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Ibrutinib inhibits platelet integrin αIIbÎČ3 outside-in signaling and thrombus stability but not adhesion to collagen
OBJECTIVE:
Ibrutinib is an irreversible Bruton tyrosine kinase inhibitor approved for treatment of Waldenstrom macroglobulinemia, chronic lymphocytic leukemia, and mantle cell lymphoma that increases the risk of bleeding among patients. Platelets from ibrutinib-treated patients exhibit deficiencies in collagen-evoked signaling in suspension; however, the significance of this observation and how it relates to bleeding risk is unclear, as platelets encounter immobile collagen in vivo. We sought to clarify the effects of ibrutinib on platelet function to better understand the mechanism underlying bleeding risk.
APPROACH AND RESULTS:
By comparing signaling in suspension and during adhesion to immobilized ligands, we found that the collagen signaling deficiency caused by ibrutinib is milder during adhesion to immobilized collagen. We also found that platelets in whole blood treated with ibrutinib adhered to collagen under arterial shear but formed unstable thrombi, suggesting that the collagen signaling deficiency caused by ibrutinib may not be the predominant cause of bleeding in vivo. However, clot retraction and signaling evoked by platelet adhesion to immobilized fibrinogen were also inhibited by ibrutinib, indicating that integrin αIIbÎČ3 outside-in signaling is also effected in addition to GPVI signaling. When ibrutinib was combined with the P2Y12 inhibitor, cangrelor, thrombus formation under arterial shear was inhibited additively.
CONCLUSIONS:
These findings suggest that (1) ibrutinib causes GPVI and integrin αIIbÎČ3 platelet signaling deficiencies that result in formation of unstable thrombi and may contribute toward bleeding observed in vivo and (2) combining ibrutinib with P2Y12 antagonists, which also inhibit thrombus stability, may have a detrimental effect on hemostasis
Sexual epigenetic dimorphism in the human placenta: implications for susceptibility during the prenatal period
Sex-based differences in response to adverse prenatal environments and infant outcomes have been observed, yet the underlying mechanisms for this are unclear. The placental epigenome may be a driver of these differences
Convergent evolution of toxin resistance in animals
Convergence is the phenomenon whereby similar phenotypes evolve independently in different lineages. One example is resistance to toxins in animals. Toxins have evolved many times throughout the tree of life. They disrupt molecular and physiological pathways in target species, thereby incapacitating prey or deterring a predator. In response, molecular resistance has evolved in many species exposed to toxins to counteract their harmful effects. Here, we review current knowledge on the convergence of toxin resistance using examples from a wide range of toxin families. We explore the evolutionary processes and molecular adaptations driving toxin resistance. However, resistance adaptations may carry a fitness cost if they disrupt the normal physiology of the resistant animal. Therefore, there is a tradeâoff between maintaining a functional molecular target and reducing toxin susceptibility. There are relatively few solutions that satisfy this tradeâoff. As a result, we see a small set of molecular adaptations appearing repeatedly in diverse animal lineages, a phenomenon that is consistent with models of deterministic evolution. Convergence may also explain what has been called âautoresistanceâ. This is often thought to have evolved for selfâprotection, but we argue instead that it may be a consequence of poisonous animals feeding on toxic prey. Toxin resistance provides a unique and compelling model system for studying the interplay between trophic interactions, selection pressures and the molecular mechanisms underlying evolutionary novelties
Analysis of Neptune's 2017 Bright Equatorial Storm
We report the discovery of a large (8500 km diameter) infrared-bright
storm at Neptune's equator in June 2017. We tracked the storm over a period of
7 months with high-cadence infrared snapshot imaging, carried out on 14 nights
at the 10 meter Keck II telescope and 17 nights at the Shane 120 inch reflector
at Lick Observatory. The cloud feature was larger and more persistent than any
equatorial clouds seen before on Neptune, remaining intermittently active from
at least 10 June to 31 December 2017. Our Keck and Lick observations were
augmented by very high-cadence images from the amateur community, which
permitted the determination of accurate drift rates for the cloud feature. Its
zonal drift speed was variable from 10 June to at least 25 July, but remained a
constant m s from 30 September until at least 15
November. The pressure of the cloud top was determined from radiative transfer
calculations to be 0.3-0.6 bar; this value remained constant over the course of
the observations. Multiple cloud break-up events, in which a bright cloud band
wrapped around Neptune's equator, were observed over the course of our
observations. No "dark spot" vortices were seen near the equator in HST imaging
on 6 and 7 October. The size and pressure of the storm are consistent with
moist convection or a planetary-scale wave as the energy source of convective
upwelling, but more modeling is required to determine the driver of this
equatorial disturbance as well as the triggers for and dynamics of the observed
cloud break-up events.Comment: 42 pages, 14 figures, 6 tables; Accepted to Icaru
Ultra-Slow Light and Enhanced Nonlinear Optical Effects in a Coherently Driven Hot Atomic Gas
We report the observation of small group velocities of order 90 meters per
second, and large group delays of greater than 0.26 ms, in an optically dense
hot rubidium gas (~360 K). Media of this kind yield strong nonlinear
interactions between very weak optical fields, and very sharp spectral
features. The result is in agreement with previous studies on nonlinear
spectroscopy of dense coherent media
Survey of the quality of experimental design, statistical analysis and reporting of research using animals
For scientific, ethical and economic reasons, experiments involving animals should be appropriately designed, correctly analysed and transparently reported. This increases the scientific validity of the results, and maximises the knowledge gained from each experiment. A minimum amount of relevant information must be included in scientific publications to ensure that the methods and results of a study can be reviewed, analysed and repeated. Omitting essential information can raise scientific and ethical concerns. We report the findings of a systematic survey of reporting, experimental design and statistical analysis in published biomedical research using laboratory animals. Medline and EMBASE were searched for studies reporting research on live rats, mice and non-human primates carried out in UK and US publicly funded research establishments. Detailed information was collected from 271 publications, about the objective or hypothesis of the study, the number, sex, age and/or weight of animals used, and experimental and statistical methods. Only 59% of the studies stated the hypothesis or objective of the study and the number and characteristics of the animals used. Appropriate and efficient experimental design is a critical component of high-quality science. Most of the papers surveyed did not use randomisation (87%) or blinding (86%), to reduce bias in animal selection and outcome assessment. Only 70% of the publications that used statistical methods described their methods and presented the results with a measure of error or variability. This survey has identified a number of issues that need to be addressed in order to improve experimental design and reporting in publications describing research using animals. Scientific publication is a powerful and important source of information; the authors of scientific publications therefore have a responsibility to describe their methods and results comprehensively, accurately and transparently, and peer reviewers and journal editors share the responsibility to ensure that published studies fulfil these criteria
Cosmology in the Next Millennium: Combining MAP and SDSS Data to Constrain Inflationary Models
The basic cosmological parameters and the primordial power spectrum together
completely specify predictions for the cosmic microwave background radiation
anisotropy and large scale structure. Here we show how we can strongly
constrain both and the cosmological parameters by combining the data
from the Microwave Anisotropy Probe (MAP) and the galaxy redshift survey from
the Sloan Digital Sky Survey (SDSS). We allow to be a free function,
and thus probe features in the primordial power spectrum on all scales. The
primordial power spectrum in 20 steps in to Mpc can
be determined to accuracy for Mpc, and to accuracy for Mpc. The uncertainty in the primordial
power spectrum increases by a factor up to 3 on small scales if we solve
simultaneously for the dimensionless Hubble constant , the cosmological
constant , the baryon fraction , the reionization optical
depth , and the effective bias between the matter density field and
the redshift space galaxy density field . Alternately, if we
restrict to be a power law, we find that inclusion of the SDSS data
breaks the degeneracy between the amplitude of the power spectrum and the
optical depth inherent in the MAP data, significantly reduces the uncertainties
in the determination of the matter density and the cosmological constant, and
allows a determination of the galaxy bias parameter. Thus, combining the MAP
and SDSS data allows the independent measurement of important cosmological
parameters, and a measurement of the primordial power spectrum independent of
inflationary models, giving us valuable information on physics in the early
Universe, and providing clues to the correct inflationary model.Comment: Substantial revisions to quantitative results as a result of more
accurate calculation of derivatives; these new numerical results strengthen
but do not change our qualitative results. Minor changes in wording. Several
references added. Final version, to appear in ApJ January 1, 1999 issue, Vol.
510 #
The clustering of massive galaxies at z~0.5 from the first semester of BOSS data
We calculate the real- and redshift-space clustering of massive galaxies at
z~0.5 using the first semester of data by the Baryon Oscillation Spectroscopic
Survey (BOSS). We study the correlation functions of a sample of 44,000 massive
galaxies in the redshift range 0.4<z<0.7. We present a halo-occupation
distribution modeling of the clustering results and discuss the implications
for the manner in which massive galaxies at z~0.5 occupy dark matter halos. The
majority of our galaxies are central galaxies living in halos of mass
10^{13}Msun/h, but 10% are satellites living in halos 10 times more massive.
These results are broadly in agreement with earlier investigations of massive
galaxies at z~0.5. The inferred large-scale bias (b~2) and relatively high
number density (nbar=3e-4 h^3 Mpc^{-3}) imply that BOSS galaxies are excellent
tracers of large-scale structure, suggesting BOSS will enable a wide range of
investigations on the distance scale, the growth of large-scale structure,
massive galaxy evolution and other topics.Comment: 11 pages, 12 figures, matches version accepted by Ap
Deletion of SA ÎČ-Gal+ Cells Using Senolytics Improves Muscle Regeneration in Old Mice
Systemic deletion of senescent cells leads to robust improvements in cognitive, cardiovascular, and whole-body metabolism, but their role in tissue reparative processes is incompletely understood. We hypothesized that senolytic drugs would enhance regeneration in aged skeletal muscle. Young (3 months) and old (20 months) male C57Bl/6J mice were administered the senolytics dasatinib (5 mg/kg) and quercetin (50 mg/kg) or vehicle bi-weekly for 4 months. Tibialis anterior (TA) was then injected with 1.2% BaCl2 or PBS 7- or 28 days prior to euthanization. Senescence-associated ÎČ-Galactosidase positive (SA ÎČ-Gal+) cell abundance was low in muscle from both young and old mice and increased similarly 7 days following injury in both age groups, with no effect of D+Q. Most SA ÎČ-Gal+ cells were also CD11b+ in young and old mice 7- and 14 days following injury, suggesting they are infiltrating immune cells. By 14 days, SA ÎČ-Gal+/CD11b+ cells from old mice expressed senescence genes, whereas those from young mice expressed higher levels of genes characteristic of anti-inflammatory macrophages. SA ÎČ-Gal+ cells remained elevated in old compared to young mice 28 days following injury, which were reduced by D+Q only in the old mice. In D+Q-treated old mice, muscle regenerated following injury to a greater extent compared to vehicle-treated old mice, having larger fiber cross-sectional area after 28 days. Conversely, D+Q blunted regeneration in young mice. In vitro experiments suggested D+Q directly improve myogenic progenitor cell proliferation. Enhanced physical function and improved muscle regeneration demonstrate that senolytics have beneficial effects only in old mice
Dietary Supplementation with Soluble Plantain Non-Starch Polysaccharides Inhibits Intestinal Invasion of Salmonella Typhimurium in the Chicken
Soluble fibres (non-starch polysaccharides, NSP) from edible plants but particularly plantain banana (Musa spp.), have been shown in vitro and ex vivo to prevent various enteric pathogens from adhering to, or translocating across, the human intestinal epithelium, a property that we have termed contrabiotic. Here we report that dietary plantain fibre prevents invasion of the chicken intestinal mucosa by Salmonella. In vivo experiments were performed with chicks fed from hatch on a pellet diet containing soluble plantain NSP (0 to 200 mg/d) and orally infected with S.Typhimurium 4/74 at 8 d of age. Birds were sacrificed 3, 6 and 10 d post-infection. Bacteria were enumerated from liver, spleen and caecal contents. In vitro studies were performed using chicken caecal crypts and porcine intestinal epithelial cells infected with Salmonella enterica serovars following pre-treatment separately with soluble plantain NSP and acidic or neutral polysaccharide fractions of plantain NSP, each compared with saline vehicle. Bacterial adherence and invasion were assessed by gentamicin protection assay. In vivo dietary supplementation with plantain NSP 50 mg/d reduced invasion by S.Typhimurium, as reflected by viable bacterial counts from splenic tissue, by 98.9% (95% CI, 98.1â99.7; P<0.0001). In vitro studies confirmed that plantain NSP (5â10 mg/ml) inhibited adhesion of S.Typhimurium 4/74 to a porcine epithelial cell-line (73% mean inhibition (95% CI, 64â81); P<0.001) and to primary chick caecal crypts (82% mean inhibition (95% CI, 75â90); P<0.001). Adherence inhibition was shown to be mediated via an effect on the epithelial cells and Ussing chamber experiments with ex-vivo human ileal mucosa showed that this effect was associated with increased short circuit current but no change in electrical resistance. The inhibitory activity of plantain NSP lay mainly within the acidic/pectic (homogalacturonan-rich) component. Supplementation of chick feed with plantain NSP was well tolerated and shows promise as a simple approach for reducing invasive salmonellosis
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