266 research outputs found
Poorly ventilated deep ocean at the Last Glacial Maximum inferred from carbon isotopes: A data‐model comparison study
CRISPR/Cas9-induced (CTG⋅CAG)n repeat instability in the myotonic dystrophy type 1 locus: implications for therapeutic genome editing
Myotonic dystrophy type 1 (DM1) is caused by (CTG⋅CAG)n-repeat expansion within the DMPK gene and thought to be mediated by a toxic RNA gain of function. Current attempts to develop therapy for this disease mainly aim at destroying or blocking abnormal properties of mutant DMPK (CUG)n RNA. Here, we explored a DNA-directed strategy and demonstrate that single clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-cleavage in either its 5′ or 3′ unique flank promotes uncontrollable deletion of large segments from the expanded trinucleotide repeat, rather than formation of short indels usually seen after double-strand break repair. Complete and precise excision of the repeat tract from normal and large expanded DMPK alleles in myoblasts from unaffected individuals, DM1 patients, and a DM1 mouse model could be achieved at high frequency by dual CRISPR/Cas9-cleavage at either side of the (CTG⋅CAG)n sequence. Importantly, removal of the repeat appeared to have no detrimental effects on the expression of genes in the DM1 locus. Moreover, myogenic capacity, nucleocytoplasmic distribution, and abnormal RNP-binding behavior of transcripts from the edited DMPK gene were normalized. Dual sgRNA-guided excision of the (CTG⋅CAG)n tract by CRISPR/Cas9 technology is applicable for developing isogenic cell lines for research and may provide new therapeutic opportunities for patients with DM1
Model Glycol-Terminated Surfaces for Adhesion Resistance
This manuscript introduces a new family of cyclic acetal-terminated alkanethiols used to prepare self-assembled monolayers (SAMs) on gold. The new SAMs, which are designed as variants of the biocompatible protein-repellant surfaces generated from thin films of oligoethylene glycol (OEG) or polyethylene glycol (PEG), were characterized by ellipsometry, contact-angle goniometry, and polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS). A preliminary study of protein adhesion was also performed using fibrinogen as a model protein. The interfacial structure and properties of the new SAMs were compared with those generated from OEG-terminated alkanethiols and from surface-grafted PEG, which have been described previously. The data show that the new adsorbates form well packed and conformationally ordered films with contact angles of water ranging from 67 to 95 , depending on the precise structure of the acetal terminus. As a whole, the new SAMs offer a unique strategy for studying and designing adhesion-resistant biocompatible inferfaces
Convection in colloidal suspensions with particle-concentration-dependent viscosity
The onset of thermal convection in a horizontal layer of a colloidal
suspension is investigated in terms of a continuum model for binary-fluid
mixtures where the viscosity depends on the local concentration of colloidal
particles. With an increasing difference between the viscosity at the warmer
and the colder boundary the threshold of convection is reduced in the range of
positive values of the separation ratio psi with the onset of stationary
convection as well as in the range of negative values of psi with an
oscillatory Hopf bifurcation. Additionally the convection rolls are shifted
downwards with respect to the center of the horizontal layer for stationary
convection (psi>0) and upwards for the Hopf bifurcation (psi<0).Comment: 8 pages, 6 figures, submitted to European Physical Journal
Seasonal distribution of genetic types of planktonic foraminifer morphospecies in the Santa Barbara Channel and its paleoceanographic implications
We present data on the temporal distribution of planktonic foraminifer genotypes (small subunit (SSU) ribosomal (r) RNA gene) and morphospecies (sediment traps) collected during 1999 in the Santa Barbara Channel. The sampling was undertaken with special emphasis on paleoceanographically important morphospecies, predominantly Globigerina bulloides. We found the same genotype of G. bulloides (type IId) in all the changing hydrographic regimes associated with this region throughout the annual cycle with the exception of January, when we recorded the additional presence of the high-latitude G. bulloides type IIa. We identified three new genotypes: Neogloboquadrina dutertrei type Ic, N. pachyderma dextral type II, and Turborotalita quinqueloba type IId. Our data suggest that G. bulloides type IId and possibly even the new genotypes listed above may be associated specifically with the complex hydrography or other environmental features characteristic of this area. Since G. bulloides type IId occurs throughout the year and its peak fluxes are related to different hydrographic regimes, we argue that the physical properties of the water column are not the major factor influencing the distribution and growth of this genotype. In sediment trap samples we found a skewed coiling ratio for G. bulloides (most likely representing type IId), which is related neither to sea surface temperature nor to genotypic difference. This study illustrates the necessity to map both the spatial and temporal distribution of the genetic types, especially in areas of paleoceanographic interest, where geochemical and paleontological proxies are being calibrated
A Tail-Anchored Myotonic Dystrophy Protein Kinase Isoform Induces Perinuclear Clustering of Mitochondria, Autophagy, and Apoptosis
Contains fulltext :
79678.pdf (publisher's version ) (Open Access)BACKGROUND: Studies on the myotonic dystrophy protein kinase (DMPK) gene and gene products have thus far mainly concentrated on the fate of length mutation in the (CTG)n repeat at the DNA level and consequences of repeat expansion at the RNA level in DM1 patients and disease models. Surprisingly little is known about the function of DMPK protein products. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate here that transient expression of one major protein product of the human gene, the hDMPK A isoform with a long tail anchor, results in mitochondrial fragmentation and clustering in the perinuclear region. Clustering occurred in a variety of cell types and was enhanced by an intact tubulin cytoskeleton. In addition to morphomechanical changes, hDMPK A expression induces physiological changes like loss of mitochondrial membrane potential, increased autophagy activity, and leakage of cytochrome c from the mitochondrial intermembrane space accompanied by apoptosis. Truncation analysis using YFP-hDMPK A fusion constructs revealed that the protein's tail domain was necessary and sufficient to evoke mitochondrial clustering behavior. CONCLUSION/SIGNIFICANCE: Our data suggest that the expression level of the DMPK A isoform needs to be tightly controlled in cells where the hDMPK gene is expressed. We speculate that aberrant splice isoform expression might be a codetermining factor in manifestation of specific DM1 features in patients
The impact of Cenozoic cooling on assemblage diversity in planktonic foraminifera
© 2016 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited. The attached file is the published version of the article
A resolution for the coiling direction paradox in Neogloboquadrina pachyderma.
We present new data on genotypic differences and biogeographic distribution of coiling types in the living planktonic foraminiferal morphospecies Neogloboquadrina pachyderma. The genetic evidence demonstrates that coiling direction in N. pachyderma is a genetic trait, heritable through time, and is not a morphological feature reflecting ecophenotypic variation. The two opposite coiling morphotypes appear to have diverged during the late Miocene, and they have distinctly different ecologies. In combination with fossil evidence, biogeography, and ecology the degree of genetic distinction between the two coiling types of N. pachyderma strongly implies that they should be considered different species. We propose the adoption of the widely recognized name N. incompta for the right coiling morphospecies. The genetic evidence also demonstrates a low level (<3%) of aberrant coiling associated with both morphotypes. The abundance of these aberrant specimens has no relationship with the environment. These findings have important consequences for the use of N. pachyderma and N. incompta as paleoceanographic signal carriers in polar and subpolar waters. Copyright 2006 by the American Geophysical Union
Assessing the impact of diagenesis on foraminiferal geochemistry from a low latitude, shallow-water drift deposit
Due to their large heat and moisture storage capabilities, the tropics are fundamental in modulating both regional and global climate. Furthermore, their thermal response during past extreme warming periods, such as super interglacials, is not fully resolved. In this regard, we present high-resolution (analytical) foraminiferal geochemical (δ18O and Mg/Ca) records for the last 1800 kyr from the shallow (487 m) Inner Sea drift deposits of the Maldives archipelago in the equatorial Indian Ocean. Considering the diagenetic susceptibility of these proxies, in carbonate-rich environments, we assess the integrity of a suite of commonly used planktonic and benthic foraminifera geochemical datasets (Globigerinoides ruber (white), Globigerinita glutinata (with bulla), Pulleniatina obliquiloculata (with cortex) and Cibicides mabahethi) and their use for future paleoceanographic reconstructions. Using a combination of spot Secondary Ion Mass Spectrometer, Electron Probe Micro-Analyzer and Scanning Electron Microscope image data, it is evident that authigenic overgrowths are present on both the external and internal test (shell) surfaces, yet the degree down-core as well as the associated bias is shown to be variable across the investigated species and proxies. Given the elevated authigenic overgrowth Mg/Ca (∼12–22 mmol/mol) and δ18O values (closer to the benthic isotopic compositions) the whole-test planktonic G. ruber (w) geochemical records are notably impacted beyond ∼627.4 ka (24.7 mcd). Yet, considering the setting (i.e. bottom water location) for overgrowth formation, the benthic foraminifera δ18O record is markedly less impacted with only minor diagenetic bias beyond ∼790.0 ka (28.7 mcd). Even though only the top of the G. ruber (w) and C. mabahethi records (whole-test data) would be suitable for paleo-reconstructions of absolute values (i.e. sea surface temperature, salinity, seawater δ18O), the long-term cycles, while dampened, appear to be preserved. Furthermore, planktonic species with thicker-tests (i.e. P. obliquiloculata (w/c)) might be better suited, in comparison to thinner-test counter-parts (i.e. G. glutinata (w/b), G. ruber (w)), for traditional whole- test geochemical studies in shallow, carbonate-rich environments. A thicker test equates to a smaller overall bias from the authigenic overgrowth. Overall, if the diagenetic impact is constrained, as done in this study, these types of diagenetically altered geochemical records can still significantly contribute to studies relating to past tropical seawater temperatures, latitudinal scale ocean current shifts and South Asian Monsoon dynamics
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