Glucagon‐like peptide‐1 (GLP‐1) receptor agonists (GLP‐1RAs) and dual GLP‐1/glucagon receptor agonists improve glycaemic control and cause significant weight loss in patients with type 2 diabetes.1 ...These effects are driven in part by augmenting glucose‐stimulated insulin release (incretin effect), reducing caloric intake and delayed gastric emptying. We developed and externally validated a novel integrated quantitative systems pharmacology (QSP) model to gain quantitative insight into the relative contributions and mechanisms of drugs modulating glucose regulatory pathways. This model (4GI model) incorporates known feedback mechanisms among glucose, GLP‐1, glucagon, glucose‐dependent insulinotropic peptide (GIP), and insulin after glucose provocation (i.e., food intake) and drug intervention utilizing published nonpharmacological and pharmacological (liraglutide, a GLP‐1RA) data. The resulting model accurately describes the aforementioned mechanisms and independently predicts the effects of the GLP‐1RAs (dulaglutide and semaglutide) on system dynamics. Therefore, the validated 4GI model represents a quantitative decision‐making tool to support the advancement of novel therapeutics and combination strategies modulating these pathways.
Apolipoprotein E (APOE) is a strong genetic risk factor for late-onset Alzheimer’s disease (LOAD). APOE4 increases and APOE2 decreases risk relative to APOE3. In the P301S mouse model of tauopathy, ...ApoE4 increases tau pathology and neurodegeneration when compared with ApoE3 or the absence of ApoE. However, the role of ApoE isoforms and lipid metabolism in contributing to tau-mediated degeneration is unknown. We demonstrate that in P301S tau mice, ApoE4 strongly promotes glial lipid accumulation and perturbations in cholesterol metabolism and lysosomal function. Increasing lipid efflux in glia via an LXR agonist or Abca1 overexpression strongly attenuates tau pathology and neurodegeneration in P301S/ApoE4 mice. We also demonstrate reductions in reactive astrocytes and microglia, as well as changes in cholesterol biosynthesis and metabolism in glia of tauopathy mice in response to LXR activation. These data suggest that promoting efflux of glial lipids may serve as a therapeutic approach to ameliorate tau and ApoE4-linked neurodegeneration.
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•Lipidomic profiling reveals changes in cholesterol metabolism in P301S/ApoE4 mice•LXR agonist GW3965 decreases tauopathy and neuroinflammation in P301S/E4 mice•LXR agonist upregulates Abca1 and reduces lipid accumulation in vivo and in vitro•Abca1 overexpression mitigates tauopathy and neuroinflammation in P301S/ApoE4 mice
Using lipidomics coupled with immunostaining, Litvinchuk et al. demonstrate that ApoE promotes changes in cholesterol metabolism and lipid accumulation in glia of 9.5-month-old P301S mice. LXR agonist GW3965 diet and Abca1 overexpression markedly decrease tauopathy, neurodegeneration, synapse loss and behavioral deficits, neuroinflammation, and glial lipid accumulation in 9.5-month-old P301S/ApoE4 mice.
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•Assessed common metrics with data from 34 cropland, grazing & integrated systems.•Compared production and phenology metrics from eddy covariance, PhenoCam and Landsat.•Correlations ...among metrics varied across diverse U.S. agroecosystems.•Devised a metric assessment framework to streamline decision making for monitoring.
Effective measurement of seasonal variations in the timing and amount of production is critical to managing spatially heterogeneous agroecosystems in a changing climate. Although numerous technologies for such measurements are available, their relationships to one another at a continental extent are unknown. Using data collected from across the Long-Term Agroecosystem Research (LTAR) network and other networks, we investigated correlations among key metrics representing primary production, phenology, and carbon fluxes in croplands, grazing lands, and crop-grazing integrated systems across the continental U.S. Metrics we examined included gross primary productivity (GPP) estimated from eddy covariance (EC) towers and modelled from the Landsat satellite, Landsat NDVI, and vegetation greenness (Green Chromatic Coordinate, GCC) from tower-mounted PhenoCams for 2017 and 2018. Overall, our analysis compared production dynamics estimated from three independent ground and remote platforms using data for 34 agricultural sites constituting 51 site-years of co-located time series.
Pairwise sensor comparisons across all four metrics revealed stronger correlation and lower root mean square error (RMSE) between end of season (EOS) dates (Pearson R ranged from 0.6 to 0.7 and RMSE from 32.5 to 67.8) than start of season (SOS) dates (0.46 to 0.69 and 40.4 to 66.2). Overall, moderate to high correlations between SOS and EOS metrics complemented one another except at some lower productivity grazing land sites where estimating SOS can be challenging. Growing season length estimates derived from 16-day satellite GPP (179.1 days) were significantly longer than those from PhenoCam GCC (70.4 days, padj < 0.0001) and EC GPP (79.6 days, padj < 0.0001). Landscape heterogeneity did not explain differences in SOS and EOS estimates. Annual integrated estimates of productivity from EC GPP and PhenoCam GCC diverged from those estimated by Landsat GPP and NDVI at sites where annual production exceeds 1000 gC/m−2 yr−1. Based on our results, we developed a “metric assessment framework” that articulates where and how metrics from satellite, eddy covariance and PhenoCams complement, diverge from, or are redundant with one another. The framework was designed to optimize instrumentation selection for monitoring, modeling, and forecasting ecosystem functioning with the ultimate goal of informing decision-making by land managers, policy-makers, and industry leaders working at multiple scales.
Despite a high paediatric tuberculosis (TB) burden globally, sensitive and specific diagnostic tools are lacking. In addition, no data exist on the impact of pulmonary TB on long-term child lung ...health in low- and middle-income countries. The prospective observational UMOYA study aims (1) to build a state-of-the-art clinical, radiological, and biological repository of well-characterised children with presumptive pulmonary TB as a platform for future studies to explore new emerging diagnostic tools and biomarkers for early diagnosis and treatment response; and (2) to investigate the short and long-term impact of pulmonary TB on lung health and quality of life in children.
We will recruit up to 600 children (0-13 years) with presumptive pulmonary TB and 100 healthy controls. Recruitment started in November 2017 and is expected to continue until May 2023. Sputum and non-sputum-based samples are collected at enrolment and during follow-up in TB cases and symptomatic controls. TB treatment is started by routine care services. Intensive follow-up for 6 months will allow for TB cases to retrospectively be classified according to international consensus clinical case definitions for TB. Long-term follow-up, including imaging, comprehensive assessment of lung function and quality of life questionnaires, are done yearly up to 4 years after recruitment.
The UMOYA study will provide a unique platform to evaluate new emerging diagnostic tools and biomarkers for early diagnosis and treatment response and to investigate long-term outcomes of pulmonary TB and other respiratory events on lung health in children.
Abstract
A molecular rotor is created when a 2,1,3‐benzothiadiazole rotator is incorporated into a rigid arylene ethynylene framework supported by pyridine coordination to a metal (Ag
+
or PdCl
2
) ...guest. Comparisons to a similarly sized naphthyl rotator via
1
H NMR spectroscopy provide insights into the movement of these bicyclic rotators relative to the rigid stator framework. Chemical shift increases of 0.3 ppm, or more, upon metal complexation are consistent with through‐space interaction of the central arene with a bound PdCl
2
guest. Further study via X‐ray crystallography illustrates that rotation of the 2,1,3‐benzothiadiazole unit in the solid state is likely hampered by relatively strong chalcogen bonding (N⋅⋅⋅S distance of 2.93 Å), forming 2S‐2N squares between benzothiadiazoles of neighboring complexes. Strong π–π interactions (3.29–3.36 Å) between neighboring complexes likewise restrict solid‐state rotation of the potential benzothiadiazole rotator. Modest changes to UV–vis spectra upon metal coordination suggest that electronic properties are mostly independent of stator configuration.
Canine adenovirus type 2 vectors (CAV-2) are promising tools to treat global central nervous system (CNS) disorders because of their preferential transduction of neurons and efficient retrograde ...axonal transport. Here we tested the potential of a helper-dependent CAV-2 vector expressing β-glucuronidase (HD-RIGIE) in a mouse model of mucopolysaccharidosis type VII (MPS VII), a lysosomal storage disease caused by deficiency in β-glucuronidase activity. MPS VII leads to glycosaminoglycan accumulation into enlarged vesicles in peripheral tissues and the CNS, resulting in peripheral and neuronal dysfunction. After intracranial administration of HD-RIGIE, we show long-term expression of β-glucuronidase that led to correction of neuropathology around the injection site and in distal areas. This phenotypic correction correlated with a decrease in secondary-elevated lysosomal enzyme activity and glycosaminoglycan levels, consistent with global biochemical correction. Moreover, HD-RIGIE-treated mice show significant cognitive improvement. Thus, injections of HD-CAV-2 vectors in the brain allow a global and sustained expression and may have implications for brain therapy in patients with lysosomal storage disease.
Red cell distribution width (RDW) is a standard component of the automated blood count, and is of prognostic value in heart failure and coronary heart disease. We investigated the association between ...RDW and cardiovascular events in patients with adult congenital heart disease (ACHD).
In this prospective cohort study, 602 consecutive patients with ACHD who routinely visited the outpatient clinic were enrolled between 2011 and 2013. RDW was measured in fresh venous blood samples at inclusion in 592 patients (median age 33 IQR 25–41 years, 58% male, 90% NYHA I) and at four annual follow-up visits. During 4.3 IQR 3.8–4.7 years of follow-up, the primary endpoint (death, heart failure, hospitalization, arrhythmia, thromboembolic events, cardiac intervention) occurred in 196 patients (33%). Median RDW was 13.4 (12.8–14.1)% versus 12.9 (12.5–13.4)% in patients with and without the primary endpoint (P < 0.001). RDW was significantly associated with the endpoint when adjusted for age, sex, clinical risk factors, CRP, and NT-proBNP (HR 1.20; 95% CI 1.06–1.35; P = 0.003). The C-index of the model including RDW was slightly, but significantly (P = 0.005) higher than the model without (0.74, 95% CI 0.70–0.78 versus 0.73, 95% CI 0.69–0.78). Analysis of repeated RDW measurements (n = 2449) did not show an increase in RDW prior to the occurrence of the endpoint.
RDW is associated with cardiovascular events in patients with ACHD, independently of age, sex, clinical risk factors, CRP, and NT-proBNP. This readily available biomarker could therefore be considered as an additive biomarker for risk stratification in these patients.
•RDW is independently associated with cardiovascular events in patients with ACHD.•This readily available biomarker can be measured worldwide at a low cost.•RDW may be useful for additive risk stratification in ACHD.
Background. A quadrivalent (types 6, 11, 16, and 18) human papillomavirus (HPV) L1 virus-like-particle (VLP) vaccine has been shown to be 95%–100% effective in preventing cervical and genital disease ...related to HPV-6, -11, -16, and -18 in 16–26-year-old women naive for HPV vaccine types. Because most women in the general population are sexually active, some will have already been infected with ⩾1 HPV vaccine types at the time vaccination is offered. Here, we assessed whether such infected women are protected against disease caused by the remaining HPV vaccine types. Methods. Two randomized, placebo-controlled trials of the quadrivalent (types 6, 11, 16, and 18) HPV vaccine enrolled 17,622 women without consideration of baseline HPV status. Among women infected with 1–3 HPV vaccine types at enrollment, efficacy against genital disease related to the HPV vaccine type or types for which subjects were naive was assessed. Results. Vaccination was 100% effective (95% confidence interval CI, 79%–100%) in preventing incident cervical intraepithelial neoplasia 2 or 3 or cervical adenocarcinoma in situ caused by the HPV type or types for which the women were negative at enrollment. Efficacy for preventing vulvar or vaginal HPV-related lesions was 94% (95% CI, 81%–99%). Conclusions. Among women positive for 1–3 HPV vaccine types before vaccination, the quadrivalent HPV vaccine protected against neoplasia caused by the remaining types. These results support vaccination of the general population without prescreening.
Abstract Objective Patients with heterozygous familial hypercholesterolemia (FH) are at severely increased risk of developing atherosclerosis at relatively young age. The aim of this study was to ...assess the prevalence of subclinical atherosclerosis and intraplaque neovascularization (IPN) in patients with FH, using contrast-enhanced ultrasound (CEUS) of the carotid arteries. Methods The study population consisted of 69 consecutive asymptomatic patients with FH (48% women, mean age 55 ± 8 years). All patients underwent carotid ultrasound to evaluate the presence and severity of carotid atherosclerosis, and CEUS to assess IPN. IPN was assessed in near wall plaques using a semi-quantitative grading scale and semi-automated quantification software. Results Carotid plaque was present in 62 patients (90%). A total of 49 patients had plaques that were eligible for the assessment of IPN: 7 patients (14%) had no IPN, 39 (80%) had mild to moderate IPN and 3 (6%) had severe IPN. Semi-automated quantification software showed no statistical significant difference in the amount of IPN between patients > 50 years and patients ≤ 50 years and between patients with a defective low-density lipoprotein receptor (LDLR) mutation and patients with a negative LDLR mutation. Plaques with irregular or ulcerated surface had significantly more IPN than plaques with a smooth surface ( p < 0.05). Conclusion Carotid ultrasound demonstrated atherosclerotic plaque in 90% of asymptomatic patients with FH without known atherosclerosis. IPN assessed with CEUS, was present in 86% of these patients. Irregular and ulcerated plaques exhibited significantly more IPN than plaques with a smooth surface.
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