The significant activity of poly(ADP-ribose)polymerase (PARP) inhibitors in the treatment of germline BRCA mutation-associated ovarian cancer, which represents ∼15% of HGS cases, has recently led to ...European Medicines Agency and food and drug administration approval of olaparib. Accumulating evidence suggests that PARP inhibitors may have a wider application in the treatment of sporadic ovarian cancers. Up to 50% of HGS ovarian cancer patients may exhibit homologous recombination deficiency (HRD) through mechanisms including germline BRCA mutations, somatic BRCA mutations, and BRCA promoter methylation. In this review, we discuss the role of somatic BRCA mutations and BRCA methylation in ovarian cancer. There is accumulating evidence for routine somatic BRCA mutation testing, but the relevance of BRCA epigenetic modifications is less clear. We explore the challenges that need to be addressed if the full potential of these markers of HRD is to be utilised in clinical practice.
Aims.
It is speculated that a merger of two massive stellar-origin black holes in a dense stellar environment may lead to the formation of a massive black hole in the pair-instability mass gap ...(∼50−135
M
⊙
). Such a merger-formed black hole is expected to typically have a high spin (
a
∼ 0.7). If such a massive black hole acquires another black hole it may lead to another merger detectable by LIGO/Virgo in gravitational waves. Acquiring a companion may be hindered by gravitational-wave kick/recoil, which accompanies the first merger and may quickly remove the massive black hole from its parent globular or nuclear cluster. We test whether it is possible for a massive merger-formed black hole in the pair-instability gap to be retained in its parent cluster and have low spin. Such a black hole would be indistinguishable from a primordial black hole.
Methods.
We employed results from numerical relativity calculations of black hole mergers to explore the range of gravitational-wave recoil velocities for various combinations of merging black hole masses and spins. We compared merger-formed massive black hole speeds with typical escape velocities from globular and nuclear clusters.
Results.
We show that a globular cluster is highly unlikely to form and retain a ∼100
M
⊙
black hole if the spin of the black hole is low (
a
≲ 0.3). Massive merger-formed black holes with low spins acquire high recoil speeds (≳ 200 km s
−1
) from gravitational-wave kick during formation that exceed typical escape speeds from globular clusters (∼ 50 km s
−1
). However, a very low-spinning (
a
∼ 0.1) and massive (∼100
M
⊙
) black hole could be formed and retained in a galactic nuclear star cluster. Even though such massive merger-formed black holes with such low spins acquire high speeds during formation (∼ 400 km s
−1
), they may avoid ejection since massive nuclear clusters have high escape velocities (∼ 300−500 km s
−1
). A future detection of a massive black hole in the pair-instability mass gap with low spin would therefore not be proof of the existence of primordial black holes, which are sometimes claimed to have low spins and arbitrarily high masses.
Morphine and its pharmacological derivatives are the most prescribed analgesics for moderate to severe pain management. However, chronic use of morphine reduces pathogen clearance and induces ...bacterial translocation across the gut barrier. The enteric microbiome has been shown to have a critical role in the preservation of the mucosal barrier function and metabolic homeostasis. Here, we show for the first time, using bacterial 16s rDNA sequencing, that chronic morphine treatment significantly alters the gut microbial composition and induces preferential expansion of Gram-positive pathogenic and reduction in bile-deconjugating bacterial strains. A significant reduction in both primary and secondary bile acid levels was seen in the gut, but not in the liver with morphine treatment. Morphine-induced microbial dysbiosis and gut barrier disruption was rescued by transplanting placebo-treated microbiota into morphine-treated animals, indicating that microbiome modulation could be exploited as a therapeutic strategy for patients using morphine for pain management.
Applying first principles electronic structure calculations and molecular dynamics (MD) simulations we have studied the structural stability, hydrogen adsorption capability and hydrogen desorption ...kinetics of Y-decorated single walled carbon nanotube (SWCNT). We have predicted that a single Y atom attached on SWCNT can physisorb up to six hydrogen molecules which is not reported so far. Our MD simulations with four Y atoms placed at the alternate hexagons of SWCNT showed no clustering effect of Y atoms at room temperature and also we found that the system is stable even at higher temperature (700 K). For the first time we showed that 100% desorption at comparatively lower temperature can be achieved in a transition metal-decorated SWCNT system. Therefore the Y-decorated SWCNT has the potential to become a promising hydrogen storage device.
A novel magnetic nano-adsorbent was developed by treating Fe
3O
4 nanoparticles with gum arabic to remove copper ions from aqueous solutions. Gum arabic was attached to Fe
3O
4 via the interaction ...between the carboxylic groups of gum arabic and the surface hydroxyl groups of Fe
3O
4. The surface modification did not result in the phase change of Fe
3O
4, while led to the formation of secondary particles with diameter in the range of 13–67
nm and the shift of isoelectric point from 6.78 to 3.6. The amount of gum arabic in the final product was about 5.1
wt%. Both the naked magnetic nanoparticles (MNP) and gum arabic modified magnetic nanoparticles (GA-MNP) could be used for the adsorption of copper ions via the complexation with the surface hydroxyl groups of Fe
3O
4 and the complexation with the amine groups of gum arabic, respectively. The adsorption rate was so fast that the equilibrium was achieved within 2
min due to the absence of internal diffusion resistance and the adsorption capacities for both MNP and GA-MNP increased with increasing the solution pH. However, the latter was significantly higher than the former. Also, both the adsorption data obeyed the Langmuir isotherm equation. The maximum adsorption capacities were 17.6 and 38.5
mg/g for MNP and GA-MNP, respectively, and the Langmuir adsorption constants were 0.013 and 0.012
L/mg for MNP and GA-MNP, respectively. Furthermore, both the adsorption processes were endothermic due to the dehydration of hydrated metal ions. The enthalpy changes were 11.5 and 9.1
kJ/mol for MNP and GA-MNP, respectively. In addition, the copper ions could desorb from GA-MNP by using acid solution and the GA-MNP exhibited good reusability.
We extend the semiclassical study of fermionic particle-hole symmetric semi-Dirac (more appropriately, semi-Dirac semi-Weyl) dispersion of quasiparticles, (ProQuest: ... denotes formulae and/or ...non-USASCII text omitted) in dimensionless units, discovered computationally in oxide heterostructures by Pardo and collaborators. This unique system is a highly anisotropic sister phase of both (symmetric) graphene and what has become known as a Weyl semimetal, having ... independent of energy, and ... being very strongly dependent on energy (varepsilon) and depending only on the effective mass m. Each of these systems is distinguished by bands crossing (sometimes referred to as touching) at a point Fermi surface, with one consequence being that for this semi-Dirac system the ratio chi sub(orb)/ chi sub(sp) of orbital to spin susceptibilities diverges at low doping. We extend the study of the low-energy behavior of the semi-Dirac system, finding the plasmon frequency to be highly anisotropic while the Hall coefficient scales with carrier density in the usual manner. The Faraday rotation behavior is also reported. For Klein tunneling at normal incidence on an arbitrarily oriented barrier, the kinetic energy mixes both linear (massless) and quadratic (massive) contributions depending on orientation. Analogous to graphene, perfect transmission occurs under resonant conditions, except for the specific orientation that eliminates massless dispersion. Comparisons of the semi-Dirac system are made throughout with both other types of point Fermi surface systems.
In this work we study certain classes of F(R,G) gravity which have appealing phenomenological features, with respect to the successful realization of the dark energy and of the inflationary era. ...Particularly, we discuss the general formalism and we demonstrate how several inflationary and dark energy evolutions can be described in the context of F(R,G) gravity. Also we propose a unified model, in the context of which the early and late-time dynamics are controlled by the F(R,G) gravity, thus producing inflation and the dark energy era, while the intermediate era is approximately identical with standard Einstein–Hilbert gravity. Also we calculate the power spectrum of the primordial curvature perturbations corresponding to the unified F(R,G) gravity model we propose, which as we demonstrate is nearly scale invariant and compatible with the latest observational data constraints.
Elevated mitochondrial O -GlcNAcylation caused by hyperglycemia, as occurs in diabetes, significantly contributes to mitochondrial dysfunction and to diabetic cardiomyopathy. However, little is known ...about the enzymology of mitochondrial O -GlcNAcylation. Herein, we investigated the enzymes responsible for cycling O -GlcNAc on mitochondrial proteins and studied the mitochondrial transport of UDP-GlcNAc. Analyses of purified rat heart mitochondria from normal and streptozocin-treated diabetic rats show increased mitochondrial O -GlcNAc transferase (OGT) and a concomitant decrease in the mito-specific O-GlcNAcase (OGA). Strikingly, OGT is mislocalized in cardiac mitochondria from diabetic rats. Interaction of OGT and complex IV observed in normal rat heart mitochondria is visibly reduced in diabetic samples, where OGT is mislocalized to the matrix. Live cell OGA activity assays establish the presence of O-GlcNAcase within the mitochondria. Furthermore, we establish that the inner mitochondrial membrane transporter, pyrimidine nucleotide carrier, transports UDP-GlcNAc from the cytosol to the inside of the mitochondria. Knockdown of this transporter substantially lowers mitochondrial O -GlcNAcylation. Inhibition of OGT or OGA activity within neonatal rat cardiomyocytes significantly affects energy production, mitochondrial membrane potential, and mitochondrial oxygen consumption. These data suggest that cardiac mitochondria not only have robust O -GlcNAc cycling, but also that dysregulation of O -GlcNAcylation likely plays a key role in mitochondrial dysfunction associated with diabetes.
Significance Mitochondrial dysfunction contributes significantly to glucose toxicity in diabetes. Increased O -GlcNAcylation is emerging as a major molecular cause of glucose toxicity via many mechanisms. The studies herein provide a direct molecular link between hyperglycemia and mitochondrial dysfunction. We show that mitochondrial O -GlcNAc transferase (OGT) and O-GlcNAcase (OGA) expression levels and localizations are strikingly different between normal and diabetic rat hearts. We also discover how UDP-GlcNAc enters the mitochondrial space. Finally our data demonstrate that OGT and OGA play significant roles in ATP production, mitochondrial membrane potential, and oxygen consumption. These studies are of general interest not only with respect to nutrient regulation of mitochondrial function, but also are important to elucidate mechanisms of diabetic complications.
ABSTRACT The role of compressible fluctuations in the energy cascade of fast solar wind turbulence is studied using a reduced form of an exact law derived recently for compressible isothermal ...magnetohydrodynamics and in situ observations from the THEMIS B/ARTEMIS P1 spacecraft. A statistical survey of the data revealed a turbulent energy cascade over a range of two decades of scales that is broader than the previous estimates made from an exact incompressible law. A term-by-term analysis of the compressible model reveals new insight into the role played by the compressible fluctuations in the energy cascade. The compressible fluctuations are shown to amplify by two to four times the turbulent cascade rate with respect to the incompressible model in of the analyzed samples. This new estimated cascade rate is shown to provide the adequate energy dissipation required to account for the local heating of the non-adiabatic solar wind.
O-GlcNAcylation, a dynamic nutrient and stress sensitive post-translational modification, occurs on myriad proteins in the cell nucleus, cytoplasm and mitochondria. O-GlcNAcylation serves as a ...nutrient sensor to regulate signaling, transcription, translation, cell division, metabolism, and stress sensitivity in all cells. Aberrant protein O-GlcNAcylation plays a critical role both in the development, as well as in the progression of a variety of age related diseases. O-GlcNAcylation underlies the etiology of diabetes, and changes in specific protein O-GlcNAc levels and sites are responsible for insulin expression and sensitivity and glucose toxicity. Abnormal O-GlcNAcylation contributes directly to diabetes related dysfunction of the heart, kidney and eyes and affects progression of cardiomyopathy, nephropathy and retinopathy. O-GlcNAcylation is a critical modification in the brain and plays a role in both plaque and tangle formation, thus making its study important in neurodegenerative disorders. O-GlcNAcylation also affects cellular growth and metabolism during the development and metastasis of cancer. Finally, alterations in O-GlcNAcylation of transcription factors in macrophages and lymphocytes affect inflammation and cytokine production. Thus, O-GlcNAcylation plays key roles in many of the major diseases associated with aging. Elucidation of its specific functions in both normal and diseased tissues is likely to uncover totally novel avenues for therapeutic intervention.
PDF
