Transcription levels of a noncoding RNA orchestrate opposing regulatory and cell fate outcomes in yeast

Transcription through noncoding regions of the genome is pervasive. How these transcription events regulate gene expression remains poorly understood. Here, we report that, in S. cerevisiae, the levels of transcription through a noncoding region, IRT2, located upstream in the promoter of the inducer of meiosis, IME1, regulate opposing chromatin and transcription states. At low levels, the act of IRT2 transcription promotes histone exchange, delivering acetylated histone H3 lysine 56 to chromatin locally. The subsequent open chromatin state directs transcription factor recruitment and induces downstream transcription to repress the IME1 promoter and meiotic entry. Conversely, increasing transcription turns IRT2 into a repressor by promoting transcription-coupled chromatin assembly. The two opposing functions of IRT2 transcription shape a regulatory circuit, which ensures a robust cell-type-specific control of IME1 expression and yeast meiosis. Our data illustrate how intergenic transcription levels are key to controlling local chromatin state, gene expression, and cell fate outcomes

Aerothermodynamic Analysis of a Reentry Brazilian Satellite

This work deals with a computational investigation on the small ballistic reentry Brazilian vehicle SARA (acronyms for SAt\'elite de Reentrada Atmosf\'erica). Hypersonic flows over the vehicle SARA at zero-degree angle of attack in a chemical equilibrium and thermal non-equilibrium are modeled by the Direct Simulation Monte Carlo (DSMC) method, which has become the main technique for studying complex multidimensional rarefied flows, and that properly accounts for the non-equilibrium aspects of the flows. The emphasis of this paper is to examine the behavior of the primary properties during the high altitude portion of SARA reentry. In this way, velocity, density, pressure and temperature field are investigated for altitudes of 100, 95, 90, 85 and 80 km. In addition, comparisons based on geometry are made between axisymmetric and planar two-dimensional configurations. Some significant differences between these configurations were noted on the flowfield structure in the reentry trajectory. The analysis showed that the flow disturbances have different influence on velocity, density, pressure and temperature along the stagnation streamline ahead of the capsule nose. It was found that the stagnation region is a thermally stressed zone. It was also found that the stagnation region is a zone of strong compression, high wall pressure. Wall pressure distributions are compared with those of available experimental data and good agreement is found along the spherical nose for the altitude range investigated.Comment: The paper will be published in Vol. 42 of the Brazilian Journal of Physic

Thermoelastic properties of magnesiowustite, (Mg1-xFex)O: determination of the Anderson-Gruneisen parameter by time-of-flight neutron powder diffraction at simultaneous high pressures and temperatures

The ability to perform neutron diffraction studies at simultaneous high pressures and high temperatures is a relatively recent development. The suitability of this technique for determining P-V-T equations of state has been investigated by measuring the lattice parameters of Mg1-xFexO ( x = 0.2, 0.3, 0.4), in the range P < 10.3 GPa and 300 < T < 986 K, by time-of-flight neutron powder diffraction. Pressures were determined using metallic Fe as a marker and temperatures were measured by neutron absorption resonance radiography. Within the resolution of the experiment, no evidence was found for any change in the temperature derivative of the isothermal incompressibility, partial derivative K-T/partial derivative T, with composition. By assuming that the equation-of-state parameters either varied linearly or were invariant with composition, the 60 measured state points were fitted simultaneously to a P-V-T-x equation of state, leading to values of partial derivative K-T/partial derivative T = -0.024 (9) GPa K-1 and of the isothermal Anderson-Gruneisen parameter delta(T) = 4.0 (16) at 300 K. Two designs of simultaneous high-P/T cell were employed during this study. It appears that, by virtue of its extended pressure range, a design using toroidal gaskets is more suitable for equation-of-state studies than is the system described by Le Godec, Dove, Francis, Kohn, Marshall, Pawley, Price, Redfern, Rhodes, Ross, Schofield, Schooneveld, Syfosse, Tucker & Welch [Mineral. Mag. (2001), 65, 737-748]. (c) 2008 International Union of Crystallography Printed in Singapore - all rights reserved

A randomised trial comparing the pharmacokinetics and safety of the biosimilar CT-P6 with reference trastuzumab

PURPOSE: Access to trastuzumab, a valuable anti-cancer treatment, can be limited by cost. The primary aim of this study was to evaluate and compare the PK profiles of CT-P6, a biosimilar of trastuzumab, and US-licensed reference trastuzumab (Herceptin®) in healthy subjects. Secondary study aims included comparison of the safety and immunogenicity of CT-P6 and reference trastuzumab in these subjects. METHODS: We performed a single-dose, randomised, double-blind, parallel group study (NCT02665637) comparing CT-P6 with reference trastuzumab (6 mg/kg, 90 min intravenous infusion) in 70 healthy adult males. Pharmacokinetics, safety and immunogenicity were evaluated up to 10 weeks post-dose. Primary endpoints were area under the serum concentration-time curve (AUC) from time 0 to infinity (AUCinf); AUC from time 0 to last quantifiable concentration (AUClast); and observed maximum serum concentration (Cmax). The pre-determined equivalence criterion was a 90% confidence interval of 80-125% for ratios of geometric least squares (LS) means. RESULTS: Equivalence of CT-P6 and reference trastuzumab was demonstrated. Ratios (CT-P6/reference trastuzumab) of geometric LS means (90% confidence interval) were: AUCinf 99.05 (93.00, 105.51); AUClast 99.30 (92.85, 106.20); Cmax 96.58 (90.93, 102.59). Safety profiles were similar; treatment-emergent adverse events occurred in ten subjects (28.6%) in the CT-P6 group and 11 (31.4%) in the reference trastuzumab group. No serious adverse events or deaths occurred. No subjects tested positive for anti-drug antibodies. CONCLUSIONS: These data add to the totality of evidence required to demonstrate biosimilarity. A phase III study of CT-P6-in which equivalent neoadjuvant efficacy to reference trastuzumab has been demonstrated-is ongoing

Infection, vascularization, remodelling - are stem cells the answers for bone diseases of the jaws?

Osteonecrosis after craniofacial radiation (ORN), osteomyelitis and bisphosphonates related necrosis of the jaw (BRONJ) are the predominant bone diseases in Cranio- and Maxillofacial surgery. Although various hypothesis for the pathophysiological mechanisms including infection, altered vascularisation or remodelling exist, the treatment is still a challenge for clinicians. As the classical pharmacological or surgical treatment protocols have only limited success, stem cells might be a promising treatment option, indicated by recently published data

Air pollution, ethnicity and telomere length in east London schoolchildren: An observational study

This study was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London, Dr. and Mrs. Lee Iu Cheung Fund, and Hackney Primary Care Trust (PCT)

Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the R6/2 Mouse Model of HD

Huntington's disease (HD) is caused by the expansion of a CAG repeat in the huntingtin (HTT) gene. The R6/2 mouse model of HD expresses a mutant version of exon 1 HTT and develops motor and cognitive impairments, a widespread huntingtin (HTT) aggregate pathology and brain atrophy. Despite the vast number of studies that have been performed on this model, the association between the molecular and cellular neuropathology with brain atrophy, and with the development of behavioral phenotypes remains poorly understood. In an attempt to link these factors, we have performed longitudinal assessments of behavior (rotarod, open field, passive avoidance) and of regional brain abnormalities determined through magnetic resonance imaging (MRI) (whole brain, striatum, cortex, hippocampus, corpus callosum), as well as an end-stage histological assessment. Detailed correlative analyses of these three measures were then performed. We found a gender-dependent emergence of motor impairments that was associated with an age-related loss of regional brain volumes. MRI measurements further indicated that there was no striatal atrophy, but rather a lack of striatal growth beyond 8 weeks of age. T2 relaxivity further indicated tissue-level changes within brain regions. Despite these dramatic motor and neuroanatomical abnormalities, R6/2 mice did not exhibit neuronal loss in the striatum or motor cortex, although there was a significant increase in neuronal density due to tissue atrophy. The deposition of the mutant HTT (mHTT) protein, the hallmark of HD molecular pathology, was widely distributed throughout the brain. End-stage histopathological assessments were not found to be as robustly correlated with the longitudinal measures of brain atrophy or motor impairments. In conclusion, modeling pre-manifest and early progression of the disease in more slowly progressing animal models will be key to establishing which changes are causally related. © 2013 Rattray et al

Quantum physics in inertial and gravitational fields

Covariant generalizations of well-known wave equations predict the existence of inertial-gravitational effects for a variety of quantum systems that range from Bose-Einstein condensates to particles in accelerators. Additional effects arise in models that incorporate Born reciprocity principle and the notion of a maximal acceleration. Some specific examples are discussed in detail.Comment: 25 pages,1 figure,to appear in "Relativity in Rotating Frame

Prime movers : mechanochemistry of mitotic kinesins

Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation

Hystricognathy vs Sciurognathy in the Rodent Jaw: A New Morphometric Assessment of Hystricognathy Applied to the Living Fossil Laonastes (Diatomyidae)

While exceptional for an intense diversification of lineages, the evolutionary history of the order Rodentia comprises only a limited number of morphological morphotypes for the mandible. This situation could partly explain the intense debates about the taxonomic position of the latest described member of this clade, the Laotian rock rat Laonastes aenigmamus (Diatomyidae). This discovery has re-launched the debate on the definition of the Hystricognathi suborder identified using the angle of the jaw relative to the plane of the incisors. Our study aims to end this ambiguity. For clarity, it became necessary to revisit the entire morphological diversity of the mandible in extant and extinct rodents. However, current and past rodent diversity brings out the limitations of the qualitative descriptive approach and highlights the need for a quantitative approach. Here, we present the first descriptive comparison of the masticatory apparatus within the Ctenohystrica clade, in combining classic comparative anatomy with morphometrical methods. First, we quantified the shape of the mandible in rodents using 3D landmarks. Then, the analysis of osteological features was compared to myological features in order to understand the biomechanical origin of this morphological diversity. Among the morphological variation observed, the mandible of Laonastes aenigmamus displays an intermediate association of features that could be considered neither as sciurognathous nor as hystricognathous