The fine equilibrium of bone homeostasis is maintained by bone-forming osteoblasts and bone-resorbing osteoclasts. Here, we show that TAM receptors MERTK and TYRO3 exert reciprocal effects in ...osteoblast biology: Osteoblast-targeted deletion of MERTK promotes increased bone mass in healthy mice and mice with cancer-induced bone loss, whereas knockout of TYRO3 in osteoblasts shows the opposite phenotype. Functionally, the interaction of MERTK with its ligand PROS1 negatively regulates osteoblast differentiation via inducing the VAV2-RHOA-ROCK axis leading to increased cell contractility and motility while TYRO3 antagonizes this effect. Consequently, pharmacologic MERTK blockade by the small molecule inhibitor R992 increases osteoblast numbers and bone formation in mice. Furthermore, R992 counteracts cancer-induced bone loss, reduces bone metastasis and prolongs survival in preclinical models of multiple myeloma, breast- and lung cancer. In summary, MERTK and TYRO3 represent potent regulators of bone homeostasis with cell-type specific functions and MERTK blockade represents an osteoanabolic therapy with implications in cancer and beyond.
Immunotherapy promotes the attack of cancer cells by the immune system; however, it is difficult to detect early responses before changes in tumor size occur. Here, we report the rational design of a ...fluorogenic peptide able to detect picomolar concentrations of active granzyme B as a biomarker of immune-mediated anticancer action. Through a series of chemical iterations and molecular dynamics simulations, we synthesize a library of FRET peptides and identify probe H5 with an optimal fit into granzyme B. We demonstrate that probe H5 enables the real-time detection of T cell-mediated anticancer activity in mouse tumors and in tumors from lung cancer patients. Furthermore, we show image-based phenotypic screens, which reveal that the AKT kinase inhibitor AZD5363 shows immune-mediated anticancer activity. The reactivity of probe H5 may enable the monitoring of early responses to anticancer treatments using tissue biopsies.
Brain amyloidosis does not invariably predict dementia. We hypothesized that high soluble 42-amino acid β amyloid (Aβ42) peptide levels are associated with normal cognition and hippocampal volume ...despite increasing brain amyloidosis.
This cross-sectional study of 598 amyloid-positive participants in the Alzheimer's Disease Neuroimaging Initiative cohort examined whether levels of soluble Aβ42 are higher in amyloid-positive normal cognition (NC) individuals compared to mild cognitive impairment (MCI) and Alzheimer's disease (AD) and whether this relationship applies to neuropsychological assessments and hippocampal volume measured within the same year. All subjects were evaluated between June 2010 and February 2019. Brain amyloid positivity was defined as positron emission tomography-based standard uptake value ratio (SUVR) ≥1.08 for 18 F-florbetaben or 1.11 for 18F-florbetapir, with higher SUVR indicating more brain amyloidosis. Analyses were adjusted for age, sex, education, APOE4, p-tau, t-tau, and centiloids levels.
Higher soluble Aβ42 levels were observed in NC (864.00 pg/ml) than in MCI (768.60 pg/ml) or AD (617.46 pg/ml), with the relationship between NC, MCI, and AD maintained across all amyloid tertiles. In adjusted analysis, there was a larger absolute effect size of soluble Aβ42 than SUVR for NC (0.82 vs. 0.40) and MCI (0.60 vs. 0.26) versus AD. Each standard deviation increase in Aβ42 was associated with greater odds of NC than AD (adjusted odds ratio, 6.26; p < 0.001) or MCI (1.42; p = 0.006). Higher soluble Aβ42 levels were also associated with better neuropsychological function and larger hippocampal volume.
Normal cognition and hippocampal volume are associated with preservation of high soluble Aβ42 levels despite increasing brain amyloidosis.
Please refer to the Funding section at the end of the article.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Syntectonic microstructural evolution is a well‐known phenomenon in the mantle and lower crust associated with two main processes: grain size reduction through dynamic recrystallization and ...development of crystallographic preferred orientation (CPO). However, the effects of annealing via static recrystallization on grain size and CPO have been largely overlooked. We investigated mantle annealing by analyzing a suite of kimberlite‐hosted garnet peridotite xenoliths from the Wyoming Craton. We focus on five xenoliths that show microstructures reflecting different degrees of recrystallization, with annealed grains characterized by distinctive faceted boundaries crosscutting surrounding, nonfaceted matrix grains. These textures are indicative of discontinuous static recrystallization (DiSRX). Electron backscatter diffraction analysis further demonstrates a ∼10°–20° misorientation between DiSRXed grains and the matrix grains, resulting in an overall weaker CPO. These characteristics are remarkably similar to microstructures observed in samples that were annealed after deformation in the laboratory. Measurements of the thermal conditions and water contents associated with the last equilibration of the xenoliths suggests that high homologous temperatures (T/Tm > 0.9) are necessary to induce DiSRX. We postulate that annealing through DiSRX occurs under high temperatures after a short episode of intense deformation (years to hundreds of years) with timescales for annealing estimated as weeks to years, significantly slower than the timescale of hours expected for a kimberlitic magma ascent. We conclude that microstructural transformation due to DiSRX will occur during transient heating events associated with mantle upwelling, plumes, and lithospheric thinning.
Plain Language Summary
Our knowledge of large‐scale processes in the mantle requires the understanding of mantle microstructures and their evolution under different conditions. During deformation and flow, grain size often decreases and rocks develop a preferred orientation of their crystallographic structure; features that correlate with the flow stress and strain magnitudes. However, there is a lack of knowledge regarding how the microstructure (e.g., grain size and crystallographic orientation) may change when deformation ceases—which promotes annealing. We investigate microstructures of mantle samples (xenoliths brought to the surface by volcanism) that experienced annealing. The partially annealed samples display evidence for a process in which some grains grow at the expense of others, resulting in a significant change to the preexisting microstructure. A comparison of the naturally annealed samples to samples that were deformed and then annealed in the laboratory reveals remarkable similarities. We discuss our results in the context of the timescales and conditions necessary to induce the relevant annealing mechanism, and demonstrate that a shift in microstructure occurs when deformed mantle undergoes a stage of heating.
Key Points
Mantle annealing under certain conditions induces discontinuous recrystallization altering its microstructure
Xenoliths from Wyoming craton show annealing microstructures similar to experiments of deformation followed by annealing
Conditions of high stresses and temperatures induce static recrystallization with calculated timescale of a week to a year
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Significance International concern about the consequences of human-induced global environmental changes has prompted a renewed focus on reducing ecological effects of biological invasions, climate ...change, and nutrient pollution. Our results show that the combined effects of nonnative species invasions and abiotic global environmental changes are often negative but no worse than invasion impacts alone. Invasion impacts are also more strongly detrimental than warming temperatures or nitrogen deposition, two common stressors. Thus, reducing the spread of invasive species is critical for mitigating harms from anthropogenic changes to global ecosystems.
Knockout (KO) mouse models play critical roles in elucidating biological processes behind disease-associated or disease-resistant traits. As a presumed consequence of gene KO, mice display certain ...phenotypes. Based on insight into the molecular role of said gene in a biological process, it is inferred that the particular biological process causally underlies the trait. This approach has been crucial towards understanding the basis of pathological and/or advantageous traits associated with
KO mice.
KO mice suffer from severe, early-onset retinal degeneration. MERTK, expressed in retinal pigment epithelia, is a receptor tyrosine kinase with a critical role in phagocytosis of apoptotic cells or cellular debris. Therefore, early-onset, severe retinal degeneration was described to be a direct consequence of failed MERTK-mediated phagocytosis of photoreceptor outer segments by retinal pigment epithelia. Here, we report that the loss of
alone is not sufficient for retinal degeneration. The widely used
KO mouse carries multiple coincidental changes in its genome that affect the expression of a number of genes, including the
paralog
. Retinal degeneration manifests only when the function of
is concomitantly lost. Furthermore,
KO mice display improved anti-tumor immunity. MERTK is expressed in macrophages. Therefore, enhanced anti-tumor immunity was inferred to result from the failure of macrophages to dispose of cancer cell corpses, resulting in a pro-inflammatory tumor microenvironment. The resistance against two syngeneic mouse tumor models observed in
KO mice is not, however, phenocopied by the loss of
alone. Neither
nor macrophage phagocytosis by alternate genetic redundancy accounts for the absence of anti-tumor immunity. Collectively, our results indicate that context-dependent epistasis of independent modifier alleles determines
KO traits.
Xenoliths play a crucial role in interpretation of mantle deformation and geochemistry. The classic work of Mercier and Nicolas (1975) introduced the concept of the peridotite deformation cycle, ...which connected observed microstructures to a physical sequence of deformation. We revisit Mercier and Nicolas' original concept, bringing in new constraints using large area EBSD maps and associated microstructural datasets, analysis of water contents in nominally anhydrous minerals, and trace element chemistry of pyroxenes and garnets. We apply these techniques to a well-characterized suite of peridotite xenoliths from the Eocene-age Homestead and Williams kimberlites in the northwestern Wyoming Craton. Pyroxene water content and trace element mineral chemistries reveal ubiquitous hydrous metasomatism beneath the craton, most likely linked to the Cenozoic Laramide Orogeny. Homestead xenoliths primarily exhibit coarse protogranular and equigranular textures, B-type olivine fabrics, and generally elevated mineral water contents compared to Williams. Xenoliths from Williams are strongly deformed, with porphyroclastic and transitional textures containing annealed olivine tablets, mostly A-type olivine fabrics, and generally lower mineral water contents. As a whole, mantle from Homestead to Williams reflects a cratonic scale deformation cycle that likely initiated in Laramide times and lasted until the end of orogeny in the Eocene. At Williams, evidence for a rapid deformation “sub-cycle” within the main deformation cycle is preserved in the tablet-bearing xenoliths, corresponding to the enigmatic “transitional” texture of Mercier and Nicolas (1975). Our results suggest that this texture reflects interruption of the main deformation cycle by processes possibly related to a rapidly forming lithospheric instability and generation of the kimberlite magma – offering a new interpretation of this ambiguous peridotite texture. Collectively, our results incorporate typically disparate geochemical and textural datasets on xenoliths to shed new insights into how metasomatism, volatiles, and deformation are connected in the deep cratonic lithosphere.
•Peridotite deformation cycle is reexamined using EBSD, water in NAMs, and mineral chemistry.•Wyoming Craton xenoliths show trends suggesting hydrous deformation followed by rapid, dry deformation.•Transitional texture may be indicative of lithospheric instability.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Previous studies of the morphology of the humerus in kangaroos showed that the shape of the proximal humerus could distinguish between arboreal and terrestrial taxa among living mammals, and that the ...extinct “giant” kangaroos (members of the extinct subfamily Sthenurinae and the extinct macropodine genus
Protemnodon
) had divergent humeral anatomies from extant kangaroos. Here, we use 2D geometric morphometrics to capture the shape of the distal humerus in a range of extant and extinct marsupials and obtain similar results: sthenurines have humeral morphologies more similar to arboreal mammals, while large
Protemnodon
species (
P. brehus
and
P. anak
) have humeral morphologies more similar to terrestrial quadrupedal mammals. Our results provide further evidence for prior hypotheses: that sthenurines did not employ a locomotor mode that involved loading the forelimbs (likely employing bipedal striding as an alternative to quadrupedal or pentapedal locomotion at slow gaits), and that large
Protemnodon
species were more reliant on quadrupedal locomotion than their extant relatives. This greater diversity of locomotor modes among large Pleistocene kangaroos echoes studies that show a greater diversity in other aspects of ecology, such as diet and habitat occupancy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In amyloid-positive individuals at risk for Alzheimer's disease (AD), high soluble 42-amino acid amyloid-β (Aβ42) levels are associated with normal cognition. It is unknown if this relationship ...applies longitudinally in a genetic cohort.
To test the hypothesis that high Aβ42 preserves normal cognition in amyloid-positive individuals with Alzheimer's disease (AD)-causing mutations (APP, PSEN1, or PSEN2) to a greater extent than lower levels of brain amyloid, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), or total tau (t-tau).
Cognitive progression was defined as any increase in Clinical Dementia Rating (CDR = 0, normal cognition; 0.5, very mild dementia; 1, mild dementia) over 3 years. Amyloid-positivity was defined as a standard uptake value ratio (SUVR) ≥1.42 by Pittsburgh compound-B positron emission tomography (PiB-PET). We used modified Poisson regression models to estimate relative risk (RR), adjusted for age at onset, sex, education, APOE4 status, and duration of follow-up. The results were confirmed with multiple sensitivity analyses, including Cox regression.
Of 232 mutation carriers, 108 were PiB-PET-positive at baseline, with 43 (39.8%) meeting criteria for progression after 3.3±2.0 years. Soluble Aβ42 levels were higher among CDR non-progressors than CDR progressors. Higher Aβ42 predicted a lower risk of progression (adjusted RR, 0.36; 95% confidence interval CI, 0.19-0.67; p = 0.002) better than lower SUVR (RR, 0.81; 95% CI, 0.68-0.96; p = 0.018). CSF Aβ42 levels predicting lower risk of progression increased with higher SUVR levels.
High CSF Aβ42 levels predict normal cognition in amyloid-positive individuals with AD-causing genetic mutations.
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