Decade Long Timing Study of the Black Widow Millisecond Pulsar J1544+4937

Results from 11 years of radio timing for eclipsing black widow millisecond pulsar (MSP) binary, J1544+4937, is presented in this paper. We report a phase-connected timing model for this MSP, using observations with the Giant Metrewave Radio Telescope (GMRT) at multiple frequencies and with Green Bank Telescope (GBT). This is the longest-duration timing study of any galactic field MSP with the GMRT. While extending the timing baseline from the existing 1.5 years to about a decade we report the first detection for a significant value of proper motion ($\mathrm{\mu_{T}} \sim$ 10.14(5) $\mathrm{mas/year}$) for this pulsar. Temporal variations of dispersion measure ($\mathrm{\Delta DM~ \sim 10^{-3}}$ pc $\mathrm{cm^{-3}}$) manifested by significant determination of 1st, 2nd, and 3rd order DM derivatives are observed along the line of sight to the pulsar. We also noticed frequency-dependent DM variations of the order of $\mathrm{10^{-3}~ pc~ cm^{-3}}$, which could arise due to spatial electron density variations in the interstellar medium. This study has revealed a secular variation of the orbital period for this MSP for the first time. We investigated possible causes and propose that variation in the gravitational quadrupole moment of the companion could be responsible for the observed temporal changes in the orbital period.Comment: 12 pages, 5 Figures, 2 Table, Accepted in the Astrophysical Journa

Human peripheral blood mononuclear cells targeted multidimensional switch for selective detection of HSO3− anion

A new ratiometric π-conjugated luminophore with donor-acceptor (D- π- A) network CM {(E)-2-(4-(2-(9-butyl-9H-carbazol-3-yl)vinyl)benzylidine)malononitrile} has been synthesized by malononitrile conjugated carbazole dye with an intervening p-styryl spacer. Here, p-styryl conjugated malononitrile is used as a recognition site for the detection of HSO3− with a fast response time (within 50 s). In a mixed aqueous solution, CM reacts with HSO3− to give a new product 1-(9-butyl-9H-carbazol-3-yl)-2-(4-(2, 2-dicyanovinyl)phenyl)ethane-1-sulfonic acid. The probe exhibits positive solvatofluorochromism with solid state red fluorescence. The restriction of intermolecular rotation of p-styryl conjugated malononitrile unit enhances the typical solid state fluorescence properties. The probe (CM and its corresponding aldehyde CA) also demonstrates a strong solvent dependence yielding blue to green to pink and even red fluorescence in commonly used organic solvents like n-hexane, toluene, diethyl ether (DEE), THF, DCM, Dioxane, CH3CN and MeOH. The chemodosimetric approach of HSO3− selectively takes place at the olefinic carbon exhibiting a prominent chromogenic as well as ratiometric fluorescence change with a 147 nm blue-shift in the fluorescence spectrum. CM can detect HSO3− as low as 1.21 × 10−8 M. Moreover, the CM can be successfully applied to detect intrinsically generated intracellular HSO3− in human peripheral blood mononuclear cells (PBMCs). CM has shown sharp intensities (2628 ± 511.8) when the cells are HSO3− untreated. At green channel (at 486 nm) almost negligible fluorescence intensities are found (423 ± 127.5) for HSO3− untreated samples. However, the green fluorescence (2863 ± 427.5) increases significantly (p < 0.05), and simultaneously the red fluorescence gets significantly (p < 0.05) diminished (515 ± 113.2) after addition of HSO3−. The CM has been effectively utilized for evaluating the bisulfite ions in food samples as well. The concentrations of HSO3− in diluted sugar samples have been determined with the recovery of 97.6–9.12%

Fosciclopirox suppresses growth of high-grade urothelial cancer by targeting the γ-secretase complex

Ciclopirox (CPX) is an FDA-approved topical antifungal agent that has demonstrated preclinical anticancer activity in a number of solid and hematologic malignancies. Its clinical utility as an oral anticancer agent, however, is limited by poor oral bioavailability and gastrointestinal toxicity. Fosciclopirox, the phosphoryloxymethyl ester of CPX (Ciclopirox Prodrug, CPX-POM), selectively delivers the active metabolite, CPX, to the entire urinary tract following parenteral administration. We characterized the activity of CPX-POM and its major metabolites in in vitro and in vivo preclinical models of high-grade urothelial cancer. CPX inhibited cell proliferation, clonogenicity and spheroid formation, and increased cell cycle arrest at S and G0/G1 phases. Mechanistically, CPX suppressed activation of Notch signaling. Molecular modeling and cellular thermal shift assays demonstrated CPX binding to γ-secretase complex proteins Presenilin 1 and Nicastrin, which are essential for Notch activation. To establish in vivo preclinical proof of principle, we tested fosciclopirox in the validated N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) mouse bladder cancer model. Once-daily intraperitoneal administration of CPX-POM for four weeks at doses of 235 mg/kg and 470 mg/kg significantly decreased bladder weight, a surrogate for tumor volume, and resulted in a migration to lower stage tumors in CPX-POM treated animals. This was coupled with a reduction in the proliferation index. Additionally, there was a reduction in Presenilin 1 and Hes-1 expression in the bladder tissues of CPX-POM treated animals. Following the completion of the first-in-human Phase 1 trial (NCT03348514), the pharmacologic activity of fosciclopirox is currently being characterized in a Phase 1 expansion cohort study of muscle-invasive bladder cancer patients scheduled for cystectomy (NCT04608045) as well as a Phase 2 trial of newly diagnosed and recurrent urothelial cancer patients scheduled for transurethral resection of bladder tumors (NCT04525131)

Differential interactions of the Mg²⁺ complexes of chromomycin A₃ and mithramycin with Poly(dG-dC)•Poly(dC-dG) and Poly(dG)•Poly(dC)

The interaction of the two anticancer antibiotics, chromomycin A3 and mithramycin, with the polynucleotides poly(dG-dC).poly(dC-dG), representative of B-DNA, and poly(dG)•poly(dC), representative of A-DNA, in the presence of Mg2+ is studied by spectroscopic techniques such as absorbance, fluorescence, and dircular dichroism (CD). The studies were done with both drug•Mg2+ complexes, I and II, having 1:1 and 2:1 stoichiometries with respect to drug and Mg2+, respectively [Aich, P., Sen, R., &#38; Dasgupta, D. (1992) Biochemistry 31, 2988−2997]. The objective of the present work is 2-fold. First, an attempt is made to understand the structural basis of the ligand−DNA interaction, particularly the role of DNA backbone conformation with its groove size and the accessibility of the 2-amino group in the minor groove of guanosine. Second, the role of the antibiotic saccharide moieties in the association with DNA was studied. For this purpose, the spectroscopic characterization of the binding was done followed by the evaluation of binding parameters and associated thermodynamics. Analysis of the observed thermodynamics for the ligand−DNA interactions in terms of the different structures of the polynucleotides was done. The salient results are as follows. Complex I does not discriminate significantly among the A- and B-forms of DNA when it binds to them in an entropy-driven process. On the other hand, complex II for both drugs recognizes B- and A-forms of DNA in different ways. This observation implies that the sequence specificity shown by this complex is a sequel to the difference in the parameters such as groove size and accessibility of the guanosine amino group. Another important finding is that binding with the same polynucleotide is not comparable for the complex II of the two drugs. It emphasizes the involvement of the sugar moieties, when the drug•Mg2+ complex binds to DNA. The presence of an acetoxy group in the sugars of chromomycin A3 imparts some distinctive specific features of the association of the chromomycin dimer•Mg2+ complex with DNA. Finally, the results are compared with those available from NMR studies of different drug−oligonucleotide complexes under conditions where complex II is the ligand

First Systematic Study Reporting the Changes in Eclipse Cutoff Frequency for Pulsar J1544+4937

We present results from long-term monitoring of frequency-dependent eclipses of the radio emission from PSR J1544+4937, which is a black widow spider millisecond pulsar (MSP) in a compact binary system. The majority of such systems often exhibit relatively long-duration radio eclipses caused by ablated material from their companion stars. With the wide spectral bandwidth of the upgraded Giant Metrewave Radio Telescope, we present the first systematic study of temporal variation of eclipse cutoff frequency. With decade-long monitoring of 39 eclipses for PSR J1544+4937, we notice significant changes in the observed cutoff frequency ranging from 343 ± 7 to ≥740 MHz. We also monitored changes in eclipse cutoff frequency on timescales of tens of days and observed a maximum change of ≥315 MHz between observations that were separated by 22 days. In addition, we observed a change of ∼47 MHz in eclipse cutoff frequency between adjacent orbits, i.e., on timescales of ∼2.9 hr. We infer that such changes in the eclipse cutoff frequency depict an eclipse environment for the PSR J1544+4937 system that is dynamically evolving, where, along with the change in electron density, the magnetic field could also be varying. We also report a significant correlation between the eclipse cutoff frequency and the mass-loss rate of the companion. This study provides the first direct evidence of mass-loss rate affecting the frequency-dependent eclipsing in a spider MSP

FRET based ratiometric switch for selective sensing of Al3+ with bio-imaging in human peripheral blood mononuclear cells

In this work, a triphenylamine and rhodamine-B (donor–acceptor) hybrid switch (TPRH) was rationally designed, synthesised and characterised as a novel fluorescence resonance energy transfer (FRET) ratiometric fluorescent chemosensor for specific sensing of Al3+ over other important metal ions in mixed aqueous solution. We proposed that the sensor in hand (TPRH) is non-toxic and can be successfully employed to detect the Al3+ ion in human peripheral blood mononuclear cells (PBMCs), showing intracellular ‘FRET-ON’ mechanism. The orientation of the probe was designed in such a way that the fluorescence (or Förster) resonance energy transfer (FRET) proceeded from the ‘donor moiety’ triphenylamine to the ‘accepter moiety’ rhodamine-B. This fluorescent probe was found to be highly selective towards Al3+ over other important guest metal ions, including Fe3+ and Cr3+. Considering the adverse effects of Al3+ ions on human health and also on the environment, the development of sensitive and specific tools for the detection of Al3+ ions is of great value. The limit of detection (LOD) of TPRH was found to be in the order of 10−8 M. The TPRH–Al3+ complex showed reversible binding with demetallation in the presence of EDTA. In accordance with this reversibility, the fluorescence output at 576 nm from two active chemical inputs, namely, Al3+ and EDTA, followed a truth table of an INHIBIT logic gate. Moreover, cytotoxic studies found that the probe was safe to use in a biological system with good cell membrane permeability. More importantly, the bio-imaging of living human peripheral blood mononuclear cells (PBMCs) showed that TPRH could be used as an effective fluorescent probe for a prominent ratiometric in vitro detection of the transition trivalent metal ion Al3+. We evidenced a significant (p < 0.05) shift from blue to red fluorescence when Al3+ was added to the cell suspension, thus proving TPRH as a good candidate to detect intracellular Al3+

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