Potential effects of phytoestrogen genistein in modulating acute methotrexate chemotherapy-induced osteoclastogenesis and bone damage in rats

Chemotherapy-induced bone damage is a frequent side effect which causes diminished bone mineral density and fracture in childhood cancer sufferers and survivors. The intensified use of anti-metabolite methotrexate (MTX) and other cytotoxic drugs has led to the need for a mechanistic understanding of chemotherapy-induced bone loss and for the development of protective treatments. Using a young rat MTX-induced bone loss model, we investigated potential bone protective effects of phytoestrogen genistein. Oral gavages of genistein (20 mg/kg) were administered daily, for seven days before, five days during, and three days after five once-daily injections (sc) of MTX (0.75 mg/kg). MTX treatment reduced body weight gain and tibial metaphyseal trabecular bone volume (p < 0.001), increased osteoclast density on the trabecular bone surface (p < 0.05), and increased the bone marrow adipocyte number in lower metaphyseal bone (p < 0.001). Genistein supplementation preserved body weight gain (p < 0.05) and inhibited ex vivo osteoclast formation of bone marrow cells from MTX-treated rats (p < 0.001). However, MTX-induced changes in bone volume, trabecular architecture, metaphyseal mRNA expression of pro-osteoclastogenic cytokines, and marrow adiposity were not significantly affected by the co-administration of genistein. This study suggests that genistein may suppress MTX-induced osteoclastogenesis; however, further studies are required to examine its potential in protecting against MTX chemotherapy-induced bone damage

Investor Competition Over Information and the Pricing of Information Asymmetry

Whether the information environment affects the cost of capital is a fundamental question in accounting and finance research. Relying on theories about competition between informed investors as well as the pricing of information asymmetry, we hypothesize a cross-sectional variation in the pricing of information asymmetry that is conditional on competition. We develop and validate empirical proxies for competition using the number and concentration of institutional investor ownership. Using these proxies, we find a lower pricing of information asymmetry when there is more competition. Overall, our results suggest that competition between informed investors has an important effect on how the information environment affects the cost of capital.Deloitte Foundatio

Telomere erosion in memory T cells induced by telomerase inhibition at the site of antigenic challenge in vivo

This work was funded by grants from the Biotechnology and Biological Sciences Research Council Experimental Research on Aging Initiative, Research Into Aging, The Sir Jules Thorne Research Trust, and The Hayward Foundation and Dermatrust

The SAMI Galaxy Survey: The role of disc fading and progenitor bias in kinematic transitions

We use comparisons between the Sydney-AAO Multi-object Integral Field Spectrograph (SAMI) Galaxy Survey and equilibrium galaxy models to infer the importance of disc fading in the transition of spirals into lenticular (S0) galaxies. The local S0 population has both higher photometric concentration and lower stellar spin than spiral galaxies of comparable mass and we test whether this separation can be accounted for by passive aging alone. We construct a suite of dynamically self-consistent galaxy models, with a bulge, disc, and halo using the galactics code. The dispersion-dominated bulge is given a uniformly old stellar population, while the disc is given a current star formation rate putting it on the main sequence, followed by sudden instantaneous quenching. We then generate mock observables (r-band images, stellar velocity, and dispersion maps) as a function of time since quenching for a range of bulge/total (B/T) mass ratios. The disc fading leads to a decline in measured spin as the bulge contribution becomes more dominant, and also leads to increased concentration. However, the quantitative changes observed after 5 Gyr of disc fading cannot account for all of the observed difference. We see similar results if we instead subdivide our SAMI Galaxy Survey sample by star formation (relative to the main sequence). We use EAGLE simulations to also take into account progenitor bias, using size evolution to infer quenching time. The EAGLE simulations suggest that the progenitors of current passive galaxies typically have slightly higher spin than present day star-forming disc galaxies of the same mass. As a result, progenitor bias moves the data further from the disc fading model scenario, implying that intrinsic dynamical evolution must be important in the transition from star-forming discs to passive discs

Mechanically activated Piezo1 channels of cardiac fibroblasts stimulate p38 mitogen-activated protein kinase activity and interleukin-6 secretion

Piezo1 is a mechanosensitive cation channel with widespread physiological importance; however, its role in the heart is poorly understood. Cardiac fibroblasts help preserve myocardial integrity and play a key role in regulating its repair and remodeling following stress or injury. Here we investigated Piezo1 expression and function in cultured human and mouse cardiac fibroblasts. RT-PCR experiments confirmed that Piezo1 mRNA in cardiac fibroblasts is expressed at levels similar to those in endothelial cells. The results of a Fura-2 intracellular Ca2+ assay validated Piezo1 as a functional ion channel that is activated by its agonist, Yoda1. Yoda1-induced Ca2+ entry was inhibited by Piezo1 blockers (gadolinium and ruthenium red) and was reduced proportionally by siRNA-mediated Piezo1 knockdown or in murine Piezo1+/− cells. Results from cell-attached patch clamp recordings on human cardiac fibroblasts established that they contain mechanically activated ion channels and that their pressure responses are reduced by Piezo1 knockdown. Investigation of Yoda1 effects on selected remodeling genes indicated that Piezo1 activation increases both mRNA levels and protein secretion of IL-6, a pro-hypertrophic and profibrotic cytokine, in a Piezo1-dependent manner. Moreover, Piezo1 knockdown reduced basal IL-6 expression from cells cultured on softer collagen-coated substrates. Multiplex kinase activity profiling combined with kinase inhibitor experiments and phosphospecific immunoblotting established that Piezo1 activation stimulates IL-6 secretion via the p38 mitogen-activated protein kinase downstream of Ca2+ entry. In summary, cardiac fibroblasts express mechanically activated Piezo1 channels coupled to secretion of the paracrine signaling molecule IL-6. Piezo1 may therefore be important in regulating cardiac remodeling

Design of the Firstâ inâ Class, Highly Potent Irreversible Inhibitor Targeting the Meninâ MLL Proteinâ Protein Interaction

The structureâ based design of Mâ 525 as the firstâ inâ class, highly potent, irreversible smallâ molecule inhibitor of the meninâ MLL interaction is presented. Mâ 525 targets cellular menin protein at subâ nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLLâ regulated gene expression in MLL leukemia cells. Mâ 525 demonstrates high cellular specificity over nonâ MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric analysis and coâ crystal structure of Mâ 525 in complex with menin firmly establish its mode of action. A single administration of Mâ 525 effectively suppresses MLLâ regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize Mâ 525. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia.Irreversible inhibitor Mâ 525 targets the meninâ MLL interaction. It is demonstrated that irreversible inhibition of menin is a promising therapeutic strategy for the treatment of MLL leukemia and may have advantages over reversible inhibitors.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141532/1/anie201711828.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141532/2/anie201711828-sup-0001-misc_information.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141532/3/anie201711828_am.pd

Design of the Firstâ inâ Class, Highly Potent Irreversible Inhibitor Targeting the Meninâ MLL Proteinâ Protein Interaction

The structureâ based design of Mâ 525 as the firstâ inâ class, highly potent, irreversible smallâ molecule inhibitor of the meninâ MLL interaction is presented. Mâ 525 targets cellular menin protein at subâ nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLLâ regulated gene expression in MLL leukemia cells. Mâ 525 demonstrates high cellular specificity over nonâ MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric analysis and coâ crystal structure of Mâ 525 in complex with menin firmly establish its mode of action. A single administration of Mâ 525 effectively suppresses MLLâ regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize Mâ 525. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia.Der irreversible Inhibitor Mâ 525 greift an der Meninâ MLLâ Wechselwirkung an. Die irreversible Inhibition von Menin erweist sich als vielversprechende Strategie für die Behandlung von MLLâ Leukämie, mit möglichen Vorteilen gegenüber dem Einsatz reversibler Inhibitoren.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141701/1/ange201711828_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141701/2/ange201711828.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141701/3/ange201711828-sup-0001-misc_information.pd

Deletion of AMPA receptor GluA1 subunit gene (Gria1) causes circadian rhythm disruption and aberrant responses to environmental cues

Dysfunction of the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 subunit and deficits in synaptic plasticity are implicated in schizophrenia and sleep and circadian rhythm disruption. To investigate the role of GluA1 in circadian and sleep behaviour, we used wheel-running, passive-infrared, and video-based home-cage activity monitoring to assess daily rest–activity profiles of GluA1-knockout mice (Gria1−/−). We showed that these mice displayed various circadian abnormalities, including misaligned, fragmented, and more variable rest–activity patterns. In addition, they showed heightened, but transient, behavioural arousal to light→dark and dark→light transitions, as well as attenuated nocturnal-light-induced activity suppression (negative masking). In the hypothalamic suprachiasmatic nuclei (SCN), nocturnal-light-induced cFos signals (a molecular marker of neuronal activity in the preceding ~1–2 h) were attenuated, indicating reduced light sensitivity in the SCN. However, there was no change in the neuroanatomical distribution of expression levels of two neuropeptides―vasoactive intestinal peptide (VIP) and arginine vasopressin (AVP)―differentially expressed in the core (ventromedial) vs. shell (dorsolateral) SCN subregions and both are known to be important for neuronal synchronisation within the SCN and circadian rhythmicity. In the motor cortex (area M1/M2), there was increased inter-individual variability in cFos levels during the evening period, mirroring the increased inter-individual variability in locomotor activity under nocturnal light. Finally, in the spontaneous odour recognition task GluA1 knockouts’ short-term memory was impaired due to enhanced attention to the recently encountered familiar odour. These abnormalities due to altered AMPA-receptor-mediated signalling resemble and may contribute to sleep and circadian rhythm disruption and attentional deficits in different modalities in schizophrenia