Reproducible control of stem cell populations, regardless of their original source, is required for the true potential of these cells to be realised as medical therapies, cell biology research tools ...and in vitro assays. To date there is a lack of consistency in successful output when these cells are used in clinical trials and even simple in vitro experiments, due to cell and material variability. The successful combination of single chemistries in nanoarray format to control stem cell, or any cellular behaviour has not been previously reported. Here we report how homogenously nanopatterned chemically modified surfaces can be used to initiate a directed cellular response, particularly mesenchymal stem cell (MSC) differentiation, in a highly reproducible manner without the need for exogenous biological factors and heavily supplemented cell media. Successful acquisition of these data should lead to the optimisation of cell selective properties of materials, further enhancing the role of nanopatterned substrates in cell biology and regenerative medicine. The successful design and comparison of homogenously molecularly nanopatterned surfaces and their direct effect on human MSC adhesion and differentiation are reported in this paper. Planar gold surfaces were patterned by dip pen nanolithography (DPN) to produce arrays of nanodots with optimised fixed diameter of 70 nanometres separated by defined spacings, ranging from 140 to 1000 nm with terminal functionalities of simple chemistries including carboxyl, amino, methyl and hydroxyl. These nanopatterned surfaces exhibited unprecedented control of initial cell interactions and subsequent control of cell phenotype and offer significant potential for the future.
The direction of individual
B
8
solar neutrinos has been reconstructed using the
SNO
+
liquid scintillator detector. Prompt, directional Cherenkov light was separated from the slower, isotropic ...scintillation light using time information, and a maximum likelihood method was used to reconstruct the direction of individual scattered electrons. A clear directional signal was observed, correlated with the solar angle. The observation was aided by a period of low primary fluor concentration that resulted in a slower scintillator decay time. This is the first time that event-by-event direction reconstruction in high light-yield liquid scintillator has been demonstrated in a large-scale detector.
Published by the American Physical Society
2024
The SNO+ detector operated initially as a water Cherenkov detector. The
implementation of a sealed covergas system midway through water data taking
resulted in a significant reduction in the activity ...of $^{222}$Rn daughters in
the detector and allowed the lowest background to the solar electron scattering
signal above 5 MeV achieved to date. This paper reports an updated SNO+ water
phase $^8$B solar neutrino analysis with a total livetime of 282.4 days and an
analysis threshold of 3.5 MeV. The $^8$B solar neutrino flux is found to be
$\left(2.32^{+0.18}_{-0.17}\text{(stat.)}^{+0.07}_{-0.05}\text{(syst.)}\right)\times10^{6}$
cm$^{-2}$s$^{-1}$ assuming no neutrino oscillations, or
$\left(5.36^{+0.41}_{-0.39}\text{(stat.)}^{+0.17}_{-0.16}\text{(syst.)}
\right)\times10^{6}$ cm$^{-2}$s$^{-1}$ assuming standard neutrino oscillation
parameters, in good agreement with both previous measurements and Standard
Solar Model Calculations. The electron recoil spectrum is presented above 3.5
MeV.
The SNO+ collaboration reports its first spectral analysis of long-baseline
reactor antineutrino oscillation using 114 tonne-years of data. Fitting the
neutrino oscillation probability to the ...observed energy spectrum yields
constraints on the neutrino mass-squared difference $\Delta m^2_{21}$. In the
ranges allowed by previous measurements, the best-fit $\Delta m^2_{21}$ is
(8.85$^{+1.10}_{-1.33}$) $\times$ 10$^{-5}$ eV$^2$. This measurement is
continuing in the next phases of SNO+ and is expected to surpass the present
global precision on $\Delta m^2_{21}$ with about three years of data.
The SNO+ detector operated initially as a water Cherenkov detector. The implementation of a sealed covergas system midway through water data taking resulted in a significant reduction in the activity ...of \(^{222}\)Rn daughters in the detector and allowed the lowest background to the solar electron scattering signal above 5 MeV achieved to date. This paper reports an updated SNO+ water phase \(^8\)B solar neutrino analysis with a total livetime of 282.4 days and an analysis threshold of 3.5 MeV. The \(^8\)B solar neutrino flux is found to be \(\left(2.32^{+0.18}_{-0.17}\text{(stat.)}^{+0.07}_{-0.05}\text{(syst.)}\right)\times10^{6}\) cm\(^{-2}\)s\(^{-1}\) assuming no neutrino oscillations, or \(\left(5.36^{+0.41}_{-0.39}\text{(stat.)}^{+0.17}_{-0.16}\text{(syst.)} \right)\times10^{6}\) cm\(^{-2}\)s\(^{-1}\) assuming standard neutrino oscillation parameters, in good agreement with both previous measurements and Standard Solar Model Calculations. The electron recoil spectrum is presented above 3.5 MeV.
Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER+ breast cancer. Structure based design ...together with systematic investigation of each region of the molecular architecture led to the identification of N-1-(3-fluoropropyl)azetidin-3-yl-6-(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo4,3-fisoquinolin-6-ylpyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.
Purpose: Excessive weight gain during early infancy and early adiposity rebound (AR) are risk factors for later obesity. AR, the age at which body mass index (BMI) begins to increase after decreasing ...from birth, typically occurs at 5-6 years. In term infants, the younger the age at which AR occurs, the greater the risk for later obesity and cardiometabolic disorders. Prematurity is also a risk factor for obesity and cardiometabolic disorders, but age of AR has not been systematically studied in children born preterm. Our objective was to assess longitudinal changes in BMI between birth and 8-9 years in children born full term and preterm in 2008, including (1) effect of age at AR on growth status at 8-9 years and (2) relationship between growth from birth to 6 months and growth at 8-9 years. Methods: An existing database that included birth anthropometrics of 500 full term and 181 preterm infants born in 2008 within the military health system(MHS) was extended by recording height and weight data from outpatient records from age 6 months through 8-9 years. Calculated variables included BMI (kg/m2), BMI Z-score, and age of AR, calculated as the nadir of a quadratic regression of BMI on age (from age 1 through 8-9 years). Results: BMI measurements to 8-9 years were available for 215 children (33% preterm) still in the MHS in 2016-17. Age of AR was calculated for 152 children with at least 4 BMI measurements (32% born preterm). Average age of AR was 5.4 years for children born full term compared to 5.3 years for children born preterm (p = 0.727). There was a significant correlation between younger age of AR and higher BMI Z-score at 8-9 years (r = -0.685)(Figure). These associations were similar in preterm and full term groups, r = -0.634 and r = -0.710, respectively. There was a direct relationship between weight Z-score change from birth to 6 months and higher weight Z-scores at 8-9 years (p=0.034). This relationship did not differ in children born full term compared to children born preterm. Conclusions: Younger age at AR correlates with significantly higher BMI Z-score at 8-9 years. This has previously been reported in children born full term but comparable data in children born preterm have been lacking. Weight gain from birth to 6 months correlates with weight Z-score at 8-9 years in both children born preterm and full term. These results further emphasize the importance of avoiding excessive early weight gain and the importance of AR as a marker of later risk for obesity and cardiometabolic morbidities.
Glucocorticoids are considered first-line therapy in a variety of eosinophilic disorders. They lead to a transient, profound decrease in circulating human eosinophils within hours of administration. ...The phenomenon of glucocorticoid-induced eosinopenia has been the basis for the use of glucocorticoids in eosinophilic disorders, and it has intrigued clinicians for 7 decades, yet its mechanism remains unexplained. To investigate, we first studied the response of circulating eosinophils to in vivo glucocorticoid administration in 3 species and found that the response in rhesus macaques, but not in mice, closely resembled that in humans. We then developed an isolation technique to purify rhesus macaque eosinophils from peripheral blood and performed live tracking of zirconium-89-oxine–labeled eosinophils by serial positron emission tomography/computed tomography imaging, before and after administration of glucocorticoids. Glucocorticoids induced rapid bone marrow homing of eosinophils. The kinetics of glucocorticoid-induced eosinopenia and bone marrow migration were consistent with those of the induction of the glucocorticoid-responsive chemokine receptor CXCR4, and selective blockade of CXCR4 reduced or eliminated the early glucocorticoid-induced reduction in blood eosinophils. Our results indicate that glucocorticoid-induced eosinopenia results from CXCR4-dependent migration of eosinophils to the bone marrow. These findings provide insight into the mechanism of action of glucocorticoids in eosinophilic disorders, with implications for the study of glucocorticoid resistance and the development of more targeted therapies. The human study was registered at ClinicalTrials.gov as #NCT02798523.
•Live cell tracking in a rhesus macaque model reveals that glucocorticoids induce bone marrow migration of eosinophils.•The effect is dependent on the glucocorticoid-responsive chemokine receptor CXCR4.
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