The importance of microtubule-dependent tension in accurate chromosome segregation

Accurate chromosome segregation is vital for cell and organismal viability. The mitotic spindle, a bipolar macromolecular machine composed largely of dynamic microtubules, is responsible for chromosome segregation during each cell replication cycle. Prior to anaphase, a bipolar metaphase spindle must be formed in which each pair of chromatids is attached to microtubules from opposite spindle poles. In this bipolar configuration pulling forces from the dynamic microtubules can generate tension across the sister kinetochores. The tension status acts as a signal that can destabilize aberrant kinetochore-microtubule attachments and reinforces correct, bipolar connections. Historically it has been challenging to isolate the specific role of tension in mitotic processes due to the interdependency of attachment and tension status at kinetochores. Recent technical and experimental advances have revealed new insights into how tension functions during mitosis. Here we summarize the evidence that tension serves as a biophysical signal that unifies multiple aspects of kinetochore and centromere function to ensure accurate chromosome segregation

Frequency dependent core shifts and parameter estimation for the blazar 3C 454.3

We study the core shift effect in the parsec scale jet of the blazar 3C 454.3 using the 4.8 GHz - 36.8 GHz radio light curves obtained from three decades of continuous monitoring. From a piecewise Gaussian fit to each flare, time lags $\Delta t$ between the observation frequencies $\nu$ and spectral indices $\alpha$ based on peak amplitudes $A$ are determined. From the fit $\Delta t \propto \nu^{1/k_r}$, $k_r = 1.10 \pm 0.18$ indicating equipartition between the magnetic field energy density and the particle energy density. From the fit $A \propto \nu^\alpha$, $\alpha$ is in the range $-0.24$ to $1.52$. A mean magnetic field strength at 1 pc, $B_1 = 0.5 \pm 0.2$ G, and at the core, $B_{\rm core} = 46 \pm 16$ mG, are inferred, consistent with previous estimates. The measure of core position offset is $\Omega_{r\nu} = 6.4 \pm 2.8$ pc GHz$^{1/k_r}$ when averaged over all frequency pairs. Based on the statistical trend shown by the measured core radius $r_{\rm core}$ as a function of $\nu$, we infer that the synchrotron opacity model may not be valid for all cases. A Fourier periodogram analysis yields power law slopes in the range $-1.6$ to $-3.5$ describing the power spectral density shape and gives bend timescales in the range $0.52 - 0.66~$yr. This result, and both positive and negative $\alpha$, indicate that the flares originate from multiple shocks in a small region. Important objectives met in our study include: the demonstration of the computational efficiency and statistical basis of the piecewise Gaussian fit; consistency with previously reported results; evidence for the core shift dependence on observation frequency and its utility in jet diagnostics in the region close to the resolving limit of very long baseline interferometry observations.Comment: 12 pages, 11 figures (23 sub-figures), 5 tables. Accepted for publication in MNRA

Differentiating between models of Epothilone binding to microtubules using tubulin mutagenesis, cytotoxicity, and molecular modeling

This is the peer reviewed version of the following article: Entwistle, R. A., Rizk, R. S., Cheng, D. M., Lushington, G. H., Himes, R. H., & Gupta, M. L. (2012). Differentiating between models of Epothilone binding to microtubules using tubulin mutagenesis, cytotoxicity, and molecular modeling. ChemMedChem, 7(9), 1580–1586. http://doi.org/10.1002/cmdc.201200286, which has been published in final form at doi.org/10.1002/cmdc.201200286. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Microtubule stabilizers are powerful anti-mitotic compounds and represent a proven cancer treatment strategy. Several classes of compounds in clinical use or trials, such as the taxanes and epothilones, bind to the same region of β-tubulin. Determining how these molecules interact with tubulin and stabilize microtubules is important both for understanding the mechanism of action and enhancing chemotherapeutic potential, e.g. reducing side effects, increasing solubility, and overcoming resistance. Structural studies using nonpolymerized tubulin or stabilized polymers have produced different models of epothilone binding. Here, we used directed mutagenesis of the binding site on Saccharomyces cerevisiae β-tubulin to analyze interactions between Epothilone B and its biologically relevant substrate, dynamic microtubules. Five engineered amino acid changes contributed to a 125-fold increase in Epothilone B cytotoxicity independent of inherent microtubule stability. The mutagenesis of endogenous β-tubulin was done in otherwise isogenic strains. This facilitated the correlation of amino acid substitutions with altered cytotoxicity using molecular mechanics simulations. The results, which are based on the interaction between Epothilone B and dynamic microtubules, most strongly support the binding mode determined by NMR spectroscopy-based studies. This work establishes a system for discriminating between potential binding modes and among various compounds and/or analogues using a sensitive biological activity-based readout

A peculiar multi-wavelength flare in the Blazar 3C 454.3

The blazar 3C454.3 exhibited a strong flare seen in gamma-rays, X-rays, and optical/NIR bands during 3--12 December 2009. Emission in the V and J bands rose more gradually than did the gamma-rays and soft X-rays, though all peaked at nearly the same time. Optical polarization measurements showed dramatic changes during the flare, with a strong anti-correlation between optical flux and degree of polarization (which rose from ~ 3% to ~ 20%) during the declining phase of the flare. The flare was accompanied by large rapid swings in polarization angle of ~ 170 degree. This combination of behaviors appear to be unique. We have cm-band radio data during the same period but they show no correlation with variations at higher frequencies. Such peculiar behavior may be explained using jet models incorporating fully relativistic effects with a dominant source region moving along a helical path or by a shock-in-jet model incorporating three-dimensional radiation transfer if there is a dominant helical magnetic field. We find that spectral energy distributions at different times during the flare can be fit using modified one-zone models where only the magnetic field strength and particle break frequencies and normalizations need change. An optical spectrum taken at nearly the same time provides an estimate for the central black hole mass of ~ 2.3 * 10^9 M_sun. We also consider two weaker flares seen during the $\sim 200$ d span over which multi-band data are available. In one of them, the V and J bands appear to lead the $\gamma$-ray and X-ray bands by a few days; in the other, all variations are simultaneous.Comment: 11 pages, 4 figures, 2 tables; MNRAS in pres

Longitudinal study on visual outcome and spectacle use after intracapsular cataract extraction in Northern India

PURPOSE: More than 3 million cataract extractions are undertaken in India annually. Almost 60% of these operations are intracapsular Cataract Extractions. The subsequent optical correction is provided by aphakic spectacles. The aim of this study is to assess visual outcome and perceived benefits of post-operative use of aphakic spectacles. METHODS: One hundred and sixty-seven persons who had undergone intracapsular cataract extraction and had been given best corrected aphakic spectacles were evaluated one year following prescription of the best corrected aphakic spectacles. Out of these, 82.6% were re-examined in this interview-based longitudinal study. RESULTS: The mean age of the male participants was 65.95 years and that of females was 71.26 years. 81.2% of the participants were using the provided spectacles. There was no significant association between the spectacle use and gender of the participant. The commonest reason stated by the respondents, for the non-use of the spectacles was 'poor vision'. 61.7% of the current users of provided spectacles had a visual acuity of 6/18 or better. 91.1% of the current users were very satisfied with the spectacles. All the current users could now manage personal activities and the spectacles had facilitated independent mobility. There was no difference in the level of satisfaction between mono-aphakics and bi-aphakics. Among the satisfied users, the modal spherical power was +10 D followed by + 11 D. About one-third of these required a cylindrical correction. CONCLUSION: Following intracapsular cataract extraction, provision of the best correction after cataract surgery is desirable to obtain an optimal visual outcome

N-(2-{[5-Bromo-2-(piperidin-1-yl)pyrimidin-4-yl]sulfan­yl}-4-meth­­oxy­phen­yl)-4-methyl­benzene­sulfonamide

In the title compound, C\sb 23H\sb 25BrN\sb 4O\sb 3S\sb 2, the benzene rings bridged by the sulfonamide group are tilted relative to each other by 69.7(1)\circ and the dihedral angle between the sulfur-bridged pyrimidine and benzene rings is 70.4(1)\circ. The mol\-ecular conformation is stabilized by a weak intra\-molecular π—π stacking inter\-action between the pyrimidine and the 4-methyl benzene rings centroid{--}centroid distance = 3.633(2){\AA}. The piperidine ring adopts a chair conformation. In the crystal, mol{\-}ecules are linked into inversion dimers by pairs of N{---}H{$\cdots$}O hydrogen bonds

Removal of hexavalent chromium of contaminated soil by coupling electrokinetic remediation and permeable reactive biobarriers

PURPOSE: In this study, a novel and ecological alternative have been developed to treat soils contaminated with hexavalent chromium coupling two well-known systems: electrokinetic remediation and permeable reactive biobarriers. The electric field promotes the electromigration of the hexavalent chromium oxyanions towards the anode. The biobarriers were placed before the anode electrode, in order to promote the reduction and retention of the chromium migrating in its direction. Thus, this technology provided a global treatment to soil removal without subsequent treatments of the contaminated effluents. METHODS: The electrokinetic system was coupled with two different permeable reactive biobarriers composed by Arthrobacter viscosus bacteria, supported either in activated carbon or zeolite. An electric field of 10 V was applied and two different treatment times of 9 and 18 days were tested. RESULTS: Removal values of 60% and 79% were obtained when electrokinetic treatment was coupled with zeolite and activated carbon biobarriers, respectively, for a test period of 18 day. The reduction of hexavalent chromium to trivalent chromium was around 45% for both systems. CONCLUSIONS: In this work, two types of biobarriers were efficiently coupled to electrokinetic treatment to decontaminate soil with Cr(VI). Furthermore, the viability of the new coupling technology developed (electrokinetic + biobarriers) to treat low-permeability polluted soils was demonstrated.This work was supported by the Spanish Ministry of Science and Innovation (CTQ2008-03059/PPQ), Xunta de Galicia (08MDS034314PR). The authors are grateful to the Spanish Ministry of Science and Innovation for providing financial support for Marta Pazos under the Ramon y Cajal program and the Fundacao para a Ciencia e Tecnologia, Ministerio da Ciencia e Tecnologia, Portugal through the PhD grant of Bruna Fonseca (SFRH/BD/27780/2006)

Multiwavelength Intraday Variability of the BL Lac S5 0716+714

We report results from a 1 week multi-wavelength campaign to monitor the BL Lac object S5 0716+714 (on December 9-16, 2009). In the radio bands the source shows rapid (~ (0.5-1.5) day) intra-day variability with peak amplitudes of up to ~ 10 %. The variability at 2.8 cm leads by about 1 day the variability at 6 cm and 11 cm. This time lag and more rapid variations suggests an intrinsic contribution to the source's intraday variability at 2.8 cm, while at 6 cm and 11 cm interstellar scintillation (ISS) seems to predominate. Large and quasi-sinusoidal variations of ~ 0.8 mag were detected in the V, R and I-bands. The X-ray data (0.2-10 keV) do not reveal significant variability on a 4 day time scale, favoring reprocessed inverse-Compton over synchrotron radiation in this band. The characteristic variability time scales in radio and optical bands are similar. A quasi-periodic variation (QPO) of 0.9 - 1.1 days in the optical data may be present, but if so it is marginal and limited to 2.2 cycles. Cross-correlations between radio and optical are discussed. The lack of a strong radio-optical correlation indicates different physical causes of variability (ISS at long radio wavelengths, source intrinsic origin in the optical), and is consistent with a high jet opacity and a compact synchrotron component peaking at ~= 100 GHz in an ongoing very prominent flux density outburst. For the campaign period, we construct a quasi-simultaneous spectral energy distribution (SED), including gamma-ray data from the FERMI satellite. We obtain lower limits for the relativistic Doppler-boosting of delta >= 12-26, which for a BL\,Lac type object, is remarkably high.Comment: 16 pages, 15 figures, table 2; Accepted for Publication in MNRA

Synthesis, structural, DFT calculations and biological studies of rhodium and iridium complexes containing azine Schiff-base ligands

The reaction of [Cp*MCl2]2 (M = Rh/Ir) with N-Nʹ azine Schiff-base ligands (L1-L4) leads to the formation of mononuclear cationic half-sandwich complexes having the general formula [Cp*M(L)Cl]+ (1–8), (M = Rh/Ir and L = (2-hydroxy-4-methoxybenzylidene)2- pyridylamidrazone (L1), (2-hydroxybenzylidene)2-pyridylamidrazone (L2), (1-(2-hydroxyphenyl)ethylidene)2-pyridylamidrazone (L3) and (1-phenylethylidene)2-pyridylamidrazone (L4). All these complexes were isolated as their hexafluorophosphate salts and fully characterized by spectroscopic and analytical techniques. The molecular structure of complexes (1), (3), (4), (7) and (8) have been determined by single crystal X-ray crystallographic studies which displayed the coordination of the ligand to the metal in a bidentate N∩N fashion through nitrogen atom of pyridine and one azine nitrogen. The chemo-sensitivity activities of the complexes were evaluated against HT-29 (human colorectal cancer) cell line and non-cancer cell line ARPE-19 (human retinal epithelial cells) which revealed that the complexes are moderately cytotoxic to cancer cells over human cells although complex 5 was the most potent among all the compounds. Theoretical studies carried out using DFT and TD-DFT at B3LYP level shows good agreement with the experimental results

The natural history of primary sclerosing cholangitis in 781 children. A multicenter, international collaboration

There are limited data on the natural history of primary sclerosing cholangitis (PSC) in children. We aimed to describe the disease characteristics and long-term outcomes of pediatric PSC. We retrospectively collected all pediatric PSC cases from 36 participating institutions and conducted a survival analysis from the date of PSC diagnosis to dates of diagnosis of portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or death. We analyzed patients grouped by disease phenotype and laboratory studies at diagnosis to identify objective predictors of long-term outcome. We identified 781 patients, median age 12 years, with 4,277 person-years of follow-up; 33% with autoimmune hepatitis, 76% with inflammatory bowel disease, and 13% with small duct PSC. Portal hypertensive and biliary complications developed in 38% and 25%, respectively, after 10 years of disease. Once these complications developed, median survival with native liver was 2.8 and 3.5 years, respectively. Cholangiocarcinoma occurred in 1%. Overall event-free survival was 70% at 5 years and 53% at 10 years. Patient groups with the most elevated total bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis had the worst outcomes. In multivariate analysis PSC-inflammatory bowel disease and small duct phenotypes were associated with favorable prognosis (hazard ratios 0.6, 95% confidence interval 0.5-0.9, and 0.7, 95% confidence interval 0.5-0.96, respectively). Age, gender, and autoimmune hepatitis overlap did not impact long-term outcome. CONCLUSION: PSC has a chronic, progressive course in children, and nearly half of patients develop an adverse liver outcome after 10 years of disease; elevations in bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis can identify patients at highest risk; small duct PSC and PSC-inflammatory bowel disease are more favorable disease phenotypes