324 research outputs found
Data arising from drilling investigations in the Loch Borralan intrusion, Sutherland, Scotland
3-Fluoro-4-hydroxyprolines:Synthesis, conformational analysis and stereoselective recognition by the VHL E3 ubiquitin ligase for targeted protein degradation
Hydroxylation and
fluorination of proline alters the pyrrolidine
ring pucker and the trans:cis amide bond ratio in a stereochemistry-dependent
fashion, affecting molecular recognition of proline-containing molecules
by biological systems. While hydroxyprolines and fluoroprolines are
common motifs in medicinal and biological chemistry, the synthesis
and molecular properties of prolines containing both modifications,
i.e., fluoro-hydroxyprolines, have not been described. Here we present
a practical and facile synthesis of all four diastereoisomers of 3-fluoro-4-hydroxyprolines
(F-Hyps), starting from readily available 4-oxo-l-proline
derivatives. Small-molecule X-ray crystallography, NMR spectroscopy,
and quantum mechanical calculations are consistent with fluorination
at C<sup>3</sup> having negligible effects on the hydrogen bond donor
capacity of the C<sup>4</sup> hydroxyl, but inverting the natural
preference of Hyp from C<sup>4</sup>-exo to C<sup>4</sup>-endo pucker.
In spite of this, F-Hyps still bind to the von Hippel–Lindau
(VHL) E3 ligase, which naturally recognizes C<sup>4</sup>-exo Hyp
in a stereoselective fashion. Co-crystal structures and electrostatic
potential calculations support and rationalize the observed preferential
recognition for (3<i>R</i>,4<i>S</i>)-F-Hyp over
the corresponding (3<i>S</i>,4<i>S</i>) epimer
by VHL. We show that (3<i>R</i>,4<i>S</i>)-F-Hyp
provides bioisosteric Hyp substitution in both hypoxia-inducible factor
1 alpha (HIF-1α) substrate peptides and peptidomimetic ligands
that form part of PROTAC (proteolysis targeting chimera) conjugates
for targeted protein degradation. Despite a weakened affinity, Hyp
substitution with (3<i>S</i>,4<i>S</i>)-F-Hyp
within the PROTAC MZ1 led to Brd4-selective cellular degradation at
concentrations >100-fold lower than the binary <i>K</i><sub>d</sub> for VHL. We anticipate that the disclosed chemistry
of 3-fluoro-4-hydroxyprolines
and their application as VHL ligands for targeted protein degradation
will be of wide interest to medicinal organic chemists, chemical biologists,
and drug discoverers alike
Efficacy of language intervention in the early years
Background: Oral language skills in the preschool and early school years are critical to educational
success and provide the foundations for the later development of reading comprehension.
Methods: In
a randomized controlled trial, 180 children from 15 UK nursery schools (n = 12 from each setting;
Mage = 4;0) were randomly allocated to receive a 30-week oral language intervention or to a waiting
control group. Children in the intervention group received 30 weeks of oral language intervention,
beginning in nursery (preschool), in three group sessions per week, continuing with daily sessions on
transition to Reception class (pre-Year 1). The intervention was delivered by nursery staff and teaching
assistants trained and supported by the research team. Following screening, children were assessed
preintervention, following completion of the intervention and after a 6-month delay.
Results: Children
in the intervention group showed significantly better performance on measures of oral language and
spoken narrative skills than children in the waiting control group immediately after the 30 week
intervention and after a 6 month delay. Gains in word-level literacy skills were weaker, though clear
improvements were observed on measures of phonological awareness. Importantly, improvements in
oral language skills generalized to a standardized measure of reading comprehension at maintenance
test.
Conclusions: Early intervention for children with oral language difficulties is effective and can
successfully support the skills, which underpin reading comprehensio
Extreme Ultra-Violet Spectroscopy of the Lower Solar Atmosphere During Solar Flares
The extreme ultraviolet portion of the solar spectrum contains a wealth of
diagnostic tools for probing the lower solar atmosphere in response to an
injection of energy, particularly during the impulsive phase of solar flares.
These include temperature and density sensitive line ratios, Doppler shifted
emission lines and nonthermal broadening, abundance measurements, differential
emission measure profiles, and continuum temperatures and energetics, among
others. In this paper I shall review some of the advances made in recent years
using these techniques, focusing primarily on studies that have utilized data
from Hinode/EIS and SDO/EVE, while also providing some historical background
and a summary of future spectroscopic instrumentation.Comment: 34 pages, 8 figures. Submitted to Solar Physics as part of the
Topical Issue on Solar and Stellar Flare
FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium
Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium.
Methods:Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression.
Results:Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95 confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2.
Conclusion:Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2. © 2014 Cancer Research UK
Representational predicaments for employees: Their impact on perceptions of supervisors\u27 individualized consideration and on employee job satisfaction
A representational predicament for a subordinate vis-à-vis his or her immediate superior involves perceptual incongruence with the superior about the subordinate\u27s work or work context, with unfavourable implications for the employee. An instrument to measure the incidence of two types of representational predicament, being neglected and negative slanting, was developed and then validated through an initial survey of 327 employees. A subsequent substantive survey with a fresh sample of 330 employees largely supported a conceptual model linking being neglected and negative slanting to perceptions of low individualized consideration by superiors and to low overall job satisfaction. The respondents in both surveys were all Hong Kong Chinese. Two case examples drawn from qualitative interviews illustrate and support the conceptual model. Based on the research findings, we recommend some practical exercises to use in training interventions with leaders and subordinates. © 2013 Copyright Taylor and Francis Group, LLC
Microflares and the Statistics of X-ray Flares
This review surveys the statistics of solar X-ray flares, emphasising the new
views that RHESSI has given us of the weaker events (the microflares). The new
data reveal that these microflares strongly resemble more energetic events in
most respects; they occur solely within active regions and exhibit
high-temperature/nonthermal emissions in approximately the same proportion as
major events. We discuss the distributions of flare parameters (e.g., peak
flux) and how these parameters correlate, for instance via the Neupert effect.
We also highlight the systematic biases involved in intercomparing data
representing many decades of event magnitude. The intermittency of the
flare/microflare occurrence, both in space and in time, argues that these
discrete events do not explain general coronal heating, either in active
regions or in the quiet Sun.Comment: To be published in Space Science Reviews (2011
Fine-Scale Mapping of the 5q11.2 Breast Cancer Locus Reveals at Least Three Independent Risk Variants Regulating MAP3K1
Peer reviewe
Refined histopathological predictors of BRCA1 and BRCA2 mutation status: A large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia
Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the
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