Skeletal muscle Akt activity stimulates muscle growth and imparts resistance to obesity, glucose intolerance and fatty liver disease. We recently found that ursolic acid increases skeletal muscle Akt ...activity and stimulates muscle growth in non-obese mice. Here, we tested the hypothesis that ursolic acid might increase skeletal muscle Akt activity in a mouse model of diet-induced obesity. We studied mice that consumed a high fat diet lacking or containing ursolic acid. In skeletal muscle, ursolic acid increased Akt activity, as well as downstream mRNAs that promote glucose utilization (hexokinase-II), blood vessel recruitment (Vegfa) and autocrine/paracrine IGF-I signaling (Igf1). As a result, ursolic acid increased skeletal muscle mass, fast and slow muscle fiber size, grip strength and exercise capacity. Interestingly, ursolic acid also increased brown fat, a tissue that shares developmental origins with skeletal muscle. Consistent with increased skeletal muscle and brown fat, ursolic acid increased energy expenditure, leading to reduced obesity, improved glucose tolerance and decreased hepatic steatosis. These data support a model in which ursolic acid reduces obesity, glucose intolerance and fatty liver disease by increasing skeletal muscle and brown fat, and suggest ursolic acid as a potential therapeutic approach for obesity and obesity-related illness.
Tree crown economics McNeil, Brenden E; Fahey, Robert T; King, Christopher J ...
Frontiers in ecology and the environment,
February 2023, Letnik:
21, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Trees respond to global change in myriad ways, many of which may be linked to adaptations relating to tree crown architecture. However, there is a paucity of theory capable of predicting the adaptive ...importance and dynamics of crown architecture, most likely because of the difficulties involved in measuring the three‐dimensional arrangement and orientation of tree leaves within individual crowns. Here, we describe a theory of tree crown economics, and use measurements from new lidar (light detection and ranging) instruments, UAVs (unoccupied aerial vehicles), and time‐lapse camera imagery to identify support for two predictions of the theory, that (1) a light competition versus water use economic trade‐off drives covariance among three tree crown functional traits (mean leaf angle, crown density, and crown rugosity), and (2) crown traits can drive spatial and temporal variability in near‐infrared spectral reflectance and related ecosystem functions. Tree crown economic theory can complement leaf economic theory in helping ecologists map and model forest ecosystem responses to global change.
As a malignant tumour of lymphatic origin, B-cell lymphoma represents a significant challenge for drug delivery, where effective therapies must access malignant cells in the blood, organs and ...lymphatics while avoiding off-target toxicity. Subcutaneous (SC) administration of nanomedicines allows preferential access to both the lymphatic and blood systems and may therefore provide a route to enhanced drug exposure to lymphomas.
Here we examine the impact of SC dosing on lymphatic exposure, pharmacokinetics (PK), and efficacy of AZD0466, a small molecule dual Bcl-2/Bcl-xL inhibitor conjugated to a ‘DEP®’ G5 poly-l-lysine dendrimer.
PK studies reveal that the plasma half-life of the dendrimer-drug conjugate is 8-times longer than that of drug alone, providing evidence of slow release from the circulating dendrimer nanocarrier. The SC dosed construct also shows preferential lymphatic transport, with over 50% of the bioavailable dose recovered in thoracic lymph. Increases in dose (up to 400 mg/kg) are well tolerated after SC administration and studies in a model of disseminated lymphoma in mice show that high dose SC treatment outperforms IV administration using doses that lead to similar total plasma exposure (lower peak concentrations but extended exposure after SC).
These data show that the DEP® dendrimer can act as a circulating drug depot accessing both the lymphatic and blood circulatory systems. SC administration improves lymphatic exposure and facilitates higher dose administration due to improved tolerability. Higher dose SC administration also results in improved efficacy, suggesting that drug delivery systems that access both plasma and lymph hold significant potential for the treatment of haematological cancers where lymphatic and extranodal dissemination are poor prognostic factors.
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•AZD0466: a G5 polylysine dendrimer conjugate, acts as a circulating reservoir for the dual Bcl-2/Bcl-xL inhibitor AZD4230.•Subcutaneous administration of AZD0466 improves lymphatic exposure and allows higher doses due to improved tolerability.•Drug delivery systems that access both blood and lymph are a promising strategy to better treat lymph resident diseases.
Coordinated care is a defining principle of primary care, but it is becoming increasingly difficult to provide as the health care delivery system in the United States becomes more complex. To guide ...recommendations for research and practice, the evidence about implementation of coordinated care and its benefits must be considered. On the basis of review of the published literature this article makes recommendations concerning needs for a better-developed evidence base to substantiate the value of care coordination, generalist practices to be the hub of care coordination for most patients, improved communication among clinicians, a team approach to achieve coordination, integration of patients and families as partners, and incorporation of medical informatics. Although coordination of care is central to generalist practice, it requires far more effort than physicians alone can deliver. To make policy recommendations, further work is needed to identify essential elements of care coordination and prove its effectiveness at improving health outcomes.
The COVID-19 pandemic has severely disrupted US educational institutions. Given potential adverse financial and psychosocial effects of campus closures, many institutions developed strategies to ...reopen campuses in the fall 2020 semester despite the ongoing threat of COVID-19. However, many institutions opted to have limited campus reopening to minimize potential risk of spread of SARS-CoV-2.
To analyze how Boston University (BU) fully reopened its campus in the fall of 2020 and controlled COVID-19 transmission despite worsening transmission in Boston, Massachusetts.
This multifaceted intervention case series was conducted at a large urban university campus in Boston, Massachusetts, during the fall 2020 semester. The BU response included a high-throughput SARS-CoV-2 polymerase chain reaction testing facility with capacity to deliver results in less than 24 hours; routine asymptomatic screening for COVID-19; daily health attestations; adherence monitoring and feedback; robust contact tracing, quarantine, and isolation in on-campus facilities; face mask use; enhanced hand hygiene; social distancing recommendations; dedensification of classrooms and public places; and enhancement of all building air systems. Data were analyzed from December 20, 2020, to January 31, 2021.
SARS-CoV-2 diagnosis confirmed by reverse transcription-polymerase chain reaction of anterior nares specimens and sources of transmission, as determined through contact tracing.
Between August and December 2020, BU conducted more than 500 000 COVID-19 tests and identified 719 individuals with COVID-19, including 496 students (69.0%), 11 faculty (1.5%), and 212 staff (29.5%). Overall, 718 individuals, or 1.8% of the BU community, had test results positive for SARS-CoV-2. Of 837 close contacts traced, 86 individuals (10.3%) had test results positive for COVID-19. BU contact tracers identified a source of transmission for 370 individuals (51.5%), with 206 individuals (55.7%) identifying a non-BU source. Among 5 faculty and 84 staff with SARS-CoV-2 with a known source of infection, most reported a transmission source outside of BU (all 5 faculty members 100% and 67 staff members 79.8%). A BU source was identified by 108 of 183 undergraduate students with SARS-CoV-2 (59.0%) and 39 of 98 graduate students with SARS-CoV-2 (39.8%); notably, no transmission was traced to a classroom setting.
In this case series of COVID-19 transmission, BU used a coordinated strategy of testing, contact tracing, isolation, and quarantine, with robust management and oversight, to control COVID-19 transmission in an urban university setting.
Abstract
Corn is the most widely grown crop in the Americas, with annual production in the United States of approximately 332 million metric tons. Improved climate forecasts, together with ...climate-related decision tools for corn producers based on these improved forecasts, could substantially reduce uncertainty and increase profitability for corn producers. The purpose of this paper is to acquaint climate information developers, climate information users, and climate researchers with an overview of weather conditions throughout the year that affect corn production as well as forecast content and timing needed by producers. The authors provide a graphic depicting the climate-informed decision cycle, which they call the climate forecast–decision cycle calendar for corn.
The pharmacokinetics, metabolism, and excretion of sitagliptin MK-0431; (2R)-4-oxo-4-3-(trifluoromethyl)-5,6-dihydro1,2,4triazolo4,3-apyrazin-7(8H)-yl-1-(2,4,5-trifluorophenyl)butan-2-amine, a potent ...dipeptidyl peptidase 4 inhibitor, were evaluated in male Sprague-Dawley rats and beagle dogs. The plasma clearance and volume of distribution of sitagliptin were higher in rats (40-48 ml/min/kg, 7-9 l/kg) than in dogs ( approximately 9 ml/min/kg, approximately 3 l/kg), and its half-life was shorter in rats, approximately 2 h compared with approximately 4 h in dogs. Sitagliptin was absorbed rapidly after oral administration of a solution of the phosphate salt. The absolute oral bioavailability was high, and the pharmacokinetics were fairly dose-proportional. After administration of (14)Csitagliptin, parent drug was the major radioactive component in rat and dog plasma, urine, bile, and feces. Sitagliptin was eliminated primarily by renal excretion of parent drug; biliary excretion was an important pathway in rats, whereas metabolism was minimal in both species in vitro and in vivo. Approximately 10 to 16% of the radiolabeled dose was recovered in the rat and dog excreta as phase I and II metabolites, which were formed by N-sulfation, N-carbamoyl glucuronidation, hydroxylation of the triazolopiperazine ring, and oxidative desaturation of the piperazine ring followed by cyclization via the primary amine. The renal clearance of unbound drug in rats, 32 to 39 ml/min/kg, far exceeded the glomerular filtration rate, indicative of active renal elimination of parent drug.
We have previously shown that the thromboxane (TXA2) receptor agonist, U46619, can directly induce ventricular arrhythmias that were associated with increases in intracellular calcium in ...cardiomyocytes. Since TXA2 is an inflammatory mediator and induces direct calcium changes in cardiomyocytes, we hypothesized that TXA2 released during ischemia or inflammation could also cause cardiac remodeling.
U46619 (0.1-10 μM) was applied to isolated adult mouse ventricular primary cardiomyocytes, mouse ventricular cardiac muscle strips, and cultured HL-1 cardiomyocytes and markers of hypertrophy and cell death were measured.
We found that TXA2 receptors were expressed in ventricular cardiomyocytes and were functional via calcium imaging. U46619 treatment for 24 h did not increase expression of pathological hypertrophy genes (atrial natriuretic peptide, β-myosin heavy chain, skeletal muscle α-actin) and it did not increase protein synthesis. There was also no increase in cardiomyocyte size after 48 h treatment with U46619 as measured by flow cytometry. However, U46619 (0.1-10 μM) caused a concentration-dependent increase in cardiomyocyte death (trypan blue, MTT assays, visual cell counts and TUNEL stain) after 24 h. Treatment of cells with the TXA2 receptor antagonist SQ29548 and inhibitors of the IP3 pathway, gentamicin and 2-APB, eliminated the increase in cell death induced by U46619.
Our data suggests that TXA2 does not induce cardiac hypertrophy, but does induce cell death that is mediated in part by IP3 signaling pathways. These findings may provide important therapeutic targets for inflammatory-induced cardiac apoptosis that can lead to heart failure.
ABSTRACT
Introduction
Personnel engaged in high-stakes occupations, such as military personnel, law enforcement, and emergency first responders, must sustain performance through a range of ...environmental stressors. To maximize the effectiveness of military personnel, an a priori understanding of traits can help predict their physical and cognitive performance under stress and adversity. This work developed and assessed a suite of measures that have the potential to predict performance during operational scenarios. These measures were designed to characterize four specific trait–based domains: cognitive, health, physical, and social-emotional.
Materials and Methods
One hundred and ninety-one active duty U.S. Army soldiers completed interleaved questionnaire–based, seated task–based, and physical task–based measures over a period of 3-5 days. Redundancy analysis, dimensionality reduction, and network analyses revealed several patterns of interest.
Results
First, unique variable analysis revealed a minimally redundant battery of instruments. Second, principal component analysis showed that metrics tended to cluster together in three to five components within each domain. Finally, analyses of cross-domain associations using network analysis illustrated that cognitive, health, physical, and social-emotional domains showed strong construct solidarity.
Conclusions
The present battery of metrics presents a fieldable toolkit that may be used to predict operational performance that can be clustered into separate components or used independently. It will aid predictive algorithm development aimed to identify critical predictors of individual military personnel and small-unit performance outcomes.
As a malignant tumour of lymphatic origin, B-cell lymphoma represents a significant challenge for drug delivery, where effective therapies must access malignant cells in the blood, organs and ...lymphatics while avoiding off-target toxicity. Subcutaneous (SC) administration of nanomedicines allows preferential access to both the lymphatic and blood systems and may therefore provide a route to enhanced drug exposure to lymphomas. Here we examine the impact of SC dosing on lymphatic exposure, pharmacokinetics (PK), and efficacy of AZD0466, a small molecule dual Bcl-2/Bcl-xL inhibitor conjugated to a 'DEP®' G5 poly-l-lysine dendrimer. PK studies reveal that the plasma half-life of the dendrimer-drug conjugate is 8-times longer than that of drug alone, providing evidence of slow release from the circulating dendrimer nanocarrier. The SC dosed construct also shows preferential lymphatic transport, with over 50% of the bioavailable dose recovered in thoracic lymph. Increases in dose (up to 400 mg/kg) are well tolerated after SC administration and studies in a model of disseminated lymphoma in mice show that high dose SC treatment outperforms IV administration using doses that lead to similar total plasma exposure (lower peak concentrations but extended exposure after SC). These data show that the DEP® dendrimer can act as a circulating drug depot accessing both the lymphatic and blood circulatory systems. SC administration improves lymphatic exposure and facilitates higher dose administration due to improved tolerability. Higher dose SC administration also results in improved efficacy, suggesting that drug delivery systems that access both plasma and lymph hold significant potential for the treatment of haematological cancers where lymphatic and extranodal dissemination are poor prognostic factors.
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