Search

We present the results obtained from the spectral studies of black hole X-ray binary GX 339−4 using AstroSat observations during its 2021 outburst. AstroSat observed the source in the intermediate state for ∼600 ks. The combined spectra of SXT and LAXPC in the 0.7−25 keV energy range are studied with phenomenological and physical models. The spectral study reveals a receding disc and a contracting corona during the observation period. The outflow rate is found to be increased though the accretion rates did not vary during the observation period. The X-ray flux decreases as the disc recedes and the spectrum becomes hard. At the same time, the Comptonized flux decreases with increasing fraction of thermal emission. This could be plausible that episodic jet ejection modified the corona and reduced Comptonized flux. An iron emission line at 6.4 keV is observed in the spectra of all the orbits of observation. We find that the equivalent width of the iron emission line correlates with the photon index, indicating a decrease in the reflection strength as the spectrum becomes hard. We observe that the disc flux does not follow F DBB − T 4 relation. [ABSTRACT FROM AUTHOR]

A transition metal free visible light mediated organo photoredox catalyzed trifluoromethylation of p -quinone methides (p -QMs) to construct fluoro-analogs of dichlorodiphenyltrichloroethane (DDT) is reported using a bench stable, inexpensive Langlois reagent as a trifluoromethyl radical source. This protocol could generate a benzylic C(sp 3 )-CF 3 bond with excellent yield under mild reaction conditions using 1,6-conjugate addition/aromatization of trifluoromethyl radical in the absence of any external additives. Further, we demonstrate di-trifluoromethylation and gram scale synthesis of this reaction. Organo photoredox catalyzed trifluoromethylation of p -quinone methides (p -QMs) to construct fluoro-analogs of dichlorodiphenyltrichloroethane (DDT) is reported. This protocol could generate a benzylic C(sp 3 )–CF 3 bond with excellent yield. We also demonstrate the di-trifluoromethylation of p -QM. Image 1 [ABSTRACT FROM AUTHOR]

Stimulator of interferon genes (STING) is an essential adaptor protein required for the inflammatory response to cytosolic DNA. dsDNA activates cGAS to generate cGAMP, which binds and activates STING triggering a conformational change, oligomerization, and the IRF3-and NFκB-dependent transcription of type I Interferons (IFNs) and inflammatory cytokines, as well as the activation of autophagy. Aberrant activation of STING is now linked to a growing number of both rare as well as common chronic inflammatory diseases. Here, we identify and characterize a potent small-molecule inhibitor of STING. This compound, BB-Cl-amidine inhibits STING signaling and production of type I IFNs, IFN-stimulated genes (ISGs) and NFκB-dependent cytokines, but not other pattern recognition receptors. In vivo, BB-Cl-amidine alleviated pathology resulting from accrual of cytosolic DNA in Trex-1 mutant mice. Mechanistically BB-Cl-amidine inhibited STING oligomerization through modification of Cys148. Collectively, our work uncovers an approach to inhibit STING activation and highlights the potential of this strategy for the treatment of STING-driven inflammatory diseases. [ABSTRACT FROM AUTHOR]

Review: [200 refs. [ABSTRACT FROM AUTHOR]

The article presents cover page of the journal along with information on an article related to biosynthesis of thyroid hormones by G. Mugesh and colleagues, published within the issue.

Die Hormone der Schilddrüse spielen eine wichtige Rolle beim Lipid‐, Kohlenhydrat‐ und Proteinmetabolismus, bei der Nervenentwicklung und für Herz‐, Nieren‐ und Hirnfunktionen. Das Prähormon l‐Thyroxin (T4) wird durch Deiodinase‐Enzyme zum biologisch aktiven Hormon T3 monodeiodiert. G. Mugesh et al. beschreiben im Aufsatz auf S. 7734 ff. die Biosynthese, den Transport, den Metabolismus und die Wirkungsweise von Schilddrüsenhormonen sowie mit der Schilddrüse verbundene Krankheitsbilder. [ABSTRACT FROM AUTHOR]

An abstract of the article "Selenium-Mediated Dehalogenation of Halogenated Nucleosides and Its Relevance to the DNA Repair Pathway" by S. Mondal and colleagues is presented.

In outburst sources, quasi-periodic oscillation (QPO) frequency is known to evolve in a certain way: in the rising phase, it monotonically goes up until a soft intermediate state is achieved. In the propagating oscillatory shock model, oscillation of the Compton cloud is thought to cause QPOs. Thus, in order to increase QPO frequency, the Compton cloud must collapse steadily in the rising phase. In decline phases, the exact opposite should be true. We investigate cause of this evolution of the Compton cloud. The same viscosity parameter that increases the Keplerian disk rate also moves the inner edge of the Keplerian component, thereby reducing the size of the Compton cloud and reducing the cooling timescale. We show that cooling of the Compton cloud by inverse Comptonization is enough for it to collapse sufficiently so as to explain the QPO evolution. In the two-component advective flow configuration of Chakrabarti-Titarchuk, centrifugal force-induced shock represents the boundary of the Compton cloud. We take the rising phase of 2010 outburst of Galactic black hole candidate H 1743-322 and find an estimation of variation of the α parameter of the sub-Keplerian flow to be monotonically rising from 0.0001 to 0.02, well within the range suggested by magnetorotational instability. We also estimate the inward velocity of the Compton cloud to be a few meters per second, which is comparable to what is found in several earlier studies of our group by empirically fitting the shock locations with the time of observations. [ABSTRACT FROM AUTHOR]

Halogenated nucleosides can be incorporated into the newly synthesized DNA of replicating cells and therefore are commonly used in the detection of proliferating cells in living tissues. Dehalogenation of these modified nucleosides is one of the key pathways involved in DNA repair mediated by the uracil-DNA glycosylase. Herein, we report the first example of a selenium-mediated dehalogenation of halogenated nucleosides. We also show that the mechanism for the debromination is remarkably different from that of deiodination and that the presence of a ribose or deoxyribose moiety in the nucleosides facilitates the deiodination. The results described herein should help in understanding the metabolism of halogenated nucleosides in DNA and RNA. [ABSTRACT FROM AUTHOR]

Summary Amino acid (AA) levels in plasma and body growth were determined in rats (n20) fed diets with different soya bean meal levels. Free AA in plasma was determined by reversed-phase high-pressure liquid chromatography. We have used four levels of protein diets like 8%, 15%, 23% and 35% in this trial. Rats which were fed the low-protein (8%) diet with low percentage of soya bean meal were found to be growth-retarded. The body weight gain of high protein group (35%) was lower than that of the 23% groups. In the rats fed with the low-soya bean meal diet, some nonessential AA (NEAA) in plasma like asparagine, aspartic acid, cysteine, glutamic acid and serine increased, whereas the essential AA (EAA), with the exception of arginine, methionine and valine decreased. Here, plasma EAA-to-NEAA ratios were not correlated to growth and experimental diet. We hypothesize that AA metabolism is associated to changes in growth in rats on different protein intake. This study has showed the sensitivity of body mass gain, feed intake, feed conversion rate of rats to four levels of protein in the diet under controlled experimental conditions. [ABSTRACT FROM AUTHOR]

Abstract: The flavour singlet axial Ward identity with Osterwalder–Seiler twisted mass Wilson fermion action is studied on a finite lattice, with finite fermion mass and the Wilson parameter r up to 1. Approach to the infinite volume chiral limit and emergence of the anomaly is significantly better than that obtained with and improved fermion actions. We have shown explicitly that up to , parity violating terms cancel in the Ward identity even at finite volume and finite lattice spacing. [Copyright &y& Elsevier]

Protein citrullination plays a role in several autoimmune diseases. Its involvement in murine and human type 1 diabetes has recently been recognized through the discovery of antibodies and T-cell reactivity against citrullinated peptides. In the current study, we demonstrate that systemic inhibition of peptidylarginine deiminases (PADs), the enzymes mediating citrullination, through BB-Cl-amidine treatment, prevents diabetes development in NOD mice. This prevention was associated with reduced levels of citrullination in the pancreas, decreased circulating autoantibody titers against citrullinated glucose-regulated protein 78, and reduced spontaneous neutrophil extracellular trap formation of bone marrow-derived neutrophils. Moreover, BB-Cl-amidine treatment induced a shift from Th1 to Th2 cytokines in the serum and an increase in the frequency of regulatory T cells in the blood and spleen. In the pancreas, BB-Cl-amidine treatment preserved insulin production and was associated with a less destructive immune infiltrate characterized by reduced frequencies of effector memory CD4+ T cells and a modest reduction in the frequency of interferon-γ-producing CD4+ and CD8+ T cells. Our results point to a role of citrullination in the pathogenesis of autoimmune diabetes, with PAD inhibition leading to disease prevention through modulation of immune pathways. These findings provide insight in the potential of PAD inhibition for treating autoimmune diseases like type 1 diabetes. [ABSTRACT FROM AUTHOR]

Sterile Alpha and Toll Interleukin Receptor Motif–containing protein 1 (SARM1) is a key therapeutic target for diseases that exhibit Wallerian–like degeneration; Wallerian degeneration is characterized by degeneration of the axon distal to the site of injury. These diseases include traumatic brain injury, peripheral neuropathy, and neurodegenerative diseases. SARM1 promotes neurodegeneration by catalyzing the hydrolysis of NAD+ to form a mixture of ADPR and cADPR. Notably, SARM1 knockdown prevents degeneration, indicating that SARM1 inhibitors will likely be efficacious in treating these diseases. Consistent with this hypothesis is the observation that NAD+ supplementation is axoprotective. To identify compounds that block the NAD+ hydrolase activity of SARM1, we developed and performed a high–throughput screen (HTS). This HTS assay exploits an NAD+ analog, etheno–NAD+ (ENAD) that fluoresces upon cleavage of the nicotinamide moiety. From this screen, we identified berberine chloride and zinc chloride as the first noncompetitive inhibitors of SARM1. Though modest in potency, the noncompetitive mode of inhibition, suggests the presence of an allosteric binding pocket on SARM1 that can be targeted for future therapeutic development. Additionally, zinc inhibition and site–directed mutagenesis reveals that cysteines 629 and 635 are critical for SARM1 catalysis, highlighting these sites for the design of inhibitors targeting SARM1. [ABSTRACT FROM AUTHOR]

Endotoxemia induced by lipopolysaccharide (LPS) is an extremely severe syndrome identified by global activation of inflammatory responses. Neutrophil extracellular traps (NETs) play an important role in the development of endotoxemia. Histone hypercitrullination catalyzed by peptidylarginine deiminases (PADs) is a key step of NET formation. We have previously demonstrated that simultaneous inhibition of PAD2 and PAD4 with pan-PAD inhibitors can decrease NETosis and improve survival in a mouse model of LPS-induced endotoxic shock. However, the effects of PAD2 specific inhibition during NETosis and endotoxic shock are poorly understood. Therefore, in the present study, we aimed to investigate the effect of the specific PAD2 or PAD4 inhibitor on LPS-induced endotoxic shock in mice. We found that PAD2 inhibition but not PAD4 inhibition improves survival. Also, the levels of proinflammatory cytokines and NETosis were significantly reduced by PAD2 inhibitor. To our knowledge, this study demonstrates for the first time that PAD2 inhibition can reduce NETosis, decrease inflammatory cytokine production, and protect against endotoxin-induced lethality. Our findings provided a novel therapeutic strategy for the treatment of endotoxic shock. [ABSTRACT FROM AUTHOR]

Protein arginine deiminase (PAD) enzymes catalyze the conversion of protein-bound arginine into citrulline, an irreversible posttranslational modification with loss of a positive charge that can influence protein-protein interactions and protein structure. Protein arginine deiminase activity depends on high intracellular calcium concentrations occurring in dying cells. In this study, we demonstrate that protein citrullination is common during pyroptotic cell death in macrophages and that inhibition of PAD enzyme activity by Cl-amidine, a pan-PAD inhibitor, blocks NLRP3 inflammasome assembly and proinflammatory IL-1β release in macrophages. Genetic deficiency of either PAD2 or PAD4 alone in murine macrophages does not impair IL-1β release; however, pharmacological inhibition or small interfering RNA knockdown of PAD2 within PAD4-/- macrophages does. Our results suggest that PAD2 and 4 activity in macrophages is required for optimal inflammasome assembly and IL-1β release, a finding of importance for autoimmune diseases and inflammation. [ABSTRACT FROM AUTHOR]

Acyl chain transfer, which perturbs the protonation equilibrium of amine and reduces the apparent pKa by 2.0–2.5 units, is used to develop a liposome-based drug delivery system. [ABSTRACT FROM AUTHOR]

We analyze three sets of gauge ensembles in our extended physics program of a particularly important BSM gauge theory with a fermion doublet in the two-index symmetric (sextet) representation of the SU(3) BSM color gauge group. Our investigations include chiral symmetry breaking in the p-regime and -regime, the mass of the composite scalar, resonance spectroscopy, new physics from gauge anomaly constraints, and the role of stable sextet BSM baryons with Electroweak interactions in dark matter searches. Important new goals include studies of the scalar entangled with Goldstone dynamics in the p-regime and the -regime, the resonance spectrum with particular attention to emerging LHC signals, like recent hints for diphoton excess at 750 GeV or diboson anomalies in the 2 TeV range. All results reported here are preliminary before journal publication including some post-conference material for the discussion. [ABSTRACT FROM AUTHOR]

Abstract: We calculate pion mass, pion decay constant, PCAC quark mass and nucleon mass in two flavour lattice QCD with unimproved Wilson fermion and gauge actions. Simulations are performed using DD-HMC algorithm at two lattice spacings and two volumes for several values of the quark mass. The cutoff effects in pion mass and nucleon mass for the explored region of parameter space are found to be negligible. We extract the average value of the up–down quark mass in the scheme at 2 GeV, which is in good agreement with the world data. The chiral behaviours of pion mass, pion decay constant and quark condensate are found to be qualitatively consistent with NLO chiral perturbation theory. The extracted values of the pion decay constant and the chiral condensate are in reasonable agreement with the world data. [Copyright &y& Elsevier]

Abstract: We address a long standing problem regarding topology in lattice simulations of QCD with unimproved Wilson fermions. Earlier attempt with unimproved Wilson fermions at to verify the suppression of topological susceptibility with decreasing quark mass () was unable to unambiguously confirm the suppression. We carry out systematic calculations for two degenerate flavours at two different lattice spacings ( and 5.8). The effects of quark mass, lattice volume and the lattice spacing on the spanning of different topological sectors are presented. We unambiguously demonstrate the suppression of the topological susceptibility with decreasing quark mass, expected from chiral Ward identity and chiral perturbation theory. [Copyright &y& Elsevier]

Background: Tamoxifen resistance presents a huge clinical challenge for breast cancer patients. An understanding of the mechanisms of tamoxifen resistance can guide development of efficient therapies to prevent drug resistance. Methods: We first tested whether peptidylarginine deiminase 2 (PAD2) may be involved in tamoxifen-resistance in breast cancer cells. The effect of depleting or inhibiting PAD2 in tamoxifen-resistant MCF-7 (MCF7/TamR) cells was evaluated both in vitro and in vivo. We then investigated the potential of Cl-amidine, a PAD inhibitor, to be used in combination with tamoxifen or docetaxel, and further explored the mechanism of the synergistic and effective drug regimen of PADs inhibitor and docetaxel on tamoxifen-resistant breast cancer cells. Results: We report that PAD2 is dramatically upregulated in tamoxifen-resistant breast cancer. Depletion of PAD2 in MCF7/TamR cells facilitated the sensitivity of MCF7/TamR cells to tamoxifen. Moreover, miRNA-125b-5p negatively regulated PAD2 expression in MCF7/TamR cells, therefore overexpression of miR-125b-5p also increased the cell sensitivity to tamoxifen. Furthermore, inhibiting PAD2 with Cl-amidine not only partially restored the sensitivity of MCF7/TamR cells to tamoxifen, but also more efficiently enhanced the efficacy of docetaxel on MCF7/TamR cells with lower doses of Cl-amidine and docetaxel both in vivo and in vivo. We then showed that combination treatment with Cl-amidine and docetaxel enhanced p53 nuclear accumulation, which synergistically induced cell cycle arrest and apoptosis. Meanwhile, p53 activation in the combination treatment also accelerated autophagy processes by synergistically decreasing the activation of Akt/mTOR signaling, thus enhancing the inhibition of proliferation. Conclusion: Our results suggest that PAD2 functions as an important new biomarker for tamoxifen-resistant breast cancers and that inhibiting PAD2 combined with docetaxel may offer a new approach to treatment of tamoxifen-resistant breast cancers. [ABSTRACT FROM AUTHOR]