An orthorhombic polymorph of 10,11-dihydrocarbamazepine

The title compound (systematic name: 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide), C15H14N2O, is shown to crystallize as an orthorhombic polymorph to complement the known monoclinic form. The molecular conformations of both forms are very similar, involving a bent conformation for the seven-membered azepine ring and an overall `butterfly' shape. The molecules assemble into chains by way of N-H center dot center dot center dot O bonds and N-H center dot center dot center dot pi inter-actions in both crystal modifications. The two polymorphs appear to form due to different van der Waals inter-actions between the layer-like sheets of molecules

Analysis of BH3-only proteins upregulated in response to oxygen/glucose deprivation in cortical neurons identifies Bmf but not Noxa as potential mediator of neuronal injury

Stress signaling in response to oxygen/glucose deprivation (OGD) and ischemic injury activates a group of pro-apoptotic genes, the Bcl-2 homology domain 3 (BH3)-only proteins, which are capable of activating the mitochondrial apoptosis pathway. Targeted studies previously identified the BH3-only proteins Puma, Bim and Bid to have a role in ischemic/hypoxic neuronal injury. We here investigated the transcriptional activation of pro-apoptotic BH3-only proteins after OGD-induced injury in murine neocortical neurons. We observed a potent and early upregulation of noxa at mRNA and protein level, and a significant increase in Bmf protein levels during OGD in neocortical neurons and in the ipsilateral cortex of mice subjected to transient middle cerebral artery occlusion (tMCAO). Surprisingly, gene deficiency in noxa reduced neither OGD- nor glutamate-induced neuronal injury in cortical neurons and failed to influence infarct size or neurological deficits after tMCAO. In contrast, bmf deficiency induced significant protection against OGD- or glutamate-induced injury in cultured neurons, and bmf-deficient mice showed reduced neurological deficits after tMCAO in vivo. Collectively, our data not only point to a role of Bmf as a BH3-only protein contributing to excitotoxic and ischemic neuronal injury but also demonstrate that the early and potent induction of noxa does not influence ischemic neuronal injury

1-(2-Bromo-5-meth­oxy­phen­yl)-8-chloro-6-(2-fluoro­phen­yl)-4H-1,2,4-triazolo[4,3-a][1,4]benzodiazepine

The title compound, Csb 23Hsb 15BrClFNsb 4O, is an analogue of sedatives such as midazolam and alprazolam. Its geometrical parameters are normal and comparable with those of related compounds. The only possible significant inter-molecular inter-action is a C-H⋅sO bond

Decoding the X-ray flare from MAXI J0709-159 using optical spectroscopy and multi-epoch photometry

We present a follow-up study on the recent detection of two X-ray flaring events by MAXI/GSC observations in soft and hard X-rays from MAXI J0709-159 in the direction of HD 54786 (LY CMa), on 2022 January 25. The X-ray luminosity during the flare was around 10^(37) erg/s (MAXI), which got reduced to 10^(32) erg/s (NuSTAR) after the flare. We took low-resolution spectra of HD 54786 from HCT and VBT facilities in India, on 2022 February 1 and 2. In addition to H-alpha emission, we found emission lines of He I in the optical spectrum of this star. By comparing our spectrum of the object with those from literature we found that He I lines show variability. Using photometric study we estimate that the star is having effective temperature of 20000 K. Although HD 54786 is reported as a supergiant in previous studies, our analysis favours it to be evolving off the main sequence in the Color-Magnitude Diagram. We could not detect any infrared excess, ruling out the possibility of IR emission from a dusty circumstellar disc. Our present study suggests that HD 54786 is a Be/X-ray binary system with a compact object companion, possibly a neutron star.Comment: 9 pages, 5 figures, 1 table, accepted for publication in ApJ

Thermomagnetic history effects in SmMn2_2Ge2_2

The intermetallic compound SmMn$_2$Ge$_2$, displaying multiple magnetic phase transitions, is being investigated in detail for its magnetization behavior near the 145 K first order ferromagnetic to antiferromagnetic transition occuring on cooling, in particular for thermomagnetic history effects in the magnetization data. The most unusual finding is that the thermomagnetic irreversibility, [= M$^{FCW}$(T)-M$^{ZFC}$(T)] at 135 K is higher in intermediate magnetic field strengths. By studying the response of the sample (i.e., thermomagnetic irreversibility and thermal hysteresis) to different histories of application of magnetic field and temperature, we demonstrate how the supercooling and superheating of the metastable magnetic phases across the first order transition at 145 K contribute to overall thermomagnetic irreversibility.Comment: 15 pages, 5 figures, to appear in Physical Review

Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration

Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox4(-/-)) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox4(-/-) mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy

Beyond the marrow:insights from comprehensive next-generation sequencing of extramedullary multiple myeloma tumors

Extramedullary multiple myeloma (EMM) is an aggressive form of multiple myeloma (MM). This study represents the most comprehensive next-generation sequencing analysis of EMM tumors (N = 14) to date, uncovering key molecular features and describing the tumor microenvironment. We observed the co-occurrence of 1q21 gain/amplification and MAPK pathway mutations in 79% of EMM samples, suggesting that these are crucial mutational events in EMM development. We also demonstrated that patients with mutated KRAS and 1q21 gain/amplification at the time of diagnosis have a significantly higher risk of EMM development (HR = 2.4, p = 0.011) using data from a large CoMMpass dataset. We identified downregulation of CXCR4 and enhanced cell proliferation, along with reduced expression of therapeutic targets (CD38, SLAMF7, GPRC5D, FCRH5), potentially explaining diminished efficacy of immunotherapy. Conversely, we identified significantly upregulated EZH2 and CD70 as potential future therapeutic options. For the first time, we report on the tumor microenvironment of EMM, revealing CD8+ T cells and NK cells as predominant immune effector cells using single-cell sequencing. Finally, this is the first longitudinal study in EMM revealing the molecular changes from the time of diagnosis to EMM relapse.</p

Role of TMPRSS2-ERG Gene Fusion in Negative Regulation of PSMA Expression

Prostate specific membrane antigen (PSMA) is overexpressed in prostatic adenocarcinoma (CaP), and its expression is negatively regulated by androgen stimulation. However, it is still unclear which factors are involved in this downregulation. TMPRSS2-ERG fusion is the most common known gene rearrangement in prostate carcinoma. Androgen stimulation can increase expression of the TMPRSS2-ERG fusion in fusion positive prostate cancer cells. The purpose of this investigation is to determine whether PSMA expression can be regulated by the TMPRSS2-ERG gene fusion. We employed two PSMA positive cell lines: VCaP cells, which harbor TMPRSS2-ERG fusion, and LNCaP cells, which lack the fusion. After 24 hours of androgen treatment, TMPRSS2-ERG mRNA level was increased in VCaP cells. PSMA mRNA level was dramatically decreased in VCaP cells, while it only has moderate change in LNCaP cells. Treatment with the androgen antagonist flutamide partially restored PSMA expression in androgen-treated VCaP cells. Knocking down ERG by siRNA in VCaP cells enhances PSMA expression both in the presence and absence of synthetic androgen R1881. Overexpressing TMPRSS2-ERG fusions in LNCaP cells downregulated PSMA both in the presence or absence of R1881, while overexpressing wild type ERG did not. Using PSMA-based luciferase reporter assays, we found TMPRSS2-ERG fusion can inhibit PSMA activity at the transcriptional level. Our data indicated that downregulation of PSMA in androgen-treated VCaP cells appears partially mediated by TMPRSS2-ERG gene fusion

Intrinsic dynamic behavior of fascin in filopodia

Author Posting. © American Society for Cell Biology, 2007. This article is posted here by permission of American Society for Cell Biology for personal use, not for redistribution. The definitive version was published in Molecular Biology of the Cell 18 (2007): 3928-3940, doi:10.1091/mbc.E07-04-0346.Recent studies showed that the actin cross-linking protein, fascin, undergoes rapid cycling between filopodial filaments. Here, we used an experimental and computational approach to dissect features of fascin exchange and incorporation in filopodia. Using expression of phosphomimetic fascin mutants, we determined that fascin in the phosphorylated state is primarily freely diffusing, whereas actin bundling in filopodia is accomplished by fascin dephosphorylated at serine 39. Fluorescence recovery after photobleaching analysis revealed that fascin rapidly dissociates from filopodial filaments with a kinetic off-rate of 0.12 s–1 and that it undergoes diffusion at moderate rates with a coefficient of 6 µm2s–1. This kinetic off-rate was recapitulated in vitro, indicating that dynamic behavior is intrinsic to the fascin cross-linker. A computational reaction–diffusion model showed that reversible cross-linking is required for the delivery of fascin to growing filopodial tips at sufficient rates. Analysis of fascin bundling indicated that filopodia are semiordered bundles with one bound fascin per 25–60 actin monomers.This work was supported by a National Institutes of Health F31National Research Service Award NS055565-01 (to Y.S.A.), Northwestern University Pulmonary and Critical Care Division T32 (to T.E.S.), and National Institutes of Health grant GM-70898 (to G.G.B.)

Sample Handling and Chemical Kinetics in an Acoustically Levitated Drop Microreactor

Accurate measurement of enzyme kinetics is an essential part of understanding the mechanisms of biochemical reactions. The typical means of studying such systems use stirred cuvettes, stopped-flow apparatus, microfluidic systems, or other small sample containers. These methods may prove to be problematic if reactants or products adsorb to or react with the container’s surface. As an alternative approach, we have developed an acoustically-levitated drop reactor eventually intended to study enzyme-catalyzed reaction kinetics related to free radical and oxidative stress chemistry. Microliter-scale droplet generation, reactant introduction, maintenance, and fluid removal are all important aspects in conducting reactions in a levitated drop. A three capillary bundle system has been developed to address these needs. We report kinetic measurements for both luminol chemiluminescence and the reaction of pyruvate with nicotinamide adenine dinucleotide, catalyzed by lactate dehydrogenase, to demonstrate the feasibility of using a levitated drop in conjunction with the developed capillary sample handling system as a microreactor