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91.
Birong Zhang James R. Kiefer Robert A. Blake Jae H. Chang Steven Hartman Ellen Rei Ingalla Tracy Kleinheinz Vidhi Mody Michelle Nannini Daniel F. Ortwine Yingqing Ran Amy Sambrone Deepak Sampath Maia Vinogradova Yu Zhong Jerome C. Nwachukwu Kendall W. Nettles Tommy Lai Jun Liang 《Bioorganic & medicinal chemistry letters》2019,29(7):905-911
Despite tremendous progress made in the understanding of the ERα signaling pathway and the approval of many therapeutic agents, ER+?breast cancer continues to be a leading cause of cancer death in women. We set out to discover compounds with a dual mechanism of action in which they not only compete with estradiol for binding with ERα, but also can induce the degradation of the ERα protein itself. We were attracted to the constrained chromenes containing a tetracyclic benzopyranobenzoxepine scaffold, which were reported as potent selective estrogen receptor modulators (SERMs). Incorporation of a fluoromethyl azetidine side chain yielded highly potent and efficacious selective estrogen receptor degraders (SERDs), such as 16aa and surprisingly, also its enantiomeric pair 16ab. Co-crystal structures of the enantiomeric pair 16aa and 16ab in complex with ERα revealed default (mimics the A-D rings of endogenous ligand estradiol) and core-flipped binding modes, rationalizing the equivalent potency observed for these enantiomers in the ERα degradation and MCF-7 anti-proliferation assays. 相似文献
92.
James T. Lamer Blake C. Ruebush Michael A. McClelland John M. Epifanio Greg G. Sass 《Ecology and evolution》2019,9(16):8978-8986
Invasive bighead (Hypophthalmichthys nobilis) and silver carp (H. molitrix) are reproductively isolated in their native range, but form a bimodal, multigenerational hybrid swarm within the Mississippi River Basin (MRB). Despite observed F1 hybrid superiority in experimental settings, effects of postzygotic selection on bighead and silver carp hybrids have not been tested in a natural system. Individual parent and hybrid genotypes were resolved at 57 species‐specific loci and used to evaluate postzygotic selection for body condition (Wr) and female reproductive potential (presence of spawning stage gonads and gonadosomatic index [GSI]) in the MRB during 2009–2011. Body condition in the Marseilles Reach, Illinois River declined with a decrease in species‐specific allele frequency from 1.0 to 0.4 for each species and early generation hybrids (F1, F2, and first‐generation backcross) had lower mean Wr than late generation hybrids (2nd+ generation backcrosses) and parentals. Proportions of stage IV and stage V (spawning stage) female gonads differed between bighead and silver carp, but not among parentals and their early and late generation hybrids within the MRB. Mean GSI values did not differ between parentals and hybrids. Because reproductive potential did not differ between hybrids and parentals, our results suggest that early generation hybrids occur in low frequency either as a factor of poor condition (Wr) and postreproductive survival, infrequent reproductive encounters by parental bighead and silver carp, or selection pressures acting on juvenile or immature life stages. Our results suggest that a combination of genetic and environmental factors may contribute to the postzygotic success of bighead and silver carp hybrids in the Mississippi River Basin. 相似文献
93.
Dystroglycan regulates structure, proliferation and differentiation of neuroepithelial cells in the developing vertebrate CNS 总被引:1,自引:0,他引:1
Schröder JE Tegeler MR Grosshans U Porten E Blank M Lee J Esapa C Blake DJ Kröger S 《Developmental biology》2007,307(1):62-78
In the developing CNS alpha- and beta-dystroglycan are highly concentrated in the endfeet of radial neuroepithelial cells at the contact site to the basal lamina. We show that injection of anti-dystroglycan Fab fragments, knockdown of dystroglycan using RNAi, and overexpression of a dominant-negative dystroglycan protein by microelectroporation in neuroepithelial cells of the chick retina and optic tectum in vivo leads to the loss of their radial morphology, to hyperproliferation, to an increased number of postmitotic neurons, and to an altered distribution of several basally concentrated proteins. Moreover, these treatments also altered the oriented growth of axons from retinal ganglion cells and from tectal projection neurons. In contrast, expression of non-cleavable dystroglycan protein in neuroepithelial cells reduced their proliferation and their differentiation to postmitotic neurons. These results demonstrate that dystroglycan plays a key role in maintaining neuroepithelial cell morphology, and that interfering with dystroglycan function influences proliferation and differentiation of neuroepithelial cells. These data also suggest that an impaired dystroglycan function in neuroepithelial cells might be responsible for some of the severe brain abnormalities observed in certain forms of congenital muscular dystrophy. 相似文献
94.
95.
M.J. Siegert A. Behar M. Bentley D. Blake S. Bowden P. Christoffersen C. Cockell H. Corr D. C. Cullen H. Edwards A. Ellery C. Ellis-Evans G. Griffiths R. Hindmarsh D. A. Hodgson E. King H. Lamb L. Lane K. Makinson M. Mowlem J. Parnell D. A. Pearce J. Priscu A. Rivera M. A. Sephton M. R. Sims A . M. Smith M. Tranter J. L. Wadham G. Wilson J. Woodward 《Reviews in Environmental Science and Biotechnology》2007,6(1-3):161-179
Antarctic subglacial lakes have, over the past few years, been hypothesised to house unique forms of life and hold detailed
sedimentary records of past climate change. Testing this hypothesis requires in situ examinations. The direct measurement
of subglacial lakes has been considered ever since the largest and best-known lake, named Lake Vostok, was identified as having
a deep water-column. The Subglacial Antarctic Lake Environments (SALE) programme, set up by the Scientific Committee on Antarctic
Research (SCAR) to oversee subglacial lakes research, state that prior exploration of smaller lakes would be a “prudent way
forward”. Over 145 subglacial lakes are known to exist in Antarctica, but one lake in West Antarctica, officially named Ellsworth
Subglacial Lake (referred to hereafter as Lake Ellsworth), stands out as a candidate for early exploration. A consortium of
over 20 scientists from seven countries and 14 institutions has been assembled to plan the exploration of Lake Ellsworth.
An eight-year programme is envisaged: 3 years for a geophysical survey, 2 years for equipment development and testing, 1 year
for field planning and operation, and 2 years for sample analysis and data interpretation. The science experiment is simple
in concept but complex in execution. Lake Ellsworth will be accessed using hot water drilling. Once lake access is achieved,
a probe will be lowered down the borehole and into the lake. The probe will contain a series of instruments to measure biological,
chemical and physical characteristics of the lake water and sediments, and will utilise a tether to the ice surface through
which power, communication and data will be transmitted. The probe will pass through the water column to the lake floor. The
probe will then be pulled up and out of the lake, measuring its environment continually as this is done. Once at the ice surface,
any water samples collected will be taken from the probe for laboratory analysis (to take place over subsequent years). The
duration of the science mission, from deployment of the probe to its retrieval, is likely to take between 24 and 36 h. Measurements
to be taken by the probe will provide data about the following: depth, pressure, conductivity and temperature; pH levels;
biomolecules (using life marker chips); anions (using a chemical analyzer); visualisation of the environment (using cameras
and light sources); dissolved gases (using chromatography); and morphology of the lake floor and sediment structures (using
sonar). After the probe has been retrieved, a sediment corer may be dropped into the lake to recover material from the lake
floor. Finally, if time permits, a thermistor string may be left in the lake water to take time-dependent measurements of
the lake’s water column over subsequent years. Given that the comprehensive geophysical survey of the lake will take place
in two seasons during 2007–2009, a two-year instrument and logistic development phase from 2008 (after the lake’s bathymetry
has been assessed) makes it possible that the exploration of Lake Ellsworth could take place at the beginning of the next
decade. 相似文献
96.
Current literature related to the impact of probiotics on the incidence of gastrointestinal tract infections (GITIs) has shown mixed results and no systematic review available with pooled analysis exists. Thus, the aim of this systematic review was to provide contemporary evidence regarding the overall and strain-specific influence of probiotics in preventing GITIs among infants and children attending childcare centres. The review shortlisted 18 RCTs after screening through the initial search results of 779 articles. However, only 15 trials were deemed eligible, addressing at least one outcome in the pooled analysis. It is concluded that the supplementation of probiotics (overall effect) may reduce the risk of GITI episode by 26%, with Lacticaseibacillus paracasei, Limosilactobacillus reuteri and Lacticaseibacillus rhamnosus GG being specifically potent probiotic strains in reducing GITI episode, duration of infection and absence from childcare respectively. There is insufficient evidence to determine the effect of Bifidobacterium animalis subsp. lactis BB-12 based on the findings of the trials included in this review. 相似文献
97.
Alptekin Burcu Erfatpour Mohammad Mangel Dylan Pauli Duke Blake Tom Turner Hannah Lachowiec Jennifer Sherman Jamie Fischer Andreas 《Molecular breeding : new strategies in plant improvement》2022,42(10):1-15
Molecular Breeding - Maize amylose is a type of high value-added starch used for medical, food, and chemical applications. Mutations in the starch branching enzyme (SBEIIb), with recessive ae... 相似文献
98.
Kimberly J. Blake Barry Hoopengardner Alejandro Centurion Stephen L. Helfand 《Genesis (New York, N.Y. : 2000)》1996,18(2):125-130
The separation of adult from pre-adult life seen with animals such as Drosophila melanogaster, which are holometabolous and undergo complete metamorphosis, provides the opportunity to examine the contribution of pre-adult rate of development on the rate of maturation and aging of the adult. Recent work has shown that when ambient temperature is used to alter the rate of development there is little effect on adult life span. From this work it has been concluded that the rate of aging is largely independent of the rate of pre-adult development. However, the techniques used to examine life span did not allow for the examination of the earliest events of adult life. Our experimental design used a molecular marker linked to life span as a sensitive measure of determining physiological age. In this way, we were able to evaluate the effect of pre-adult rate of development on the earliest events of adult life. Using ambient temperature to alter both the rate of development in the pre-adult and the rate of aging in the adult independently, we were able to show that it is the ambient temperature at which the adults are living that is the principle determinant of the rate of maturation and aging of the adult. Little effect was seen on the rate of adult maturation in response to an acceleration or a slowing down of the rate of pre-adult development as measured by our molecular marker. These data support the conclusions drawn by others who examined the effect of the rate of development on adult life expectancy. The timing mechanisms at work during pre-adult and adult life appear to be largely regulated separately. If there is such a thing as a physiological clock, it appears to be reset upon eclosion. © 1996 Wiley-Liss, Inc. 相似文献
99.
Rebecca Oester Ryan Greenway Marvin Moosmann Ruben Sommaruga Barbara Tartarotti Jakob Brodersen Blake Matthews 《Ecology and evolution》2022,12(4)
Trait expression of natural populations often jointly depends on prevailing abiotic environmental conditions and predation risk. Copepods, for example, can vary their expression of compounds that confer protection against ultraviolet radiation (UVR), such as astaxanthin and mycosporine‐like amino acids (MAAs), in relation to predation risk. Despite ample evidence that copepods accumulate less astaxanthin in the presence of predators, little is known about how the community composition of planktivorous fish can affect the overall expression of photoprotective compounds. Here, we investigate how the (co‐)occurrence of Arctic charr (Salvelinus alpinus) and threespine stickleback (Gasterosteus aculeatus) affects the photoprotective phenotype of the copepod Leptodiaptomus minutus in lake ecosystems in southern Greenland. We found that average astaxanthin and MAA contents were lowest in lakes with stickleback, but we found no evidence that these photoprotective compounds were affected by the presence of charr. Furthermore, variance in astaxanthin among individual copepods was greatest in the presence of stickleback and the astaxanthin content of copepods was negatively correlated with increasing stickleback density. Overall, we show that the presence and density of stickleback jointly affect the content of photoprotective compounds by copepods, illustrating how the community composition of predators in an ecosystem can determine the expression of prey traits that are also influenced by abiotic stressors. 相似文献