activity. As RNF168 knockdown impairs viral genome amplification in differentiated keratinocytes, we propose that E7 hijacks the E3 ligase to promote the viral replicative cycle. This study reveals a mechanism by which tumor viruses reshape the cellular response to DNA damage by manipulating RNF168-dependent ubiquitin signaling. Importantly, our findings reveal a pathway by which HPV may promote the genomic instability that drives oncogenesis.