Density functional theory study of the multimode Jahn-Teller effect – ground state distortion of benzene cation

The multideterminental-DFT approach performed to analyze Jahn-Teller (JT) active molecules is described. Extension of this method for the analysis of the adiabatic potential energy surfaces and the multimode JT effect is presented. Conceptually a simple model, based on the analogy between the JT distortion and reaction coordinates gives further information about microscopic origin of the JT effect. Within the harmonic approximation the JT distortion can be expressed as a linear combination of all totally symmetric normal modes in the low symmetry minimum energy conformation, which allows calculating the Intrinsic Distortion Path, IDP, exactly from the high symmetry nuclear configuration to the low symmetry energy minimum. It is possible to quantify the contribution of different normal modes to the distortion, their energy contribution to the total stabilization energy and how their contribution changes along the IDP. It is noteworthy that the results obtained by both multideterminental-DFT and IDP methods for different classes of JT active molecules are consistent and in agreement with available theoretical and experimental values. As an example, detailed description of the ground state distortion of benzene cation is given

Effect of promoter architecture on the cell-to-cell variability in gene expression

According to recent experimental evidence, the architecture of a promoter, defined as the number, strength and regulatory role of the operators that control the promoter, plays a major role in determining the level of cell-to-cell variability in gene expression. These quantitative experiments call for a corresponding modeling effort that addresses the question of how changes in promoter architecture affect noise in gene expression in a systematic rather than case-by-case fashion. In this article, we make such a systematic investigation, based on a simple microscopic model of gene regulation that incorporates stochastic effects. In particular, we show how operator strength and operator multiplicity affect this variability. We examine different modes of transcription factor binding to complex promoters (cooperative, independent, simultaneous) and how each of these affects the level of variability in transcription product from cell-to-cell. We propose that direct comparison between in vivo single-cell experiments and theoretical predictions for the moments of the probability distribution of mRNA number per cell can discriminate between different kinetic models of gene regulation.Comment: 35 pages, 6 figures, Submitte

Reduction of neutrophil activity decreases early microvascular injury after subarachnoid haemorrhage

<p>Abstract</p> <p>Background</p> <p>Subarachnoid haemorrhage (SAH) elicits rapid pathological changes in the structure and function of parenchymal vessels (≤ 100 μm). The role of neutrophils in these changes has not been determined. This study investigates the role of neutrophils in early microvascular changes after SAH</p> <p>Method</p> <p>Rats were either untreated, treated with vinblastine or anti-polymorphonuclear (PMN) serum, which depletes neutrophils, or treated with pyrrolidine dithiocarbamate (PDTC), which limits neutrophil activity. SAH was induced by endovascular perforation. Neutrophil infiltration and the integrity of vascular endothelium and basement membrane were assessed immunohistochemically. Vascular collagenase activity was assessed by <it>in situ </it>zymography.</p> <p>Results</p> <p>Vinblastine and anti-PMN serum reduced post-SAH accumulation of neutrophils in cerebral vessels and in brain parenchyma. PDTC increased the neutrophil accumulation in cerebral vessels and decreased accumulation in brain parenchyma. In addition, each of the three agents decreased vascular collagenase activity and post-SAH loss of vascular endothelial and basement membrane immunostaining.</p> <p>Conclusions</p> <p>Our results implicate neutrophils in early microvascular injury after SAH and indicate that treatments which reduce neutrophil activity can be beneficial in limiting microvascular injury and increasing survival after SAH.</p

Metformin as an Adjunctive Therapy for Pancreatic Cancer: A Review of the Literature on Its Potential Therapeutic Use

Pancreatic ductal adenocarcinoma has the worst prognosis of any cancer. New adjuvant chemotherapies are urgently required, which are well tolerated by patients with unresectable cancers. This paper reviews the existing proof of concept data, namely laboratory, pharmacoepidemiological, experimental medicine and clinical trial evidence for investigating metformin in patients with pancreatic ductal adenocarcinoma. Laboratory evidence shows metformin inhibits mitochondrial ATP synthesis which directly and indirectly inhibits carcinogenesis. Drug–drug interactions of metformin with proton pump inhibitors and histamine H2-receptor antagonists may be of clinical relevance and pertinent to future research of metformin in pancreatic ductal adenocarcinoma. To date, most cohort studies have demonstrated a positive association with metformin on survival in pancreatic ductal adenocarcinoma, although there are many methodological limitations with such study designs. From experimental medicine studies, there are sparse data in humans. The current trials of metformin have methodological limitations. Two small randomized controlled trials (RCTs) reported null findings, but there were potential inequalities in cancer staging between groups and poor compliance with the intervention. Proof of concept data, predominantly from laboratory work, supports assessing metformin as an adjunct for pancreatic ductal adenocarcinoma in RCTs. Ideally, more experimental medicine studies are needed for proof of concept. However, many feasibility criteria need to be answered before such trials can progress

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

A Detailed History of Intron-rich Eukaryotic Ancestors Inferred from a Global Survey of 100 Complete Genomes

Protein-coding genes in eukaryotes are interrupted by introns, but intron densities widely differ between eukaryotic lineages. Vertebrates, some invertebrates and green plants have intron-rich genes, with 6–7 introns per kilobase of coding sequence, whereas most of the other eukaryotes have intron-poor genes. We reconstructed the history of intron gain and loss using a probabilistic Markov model (Markov Chain Monte Carlo, MCMC) on 245 orthologous genes from 99 genomes representing the three of the five supergroups of eukaryotes for which multiple genome sequences are available. Intron-rich ancestors are confidently reconstructed for each major group, with 53 to 74% of the human intron density inferred with 95% confidence for the Last Eukaryotic Common Ancestor (LECA). The results of the MCMC reconstruction are compared with the reconstructions obtained using Maximum Likelihood (ML) and Dollo parsimony methods. An excellent agreement between the MCMC and ML inferences is demonstrated whereas Dollo parsimony introduces a noticeable bias in the estimations, typically yielding lower ancestral intron densities than MCMC and ML. Evolution of eukaryotic genes was dominated by intron loss, with substantial gain only at the bases of several major branches including plants and animals. The highest intron density, 120 to 130% of the human value, is inferred for the last common ancestor of animals. The reconstruction shows that the entire line of descent from LECA to mammals was intron-rich, a state conducive to the evolution of alternative splicing

Structural and Topographic Dynamics of Pulmonary Histopathology and Local Cytokine Profiles in Paracoccidioides brasiliensis Conidia-Infected Mice

Paracoccidioidomycosis (PCM), an endemic fungal infection of pulmonary origin resulting in severe disseminated disease, occurs in rural areas of most South American countries and presents several clinical forms. The infection is acquired by inhalation of specific fungal propagules, called conidia. Considering the difficulties encountered when studying the infection in humans, this work was done in mice infected by inhalation of infective fungal conidia thus mimicking the human natural infection. The lungs of mice were sequentially studied by histopathological and multiplex cytokine methods from 2 h to 16 weeks after infection to verify the course of the disease. The mycosis presented different morphologic aspects during the course of time, affecting several pulmonary compartments. Otherwise and based on the analysis of 30 cytokines, the immune response also showed heterogeneous responses, which were up or down regulated depending on the time of infection. By recognizing the different stages that correspond to the evolution of pulmonary lesions, the severity (benign, chronic or fibrotic) of the disease could be predicted and the probable prognosis of the illness be inferred

p53 mutations in classic and pleomorphic invasive lobular carcinoma of the breast

Contains fulltext : 110338.pdf (publisher's version ) (Open Access)BACKGROUND: p53 is a tumor suppressor that is frequently mutated in human cancers. Although alterations in p53 are common in breast cancer, few studies have specifically investigated TP53 mutations in the breast cancer subtype invasive lobular carcinoma (ILC). Recently reported conditional mouse models have indicated that functional p53 inactivation may play a role in ILC development and progression. Since reports on the detection of TP53 mutations in the relatively favorable classic and more aggressive pleomorphic variants of ILC (PILC) are rare and ambiguous, we performed a comprehensive analysis to determine the mutation status of TP53 in these breast cancer subtypes. METHODS: To increase our understanding of p53-mediated pathways and the roles they may play in the etiology of classic ILC and PILC, we investigated TP53 mutations and p53 accumulation in a cohort of 22 cases of classic and 19 cases of PILC by direct DNA sequencing and immunohistochemistry. RESULTS: We observed 11 potentially pathogenic TP53 mutations, of which three were detected in classic ILC (13.6%) and 8 in PILC (42.1%; p = 0.04). While p53 protein accumulation was not significantly different between classic and pleomorphic ILC, mutations that affected structure and protein function were significantly associated with p53 protein levels. CONCLUSION: TP53 mutations occur more frequently in PILC than classic ILC.1 april 201

3066 consecutive Gamma Nails. 12 years experience at a single centre

<p>Abstract</p> <p>Background</p> <p>Fixation of trochanteric hip fractures using the Gamma Nail has been performed since 1988 and is today well established and wide-spread. However, a number of reports have raised serious concerns about the implant's complication rate. The main focus has been the increased risk of a subsequent femoral shaft fracture and some authors have argued against its use despite other obvious advantages, when this implant is employed.</p> <p>Through access to a uniquely large patient data base available, which is available for analysis of trochanteric fractures; we have been able to evaluate the performance of the Gamma Nail over a twelve year period.</p> <p>Methods</p> <p>3066 consecutive patients were treated for trochanteric fractures using Gamma Nails between 1990 and 2002 at the Centre de Traumatologie et de l'Orthopedie (CTO), Strasbourg, France. These patients were retrospectively analysed. Information on epidemiological data, intra- and postoperative complications and patients' outcome was retrieved from patient notes. All available radiographs were assessed by a single reviewer (AJB).</p> <p>Results</p> <p>The results showed a low complication rate with the use of the Gamma Nail. There were 137 (4.5%) intraoperative fracture-related complications. Moreover 189 (6.2%) complications were detected postoperatively and during follow-up. Cut-out of the lag screw from the femoral head was the most frequent mechanical complication (57 patients, 1.85%), whereas a postoperative femoral shaft fracture occurred in 19 patients (0.6%). Other complications, such as infection, delayed healing/non-union, avascular femoral head necrosis and distal locking problems occurred in 113 patients (3.7%).</p> <p>Conclusions</p> <p>The use of the Gamma Nail in trochanteric hip fractures is a safe method with a low complication rate. In particular, a low rate of femoral shaft fractures was reported. The low complication rate reported in this series can probably be explained by strict adherence to a proper surgical technique.</p