ALBERT

Beschreibung: Sequence developments in rift basins are considered to be influenced largely by tectonics and to a lesser extent by eustatic sea-level and climate. Studies indicate that in passive margin basins climate can mask the effects of tectonics and eustasy by modulating the sediment supply. It is, however, less understood how the sedimentary sequence in rift basins might respond to strong climatic fluctuations where tectonic pulses generate rapid accommodation space. Here a case study has been provided to assess the effect of climate vis à vis sea-level and tectonics on sequence development in the Cambay rift basin, western India, during the Early Palaeogene (Late Palaeocene to Early Eocene) super greenhouse globe. Facies analysis of this shale–lignite sequence suggests deposition in a lagoon/bay, developed over the Deccan Trap basement. Detailed sequence stratigraphic analysis using basin-wide representative composite sections, marker lignite seam, event bed and high resolution carbon isotope ( δ 13 C) chemostratigraphy suggest an overall transgressive motif. Among the three prominent Early Eocene eustatic highstands, only the one at ca 53.7 Ma is expressed by the thickest coal accumulation throughout the basin. Expression of the other sequence stratigraphic surfaces is subdued and can be due to the overall finer grain size of the sediment or local variation in the subsidence rate at different fault controlled mini-basins. Enigmatic presence of a maximum flooding surface coinciding with the 53.7 Ma climate event (Eocene thermal maximum 2), manifested by negative carbon isotope excursion, indicates possible influence of climate over and above tectonics in developing the rift sequence. Qualitative rainfall variation assessed using the magnitude of the carbon isotope excursion and pollen abundance, show that relatively dry/low precipitation climatic phase during the Eocene thermal maximum 2 hindered the siliclastic supply to the basin. Thus, it has been inferred that climate induced high siliciclastic supply possibly enhanced the autocyclic reorganization, hindering the development of the key sequence stratigraphic surfaces across the basin during climate extremes. This article is protected by copyright. All rights reserved.

Beschreibung: Motivation: The alignment of sequencing reads to a transcriptome is a common and important step in many RNA-seq analysis tasks. When aligning RNA-seq reads directly to a transcriptome (as is common in the de novo setting or when a trusted reference annotation is available), care must be taken to report the potentially large number of multi-mapping locations per read. This can pose a substantial computational burden for existing aligners, and can considerably slow downstream analysis. Results: We introduce a novel concept, quasi-mapping, and an efficient algorithm implementing this approach for mapping sequencing reads to a transcriptome. By attempting only to report the potential loci of origin of a sequencing read, and not the base-to-base alignment by which it derives from the reference, RapMap—our tool implementing quasi-mapping—is capable of mapping sequencing reads to a target transcriptome substantially faster than existing alignment tools. The algorithm we use to implement quasi-mapping uses several efficient data structures and takes advantage of the special structure of shared sequence prevalent in transcriptomes to rapidly provide highly-accurate mapping information. We demonstrate how quasi-mapping can be successfully applied to the problems of transcript-level quantification from RNA-seq reads and the clustering of contigs from de novo assembled transcriptomes into biologically meaningful groups. Availability and implementation: RapMap is implemented in C ++11 and is available as open-source software, under GPL v3, at https://github.com/COMBINE-lab/RapMap . Contact: rob.patro@cs.stonybrook.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Beschreibung: Moly-TZM was deformed at constant strain rate of 1.0 s ?1 to investigate the high strain rate deformation behaviour by micro structural and stress response change within a temperature range of 1400-1700 ?C. To correlate the deformation behaviour with orientational change, recrystallization and recovery of the material, the microstructural investigation was undertaken using scanning electron microscopy (SEM) of electron back scattered diffraction (EBSD). Depending on the grain size and orientation spread recrystallized grains were identified and texture was calculated. Change in grain boundary characteristics with increasing temperature was determined by the misorientation angle distribution for the deformed and recrystallized grains. Subgrain coalescence and increase in subgrain size with increasing temperature was observed, indicating recrystallization not only occurred from the nucleation of the dislocation free grains in grain boundaries but also from the subgrain ro...

Beschreibung: This study investigates the first-order Himalayan mountain topography from the perspective of deep-crustal flow patterns in the Indo-Asia collision zone. Using a thin-viscous-sheet model we theoretically predict that flat hinterland topography with a stable elevation (Type I) can develop only when the lithospheric slab underthrusts with a threshold velocity ( V s * ). For V s 〉 V s * , the hinterland continuously gains in elevation, leading to Type II topography. This type is characterized by varying first-order surface slopes, but always facing the mountain front. Conversely, the elevated hinterland masses undergo gravity-driven subsidence, forming a topography (Type III) with characteristic backward surface slopes when V s 〈 V s * . We evaluate V s * as a function of: (i) the regional slope of the initial first-order surface topography (α); (ii) the angle of underthrusting (β); and (iii) the relative width of foreland plain (), assuming little effects of surface erosion. Our model shows two characteristic deep-crustal flow patterns: corner flow and vortex flow. The corner flow pattern, described by upwardly pointed hyperbolic streamlines, is responsible for Type II topography. Conversely, the vortex flow leads to Type III, whereas the transition between the two gives rise to Type I. This corner-to-vortex type flow transition commences on decreasing V s .

Beschreibung: Nucleosome positioning maps of several organisms have shown that Transcription Start Sites (TSSs) are marked by nucleosome depleted regions flanked by strongly positioned nucleosomes. Using genome-wide nucleosome maps and histone variant occupancy in the mouse liver, we show that the majority of genes were associated with a single prominent H2A.Z containing nucleosome in their promoter region. We classified genes into clusters depending on the proximity of H2A.Z to the TSS. The genes with no detectable H2A.Z showed lowest expression level, whereas H2A.Z was positioned closer to the TSS of genes with higher expression levels. We confirmed this relation between the proximity of H2A.Z and expression level in the brain. The proximity of histone variant H2A.Z, but not H3.3 to the TSS, over seven consecutive nucleosomes, was correlated with expression. Further, a nucleosome was positioned over the TSS of silenced genes while it was displaced to expose the TSS in highly expressed genes. Our results suggest that gene expression levels in vivo are determined by accessibility of the TSS and proximity of H2A.Z.

Beschreibung: Neurodegeneration is a devastating manifestation in the majority of 〉50 lysosomal storage disorders (LSDs). Neuronal ceroid lipofuscinoses (NCLs) are the most common childhood neurodegenerative LSDs. Mutations in 13 different genes (called CLN s) underlie various types of NCLs, of which the infantile NCL (INCL) and congenital NCL (CNCL) are the most lethal. Although inactivating mutations in the CLN1 gene encoding palmitoyl-protein thioesterase-1 (PPT1) cause INCL, those in the CLN10 gene encoding cathepsin D (CD) underlie CNCL. PPT1 is a lysosomal thioesterase that cleaves the thioester linkage in S -acylated proteins required for their degradation by lysosomal hydrolases like CD. Thus, PPT1 deficiency causes lysosomal accumulation of these lipidated proteins (major constituents of ceroid) leading to INCL. We sought to determine whether there is a common pathogenic link between INCL and CNCL. Using biochemical, histological and confocal microscopic analyses of brain tissues and cells from Cln1 –/– mice that mimic INCL, we uncovered that Cln10 /CD is overexpressed. Although synthesized in the endoplasmic reticulum, the CD-precursor protein (pro-CD) is transported through endosome to the lysosome where it is proteolytically processed to enzymatically active-CD. We found that despite Cln10 overexpression, the maturation of pro-CD to enzymatically active-CD in lysosome was disrupted. This defect impaired lysosomal degradative function causing accumulation of undegraded cargo in lysosome leading to INCL. Notably, treatment of intact Cln1 –/– mice as well as cultured brain cells derived from these animals with a thioesterase-mimetic small molecule, N - tert -butyl-hydroxylamine, ameliorated the CD-processing defect. Our findings are significant in that they define a pathway in which Cln1 mutations disrupt the maturation of a major degradative enzyme in lysosome contributing to neuropathology in INCL and suggest that lysosomal CD deficiency is a common pathogenic link between INCL and CNCL.

Beschreibung: Disruption of the blood-brain barrier (BBB) is a serious complication frequently encountered in neurodegenerative disorders. Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating childhood neurodegenerative lysosomal storage disorder caused by palmitoyl-protein thioesterase-1 (PPT1) deficiency. It remains unclear whether BBB is disrupted in INCL and if so, what might be the molecular mechanism(s) of this complication. We previously reported that the Ppt1 -knockout ( Ppt1 -KO) mice that mimic INCL manifest high levels of oxidative stress and neuroinflammation. Recently, it has been reported that CD4 + T-helper 17 (T H 17) lymphocytes may mediate BBB disruption and neuroinflammation, although the precise molecular mechanism(s) remain unclear. We sought to determine: (i) whether the BBB is disrupted in Ppt1 -KO mice, (ii) if so, do T H 17-lymphocytes underlie this complication, and (iii) how might T H 17 lymphocytes breach the BBB. Here, we report that the BBB is disrupted in Ppt1 -KO mice and that T H 17 lymphocytes producing IL-17A mediate disruption of the BBB by stimulating production of matrix metalloproteinases (MMPs), which degrade the tight junction proteins essential for maintaining BBB integrity. Importantly, dietary supplementation of resveratrol (RSV), a naturally occurring antioxidant/anti-inflammatory polyphenol, markedly reduced the levels of T H 17 cells, IL-17A and MMPs, and elevated the levels of tight junction proteins, which improved the BBB integrity in Ppt1 -KO mice. Intriguingly, we found that RSV suppressed the differentiation of CD4 + T lymphocytes to IL-17A-positive T H 17 cells. Our findings uncover a mechanism by which T H 17 lymphocytes mediate BBB disruption and suggest that small molecules such as RSV that suppress T H 17 differentiation are therapeutic targets for neurodegenerative disorders such as INCL.

Beschreibung: Computational models are valuable tools for predicting the population effects prior to Food and Drug Administration (FDA) authorization of a modified risk claim on a tobacco product. We have developed and validated a population model using best modeling practices. Our model consists of a Markov compartmental model based on cohorts starting at a defined age and followed up to a specific age accounting for 29 tobacco-use states based on a cohort members transition pathway. The Markov model is coupled with statistical mortality models and excess relative risk ratio estimates to determine survival probabilities from use of smokeless tobacco. Our model estimates the difference in premature deaths prevented by comparing Base Case (“world-as-is”) and Modified Case (the most likely outcome given that a modified risk claim is authorized) scenarios. Nationally representative transition probabilities were used for the Base Case. Probabilities of key transitions for the Modified Case were estimated based on a behavioral intentions study in users and nonusers. Our model predicts an estimated 93,000 premature deaths would be avoided over a 60-year period upon authorization of a modified risk claim. Our sensitivity analyses using various reasonable ranges of input parameters do not indicate any scenario under which the net benefit could be offset entirely.

Beschreibung: Author(s): A. Zecca, L. Chiari, E. Trainotti, A. Sarkar, S. d’A. Sanchez, M. H. F. Bettega, M. T. do N. Varella, M. A. P. Lima, and M. J. Brunger We report on measurements of total cross sections for positron scattering from the fundamental organic molecule methane (CH 4 ). The energy range of these measurements was 0.1–50 eV, whereas the energy resolution was ∼ 100 meV when our Ni moderator was used and ∼ 260 meV when the W moderator was employe... [Phys. Rev. A 85, 012707] Published Thu Jan 19, 2012

Beschreibung: We have sequenced miRNA libraries from human embryonic, neural and foetal mesenchymal stem cells. We report that the majority of miRNA genes encode mature isomers that vary in size by one or more bases at the 3' and/or 5' end of the miRNA. Northern blotting for individual miRNAs showed that the proportions of isomiRs expressed by a single miRNA gene often differ between cell and tissue types. IsomiRs were readily co-immunoprecipitated with Argonaute proteins in vivo and were active in luciferase assays, indicating that they are functional. Bioinformatics analysis predicts substantial differences in targeting between miRNAs with minor 5' differences and in support of this we report that a 5' isomiR-9–1 gained the ability to inhibit the expression of DNMT3B and NCAM2 but lost the ability to inhibit CDH1 in vitro . This result was confirmed by the use of isomiR-specific sponges. Our analysis of the miRGator database indicates that a small percentage of human miRNA genes express isomiRs as the dominant transcript in certain cell types and analysis of miRBase shows that 5' isomiRs have replaced canonical miRNAs many times during evolution. This strongly indicates that isomiRs are of functional importance and have contributed to the evolution of miRNA genes.