Structural Insights into the Incorporation of the Mo Cofactor into Sulfite Oxidase from Site-Directed Spin Labeling

Mononuclear molybdoenzymes catalyze a broad range of redox reactions and are highly conserved in all kingdoms of life. This study addresses the question of how the Mo cofactor (Moco) is incorporated into the apo form of human sulfite oxidase (hSO) by using site-directed spin labeling to determine intramolecular distances in the nanometer range. Comparative measurements of the holo and apo forms of hSO enabled the localization of the corresponding structural changes, which are localized to a short loop (residues 263–273) of the Moco-containing domain. A flap-like movement of the loop provides access to the Moco binding- pocket in the apo form of the protein and explains the earlier studies on the in vitro reconstitution of apo-hSO with Moco. Remarkably, the loop motif can be found in a variety of structurally similar molybdoenzymes among various organisms, thus suggesting a common mechanism of Moco incorporation

Reverberation mapping of optical emission lines in five active galaxies

For a video summarizing the main results, see https://www.youtube.com/watch?v=KaC-jPsIY0QWe present the first results from an optical reverberation mapping campaign executed in 2014 targeting the active galactic nuclei (AGNs) MCG+08-11-011, NGC 2617, NGC 4051, 3C 382, and Mrk 374. Our targets have diverse and interesting observational properties, including a "changing look" AGN and a broad-line radio galaxy. Based on continuum-Hβ lags, we measure black hole masses for all five targets. We also obtain Hγ and He ii λ4686 lags for all objects except 3C 382. The He ii λ4686 lags indicate radial stratification of the BLR, and the masses derived from different emission lines are in general agreement. The relative responsivities of these lines are also in qualitative agreement with photoionization models. These spectra have extremely high signal-to-noise ratios (100–300 per pixel) and there are excellent prospects for obtaining velocity-resolved reverberation signatures.Publisher PDFPeer reviewe

Continuum Reverberation Mapping of the Accretion Disks in Two Seyfert 1 Galaxies

K.H.acknowledges support from STFC grant ST/M001296/1.We present optical continuum lags for two Seyfert 1 galaxies, MCG+08-11-011 and NGC 2617, using monitoring data from a reverberation mapping campaign carried out in 2014. Our light curves span the ugriz filters over four months, with median cadences of 1.0 and 0.6 days for MCG+08-11-011 and NGC 2617, respectively, combined with roughly daily X-ray and near-UV data from Swift for NGC 2617. We find lags consistent with geometrically thin accretion-disk models that predict a lag-wavelength relation of τ ∝ λ 4/3. However, the observed lags are larger than predictions based on standard thin-disk theory by factors of 3.3 for MCG+08-11-011 and 2.3 for NGC 2617. These differences can be explained if the mass accretion rates are larger than inferred from the optical luminosity by a factor of 4.3 in MCG+08-11-011 and a factor of 1.3 in NGC 2617, although uncertainty in the SMBH masses determines the significance of this result. While the X-ray variability in NGC 2617 precedes the UV/optical variability, the long (2.6 day) lag is problematic for coronal reprocessing models.Publisher PDFPeer reviewe

Structurally Related Flavonoids CT1 and CT3 Have Cytotoxic Activity On Triple Negative MDA-MB-231 Breast Cancer Cells By Targeting The MEK-ERK Pathway

Breast cancer is the most commonly diagnosed cancer in women with an estimated 287,850 cases in 2022. Approximately 684,000 deaths each year are associated with breast cancer across the world. Risk factors of breast cancer include increased estrogen exposure, family history of breast cancer, and environmental factors. Treatment of breast cancer is highly dependent on the presence of HER2, estrogen, and progesterone receptors. Breast cancers that present with increased receptors for estrogen, progesterone, and HER2 are typically the least aggressive and the easiest to treat. The percentage of cases in the United States associated with hormone receptor positive and HER-2 negative or positive are approximately 82%. Absence of receptors for estrogen, progesterone, and HER2 is known as triple negative breast cancer. In the United States, only about 10% of cases are associated with this form. However, it is considered the most aggressive and difficult to treat. Two emerging flavonoids known as CT1 and CT3 have shown cytotoxic activity against cell lines that represent some of the most common breast cancers: MCF7, MDA-MB-231, and SKBr3. CT1 and CT3 were extracted from the leaves of Chromolaena tacotana using a Soxhlet extractor and the compounds then underwent isolation and purification. The cells were then treated with CT1 or CT3 at concentrations of 5, 10, 20, 40 and 80 µM. MTT assays were then used to determine cell viability. MDA-MB-231, the most aggressive type of breast cancer cells, responded to both CT1 and CT3. The most profound cytotoxic effects of CT1 were seen with MCF7 and MDA-MB-231, while CT3 exhibited a greater toxicity against SKBr3 cells. Preliminary results indicate that CT1 and CT3 target the MEK-ERK signaling pathway. Further studies need to be completed to determine mechanistically how these compounds lead to receptor-independent toxicity