Both sides now Wells, Amy Stuart; u.a
2009, 20081221, 2009-01-20
eBook, Book
This is the untold story of a generation that experienced one of the most extraordinary chapters in our nation's history-school desegregation. Many have attempted to define desegregation, which ...peaked in the late 1970s, as either a success or a failure; surprisingly few have examined the experiences of the students who lived though it. Featuring the voices of blacks, whites, and Latinos who graduated in 1980 from racially diverse schools,Both Sides Nowoffers a powerful firsthand account of how desegregation affected students-during high school and later in life. Their stories, set in a rich social and historical context, underscore the manifold benefits of school desegregation while providing an essential perspective on the current backlash against it.
Zoo-based (ex situ) conservation breeding programs provide invaluable opportunities to uncover enigmatic behaviors and traits of focal species under managed care, which can support research and ...conservation management efforts. A suite of factors and a limited range have yielded population declines in the threatened narrow-headed gartersnake (Thamnophis rufipunctatus). Better understanding its cryptic ecology and life history (e.g., reproductive ecology) offers conservation benefits. We analyzed data on courtship behavior, parity and litter size, offspring size, and neonatal growth from an ex situ T. rufipunctatus population at the Phoenix Zoo from 2009 to 2018. Courtship behavior and parturition phenology are likely linked with the North American monsoon season, yet the courtship window may be wider than realized. We document the first instances of interannual iteroparity and multigenerational rearing of successful breeders at the ex situ level. Litter sizes varied but were relative to maternal body mass, suggesting that fecundity may be driven by intrinsic condition (e.g., age and size) of breeding females. Mean offspring body masses were equivalent between sexes, and neonate growth trends were quadratic during their first 9 months. Sexual dimorphism became apparent around 4-5 months age. Much of these data are novel for T. rufipunctatus and provide insight into their reproductive ecology. Phenology of reproductive ecology and body size metrics can guide field surveillance, age estimations, and population ecology monitoring, as well as inform ex situ adaptive management practices. Strategies spanning the ex situ-in situ spectrum are applicable to other imperiled taxa to better inform conservation management decisions.
Removal of the basic piperazine nitrogen atom, introduction of a solubilising end group and partial reduction of the triazolopyridazine moiety in the previously-described lead androgen receptor ...downregulator 1 addressed hERG and physical property issues and led to clinical candidate AZD3514 (12), that is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.
Removal of the basic piperazine nitrogen atom, introduction of a solubilising end group and partial reduction of the triazolopyridazine moiety in the previously-described lead androgen receptor downregulator 6-4-(4-cyanobenzyl)piperazin-1-yl-3-(trifluoromethyl)1,2,4triazolo4,3-bpyridazine (1) addressed hERG and physical property issues, and led to clinical candidate 6-(4-{4-2-(4-acetylpiperazin-1-yl)ethoxyphenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro1,2,4triazolo4,3-bpyridazine (12), designated AZD3514, that is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.
The Arabian oryx (
Oryx leucoryx
) historically ranged across the Arabian Peninsula and neighboring countries until its extirpation in 1972. In 1963–1964 a captive breeding program for this species ...was started at the Phoenix Zoo (PHX); it ultimately consisted of 11 animals that became known as the ‘World Herd’. In 1978
–
1979 a wild population was established at the Shaumari Wildlife Reserve (SWR), Jordan, with eight descendants from the World Herd and three individuals from Qatar. We described the mtDNA and nuclear genetic diversity and structure of PHX and SWR. We also determined the long-term demographic and genetic viability of these populations under different reciprocal translocation scenarios. PHX displayed a greater number of mtDNA haplotypes (
n
= 4) than SWR (
n
= 2). Additionally, PHX and SWR presented nuclear genetic diversities of
N
¯
A
= 2.88 vs. 2.75,
H
¯
O
= 0.469 vs. 0.387, and
H
¯
E
= 0.501 vs. 0.421, respectively. Although these populations showed no signs of inbreeding (
F
¯
IS
≈ 0), they were highly differentiated (
G
ST
″
= 0.580;
P
< 0.001). Migration between PHX and SWR (
Nm
= 1, 4, and 8 individuals/generation) increased their genetic diversity in the short-term and substantially reduced the probability of extinction in PHX during 25 generations. Under such scenarios, maximum genetic diversities were achieved in the first generations before the effects of genetic drift became predominant. Although captive populations can function as sources of genetic variation for reintroduction programs, we recommend promoting mutual and continuous gene flow with wild populations to ensure the long-term survival of this species.
Two structurally distinct series of novel, MAPK-activated kinase-2 prevention of activation inhibitors have been discovered by high throughput screening. Preliminary structure–activity relationship ...(SAR) studies revealed substructural features that influence the selective inhibition of the activation by p38α of the downstream kinase MK2 in preference to an alternative substrate, MSK1. Enzyme kinetics, surface plasmon resonance (SPR), 2D protein NMR, and X-ray crystallography were used to determine the binding mode and the molecular mechanism of action. The compounds bind competitively to the ATP binding site of p38α but unexpectedly with higher affinity in the p38α–MK2 complex compared with p38α alone. This observation is hypothesized to be the origin of the substrate selectivity. The two lead series identified are suitable for further investigation for their potential to treat chronic inflammatory diseases with improved tolerability over previously studied p38α inhibitors.
Dipeptidyl nitrile inhibitors of Cathepsin L Asaad, Nabil; Bethel, Paul A.; Coulson, Michelle D. ...
Bioorganic & medicinal chemistry letters,
08/2009, Letnik:
19, Številka:
15
Journal Article
Recenzirano
A series of potent Cathepsin L inhibitors with good selectivity with respect to other cysteine Cathepsins is described and SAR is discussed with reference to the crystal structure of a protein-ligand ...complex.
New details on the east Antarctic gravity field from the Gravity Recovery and Climate Experiment (GRACE) mission reveal a prominent positive free‐air gravity anomaly over a roughly 500‐km diameter ...subglacial basin centered on (70°S, 120°E) in north central Wilkes Land. This regional inverse correlation between topography and gravity is quantitatively consistent with thinned crust from a giant meteorite impact underlain by an isostatically disturbed mantle plug. The inferred impact crater is nearly three times the size of the Chicxulub crater and presumably formed before the Cretaceous formation of the east Antarctic coast that cuts the projected ring faults. It extensively thinned and disrupted the Wilkes Land crust where the Kerguelen hot spot and Gondwana rifting developed but left the adjacent Australian block relatively undisturbed. The micrometeorite and fossil evidence suggests that the impact may have occurred at the beginning of the greatest extinction of life on Earth at ∼260 Ma when the Siberian Traps were effectively antipodal to it. Antipodal volcanism is common to large impact craters of the Moon and Mars and may also account for the antipodal relationships of essentially half of the Earth's large igneous provinces and hot spots. Thus, the impact may have triggered the “Great Dying” at the end of the Permian and contributed to the development of the hot spot that produced the Siberian Traps and now may underlie Iceland. The glacial ice up to a few kilometers thick that has covered the crater for the past 30–40 Ma poses formidable difficulties to sampling the subglacial geology. Thus, the most expedient and viable test of the prospective crater is to survey it for relevant airborne gravity and magnetic anomalies.
A growing body of school choice research has shown that when school choice policies are not designed to racially or socioeconomically integrate schools, that is, are “colorblind” policies, they ...generally manage to do the opposite, leading to greater stratification and separation of students by race and ethnicity across schools and programs. Since white, advantaged parents are more likely to get their children into the highest-status schools regardless of the school choice policy in place, we believed that more research was needed on how those parents interact with school choice policies and whether they would support changes to those policies that would lead to less segregation across schools. Our interviews with advantaged New York City parents suggest that many are bothered by the segregation but that they are concerned that their children gain access to the “best” (mostly white) schools. The contradictions inherent in their choices are reconcilable, we argue, by offering more diverse and undivided school options.
Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a ...number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.
N-Nitrosamine risk assessment of pharmaceuticals has moved from an initial focus on the potential presence of known small-molecule N-nitrosamines such as N-nitrosodimethylamine (NDMA) and ...N-nitrosodiethylamine (NDEA) in active substances toward the potential for generation of more complex nitrosamine drug substance-related impurities (NDSRIs) in drug products. While N-nitrosation of simple secondary amines is well-understood, more complex amines can undergo alternative reaction pathways that can be more challenging to predict. A number of such complex amines are known not to undergo N-nitrosation but are either unreactive or react by alternative pathways such as C-nitrosation or nitration to generate non-N-nitrosamine products. This article proposes a standard set of three orthogonal nitrosation forced degradation type reaction conditions that can be used to investigate the potential for generation of novel N-nitrosamines by nitrosation of complex amines. These complementary reaction conditions are considered to provide a thorough evaluation of the potential for N-nitrosamine formation from complex amines with respect to risk factors within pharmaceutical manufacturing. If, after investigation of nitrosation under the proposed conditions, formation and isolation of an N-nitrosamine is not possible, the resultant understanding of chemical reactivity and stability can be used to justify that the N-nitrosamine in question would not be expected to be generated from the complex amine in the drug substance or product. If an N-nitrosamine is formed under these reaction conditions, the information gained can be used as part of the risk assessment and also provides a starting point for the development of a process to synthesize a discrete sample for further testing. Additionally, synthetic and analytical considerations that should be taken into account during preparation of novel N-nitrosamines for use in analytical or toxicological studies are discussed.
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