Through the use of empirical and computational methods, phosphinate-based inhibitors of MMP-1 and MMP-13 that bind into the S
2 pocket of these enzymes were designed. The synthesis and testing of
2 ...suggested that binding was occurring as hypothesized. Structure determination of a co-crystal of
2 bound to the catalytic domain of MMP-1 confirmed the binding mode. Substituents binding into S
2, S
1′, S
2′ and S
3′, were optimized yielding compounds with low double-digit nM IC
50's against these enzymes.
Through the use of empirical and computational methods, phosphinate-based inhibitors of MMP-1 and MMP-13 that bind into the S
2 pocket of these enzymes were designed.
The SNO+ experiment collected data as a low-threshold water Cherenkov detector from September 2017 to July 2019. Measurements of the 2.2-MeV \(\gamma\) produced by neutron capture on hydrogen have ...been made using an Am-Be calibration source, for which a large fraction of emitted neutrons are produced simultaneously with a 4.4-MeV \(\gamma\). Analysis of the delayed coincidence between the 4.4-MeV \(\gamma\) and the 2.2-MeV capture \(\gamma\) revealed a neutron detection efficiency that is centered around 50% and varies at the level of 1% across the inner region of the detector, which to our knowledge is the highest efficiency achieved among pure water Cherenkov detectors. In addition, the neutron capture time constant was measured and converted to a thermal neutron-proton capture cross section of \(336.3^{+1.2}_{-1.5}\) mb.
Extensive experience with isotransplants of 27 different tumours (leukaemias, sarcomata, carcinomata), all of strictly spontaneous origin in laboratory bred mice of low cancer strains CBA/Ht and ...WHT/Ht, has revealed no evidence of tumour immunogenicity. Of approximately 20,000 maintenance transplants, none failed and none regressed; of almost 10,000 carefully observed tumours arising from small or minimal inocula of tumour cells, none spontaneously regressed. The number of injected viable tumour cells required to give a 50% probability of successful transplantation (the TD50) ranged from approximately 1 cell to greater than 10,000 cells among the 27 tumours; high TD50 values, which were dramatically reduced by various procedures having no immunological significance, did not signify active "resistance" of the hosts. In the case of all of 7 randomly selected tumours, prior "immunization" of recipients with homologous lethally irradiated cells increased their tumour receptivity. Several experiments using various tumours failed to give evidence that immunity could be non-specifically induced or that a massive preponderance of lymphocytes from specifically sensitized mice could inhibit tumour transplantation or growth in vivo; no trace of "resistance" to tumour was adopted by isogeneic recipients of lymphocytes from regional nodes of tumour bearers. A limited review of the recent literature on tumour immunity shows that practically all the animal data presented in support of a general theory of tumour immunogenicity or to provide a basis for active clinical immunotherapy have been obtained from transplanted tumour systems which entail artefactual immunity associated with viral or chemical induction of the tumours or their allogeneic transplantation. It is suggested that isotransplants of spontaneously arising tumours are the only appropriate models of human cancer and that any genuine rapport between the animal laboratory and the clinic requires their exclusive use.
In this work we use Lagrangian perturbation theory to analyze the harmonic
space galaxy clustering signal of Bright Galaxy Survey (BGS) and Luminous Red
Galaxies (LRGs) targeted by the Dark Energy ...Spectroscopic Instrument (DESI),
combined with the galaxy--galaxy lensing signal measured around these galaxies
using Dark Energy Survey Year 3 source galaxies. The BGS and LRG galaxies are
extremely well characterized by DESI spectroscopy and, as a result, lens galaxy
redshift uncertainty and photometric systematics contribute negligibly to the
error budget of our ``$2\times2$-point'' analysis. On the modeling side, this
work represents the first application of the \texttt{spinosaurus} code,
implementing an effective field theory model for galaxy intrinsic alignments,
and we additionally introduce a new scheme (\texttt{MAIAR}) for marginalizing
over the large uncertainties in the redshift evolution of the intrinsic
alignment signal. Furthermore, this is the first application of a hybrid
effective field theory (HEFT) model for galaxy bias based on the
$\texttt{Aemulus}\, \nu$ simulations. Our main result is a measurement of the
amplitude of the lensing signal, $S_8=\sigma_8 \left(\Omega_m/0.3\right)^{0.5}
= 0.850^{+0.042}_{-0.050}$, consistent with values of this parameter derived
from the primary CMB. This constraint is artificially improved by a factor of
$51\%$ if we assume a more standard, but restrictive parameterization for the
redshift evolution and sample dependence of the intrinsic alignment signal, and
$63\%$ if we additionally assume the nonlinear alignment model. We show that
when fixing the cosmological model to the best-fit values from Planck PR4 there
is $> 5 \sigma$ evidence for a deviation of the evolution of the intrinsic
alignment signal from the functional form that is usually assumed in cosmic
shear and galaxy--galaxy lensing studies.
SNO+ is a large-scale liquid scintillator experiment with the primary goal of searching for neutrinoless double beta decay, and is located approximately 2 km underground in SNOLAB, Sudbury, Canada. ...The detector acquired data for two years as a pure water Cherenkov detector, starting in May 2017. During this period, the optical properties of the detector were measured in situ using a deployed light diffusing sphere, with the goal of improving the detector model and the energy response systematic uncertainties. The measured parameters included the water attenuation coefficients, effective attenuation coefficients for the acrylic vessel, and the angular response of the photomultiplier tubes and their surrounding light concentrators, all across different wavelengths. The calibrated detector model was validated using a deployed tagged gamma source, which showed a 0.6% variation in energy scale across the primary target volume.
This study examined the relationship of psychosocial factors and health behaviors to frequent dieting and purging behaviors in Native American adolescent boys and girls.
School-based health survey.
A ...total sample of 13 454 Native American youth in grades 7 through 12 living on or near reservations from eight Indian Health Service areas completed a self-report, school-based health questionnaire.
Almost half (48.3%) of the girls and one third (30.5%) of the boys had dieted in the past year. More than one fourth (28%) of the girls and 21% of the boys reported purging behavior of some type. Dieting frequency and purging status were associated with negative psychosocial factors and health risk behaviors. Dieting frequency in girls was associated with weight dissatisfaction, concerns about being overweight, high emotional stress, binge eating, alcohol use, tobacco use, suicide ideation and attempts, delinquent behaviors, and physical and sexual abuse. Purging status was positively and independently associated with negative psychosocial and health behavior risk factors. There were fewer significant relationships in boys.
Findings from this study suggest that dieting and purging are associated with similar psychosocial factors and health-compromising behaviors in Native American and white youth. Implications for future research and prevention programs are discussed.
PorB proteins constitute the vast majority of channels in neisserial outer membranes and can be subdivided within meningococcal strains into two distinct and mutually exclusive families that are ...designated as class 2 and class 3 proteins. We recently characterized the functional activity and conformational stability of a PorB class 2 protein from Neisseria meningitidis (Minetti, C. A. S. A., Tai, J. Y., Blake, M. S., Pullen, J. K., Liang, S. M., and Remeta, D. P. (1997)J. Biol. Chem. 272, 10710–10720). To evaluate the structure-function relatedness among the PorB proteins, we have employed a combination of electrophoretic and spectroscopic techniques to assess the conformational stability of zwittergent-solubilized class 3 trimers. The functional, physicochemical, and structural properties of the meningococcal class 2 and class 3 proteins are comparable with the notable exception that the latter exhibits a significantly higher susceptibility to SDS. The SDS-induced dissociation and partial unfolding of PorB class 3 is characterized by a single two-state transition with a midpoint at 0.35% SDS. The native trimeric assembly dissociates reversibly, forming partially folded monomers that retain the characteristic β-sheet content of the transmembrane domain with a concomitant increase in random coil structure arising from unfolding the rigid surface loops. These results provide new insight into the elucidation of porin folding pathways and the factors that govern the overall structural stability of meningococcal proteins.
BACKGROUND: The purpose of this study was to assess the efficacy and hatching characteristics of in-vitro cultured human embryos subjected to laser zona pellucida thinning. METHOD: Zona thinning was ...performed on 110 embryos using a non-contact 1.48 mum diode laser and the hatch rate in vitro was compared with 42 control embryos. Variation of zona thickness and degree of zona expansion was assessed. Scanning electron microscopy was performed on embryos entrapped during hatching to identify the site of hatching. RESULTS: The rate of hatching was significantly higher in laser thinned blastocysts compared with control embryos (68 versus 33% respectively, P < 0.01). Laser thinning increased the variation of zona thickness in embryos from 11.6-27.3%. Natural zona thinning occurred in 92% of laser thinned hatching blastocysts and 100% of control embryos. CONCLUSION: These results suggest that laser zona thinning is effective and may provide significant advantages over conventional assisted hatching techniques, which create holes.
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