Pediatric clinical laboratories commonly measure tricarboxylic acid cycle intermediates for screening, diagnosis, and monitoring of specific inborn errors of metabolism, such as organic acidurias. In ...the past decade, the same tricarboxylic acid cycle metabolites have been implicated and studied in cancer. The accumulation of these metabolites in certain cancers not only serves as a biomarker but also directly contributes to cellular transformation, therefore earning them the designation of oncometabolites.
-2-hydroxyglutarate,
-2-hydroxyglutarate, succinate, and fumarate are the currently recognized oncometabolites. They are structurally similar and share metabolic proximity in the tricarboxylic acid cycle. As a result, they promote tumorigenesis in cancer cells through similar mechanisms. This review summarizes the currently understood common and distinct biological features of these compounds. In addition, we will review the current laboratory methodologies that can be used to quantify these metabolites and their downstream targets.
Oncometabolites play an important role in cancer biology. The metabolic pathways that lead to the production of oncometabolites and the downstream signaling pathways that are activated by oncometabolites represent potential therapeutic targets. Clinical laboratories have a critical role to play in the management of oncometabolite-associated cancers through development and validation of sensitive and specific assays that measure oncometabolites and their downstream effectors. These assays can be used as screening tools and for follow-up to measure response to treatment, as well as to detect minimal residual disease and recurrence.
Abstract
We present
TRICERATOPS
, a new Bayesian tool that can be used to vet and validate TESS Objects of Interest (TOIs). We test the tool on 68 TOIs that have been previously confirmed as planets ...or rejected as astrophysical false positives. By looking in the false-positive probability (FPP)−nearby false-positive probability (NFPP) plane, we define criteria that TOIs must meet to be classified as validated planets (FPP < 0.015 and NFPP < 10
−3
), likely planets (FPP < 0.5 and NFPP < 10
−3
), and likely nearby false positives (NFPP > 10
−1
). We apply this procedure on 384 unclassified TOIs and statistically validate 12, classify 125 as likely planets, and classify 52 as likely nearby false positives. Of the 12 statistically validated planets, 9 are newly validated.
TRICERATOPS
is currently the only TESS vetting and validation tool that models transits from nearby contaminant stars in addition to the target star. We therefore encourage use of this tool to prioritize follow-up observations that confirm bona fide planets and identify false positives originating from nearby stars.
Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor agonist, delivered superior glycemic control and weight loss compared to GLP-1 receptor (GLP-1R) agonism in patients with type 2 diabetes. ...However, the mechanism by which tirzepatide improves efficacy and how GIP receptor (GIPR) agonism contributes is not fully understood. Here, we show that tirzepatide is an effective insulin sensitizer, improving insulin sensitivity in obese mice to a greater extent than GLP-1R agonism. To determine if GIPR agonism contributes, we compared the effect of tirzepatide in obese wild-type and Glp-1r null mice. In the absence of GLP-1R-induced weight loss, tirzepatide improved insulin sensitivity by enhancing glucose disposal in white adipose tissue (WAT). In support, a long-acting GIPR agonist (LAGIPRA) was found to enhance insulin sensitivity by augmenting glucose disposal in WAT. Interestingly, the effect of tirzepatide and LAGIPRA on insulin sensitivity was associated with reduced branched-chain amino (BCAAs) and keto-acids in the circulation. Insulin sensitization was associated with upregulation of genes associated with the catabolism of glucose, lipid and BCAAs in brown adipose tissue. Together, our studies show that tirzepatide improved insulin sensitivity in a weight-dependent and -independent manner. These results highlight how GIPR agonism contributes to the therapeutic profile of dual receptor agonism, offering mechanistic insights into the clinical efficacy of tirzepatide.
Abstract
Young eclipsing binaries (EBs) are powerful probes of early stellar evolution. Current models are unable to simultaneously reproduce the measured and derived properties that are accessible ...for EB systems (e.g., mass, radius, temperature, and luminosity). In this study we add a benchmark EB to the pre-main-sequence population with our characterization of TOI 450 (TIC 77951245). Using Gaia astrometry to identify its comoving, coeval companions, we confirm TOI 450 is a member of the ∼40 Myr Columba association. This eccentric (
e
= 0.2969), equal-mass (
q
= 1.000) system provides only one grazing eclipse. Despite this, our analysis achieves the precision of a double-eclipsing system by leveraging information in our high-resolution spectra to place priors on the surface-brightness and radius ratios. We also introduce a framework to include the effect of star spots on the observed eclipse depths. Multicolor eclipse light curves play a critical role in breaking degeneracies between the effects of star spots and limb-darkening. Including star spots reduces the derived radii by ∼2% from a unspotted model (>2
σ
) and inflates the formal uncertainty in accordance with our lack of knowledge regarding the starspot orientation. We derive masses of 0.1768( ± 0.0004) and 0.1767( ± 0.0003)
M
⊙
, and radii of 0.345(±0.006) and 0.346(±0.006)
R
⊙
for the primary and secondary, respectively. We compare these measurements to multiple stellar evolution isochones, finding good agreement with the association age. The MESA MIST and SPOTS (
f
s
= 0.17) isochrones perform the best across our comparisons, but detailed agreement depends heavily on the quantities being compared.
Knowledge management systems try to elicit and support the flow of ideas and experiences among groups of employees (sometimes referred to as knowledge communities). Whereas numerous information and ...communication systems have been developed to support such knowledge exchanges, practical applications have found that technology alone cannot ensure that knowledge will indeed be volunteered and exchanged, and whereas researchers and consultants alike have argued that culture and other human variables constitute key success factors, it is not clear what specific variables are at play, nor what management practices can affect those variables. This exploratory research investigates some of the psychological, organizational and system-related variables that may determine individual engagement in intra-organizational knowledge sharing. Results from a survey of 372 employees from a large multinational show that self-efficacy, openness to experience, perceived support from colleagues and supervisors and, to a lesser extent, organizational commitment, job autonomy, perceptions about the availability and quality of knowledge management systems, and perceptions of rewards associated with sharing knowledge, significantly predicted self-reports of participation in knowledge exchange.
Abstract Non-invasive techniques for quantifying early biochemical and biomechanical changes in articular cartilage may provide a means of more precisely assessing osteoarthritis (OA) progression. ...The goals of this study were to determine the relationship between T1rho magnetic resonance (MR) imaging relaxation times and changes in cartilage composition, cartilage mechanical properties, and synovial fluid biomarker levels and to demonstrate the application of T1rho imaging to evaluate cartilage composition in human subjects in vivo . Femoral condyles and synovial fluid were harvested from healthy and OA porcine knee joints. Sagittal T1rho relaxation MR images of the condyles were acquired. OA regions of OA joints exhibited an increase in T1rho relaxation times as compared to non-OA regions. Furthermore in these regions, cartilage sGAG content and aggregate modulus decreased, while percent degraded collagen and water content increased. In OA joints, synovial fluid concentrations of sGAG decreased and C2C concentrations increased compared to healthy joints. T1rho relaxation times were negatively correlated with cartilage and synovial fluid sGAG concentrations and aggregate modulus and positively correlated with water content and permeability. Additionally, we demonstrated the application of these in vitro findings to the study of human subjects. Specifically, we demonstrated that walking results in decreased T1rho relaxation times, consistent with water exudation and an increase in proteoglycan concentration with in vivo loading. Together, these findings demonstrate that cartilage MR imaging and synovial fluid biomarkers provide powerful non-invasive tools for characterizing changes in the biochemical and biomechanical environment of the joint.
The respiratory release of carbon dioxide (CO₂) from soil is a major yet poorly understood flux in the global carbon cycle. Climatic warming is hypothesized to increase rates of soil respiration, ...potentially fueling further increases in global temperatures. However, despite considerable scientific attention in recent decades, the overall response of soil respiration to anticipated climatic warming remains unclear. We synthesize the largest global dataset to date of soil respiration, moisture, and temperature measurements, totaling >3,800 observations representing 27 temperature manipulation studies, spanning nine biomes and over 2 decades of warming. Our analysis reveals no significant differences in the temperature sensitivity of soil respiration between control and warmed plots in all biomes, with the exception of deserts and boreal forests. Thus, our data provide limited evidence of acclimation of soil respiration to experimental warming in several major biome types, contrary to the results from multiple single-site studies. Moreover, across all nondesert biomes, respiration rates with and without experimental warming follow a Gaussian response, increasing with soil temperature up to a threshold of ∼25 °C, above which respiration rates decrease with further increases in temperature. This consistent decrease in temperature sensitivity at higher temperatures demonstrates that rising global temperatures may result in regionally variable responses in soil respiration, with colder climates being considerably more responsive to increased ambient temperatures compared with warmer regions. Our analysis adds a unique cross-biome perspective on the temperature response of soil respiration, information critical to improving our mechanistic understanding of how soil carbon dynamics change with climatic warming.
Decision-makers often seek to design policies that support sustainable development. Prospective evaluations of how effectively such policies are likely to meet sustainability goals have nonetheless ...remained challenging. Evaluating policies against sustainability goals can be facilitated through the inclusive wealth framework, which characterizes development in terms of the value to society of its underlying capital assets, and defines development to be potentially sustainable if that value does not decline over time. The inclusive wealth approach has been developed at a theoretical level and applied to retrospective evaluations. Here, we apply inclusive wealth theory to prospective policy evaluation coupled with dynamic simulation modeling, using a case of electricity infrastructure policies in oil-exporting countries. To demonstrate the prospective evaluation, we analyze investment policies in non-fossil electricity capacity in terms of their forecast impact on several dimensions of inclusive wealth. Illustrative results show that investing in non-fossil capacity in Saudi Arabia and Kuwait can increase components of the countries' inclusive wealth, though the impacts depend on future uncertainties. In contrast, comparable components of the UAE's net inclusive wealth decline under similar investment policies. Finally, including human capital improvements in estimates of inclusive wealth substantially increases its value, though the amount varies across the countries.
•We apply inclusive wealth theory to prospective policy analysis using dynamic model.•We use a case of electricity infrastructure policies in oil-exporting countries.•We analyze non-fossil policies in terms of forecast impact to inclusive wealth.•Impacts vary depending on electricity technology, country, and future uncertainties.•We discuss implications of our approach on future policy analysis cases.
The appropriate use criteria process synthesizes evidence-based medicine, clinical practice experience, and expert judgment. The American Academy of Dermatology in collaboration with the American ...College of Mohs Surgery, the American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery has developed appropriate use criteria for 270 scenarios for which Mohs micrographic surgery (MMS) is frequently considered based on tumor and patient characteristics. This document reflects the rating of appropriateness of MMS for each of these clinical scenarios by a ratings panel in a process based on the appropriateness method developed by the RAND Corp (Santa Monica, CA)/University of California–Los Angeles (RAND/UCLA). At the conclusion of the rating process, consensus was reached for all 270 (100%) scenarios by the Ratings Panel, with 200 (74.07%) deemed as appropriate, 24 (8.89%) as uncertain, and 46 (17.04%) as inappropriate. For the 69 basal cell carcinoma scenarios, 53 were deemed appropriate, 6 uncertain, and 10 inappropriate. For the 143 squamous cell carcinoma scenarios, 102 were deemed appropriate, 7 uncertain, and 34 inappropriate. For the 12 lentigo maligna and melanoma in situ scenarios, 10 were deemed appropriate, 2 uncertain, and 0 inappropriate. For the 46 rare cutaneous malignancies scenarios, 35 were deemed appropriate, 9 uncertain, and 2 inappropriate. These appropriate use criteria have the potential to impact health care delivery, reimbursement policy, and physician decision making on patient selection for MMS, and aim to optimize the use of MMS for scenarios in which the expected clinical benefit is anticipated to be the greatest. In addition, recognition of those scenarios rated as uncertain facilitates an understanding of areas that would benefit from further research. Each clinical scenario identified in this document is crafted for the average patient and not the exception. Thus, the ultimate decision regarding the appropriateness of MMS should be determined by the expertise and clinical experience of the physician.
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