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The Beatles en Colombia, el club de los 27 y Sinatra y la mafia: Bellón revela datos inéditos

El reconocido locutor y experto en música Pop compartió en 6AM algunas de las historias que reúne en su más reciente libro: ‘Conspiraciones, mitos y leyendas en la historia de la música’ en el que desentraña algunas de las leyendas y mitos que han acompañado al rock & roll




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The Beatles en Colombia, el club de los 27 y Sinatra y la mafia: Bellón revela datos inéditos del rock

El reconocido locutor y experto en música Pop compartió en 6AM algunas de las historias que reúne en su más reciente libro: ‘Conspiraciones, mitos y leyendas en la historia de la música’ en el que desentraña algunas de las leyendas y mitos que han acompañado al rock & roll




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The Beatles en Colombia, el club de los 27 y Sinatra y la mafia: Bellón revela datos inéditos del rock

El reconocido locutor y experto en música Pop compartió en 6AM algunas de las historias que reúne en su más reciente libro: ‘Conspiraciones, mitos y leyendas en la historia de la música’ en el que desentraña algunas de las leyendas y mitos que han acompañado al rock & roll




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Claim SatoshiDEX (SATX) Scam

What is the fake "Claim SatoshiDEX (SATX)" website?

"Claim SatoshiDEX (SATX)" is a scam that is almost a perfect visual copy of SatoshiDEX (satoshidex.ai). Upon inspection, we determined that this fake page (satoshidex-ai[.]org and potentially others) is a cryptocurrency drainer. The scheme lures users into exposing their digital wallets to steal the assets stored therein.




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Undercurrents: Episode 43 - The UK Election, and Svyatoslav Vakarchuk on the Future of Ukraine




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Theranostics for Meningioma on the Rise: New EANM/EANO/RANO/SNMMI Guidelines Pave the Way to Improved Patient Outcomes Using Radiolabeled Somatostatin Receptor Ligands




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Novel Proteomic Profiling of Epididymal Extracellular Vesicles in the Domestic Cat Reveals Proteins Related to Sequential Sperm Maturation with Differences Observed between Normospermic and Teratospermic Individuals

Tricia Rowlison
Dec 1, 2020; 19:2090-2103
Research




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Deletion of lysophosphatidylcholine acyltransferase3 in myeloid cells worsens hepatic steatosis after a high fat diet

Thibaut Bourgeois
Dec 11, 2020; 0:jlr.RA120000737v1-jlr.RA120000737
Research Articles




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Membrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice

Abudukadier Abulizi
Dec 1, 2020; 61:1565-1576
Research Articles




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Deletion of lysophosphatidylcholine acyltransferase3 in myeloid cells worsens hepatic steatosis after a high fat diet [Research Articles]

Recent studies have highlighted an important role for lysophosphatidylcholine acyltransferase 3 (LPCAT3) in controlling the PUFA composition of cell membranes in the liver and intestine. In these organs, LPCAT3 critically supports cell membrane-associated processes such as lipid absorption or lipoprotein secretion. However, the role of LPCAT3 in macrophages remains controversial. Here, we investigated LPCAT3’s role in macrophages both in vitro and in vivo in mice with atherosclerosis and obesity. To accomplish this, we used the LysMCre strategy to develop a mouse model with conditional Lpcat3 deficiency in myeloid cells (Lpcat3KOMac). We observed that partial Lpcat3 deficiency (approx. 75% reduction) in macrophages alters the PUFA composition of all phospholipid (PL) subclasses, including phosphatidylinositols and phosphatidylserines. A reduced incorporation of C20 PUFAs (mainly arachidonic acid [AA]) into PLs was associated with a redistribution of these FAs toward other cellular lipids such as cholesteryl esters. Lpcat3 deficiency had no obvious impact on macrophage inflammatory response or endoplasmic reticulum (ER) stress; however, Lpcat3KOMac macrophages exhibited a reduction in cholesterol efflux in vitro. In vivo, myeloid Lpcat3 deficiency did not affect atherosclerosis development in LDL receptor deficient mouse (Ldlr-/-) mice. Lpcat3KOMac mice on a high-fat diet displayed a mild increase in hepatic steatosis associated with alterations in several liver metabolic pathways and in liver eicosanoid composition. We conclude that alterations in AA metabolism along with myeloid Lpcat3 deficiency may secondarily affect AA homeostasis in the whole liver, leading to metabolic disorders and triglyceride accumulation.




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Membrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice [Research Articles]

Microsomal triglyceride transfer protein (MTTP) deficiency results in a syndrome of hypolipidemia and accelerated NAFLD. Animal models of decreased hepatic MTTP activity have revealed an unexplained dissociation between hepatic steatosis and hepatic insulin resistance. Here, we performed comprehensive metabolic phenotyping of liver-specific MTTP knockout (L-Mttp–/–) mice and age-weight matched wild-type control mice. Young (10–12-week-old) L-Mttp–/– mice exhibited hepatic steatosis and increased DAG content; however, the increase in hepatic DAG content was partitioned to the lipid droplet and was not increased in the plasma membrane. Young L-Mttp–/– mice also manifested normal hepatic insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamps, no PKC activation, and normal hepatic insulin signaling from the insulin receptor through AKT Ser/Thr kinase. In contrast, aged (10-month-old) L-Mttp–/– mice exhibited glucose intolerance and hepatic insulin resistance along with an increase in hepatic plasma membrane sn-1,2-DAG content and PKC activation. Treatment with a functionally liver-targeted mitochondrial uncoupler protected the aged L-Mttp–/– mice against the development of hepatic steatosis, increased plasma membrane sn-1,2-DAG content, PKC activation, and hepatic insulin resistance. Furthermore, increased hepatic insulin sensitivity in the aged controlled-release mitochondrial protonophore-treated L-Mttp–/– mice was not associated with any reductions in hepatic ceramide content. Taken together, these data demonstrate that differences in the intracellular compartmentation of sn-1,2-DAGs in the lipid droplet versus plasma membrane explains the dissociation of NAFLD/lipid-induced hepatic insulin resistance in young L-Mttp–/– mice as well as the development of lipid-induced hepatic insulin resistance in aged L-Mttp–/– mice.




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Novel Proteomic Profiling of Epididymal Extracellular Vesicles in the Domestic Cat Reveals Proteins Related to Sequential Sperm Maturation with Differences Observed between Normospermic and Teratospermic Individuals [Research]

Extracellular vesicles (EVs) secreted by the epididymal epithelium transfer to spermatozoa key proteins that are essential in promoting motility and subsequent fertilization success. Using the domestic cat model, the objectives were to (1) characterize and compare protein content of EVs between segments of the epididymis, and (2) compare EV protein compositions between normo- and teratospermic individuals (producing >60% of abnormal spermatozoa). Epididymal EVs from adult cats were isolated and assessed via liquid chromatography tandem MS. Both male types shared 3008 proteins in total, with 98 and 20 EV proteins unique to normospermic and teratospermic males, respectively. Expression levels of several proteins changed between epididymal segments in both male types. Several proteins in both groups were related to sperm motility (e.g. hexokinase 1, adenylate kinase isoenzyme) and zona pellucida or oolemma binding (e.g. disintegrin and metalloproteinase domain proteins, zona binding proteins 1 and 2). Interestingly, seven cauda-derived EV proteins trended downward in teratospermic compared with normospermic males, which may relate to poor sperm quality. Collective results revealed, for the first time, EV proteins related to sequential sperm maturation with differences observed between normospermic and teratospermic individuals.




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Dual Somatostatin Receptor/18F-FDG PET/CT Imaging in Patients with Well-Differentiated, Grade 2 and 3 Gastroenteropancreatic Neuroendocrine Tumors

Our purpose was to prospectively assess the distribution of NETPET scores in well-differentiated (WD) grade 2 and 3 gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) and to determine the impact of the NETPET score on clinical management. Methods: This single-arm, institutional ethics review board–approved prospective study included 40 patients with histologically proven WD GEP NETs. 68Ga-DOTATATE PET and 18F-FDG PET were performed within 21 d of each other. NETPET scores were evaluated qualitatively by 2 reviewers, with up to 10 marker lesions selected for each patient. The quantitative parameters that were evaluated included marker lesion SUVmax for each tracer; 18F-FDG/68Ga-DOTATATE SUVmax ratios; functional tumor volume (FTV) and metabolic tumor volume (MTV) on 68Ga-DOTATATE and 18F-FDG PET, respectively; and FTV/MTV ratios. The treatment plan before and after 18F-FDG PET was recorded. Results: There were 22 men and 18 women (mean age, 60.8 y) with grade 2 (n = 24) or grade 3 (n = 16) tumors and a mean Ki-67 index of 16.1%. NETPET scores of P0, P1, P2A, P2B, P3B, P4B, and P5 were documented in 2 (5%), 5 (12.5%), 5 (12.5%) 20 (50%), 2 (5%), 4 (10%), and 2 (5%) patients, respectively. No association was found between the SUVmax of target lesions on 68Ga-DOTATATE and the SUVmax of target lesions on 18F-FDG PET (P = 0.505). 18F-FDG/68Ga-DOTATATE SUVmax ratios were significantly lower for patients with low (P1–P2) primary NETPET scores than for those with high (P3–P5) primary NETPET scores (mean ± SD, 0.20 ± 0.13 and 1.68 ± 1.44, respectively; P < 0.001). MTV on 18F-FDG PET was significantly lower for low primary NETPET scores than for high ones (mean ± SD, 464 ± 601 cm3 and 66 ± 114 cm3, respectively; P = 0.005). A change in the type of management was observed in 42.5% of patients after 18F-FDG PET, with the most common being a change from systemic therapy to peptide receptor radionuclide therapy and from debulking surgery to systemic therapy. Conclusion: There was a heterogeneous distribution of NETPET scores in patients with WD grade 2 and 3 GEP NETs, with more than 1 in 5 patients having a high NETPET score and a frequent change in management after 18F-FDG PET. Quantitative parameters including 18F-FDG/68Ga-DOTATATE SUVmax ratios in target lesions and FTV/MTV ratios can discriminate between patients with high and low NETPET scores.




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Reimagining Biologically Adapted Somatostatin Receptor-Targeted Radionuclide Therapy: Perspectives Based on Personal Experience and Observations on Recent Trials




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Somatostatin: Linking Cognition and Alzheimer Disease to Therapeutic Targeting [Review Article]

Over 4 decades of research support the link between Alzheimer disease (AD) and somatostatin [somatotropin-releasing inhibitory factor (SRIF)]. SRIF and SRIF-expressing neurons play an essential role in brain function, modulating hippocampal activity and memory formation. Loss of SRIF and SRIF-expressing neurons in the brain rests at the center of a series of interdependent pathological events driven by amyloid-β peptide (Aβ), culminating in cognitive decline and dementia. The connection between the SRIF and AD further extends to the neuropsychiatric symptoms, seizure activity, and inflammation, whereas preclinical AD investigations show SRIF or SRIF receptor agonist administration capable of enhancing cognition. SRIF receptor subtype-4 activation in particular presents unique attributes, with the potential to mitigate learning and memory decline, reduce comorbid symptoms, and enhance enzymatic degradation of Aβ in the brain. Here, we review the links between SRIF and AD along with the therapeutic implications.

Significance Statement

Somatostatin and somatostatin-expressing neurons in the brain are extensively involved in cognition. Loss of somatostatin and somatostatin-expressing neurons in Alzheimer disease rests at the center of a series of interdependent pathological events contributing to cognitive decline and dementia. Targeting somatostatin-mediated processes has significant therapeutic potential for the treatment of Alzheimer disease.




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Stratosphere Casino, Hotel & Tower Wants You to "Take Vegas Back" and Receive Random Acts of Rewards - Stratosphere on mixologists

Stratosphere is taking Vegas back from the pricey and pretentious. From the casino to the top of the Tower, Stratosphere offers great fun and real values backed up by an unforgettable experience.




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Hunt for Bitcoin's elusive creator Satoshi Nakamoto hits another dead-end

Why are still no closer to unmasking the mysterious Satoshi Nakamoto?




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LeBron James Approaches Michael Jordan’s Stratosphere

LeBron James’s ever-growing playoff resume has raised a question once unthinkable: How much more would he have to do to surpass Michael Jordan?




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3-Thio-3,4,5-Trisubstituted-1,2,4-Triazoles: High Affinity Somatostatin Receptor-4 Agonist Synthesis and Structure-Activity Relationships

RSC Med. Chem., 2024, Accepted Manuscript
DOI: 10.1039/D4MD00597J, Research Article
Albert Michael Crider, Audrey Hospital, Karin Sandoval, William Neumann, Stephen Kukielski, Lejla Garic, Kristen Ingold, Matthew Dunahoo, Khush Srabony, Rafael Frare, Olivia Slater, Nathan Peel, Maria Kontoyianni, Ken Witt
Somatostatin receptor-4 (SST4) is a therapeutic target for several conditions, including Alzheimer’s disease, seizures, neuropsychiatric disorders, and pain. Our previous work on 1,2,4-triazole derivatives led to enhanced SST4 binding affinity,...
The content of this RSS Feed (c) The Royal Society of Chemistry




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Martinů's subliminal states: a study of the composer's writings and reception, with a translation of his American diaries / Thomas D. Svatos

Lewis Library - ML410.M382 A3 2018




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Dr. Elsie I. Pares-Matos Celebrated for Dedication to the Field of Chemistry Education

Dr. Pares-Matos parlays decades of academic experience into her role with the University of Puerto Rico at Mayaguez




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Southern California's Premier FBO Partners with StratosShare Vehicles

Now Offering the Toyota Mirai, Zero-Emission, Hydrogen Fuel Cell Electric Vehicles




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You Say Tomato, I Say Tomatosphere: Investigation Brings Space Station Science to the Classroom

Stewed, canned or on the vine, there are lots of ways to buy tomatoes- but have you ever seen "flown in space" on a supermarket sticker?




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John Varvatos files for relief under Chapter 11




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El nuevo registro de datos de pacientes con COVID-19 proporcionará perspectivas sobre la atención y los resultados cardiovasculares adversos

DALLAS, 3 de abril del 2020 – Debido al esfuerzo de médicos, científicos e investigadores de todo el mundo por comprender la pandemia del coronavirus (COVID-19), la American Heart Association está desarrollando un nuevo registro para agregar datos y...




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Somatostatin analogues

The invention provides cyclo[{4-(NH2—C2H4—NH—CO—O—)Pro}-Phg-DTrp-Lys-Tyr(4-Benzyl)-Phe], optionally in protected form, or a pharmaceutically acceptable salt or complex thereof, which has interesting pharmaceutical properties.




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Apparatus and method of simulating a somatosensory experience in space

A method of providing a user with an extra-terrestrial somatosensory experience includes equipping the user with an underwater breathing apparatus, having the user occupy an underwater environment, such environment providing buoyancy to the user, and while the user occupies the underwater environment, using a computer-implemented virtual reality system to present to the user a virtual reality environment modeling an extra-terrestrial setting. The virtual reality system inhibits visual perception by the user of items outside of the virtual reality environment so that the user experiences the virtual reality environment under a buoyancy condition provided by the underwater environment. The buoyancy condition enhances the experience of the virtual reality environment.




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Stratosphere tethered photovoltaic power platform

The present invention is realized by apparatus and methods for placing a large utility scale photovoltaic array in the low stratosphere of earth's atmosphere at an altitude of about 20 km, above clouds, moisture, dust, and wind. This is accomplished using a large light-weight, rigid, buoyant structure to support the large photovoltaic array. Long, strong and light tethers connect the buoyant structure to the ground and hold it in position against wind forces. The electricity output from the photovoltaic array is then coupled to high voltage transmission lines which connect from the platform to the earth's surface. The electricity is then transmitted through the high voltage transmission lines to the earth's surface where it is connected to the electrical supply grid and provides lower cost, more reliable electricity.




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Stratosphere tethered platform for multiple uses

The present invention is realized by apparatus and methods for placing a large rigid buoyant platform in the low stratosphere of earth's atmosphere at an altitude of about 20 km, above clouds, moisture, dust, and wind. The platform can serve several uses, either individually or in any combination. These uses include uninterrupted radio and light communications, radar and optical observation including very powerful radars and solar power electricity generation. Long, strong and light tethers connect the buoyant structure to the ground which hold it in position against wind forces. The electricity output from a photovoltaic array is used to power platform uses and can also be coupled to high voltage transmission lines which transmit power from the platform to the earth's surface during daylight hours. Power can also be transmitted up to the platform during darkness to power facilities mounted on the platform ensuring continuous operation.





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Presenta IBM nueva generación de almacenamiento Flash para acelerar la analítica de grandes volúmenes de datos

IBM anunció dos nuevas soluciones de almacenamiento empresarial completamente basadas en tecnología flash, las cuales ofrecen avanzada eficiencia e incremento en desempeño, así como una sobresaliente confiabilidad para ayudar a reducir costos, y acelerar infraestructuras y aplicaciones con manejo intensivo de datos.




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IBM lidera Cuadrante Mágico de Gartner en software de recuperación y respaldo de centro de datos

IBM fue reconocido como líder de software de almacenamiento en el Cuadrante Mágico de Gartner para Software de Recuperación y Respaldo en Centro de Datos1. En sus “cuadrantes mágicos”, los analistas de Gartner evalúan tecnología y soluciones con la “capacidad de ejecución” y una “visión completa”.




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IBM X-Force revela récord histórico de datos filtrados y vulnerabilidades en 2016

IBM Security dio a conocer los resultados de su informe 2017 IBM X-Force Threat Intelligence Index, cuyas conclusiones revelan que el número de registros comprometidos se ha incrementado un 566% en 2016, pasando de 600 millones a más de 4.000 millones. Estas filtraciones incluyen datos en los que los ciberdelincuentes tradicionalmente han puesto foco como tarjetas de crédito, contraseñas e información personal médica; sin embargo se hace notar un cambio en las estrategias de los ciberdelincuentes. En 2016, numerosas brechas de seguridad estaban relacionadas con datos no estructurados como archivos de email, documentos empresariales, de propiedad intelectual y códigos fuente.




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¿Cuánto le cuesta a una compañía una violación de datos?

IBM Security anunció los resultados de un estudio global que explora las implicaciones y los efectos de las brechas de datos en los negocios. Patrocinado por IBM Security y realizado por Ponemon Institute, el estudio encontró que el costo promedio de una violación de datos es de $3,62 millones de dólares a nivel mundial, una disminución del 10 por ciento a partir de los resultados de 2016. Esta es la primera vez, desde la creación del estudio, en que ha habido una disminución general en el costo. Según el reporte, estas brechas de datos cuestan a las compañías en promedio $141 dólares por registro perdido o robado.




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IBM X-Force descubre que el número de datos filtrados se redujo en 2017 mientras cibercriminales se enfocaban en el ransomware

IBM Security anunció hoy los resultados de su informe 2018 IBM X-Force Threat Intelligence Index, en donde se muestra que la cantidad de registros infringidos cayó casi un 25% en 2017 a medida que los cibercriminales cambiaron el enfoque en el lanzamiento de ransomware y ataques destructivos que buscaban retener o destruir información a menos que la víctima pagara algún rescate.




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IBM Security: Los costos ocultos de las brechas de datos aumentan los gastos para las empresas

IBM Security anunció hoy los resultados de un estudio global que examina el impacto financiero de una violación de datos en los resultados de una empresa. El estudio descubrió que los costos ocultos en las brechas de datos, como la pérdida de negocios, el impacto negativo en la reputación y el tiempo empleado en la recuperación, son difíciles y costosos de administrar. Por ejemplo, encontró que un tercio del costo de las mega infracciones (más de 1 millón de registros perdidos) se derivan del negocio perdido.




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Impulsa IBM ejes de cambio para la transformación de las empresas: datos, interacción y nube

Las estrategias de negocio con las que organizaciones líderes están transformando su negocio para obtener mayores eficiencias se basan en tecnologías para mejorar el manejo de la información, la interacción con clientes y modelos de negocio en la nube. Estas tecnologías son impulsadas por IBM, reconociendo las necesidades de las compañías mexicanas.




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Fila para UTI e falta de testes: os relatos do colapso na saúde que leva o Rio a planejar lockdown

Profissionais de enfermagem relatam falta de equipamentos de proteção, baixas nas equipes e lotação; em ofício, governador Witzel reconhece que esforços contra a covid-19 não foram suficientes e que estuda endurecer confinamento.




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Undercurrents: Episode 43 - The UK Election, and Svyatoslav Vakarchuk on the Future of Ukraine




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64Cu-DOTATATE PET/CT for Imaging Patients with Known or Suspected Somatostatin Receptor-Positive Neuroendocrine Tumors: Results of the First US Prospective, Reader-Blinded Clinical Trial

Studies demonstrate that the investigational 64Cu-DOTATATE radiopharmaceutical may provide diagnostic and logistical benefits over available imaging agents for patients with somatostatin receptor (SSTR)-positive neuroendocrine tumors (NETs). Accordingly, we aimed to prospectively determine the lowest dose of 64Cu-DOTATATE that facilitates diagnostic quality scans and evaluated the diagnostic performance and safety in a phase III study of patients with SSTR-expressing NETs. Methods: A dose-ranging study was conducted in 12 patients divided into 3 dose groups (111 MBq [3.0 mCi], 148 MBq [4.0 mCi], and 185 MBq [5.0 mCi] ± 10%) to determine the lowest dose of 64Cu-DOTATATE that produced diagnostic quality PET/CT images. Using the 64Cu-DOTATATE dose identified in the dose-ranging study, 3 independent nuclear medicine physicians who were blinded to all clinical information read PET/CT scans from 21 healthy volunteers and 42 NET-positive patients to determine those with "Disease" and "No Disease," as well as "Localized" versus "Metastatic" status. Blinded-reader evaluations were compared to a patient-specific standard of truth (SOT), which was established by an independent oncologist who used all previously available pathology, clinical, and conventional imaging data. Diagnostic performance calculated for 64Cu-DOTATATE included sensitivity, specificity, negative predictive value, positive predictive value, and accuracy. Inter- and intra-reader reliability, as well as ability to differentiate between localized and metastatic disease, was also determined. Adverse events (AEs) were recorded from 64Cu-DOTATATE injection through 48 hours post-injection. Results: The dose-ranging study identified 148 MBq (4.0 mCi) as the optimal dose to obtain diagnostic quality PET/CT images. Following database lock, diagnostic performance from an initial majority read of the 3 independent readers showed a significant 90.9% sensitivity (P = 0.0042) and 96.6% specificity (P < 0.0001) for detecting NETs, which translated to a 100.0% sensitivity and 96.8% specificity after correcting for an initial SOT misread. Excellent inter- and intra-reader reliability, as well as ability to distinguish between localized and metastatic disease, was also noted. No AEs were related to 64Cu-DOTATATE, and no serious AEs were observed. Conclusion: 64Cu-DOTATATE PET/CT is a safe imaging technique that provides high-quality and accurate images at a dose of 148 MBq (4.0 mCi) for the detection of somatostatin-expressing NETs.




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Erratum: FTY720/fingolimod decreases hepatic steatosis and expression of fatty acid synthase in diet-induced nonalcoholic fatty liver disease in mice [Errata]




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Glucagon Resistance at the Level of Amino Acid Turnover in Obese Subjects with Hepatic Steatosis

Glucagon secretion is regulated by circulating glucose, but it has turned out that amino acids also play an important role, and that hepatic amino acid metabolism and glucagon are linked in a mutual feed-back cycle, the liver-alpha cell axis. On this background, we hypothesized that hepatic steatosis might impair glucagon’s action on hepatic amino acid metabolism and lead to hyperaminoacidemia and hyperglucagonemia.

We subjected 15 healthy lean and 15 obese steatotic male participants to a pancreatic clamp with somatostatin and evaluated hepatic glucose and amino acid metabolism during basal and high physiological levels of glucagon. The degree of steatosis was evaluated from liver biopsies.

Total RNA sequencing of liver biopsies revealed perturbations in the expression of genes predominantly involved in amino acid metabolism in the obese steatotic individuals. This group was also characterized by fasting hyperglucagonemia, hyperaminoacidemia and an absent lowering of amino acid levels in response to high levels of glucagon. Endogenous glucose production was similar between lean and obese individuals.

Our results suggest that hepatic steatosis causes resistance to the effect of glucagon on amino acid metabolism resulting in increased amino acid concentrations as well as increased glucagon secretion providing a likely explanation of fatty liver-associated hyperglucagonemia.




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Repurposing Doxepin to Ameliorate Steatosis and Hyperglycemia by Activating FAM3A Signaling Pathway

Mitochondrial protein FAM3A suppresses hepatic gluconeogenesis and lipogenesis. This study aimed to screen drug(s) that activates FAM3A expression and evaluate its effect(s) on hyperglycemia and steatosis. Drug-repurposing methodology predicted that antidepressive drug doxepin was among the drugs that potentially activated FAM3A expression. Doxepin was further validated to stimulate the translocation of transcription factor HNF4α from the cytoplasm into the nucleus, where it promoted FAM3A transcription to enhance ATP synthesis, suppress gluconeogenesis, and reduce lipid deposition in hepatocytes. HNF4α antagonism or FAM3A deficiency blunted doxepin-induced suppression on gluconeogenesis and lipid deposition in hepatocytes. Doxepin administration attenuated hyperglycemia, steatosis, and obesity in obese diabetic mice with upregulated FAM3A expression in liver and brown adipose tissues (BAT). Notably, doxepin failed to correct dysregulated glucose and lipid metabolism in FAM3A-deficient mice fed on high-fat diet. Doxepin’s effects on ATP production, Akt activation, gluconeogenesis, and lipogenesis repression were also blunted in FAM3A-deficient mouse livers. In conclusion, FAM3A is a therapeutic target for diabetes and steatosis. Antidepressive drug doxepin activates FAM3A signaling pathways in liver and BAT to improve hyperglycemia and steatosis of obese diabetic mice. Doxepin might be preferentially recommended as an antidepressive drug in potential treatment of patients with diabetes complicated with depression.




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Epigenetic Regulation of Hepatic Lipogenesis: Role in Hepatosteatosis and Diabetes

Hepatosteatosis, which is frequently associated with development of metabolic syndrome and insulin resistance, manifests when triglyceride (TG) input in the liver is greater than TG output, resulting in the excess accumulation of TG. Dysregulation of lipogenesis therefore has the potential to increase lipid accumulation in the liver, leading to insulin resistance and type 2 diabetes. Recently, efforts have been made to examine the epigenetic regulation of metabolism by histone-modifying enzymes that alter chromatin accessibility for activation or repression of transcription. For regulation of lipogenic gene transcription, various known lipogenic transcription factors, such as USF1, ChREBP, and LXR, interact with and recruit specific histone modifiers, directing specificity toward lipogenesis. Alteration or impairment of the functions of these histone modifiers can lead to dysregulation of lipogenesis and thus hepatosteatosis leading to insulin resistance and type 2 diabetes.




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Exercise Combats Hepatic Steatosis: Potential Mechanisms and Clinical Implications

Hepatic steatosis, the excess storage of intrahepatic lipids, is a rampant clinical problem associated with the obesity epidemic. Hepatic steatosis is linked to increased risk for insulin resistance, type 2 diabetes, and cardiovascular and advanced liver disease. Accumulating evidence shows that physical activity, exercise, and aerobic capacity have profound effects on regulating intrahepatic lipids and mediating susceptibility for hepatic steatosis. Moreover, exercise can effectively reduce hepatic steatosis independent of changes in body mass. In this perspective, we highlight 1) the relationship between obesity and metabolic pathways putatively driving hepatic steatosis compared with changes induced by exercise; 2) the impact of physical activity, exercise, and aerobic capacity compared with caloric restriction on regulating intrahepatic lipids and steatosis risk; 3) the effects of exercise training (modalities, volume, intensity) for treatment of hepatic steatosis, and 4) evidence for a sustained protection against steatosis induced by exercise. Overall, evidence clearly indicates that exercise powerfully regulates intrahepatic storage of fat and risk for steatosis.




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Myeloid HMG-CoA Reductase Determines Adipose Tissue Inflammation, Insulin Resistance, and Hepatic Steatosis in Diet-Induced Obese Mice

Adipose tissue macrophages (ATMs) are involved in the development of insulin resistance in obesity. We have recently shown that myeloid cell–specific reduction of HMG-CoA reductase (Hmgcrm–/m–), which is the rate-limiting enzyme in cholesterol biosynthesis, protects against atherosclerosis by inhibiting macrophage migration in mice. We hypothesized that ATMs are harder to accumulate in Hmgcrm–/m– mice than in control Hmgcrfl/fl mice in the setting of obesity. To test this hypothesis, we fed Hmgcrm–/m– and Hmgcrfl/fl mice a high-fat diet (HFD) for 24 weeks and compared plasma glucose metabolism as well as insulin signaling and histology between the two groups. Myeloid cell–specific reduction of Hmgcr improved glucose tolerance and insulin sensitivity without altering body weight in the HFD-induced obese mice. The improvement was due to a decrease in the number of ATMs. The ATMs were reduced by decreased recruitment of macrophages as a result of their impaired chemotactic activity. These changes were associated with decreased expression of proinflammatory cytokines in adipose tissues. Myeloid cell–specific reduction of Hmgcr also attenuated hepatic steatosis. In conclusion, reducing myeloid HMGCR may be a promising strategy to improve insulin resistance and hepatic steatosis in obesity.




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Somatostatin-Expressing Interneurons in the Auditory Cortex Mediate Sustained Suppression by Spectral Surround

Sensory systems integrate multiple stimulus features to generate coherent percepts. Spectral surround suppression, the phenomenon by which sound-evoked responses of auditory neurons are suppressed by stimuli outside their receptive field, is an example of this integration taking place in the auditory system. While this form of global integration is commonly observed in auditory cortical neurons, and potentially used by the nervous system to separate signals from noise, the mechanisms that underlie this suppression of activity are not well understood. We evaluated the contributions to spectral surround suppression of the two most common inhibitory cell types in the cortex, parvalbumin-expressing (PV+) and somatostatin-expressing (SOM+) interneurons, in mice of both sexes. We found that inactivating SOM+ cells, but not PV+ cells, significantly reduces sustained spectral surround suppression in excitatory cells, indicating a dominant causal role for SOM+ cells in the integration of information across multiple frequencies. The similarity of these results to those from other sensory cortices provides evidence of common mechanisms across the cerebral cortex for generating global percepts from separate features.

SIGNIFICANCE STATEMENT To generate coherent percepts, sensory systems integrate simultaneously occurring features of a stimulus, yet the mechanisms by which this integration occurs are not fully understood. Our results show that neurochemically distinct neuronal subtypes in the primary auditory cortex have different contributions to the integration of different frequency components of an acoustic stimulus. Together with findings from other sensory cortices, our results provide evidence of a common mechanism for cortical computations used for global integration of stimulus features.




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Neurofibromatosis Type 1 and Autism Spectrum Disorder

NF1 is the commonest single-gene neurodevelopmental disorder with known neurobiology and developmental impact on attention and cognition. Its impact on social functioning is described but poorly understood, with no population-based study of autism spectrum disorder (ASD) prevalence in the disorder.

This epidemiological study shows high prevalence of 25% ASD in NF1 not explained by learning difficulties. ASD should be considered during clinical practice with NF1. Further research into NF1 as a single-gene model of ASD is warranted. (Read the full article)




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Outcomes in Hospitalized Pediatric Patients With Systemic Lupus Erythematosus

Systematic health disparities in adults with systemic lupus erythematosus are well documented and are likely driven by biologic as well as modifiable factors. Sociodemographic factors and health care delivery characteristics have been associated with poor outcomes.

In hospitalized children with systemic lupus erythematosus, race and ethnicity were associated with increased risk for ICU admissions, end-stage renal disease, and death. Identification of sociodemographic factors associated with outcomes is important to address the needs of these vulnerable patients. (Read the full article)




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Cuatro retratos de los redimidos agradecidos

La enseñanza bíblica en profundidad de John MacArthur lleva la verdad transformadora de la Palabra de Dios a millones de personas cada día.