Finite temperature effects on the structural stability of Si-doped HfO2_{2} using first-principles calculations

The structural stabilities of the monoclinic and tetragonal phases of Si-doped HfO$_{2}$ at finite temperatures were analyzed using a computational scheme to assess the effects of impurity doping. The finite temperature effects considered in this work represented lattice vibration and impurity configuration effects. The results show that 6% Si doping stabilizes the tetragonal phase at room temperature, although a higher concentration of Si is required to stabilize the tetragonal phase at zero temperature. These data indicate that lattice vibration and impurity configuration effects are important factors determining structural stability at finite temperatures.Comment: 5 pages, 3 figure

A Novel Mutation in the Upstream Open Reading Frame of the CDKN1B Gene Causes a MEN4 Phenotype

PubMed ID: 23555276This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Inner ear hair cells produced in vitro by a mesenchymal-to-epithelial transition

Author Posting. © The Author(s), 2007. This is the author's version of the work. It is posted here by permission of National academy of Sciences for personal use, not for redistribution. The definitive version was published in Proceedings of the National Academy of Sciences 104 (2007): 16675-16680, doi:10.1073/pnas.0704576104.Sensory hair cell loss is a major contributor to disabling hearing and balance deficits that affect >250 million people worldwide. Sound exposures, infections, drug toxicity, genetic disorders, and aging all can cause hair cell loss and lead to permanent sensory deficits. Progress toward treatments for these deficits has been limited, in part because hair cells have only been obtainable via microdissection of the anatomically complex internal ear. Attempts to produce hair cells in vitro have resulted in reports of some success, but have required transplantation into embryonic ears or co-culturing with other tissues. Here we show that avian inner ear cells can be cultured and passaged for months, frozen, and expanded to large numbers without other tissues. At any point from passage 6 up to at least passage 23, these cultures can be fully dissociated and then aggregated in suspension to induce a mesenchymal-to-epithelial transition that reliably yields new polarized sensory epithelia. Those epithelia develop numerous hair cells that are crowned by hair bundles, comprised of a single kinocilium and an asymmetric array of stereocilia. These hair cells exhibit rapid permeance to FM1-43, a dye that passes through open mechanotransducing channels. Since a vial of frozen cells can now provide the capacity to produce bona fide hair cells completely in vitro, these discoveries should open new avenues of research that may ultimately contribute to better treatments for hearing loss and other inner ear disorders.Supported by NIH grants DC00200 and DC006182to J.T.C

Performance benchmarks for a next generation numerical dynamo model

Numerical simulations of the geodynamo have successfully represented many observable characteristics of the geomagnetic field, yielding insight into the fundamental processes that generate magnetic fields in the Earth's core. Because of limited spatial resolution, however, the diffusivities in numerical dynamo models are much larger than those in the Earth's core, and consequently, questions remain about how realistic these models are. The typical strategy used to address this issue has been to continue to increase the resolution of these quasi-laminar models with increasing computational resources, thus pushing them toward more realistic parameter regimes. We assess which methods are most promising for the next generation of supercomputers, which will offer access to O(106) processor cores for large problems. Here we report performance and accuracy benchmarks from 15 dynamo codes that employ a range of numerical and parallelization methods. Computational performance is assessed on the basis of weak and strong scaling behavior up to 16,384 processor cores. Extrapolations of our weak-scaling results indicate that dynamo codes that employ two-dimensional or three-dimensional domain decompositions can perform efficiently on up to ∼106 processor cores, paving the way for more realistic simulations in the next model generation

Mast Cell Survival and Mediator Secretion in Response to Hypoxia

Tissue hypoxia is a consequence of decreased oxygen levels in different inflammatory conditions, many associated with mast cell activation. However, the effect of hypoxia on mast cell functions is not well established. Here, we have investigated the effect of hypoxia per se on human mast cell survival, mediator secretion, and reactivity. Human cord blood derived mast cells were subjected to three different culturing conditions: culture and stimulation in normoxia (21% O2); culture and stimulation in hypoxia (1% O2); or 24 hour culture in hypoxia followed by stimulation in normoxia. Hypoxia, per se, did not induce mast cell degranulation, but we observed an increased secretion of IL-6, where autocrine produced IL-6 promoted mast cell survival. Hypoxia did not have any effect on A23187 induced degranulation or secretion of cytokines. In contrast, cytokine secretion after LPS or CD30 treatment was attenuated, but not inhibited, in hypoxia compared to normoxia. Our data suggests that mast cell survival, degranulation and cytokine release are sustained under hypoxia. This may be of importance for host defence where mast cells in a hypoxic tissue can react to intruders, but also in chronic inflammations where mast cell reactivity is not inhibited by the inflammatory associated hypoxia

Coupled evolution of temperature and carbonate chemistry during the Paleocene–Eocene; new trace element records from the low latitude Indian Ocean

This is the final version. Available on open access from Elsevier via the DOI in this recordThe early Paleogene represents the most recent interval in Earth’s history characterized by global greenhouse warmth on multi-million year timescales, yet our understanding of long-term climate and carbon cycle evolution in the low latitudes, and in particular the Indian Ocean, remains very poorly constrained. Here we present the first long-term sub-eccentricity-resolution stable isotope (δ13 30 C and δ 18 O) and trace element (Mg/Ca and B/Ca) records spanning the late Paleocene–early Eocene (~58– 53 Ma) across a surface–deep hydrographic reconstruction of the northern Indian Ocean, resolving late Paleocene 405-kyr paced cyclicity and a portion of the PETM recovery. Our new records reveal a long-term warming of ~4–5°C at all depths in the water column, with absolute surface ocean temperatures and magnitudes of warming comparable to the low latitude Pacific. As a result of warming, we observe a long-term increase in δ 18 Osw of the mixed layer, implying an increase in net evaporation. We also observe a collapse in the temperature gradient between mixed layer- and thermocline-dwelling species from ~57–54 Ma, potentially due to either the development of a more homogeneous water column with a thicker mixed layer, or depth migration of the Morozovella in response to warming. Synchronous warming at both low and high latitudes, along with decreasing B/Ca ratios in planktic foraminifera indicating a decrease in ocean pH and/or increasing dissolved inorganic carbon, suggest that global climate was forced by rising atmospheric CO2 concentrations during this time.European Consortium for Ocean Research Drilling (ECORD)International Association of Sedimentologists (IAS)NSFNatural Environment Research Council (NERC

Mechanisms of Hearing Loss after Blast Injury to the Ear

Given the frequent use of improvised explosive devices (IEDs) around the world, the study of traumatic blast injuries is of increasing interest. The ear is the most common organ affected by blast injury because it is the bodyﾒs most sensitive pressure transducer. We fabricated a blast chamber to re-create blast profiles similar to that of IEDs and used it to develop a reproducible mouse model to study blast-induced hearing loss. The tympanic membrane was perforated in all mice after blast exposure and found to heal spontaneously. Micro-computed tomography demonstrated no evidence for middle ear or otic capsule injuries; however, the healed tympanic membrane was thickened. Auditory brainstem response and distortion product otoacoustic emission threshold shifts were found to be correlated with blast intensity. As well, these threshold shifts were larger than those found in control mice that underwent surgical perforation of their tympanic membranes, indicating cochlear trauma. Histological studies one week and three months after the blast demonstrated no disruption or damage to the intra-cochlear membranes. However, there was loss of outer hair cells (OHCs) within the basal turn of the cochlea and decreased spiral ganglion neurons (SGNs) and afferent nerve synapses. Using our mouse model that recapitulates human IED exposure, our results identify that the mechanisms underlying blast-induced hearing loss does not include gross membranous rupture as is commonly believed. Instead, there is both OHC and SGN loss that produce auditory dysfunction

NF-Y Dependent Epigenetic Modifications Discriminate between Proliferating and Postmitotic Tissue

The regulation of gene transcription requires posttranslational modifications of histones that, in concert with chromatin remodeling factors, shape the structure of chromatin. It is currently under intense investigation how this structure is modulated, in particular in the context of proliferation and differentiation. Compelling evidence suggests that the transcription factor NF-Y acts as a master regulator of cell cycle progression, activating the transcription of many cell cycle regulatory genes. However, the underlying molecular mechanisms are not yet completely understood. Here we show that NF-Y exerts its effect on transcription through the modulation of the histone “code”. NF-Y colocalizes with nascent RNA, while RNA polymerase II is I phosphorylated on serine 2 of the YSPTSPS repeats within its carboxyterminal domain and histones are carrying modifications that represent activation signals of gene expression (H3K9ac and PAN-H4ac). Comparing postmitotic muscle tissue from normal mice and proliferating muscles from mdx mice, we demonstrate by chromatin immunoprecipitation (ChIP) that NF-Y DNA binding activity correlates with the accumulation of acetylated histones H3 and H4 on promoters of key cell cycle regulatory genes, and with their active transcription. Accordingly, p300 is recruited onto the chromatin of NF-Y target genes in a NF-Y-dependent manner, as demonstrated by Re-ChIP. Conversely, the loss of NF-Y binding correlates with a decrease of acetylated histones, the recruitment of HDAC1, and a repressed heterochromatic state with enrichment of histones carrying modifications known to mediate silencing of gene expression (H3K9me3, H3K27me2 and H4K20me3). As a consequence, NF-Y target genes are downregulated in this context. In conclusion, our data indicate a role of NF-Y in modulating the structure and transcriptional competence of chromatin in vivo and support a model in which NF-Y-dependent histone “code” changes contribute to the proper discrimination between proliferating and postmitotic cells in vivo and in vitro

Inferring the Transcriptional Landscape of Bovine Skeletal Muscle by Integrating Co-Expression Networks

Background: Despite modern technologies and novel computational approaches, decoding causal transcriptional regulation remains challenging. This is particularly true for less well studied organisms and when only gene expression data is available. In muscle a small number of well characterised transcription factors are proposed to regulate development. Therefore, muscle appears to be a tractable system for proposing new computational approaches. Methodology/Principal Findings: Here we report a simple algorithm that asks "which transcriptional regulator has the highest average absolute co-expression correlation to the genes in a co-expression module?" It correctly infers a number of known causal regulators of fundamental biological processes, including cell cycle activity (E2F1), glycolysis (HLF), mitochondrial transcription (TFB2M), adipogenesis (PIAS1), neuronal development (TLX3), immune function (IRF1) and vasculogenesis (SOX17), within a skeletal muscle context. However, none of the canonical pro-myogenic transcription factors (MYOD1, MYOG, MYF5, MYF6 and MEF2C) were linked to muscle structural gene expression modules. Co-expression values were computed using developing bovine muscle from 60 days post conception (early foetal) to 30 months post natal (adulthood) for two breeds of cattle, in addition to a nutritional comparison with a third breed. A number of transcriptional landscapes were constructed and integrated into an always correlated landscape. One notable feature was a 'metabolic axis' formed from glycolysis genes at one end, nuclear-encoded mitochondrial protein genes at the other, and centrally tethered by mitochondrially-encoded mitochondrial protein genes. Conclusions/Significance: The new module-to-regulator algorithm complements our recently described Regulatory Impact Factor analysis. Together with a simple examination of a co-expression module's contents, these three gene expression approaches are starting to illuminate the in vivo transcriptional regulation of skeletal muscle development