Identification of methotrexate as a heterochromatin-promoting drug.

Heterochromatin is a tightly packed form of DNA involved in gene silencing, chromosome segregation, and protection of genome stability. Heterochromatin is becoming more recognized in tumor suppression and may thus serve as a potential target for cancer therapy. However, to date there are no drugs that are well established to specifically promote heterochromatin formation. Here, we describe a screening method using Drosophila to identify small molecule compounds that promote heterochromatin formation, with the purpose of developing epigenetic cancer therapeutics. We took advantage of a Drosophila strain with a variegated eye color phenotype that is sensitive to heterochromatin levels, and screened a library of 97 FDA approved oncology drugs. This screen identified methotrexate as the most potent small molecule drug, among the 97 oncology drugs screened, in promoting heterochromatin formation. Interestingly, methotrexate has been identified as a JAK/STAT inhibitor in a functional screen, causing reduced phosphorylation of STAT proteins. These findings are in line with our previous observation that unphosphorylated STAT (uSTAT) promotes heterochromatin formation in both Drosophila and human cells and suppresses tumor growth in mouse xenografts. Thus, Drosophila with variegated eye color phenotypes could be an effective tool for screening heterochromatin-promoting compounds that could be candidates as cancer therapeutics

Roles of TRPV1 and neuropeptidergic receptors in dorsal root reflex-mediated neurogenic inflammation induced by intradermal injection of capsaicin

<p>Abstract</p> <p>Background</p> <p>Acute cutaneous neurogenic inflammation initiated by activation of transient receptor potential vanilloid-1 (TRPV₁) receptors following intradermal injection of capsaicin is mediated mainly by dorsal root reflexes (DRRs). Inflammatory neuropeptides are suggested to be released from primary afferent nociceptors participating in inflammation. However, no direct evidence demonstrates that the release of inflammatory substances is due to the triggering of DRRs and how activation of TRPV₁receptors initiates neurogenic inflammation via triggering DRRs.</p> <p>Results</p> <p>Here we used pharmacological manipulations to analyze the roles of TRPV₁and neuropeptidergic receptors in the DRR-mediated neurogenic inflammation induced by intradermal injection of capsaicin. The degree of cutaneous inflammation in the hindpaw that followed capsaicin injection was assessed by measurements of local blood flow (vasodilation) and paw-thickness (edema) of the foot skin in anesthetized rats. Local injection of capsaicin, calcitonin gene-related peptide (CGRP) or substance P (SP) resulted in cutaneous vasodilation and edema. Removal of DRRs by either spinal dorsal rhizotomy or intrathecal administration of the GABA_Areceptor antagonist, bicuculline, reduced dramatically the capsaicin-induced vasodilation and edema. In contrast, CGRP- or SP-induced inflammation was not significantly affected after DRR removal. Dose-response analysis of the antagonistic effect of the TRPV₁receptor antagonist, capsazepine administered peripherally, shows that the capsaicin-evoked inflammation was inhibited in a dose-dependent manner, and nearly completely abolished by capsazepine at doses between 30–150 μg. In contrast, pretreatment of the periphery with different doses of CGRP_8–37(a CGRP receptor antagonist) or spantide I (a neurokinin 1 receptor antagonist) only reduced the inflammation. If both CGRP and NK₁receptors were blocked by co-administration of CGRP_8–37and spantide I, a stronger reduction in the capsaicin-initiated inflammation was produced.</p> <p>Conclusion</p> <p>Our data suggest that 1) the generation of DRRs is critical for driving the release of neuropeptides antidromically from primary afferent nociceptors; 2) activation of TRPV₁receptors in primary afferent nociceptors following intradermal capsaicin injection initiates this process; 3) the released CGRP and SP participate in neurogenic inflammation.</p

Diurnal seismicity cycle linked to subsurface melting on an ice shelf

ABSTRACTSeismograms acquired on the McMurdo Ice Shelf, Antarctica, during an Austral summer melt season (November 2016–January 2017) reveal a diurnal cycle of seismicity, consisting of hundreds of thousands of small ice quakes limited to a 6–12 hour period during the evening, in an area where there is substantial subsurface melting. This cycle is explained by thermally induced bending and fracture of a frozen surface superimposed on a subsurface slush/water layer that is supported by solar radiation penetration and absorption. A simple, one-dimensional model of heat transfer driven by observed surface air temperature and shortwave absorption reproduces the presence and absence (as daily weather dictated) of the observed diurnal seismicity cycle. Seismic event statistics comparing event occurrence with amplitude suggest that the events are generated in a fractured medium featuring relatively low stresses, as is consistent with a frozen surface superimposed on subsurface slush. Waveforms of the icequakes are consistent with hydroacoustic phases at frequency ${\bf \gt} \bf 75\,{\bf Hz}$ and flexural-gravity waves at frequency $\bf {\bf \lt}25\,{\bf Hz}$. Our results suggest that seismic observation may prove useful in monitoring subsurface melting in a manner that complements other ground-based methods as well as remote sensing.</jats:p

Diurnal seismicity cycle linked to subsurface melting on an ice shelf

Seismograms acquired on the McMurdo Ice Shelf, Antarctica, during an Austral summer melt season (November 2016–January 2017) reveal a diurnal cycle of seismicity, consisting of hundreds of thousands of small ice quakes limited to a 6–12 hour period during the evening, in an area where there is substantial subsurface melting. This cycle is explained by thermally induced bending and fracture of a frozen surface superimposed on a subsurface slush/water layer that is supported by solar radiation penetration and absorption. A simple, one-dimensional model of heat transfer driven by observed surface air temperature and shortwave absorption reproduces the presence and absence (as daily weather dictated) of the observed diurnal seismicity cycle. Seismic event statistics comparing event occurrence with amplitude suggest that the events are generated in a fractured medium featuring relatively low stresses, as is consistent with a frozen surface superimposed on subsurface slush. Waveforms of the icequakes are consistent with hydroacoustic phases at frequency and flexural-gravity waves at frequency . Our results suggest that seismic observation may prove useful in monitoring subsurface melting in a manner that complements other ground-based methods as well as remote sensing

Spectral method for matching exterior and interior elliptic problems

A spectral method is described for solving coupled elliptic problems on an interior and an exterior domain. The method is formulated and tested on the two-dimensional interior Poisson and exterior Laplace problems, whose solutions and their normal derivatives are required to be continuous across the interface. A complete basis of homogeneous solutions for the interior and exterior regions, corresponding to all possible Dirichlet boundary values at the interface, are calculated in a preprocessing step. This basis is used to construct the influence matrix which serves to transform the coupled boundary conditions into conditions on the interior problem. Chebyshev approximations are used to represent both the interior solutions and the boundary values. A standard Chebyshev spectral method is used to calculate the interior solutions. The exterior harmonic solutions are calculated as the convolution of the free-space Green's function with a surface density; this surface density is itself the solution to an integral equation which has an analytic solution when the boundary values are given as a Chebyshev expansion. Properties of Chebyshev approximations insure that the basis of exterior harmonic functions represents the external near-boundary solutions uniformly. The method is tested by calculating the electrostatic potential resulting from charge distributions in a rectangle. The resulting influence matrix is well-conditioned and solutions converge exponentially as the resolution is increased. The generalization of this approach to three-dimensional problems is discussed, in particular the magnetohydrodynamic equations in a finite cylindrical domain surrounded by a vacuum

2009-2010 Mostly Music: Haydn

https://spiral.lynn.edu/conservatory_mostlymusic/1006/thumbnail.jp

Considerations for widespread implementation of blood-based biomarkers of Alzheimer\u27s disease

Diagnosing Alzheimer\u27s disease (AD) poses significant challenges to health care, often resulting in delayed or inadequate patient care. The clinical integration of blood-based biomarkers (BBMs) for AD holds promise in enabling early detection of pathology and timely intervention. However, several critical considerations, such as the lack of consistent guidelines for assessing cognition, limited understanding of BBM test characteristics, insufficient evidence on BBM performance across diverse populations, and the ethical management of test results, must be addressed for widespread clinical implementation of BBMs in the United States. The Global CEO Initiative on Alzheimer\u27s Disease BBM Workgroup convened to address these challenges and provide recommendations that underscore the importance of evidence-based guidelines, improved training for health-care professionals, patient empowerment through informed decision making, and the necessity of community-based studies to understand BBM performance in real-world populations. Multi-stakeholder engagement is essential to implement these recommendations and ensure credible guidance and education are accessible to all stakeholders

An hydrodynamic shear instability in stratified disks

We discuss the possibility that astrophysical accretion disks are dynamically unstable to non-axisymmetric disturbances with characteristic scales much smaller than the vertical scale height. The instability is studied using three methods: one based on the energy integral, which allows the determination of a sufficient condition of stability, one using a WKB approach, which allows the determination of the necessary and sufficient condition for instability and a last one by numerical solution. This linear instability occurs in any inviscid stably stratified differential rotating fluid for rigid, stress-free or periodic boundary conditions, provided the angular velocity $\Omega$ decreases outwards with radius $r$. At not too small stratification, its growth rate is a fraction of $\Omega$. The influence of viscous dissipation and thermal diffusivity on the instability is studied numerically, with emphasis on the case when $d \ln \Omega / d \ln r =-3/2$ (Keplerian case). Strong stratification and large diffusivity are found to have a stabilizing effect. The corresponding critical stratification and Reynolds number for the onset of the instability in a typical disk are derived. We propose that the spontaneous generation of these linear modes is the source of turbulence in disks, especially in weakly ionized disks.Comment: 19 pages, 13 figures, to appear in A&