Evaluation of Cardiac Function in Women With a History of Preeclampsia : A Systematic Review and Meta-Analysis

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Bioanalytical method validation and application to a phase 1, double-blind, randomized pharmacokinetic trial of a standardized Centella asiatica (L.) Urban water extract product in healthy older adults

Introduction:Centella asiatica is an herbaceous plant reputed in Eastern medicine to improve memory. Preclinical studies have shown that C. asiatica aqueous extract (CAW) improves neuronal health, reduces oxidative stress, and positively impacts learning and cognition. This study aimed to develop and validate bioanalytical methods for detecting known bioactive compounds from C. asiatica in human biological matrices and apply them to a human pharmacokinetic trial in healthy older adults.Methods: High performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used for detecting triterpenes and caffeoylquinic acids from C. asiatica, or their metabolites, in human plasma and urine. Validation parameters including linearity, precision, accuracy, recovery and thermal stability were evaluated. The method was applied to a Phase I, randomized, double-blind, crossover trial of two doses (2 or 4 g) of a standardized C. asiatica water extract product (CAP) in eight healthy older adults. Pharmacokinetic parameters were measured over a 12-h post administration period and acute safety was assessed.Results: The method satisfied US Food & Drug Administration criteria for linearity and recovery of the analytes of interest in human plasma and urine. The method also satisfied criteria for precision and accuracy at medium and high concentrations. Single administration of 2 and 4 g of CAP was well tolerated and safe in healthy older adults. The parent triterpene glycosides, asiaticoside and madecassoside, were not detected in plasma and in minimal amounts in urinary excretion analyses, while the aglycones, asiatic acid and madecassic acid, showed readily detectable pharmacokinetic profiles. Similarly, the di-caffeoylquinic acids and mono-caffeoylquinic acids were detected in low quantities, while their putative metabolites showed readily detectable pharmacokinetic profiles and urinary excretion.Discussion: This method was able to identify and calculate the concentration of triterpenes and caffeoylquinic acids from C. asiatica, or their metabolites, in human plasma and urine. The oral absorption of these key compounds from CAP, and its acute safety in healthy older adults, support the use of this C. asiatica product in future clinical trials

Theory of Bose-Einstein condensation in trapped gases

The phenomenon of Bose-Einstein condensation of dilute gases in traps is reviewed from a theoretical perspective. Mean-field theory provides a framework to understand the main features of the condensation and the role of interactions between particles. Various properties of these systems are discussed, including the density profiles and the energy of the ground state configurations, the collective oscillations and the dynamics of the expansion, the condensate fraction and the thermodynamic functions. The thermodynamic limit exhibits a scaling behavior in the relevant length and energy scales. Despite the dilute nature of the gases, interactions profoundly modify the static as well as the dynamic properties of the system; the predictions of mean-field theory are in excellent agreement with available experimental results. Effects of superfluidity including the existence of quantized vortices and the reduction of the moment of inertia are discussed, as well as the consequences of coherence such as the Josephson effect and interference phenomena. The review also assesses the accuracy and limitations of the mean-field approach.Comment: revtex, 69 pages, 38 eps figures, new version with more references, new figures, various changes and corrections, for publ. in Rev. Mod. Phys., available also at http://www-phys.science.unitn.it/bec/BEC.htm

Antibody attributes that predict the neutralization and effector function of polyclonal responses to SARS-CoV-2

BACKGROUND: While antibodies can provide significant protection from SARS-CoV-2 infection and disease sequelae, the specific attributes of the humoral response that contribute to immunity are incompletely defined. METHODS: We employ machine learning to relate characteristics of the polyclonal antibody response raised by natural infection to diverse antibody effector functions and neutralization potency with the goal of generating both accurate predictions of each activity based on antibody response profiles as well as insights into antibody mechanisms of action. RESULTS: To this end, antibody-mediated phagocytosis, cytotoxicity, complement deposition, and neutralization were accurately predicted from biophysical antibody profiles in both discovery and validation cohorts. These models identified SARS-CoV-2-specific IgM as a key predictor of neutralization activity whose mechanistic relevance was supported experimentally by depletion. CONCLUSIONS: Validated models of how different aspects of the humoral response relate to antiviral antibody activities suggest desirable attributes to recapitulate by vaccination or other antibody-based interventions

JWST MIRI flight performance: The Medium-Resolution Spectrometer

The Medium-Resolution Spectrometer (MRS) provides one of the four operating modes of the Mid-Infrared Instrument (MIRI) on board the James Webb Space Telescope (JWST). The MRS is an integral field spectrometer, measuring the spatial and spectral distributions of light across the 5-28 $\mu m$ wavelength range with a spectral resolving power between 3700-1300. We present the MRS's optical, spectral, and spectro-photometric performance, as achieved in flight, and we report on the effects that limit the instrument's ultimate sensitivity. The MRS flight performance has been quantified using observations of stars, planetary nebulae, and planets in our Solar System. The precision and accuracy of this calibration was checked against celestial calibrators with well-known flux levels and spectral features. We find that the MRS geometric calibration has a distortion solution accuracy relative to the commanded position of 8 mas at 5 $\mu m$ and 23 mas at 28 $\mu m$. The wavelength calibration is accurate to within 9 km/sec at 5 $\mu m$ and 27 km/sec at 28 $\mu m$. The uncertainty in the absolute spectro-photometric calibration accuracy was estimated at 5.6 +- 0.7 %. The MIRI calibration pipeline is able to suppress the amplitude of spectral fringes to below 1.5 % for both extended and point sources across the entire wavelength range. The MRS point spread function (PSF) is 60 % broader than the diffraction limit along its long axis at 5 $\mu m$ and is 15 % broader at 28 $\mu m$. The MRS flight performance is found to be better than prelaunch expectations. The MRS is one of the most subscribed observing modes of JWST and is yielding many high-profile publications. It is currently humanity's most powerful instrument for measuring the mid-infrared spectra of celestial sources and is expected to continue as such for many years to come.Comment: 16 pages, 21 figure

Nitrogen Increases Early-Stage and Slows Late-Stage Decomposition Across Diverse Grasslands

To evaluate how increased anthropogenic nutrient inputs alter carbon cycling in grasslands, we conducted a litter decomposition study across 20 temperate grasslands on three continents within the Nutrient Network, a globally distributed nutrient enrichment experiment We determined the effects of addition of experimental nitrogen (N), phosphorus (P) and potassium plus micronutrient (Kμ) on decomposition of a common tree leaf litter in a long-term study (maximum of 7 years; exact deployment period varied across sites). The use of higher order decomposition models allowed us to distinguish between the effects of nutrients on early- versus late-stage decomposition. Across continents, the addition of N (but not other nutrients) accelerated early-stage decomposition and slowed late-stage decomposition, increasing the slowly decomposing fraction by 28% and the overall litter mean residence time by 58%. Synthesis. Using a novel, long-term cross-site experiment, we found widespread evidence that N enhances the early stages of above-ground plant litter decomposition across diverse and widespread temperate grassland sites but slows late-stage decomposition. These findings were corroborated by fitting the data to multiple decomposition models and have implications for N effects on soil organic matter formation. For example, following N enrichment, increased microbial processing of litter substrates early in decomposition could promote the production and transfer of low molecular weight compounds to soils and potentially enhance the stabilization of mineral-associated organic matter. By contrast, by slowing late-stage decomposition, N enrichment could promote particulate organic matter (POM) accumulation. Such hypotheses deserve further testing

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Belowground biomass response to nutrient enrichment depends on light limitation across globally distributed grasslands

Anthropogenic activities are increasing nutrient inputs to ecosystems worldwide, with consequences for global carbon and nutrient cycles. Recent meta-analyses show that aboveground primary production is often co-limited by multiple nutrients; however, little is known about how root production responds to changes in nutrient availability. At twenty-nine grassland sites on four continents, we quantified shallow root biomass responses to nitrogen (N), phosphorus (P) and potassium plus micronutrient enrichment and compared below- and aboveground responses. We hypothesized that optimal allocation theory would predict context dependence in root biomass responses to nutrient enrichment, given variation among sites in the resources limiting to plant growth (specifically light versus nutrients). Consistent with the predictions of optimal allocation theory, the proportion of total biomass belowground declined with N or P addition, due to increased biomass aboveground (for N and P) and decreased biomass belowground (N, particularly in sites with low canopy light penetration). Absolute root biomass increased with N addition where light was abundant at the soil surface, but declined in sites where the grassland canopy intercepted a large proportion of incoming light. These results demonstrate that belowground responses to changes in resource supply can differ strongly from aboveground responses, which could significantly modify predictions of future rates of nutrient cycling and carbon sequestration. Our results also highlight how optimal allocation theory developed for individual plants may help predict belowground biomass responses to nutrient enrichment at the ecosystem scale across wide climatic and environmental gradients

Suppression of Radiation-Induced Salivary Gland Dysfunction by IGF-1

Radiation is a primary or secondary therapeutic modality for treatment of head and neck cancer. A common side effect of irradiation to the neck and neck region is xerostomia caused by salivary gland dysfunction. Approximately 40,000 new cases of xerostomia result from radiation treatment in the United States each year. The ensuing salivary gland hypofunction results in significant morbidity and diminishes the effectiveness of anti-cancer therapies as well as the quality of life for these patients. Previous studies in a rat model have shown no correlation between induction of apoptosis in the salivary gland and either the immediate or chronic decrease in salivary function following gamma-radiation treatment.A significant level of apoptosis can be detected in the salivary glands of FVB mice following gamma-radiation treatment of the head and neck and this apoptosis is suppressed in transgenic mice expressing an activated mutant of Akt (myr-Akt1). Importantly, this suppression of apoptosis in myr-Akt1 mice preserves salivary function, as measured by saliva output, three and thirty days after gamma-radiation treatment. In order to translate these studies into a preclinal model we found that intravenous injection of IGF1 stimulated activation of endogenous Akt in the salivary glands in vivo. A single injection of IGF1 prior to exposure to gamma-radiation diminishes salivary acinar cell apoptosis and completely preserves salivary gland function three and thirty days following irradiation.These studies suggest that apoptosis of salivary acinar cells underlies salivary gland hypofunction occurring secondary to radiation of the head and neck region. Targeted delivery of IGF1 to the salivary gland of patients receiving head and neck irradiation may be useful in reducing or eliminating xerostomia and restoring quality of life to these patients