The double Smiles rearrangement in neutral conditions leading to one of 10-(nitropyridinyl)dipyridothiazine isomers

© 2016 Elsevier B.V.Phenothiazines are reported to exhibit very promising anticancer, antibacterial, antifungal, anti-inflammatory activities, reversal of multidrug resistance and many other actions. Synthesis of phenotiazines is mostly carried cyclization of o-aminodiphenyl sulfides proceeded through the Smiles rearrangement. The modifications of the phenothiazine structure via the substitution of the benzene ring with the pyridine ring gave various pyridobenzothiazines and dipyridothiazines. The reaction of 3-amino-3’-nitro-2,2’-dipyridinyl sulfide with 4-chloro-3-nitropyridine in sole DMF led to one of four possible isomeric nitropyridinyldipyridothiazines. Two-dimensional 1H and 13C NMR experiments (COSY, ROESY, HSQC and HMBC) were used to reveal the right product structure as 10-(3'-nitro-4'-pyridinyl)dipyrido[2,3-b; 2',3’-e] [1,4]thiazine (10-(3'-nitro-4'-pyridinyl)-1,6-diazaphenothiazine). The final structure confirmation came from a single crystal X-ray analysis. This structure is the result of very rare reaction mechanism involving the double Smiles rearrangement of the S[sbnd]N type. The tricyclic dipyridothiazine system is unexpectedly almost planar, with the butterfly angle of 176.39(4)° between two pyridine rings and 174.17(6)° between the halves of the thiazine ring (the NCCS) planes. The pyridinyl substituent is rotated about N10[sbnd]C11 bond and oriented almost perpendicularly to the tricyclic ring system with the dihedral angle between the two planar systems of 94.93(3)°. The nitropyridinyl substituent is located quasi-equatorially with the S⋯N10‒C11 angle of 176.92(8)°. The nitro group is tilted from the pyridine ring by 128.44(8)°

Particle Correlations with Heavy Ions at LHC Energies

The ALICE detector will offer very good conditions to study the space-time characteristics of particle production in heavy-ion collisions at LHC from measurements of the correlation function of identical and non-identical particles at small relative velocities. The correlations - induced by Coulomb and nuclear final-state interactions - of non-identical particles appear to be directly sensitive to the space-time asymmetries of particle production allowing, in particular, a measurement of the mean relative delays in particle emission at time scales as small as few fm/c. The problem of Coulomb interaction of the correlated particles is particularly important in the case of the large effective volumes formed in ultra-relativistic heavy-ion reactions

A New Statistical Image Analysis Approach and Its Application to Hippocampal Morphometry

In this work, we propose a novel and powerful image analysis framework for hippocampal morphometry in early mild cognitive impairment (EMCI), an early prodromal stage of Alzheimer’s disease (AD). We create a hippocampal surface atlas with subfield information, model each hippocampus using the SPHARM technique, and register it to the atlas to extract surface deformation signals. We propose a new alternative to standard random field theory (RFT) and permutation image analysis methods, Statistical Parametric Mapping (SPM) Distribution Analysis or SPM-DA, to perform statistical shape analysis and compare its performance with that of RFT methods on both simulated and real hippocampal surface data. The major strengths of our framework are twofold: (a) SPM-DA provides potentially more powerful algorithms than standard RFT methods for detecting weak signals, and (b) the framework embraces the important hippocampal subfield information for improved biological interpretation. We demonstrate the effectiveness of our method via an application to an AD cohort, where an SPM-DA method detects meaningful hippocampal shape differences in EMCI that are undetected by standard RFT methods

Safety and Feasibility of Long-term Intravenous Sodium Nitrite Infusion in Healthy Volunteers

BACKGROUND: Infusion of sodium nitrite could provide sustained therapeutic concentrations of nitric oxide (NO) for the treatment of a variety of vascular disorders. The study was developed to determine the safety and feasibility of prolonged sodium nitrite infusion. METHODOLOGY: Healthy volunteers, aged 21 to 60 years old, were candidates for the study performed at the National Institutes of Health (NIH; protocol 05-N-0075) between July 2007 and August 2008. All subjects provided written consent to participate. Twelve subjects (5 males, 7 females; mean age, 38.8±9.2 years (range, 21-56 years)) were intravenously infused with increasing doses of sodium nitrite for 48 hours (starting dose at 4.2 µg/kg/hr; maximal dose of 533.8 µg/kg/hr). Clinical, physiologic and laboratory data before, during and after infusion were analyzed. FINDINGS: The maximal tolerated dose for intravenous infusion of sodium nitrite was 267 µg/kg/hr. Dose limiting toxicity occurred at 446 µg/kg/hr. Toxicity included a transient asymptomatic decrease of mean arterial blood pressure (more than 15 mmHg) and/or an asymptomatic increase of methemoglobin level above 5%. Nitrite, nitrate, S-nitrosothiols concentrations in plasma and whole blood increased in all subjects and returned to preinfusion baseline values within 12 hours after cessation of the infusion. The mean half-life of nitrite estimated at maximal tolerated dose was 45.3 minutes for plasma and 51.4 minutes for whole blood. CONCLUSION: Sodium nitrite can be safely infused intravenously at defined concentrations for prolonged intervals. These results should be valuable for developing studies to investigate new NO treatment paradigms for a variety of clinical disorders, including cerebral vasospasm after subarachnoid hemorrhage, and ischemia of the heart, liver, kidney and brain, as well as organ transplants, blood-brain barrier modulation and pulmonary hypertension. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov; NCT00103025

DNA content of a functioning chicken kinetochore

© The Author(s) 2014. In order to understand the three-dimensional structure of the functional kinetochore in vertebrates, we require a complete list and stoichiometry for the protein components of the kinetochore, which can be provided by genetic and proteomic experiments. We also need to know how the chromatin-containing CENP-A, which makes up the structural foundation for the kinetochore, is folded, and how much of that DNA is involved in assembling the kinetochore. In this MS, we demonstrate that functioning metaphase kinetochores in chicken DT40 cells contain roughly 50 kb of DNA, an amount that corresponds extremely closely to the length of chromosomal DNA associated with CENP-A in ChIP-seq experiments. Thus, during kinetochore assembly, CENP-A chromatin is compacted into the inner kinetochore plate without including significant amounts of flanking pericentromeric heterochromatin. © 2014 The Author(s).Wellcome Trust [grant number 073915]; Wellcome Trust Centre for Cell Biology (core grant numbers 077707 and 092076); Darwin Trust of Edinburg