Nucleosomes are disrupted transiently during eukaryotic transcription, yet the displaced histones must be retained and redeposited onto DNA, to preserve nucleosome density and associated histone ...modifications. Here, we show that the essential Spt5 processivity factor of RNA polymerase II (Pol II) plays a direct role in this process in budding yeast. Functional orthologues of eukaryotic Spt5 are present in archaea and bacteria, reflecting its universal role in RNA polymerase processivity. However, eukaryotic Spt5 is unique in having an acidic amino terminal tail (Spt5N) that is sandwiched between the downstream nucleosome and the upstream DNA that emerges from Pol II. We show that Spt5N contains a histone‐binding motif that is required for viability in yeast cells and prevents loss of nucleosomal histones within actively transcribed regions. These findings indicate that eukaryotic Spt5 combines two essential activities, which together couple processive transcription to the efficient capture and re‐deposition of nucleosomal histones.
SYNOPSIS
Repositioning of histones displaced during transcription is key for preserving nucleosome density and chromatin modifications. Here, a conserved histone‐binding motif in RNA polymerase II processivity factor Spt5 is found as essential for yeast viability and prevention of histone loss from actively transcribed regions.
All living cells use orthologues of Spt5 to support processive transcription by RNA polymerases, but eukaryotic Spt5 is unique in having an acidic amino terminal tail (Spt5N) with a conserved histone‐binding motif.
Mutation of conserved residues in budding yeast Spt5N impairs histone binding and leads to loss of nucleosomal histones during transcription by RNA polymerase II.
Eukaryotic Spt5 couples processive transcription to the efficient capture and re‐deposition of nucleosomal histones.
A eukaryote‐specific histone‐binding motif in a conserved PolII processivity factor is essential for yeast viability and prevents loss of nucleosomal histones from actively transcribed regions.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Increased motility and invasiveness of pancreatic cancer cells are associated with epithelial to mesenchymal transition (EMT). Snai1 and Slug are zinc-finger transcription factors that trigger this ...process by repressing E-cadherin and enhancing vimentin and N-cadherin protein expression. However, the mechanisms that regulate this activation in pancreatic tumors remain elusive. MUC1, a transmembrane mucin glycoprotein, is associated with the most invasive forms of pancreatic ductal adenocarcinomas (PDA). In this study, we show that over expression of MUC1 in pancreatic cancer cells triggers the molecular process of EMT, which translates to increased invasiveness and metastasis. EMT was significantly reduced when MUC1 was genetically deleted in a mouse model of PDA or when all seven tyrosines in the cytoplasmic tail of MUC1 were mutated to phenylalanine (mutated MUC1 CT). Using proteomics, RT-PCR and western blotting, we revealed a significant increase in vimentin, Slug and Snail expression with repression of E-Cadherin in MUC1-expressing cells compared with cells expressing the mutated MUC1 CT. In the cells that carried the mutated MUC1 CT, MUC1 failed to co-immunoprecipitate with β-catenin and translocate to the nucleus, thereby blocking transcription of the genes associated with EMT and metastasis. Thus, functional tyrosines are critical in stimulating the interactions between MUC1 and β-catenin and their nuclear translocation to initiate the process of EMT. This study signifies the oncogenic role of MUC1 CT and is the first to identify a direct role of the MUC1 in initiating EMT during pancreatic cancer. The data may have implications in future design of MUC1-targeted therapies for pancreatic cancer.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•Effect of proton irradiation on Nb-1Zr-0.1C alloy proposed for CHTR.•XRD line profile analyses of the data collected using synchrotron source.•Prediction of dislocation loop formation with XRDLPA ...and supported by TEM analysis.•Microstructure-mechanical property correlation by tensile and nanoindentation test.•Comparison of microstructure and mechanical properties with proton irradiated pure Nb.
The microstructural evolution and corresponding changes in mechanical properties of proton irradiated Nb-1Zr-0.1C alloy have been studied as a function of irradiation dose. Different XRD line profile analyses (XRDLPA) have been carried out using synchrotron XRD data to evaluate the microstructural parameters. It is observed that coherent domain size decreases with an increasing microstrain within the domain as a function of dose. The dislocation density also increases and shows saturation at the highest dose. The Wilkens arrangement parameter decreases as a function of dose indicating the formation of correlated dislocations in the alloy matrix. Transmission electron microscopy (TEM) analysis confirms the presence of dislocation loops in the highest dose sample supporting the findings of XRDLPA. The strength and ductility of unirradiated and all irradiated samples have been evaluated as a function of dose. It is observed that the ductility reduces continuously along with increasing yield strength (YS) and ultimate tensile strength (UTS) as a function of dose. Nanoindentation was also carried out to measure the change in hardness of the alloy with dose. It is observed that the value of the nanohardness increases continuously from 1.74 GPa for the unirradiated sample to 2.43 GPa in the highest dose irradiated sample. Systematic changes are observed on the morphology of fracture surface as a function of dose. Signature of ductile failure is observed in the unirradiated sample whereas brittle failure is prominent in the irradiated samples with higher dose. The change in microstructure in terms of dislocation density is corroborated with the change in mechanical properties in terms of YS of the irradiated alloy. Contradistinction of the findings of Nb-1Zr-0.1C with those of pure Nb contemplated the role of the alloying additions, especially carbon, in governing the irradiation behaviour of the alloy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Carbon nanotubes (CNTs) may elicit inflammatory responses following pulmonary exposure. Conversely, enzymatic biodegradation of CNTs by inflammatory cells has also been reported. The aim of this ...study was to study the degradation of oxidized single-walled CNTs (ox-SWCNTs) by lactoperoxidase (LPO), a secreted peroxidase present in the airways, and whether pulmonary surfactant affects this biodegradation. To this end, ox-SWCNTs were incubated in vitro with recombinant bovine LPO+H2O2+NaSCN in the presence and absence of porcine lung surfactant (Curosurf®) and biodegradation was monitored using UV–Vis–NIR spectroscopy, Raman spectroscopy, and scanning electron microscopy. The interaction of recombinant LPO with bundles of ox-SWCNTs was confirmed by atomic force microscopy. Cell-free biodegradation of ox-SWCNTs was also observed ex vivo in murine bronchoalveolar lavage fluid in the presence of H2O2+NaSCN. Our study provides evidence for biodegradation of ox-SWCNTs with a lung surfactant ‘bio-corona’ and expands the repertoire of mammalian peroxidases capable of biodegradation of ox-SWCNTs. These findings are relevant to inhalation exposure to these materials, as LPO serves as an important component of the airway defense system.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Central-line-associated bloodstream infections are increasingly recognized to be associated with intraluminal microbial biofilms, and effective measures for the prevention and treatment of ...bloodstream infections remain lacking. This report evaluates a new commercially developed antimicrobial catheter lock solution (ACL), containing trimethoprim (5 mg/ml), ethanol (25%), and calcium EDTA (Ca-EDTA) (3%), for activity against bacterial and fungal biofilms, using
and
(rabbit) catheter biofilm models. Biofilms were formed by bacterial (seven different species, including vancomycin-resistant
VRE) or fungal (
) species on catheter materials. Biofilm formation was evaluated by quantitative culture (CFU) and scanning electron microscopy (SEM). Treatment with ACL inhibited the growth of adhesion-phase biofilms
after 60 min (VRE) or 15 min (all others), while mature biofilms were completely inhibited after exposure for 2 or 4 h, compared to control. Similar results were observed for drug-resistant bacteria. Compared to the heparinized saline controls, ACL lock therapy significantly reduced the catheter bacterial (3.49 ± 0.75 versus 0.03 ± 0.06 log CFU/catheter;
= 0.016) and fungal (2.48 ± 1.60 versus 0.55 ± 1.19 log CFU/catheter segment;
= 0.013) burdens in the catheterized rabbit model. SEM also demonstrated eradication of bacterial and fungal biofilms
on catheters exposed to ACL, while vigorous biofilms were observed on untreated control catheters. Our results demonstrated that ACL was efficacious against both adhesion-phase and mature biofilms formed by bacteria and fungi
and
.
Neuroimaging biomarkers that can detect white matter (WM) pathology after mild traumatic brain injury (mTBI) and predict long-term outcome are needed to improve care and develop therapies. We used ...diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) to investigate WM microstructure cross-sectionally and longitudinally after mTBI and correlate these with neuropsychological performance. Cross-sectionally, early decreases of fractional anisotropy and increases of mean diffusivity corresponded to WM regions with elevated free water fraction on NODDI. This elevated free water was more extensive in the patient subgroup reporting more early postconcussive symptoms. The longer-term longitudinal WM changes consisted of declining neurite density on NODDI, suggesting axonal degeneration from diffuse axonal injury for which NODDI is more sensitive than DTI. Therefore, NODDI is a more sensitive and specific biomarker than DTI for WM microstructural changes due to mTBI that merits further study for mTBI diagnosis, prognosis, and treatment monitoring.
Using a microfabricated porous media mimic platform, we investigated how fluid flow influences the formation of filamentous structures, known as streamers, between porous media structures. We ...demonstrate how hydrodynamics govern the formation, morphology and the distribution of these biofilm streamers in the device. Our work establishes that, under favorable hydrodynamic conditions, streamers can often act as precursors to mature microbial structures found in complex geometries, such as those involved in porous media.
Precision medicine is an approach to disease diagnosis, treatment, and prevention that relies on quantitative biomarkers that minimize the variability of individual patient measurements. The aim of ...this study was to assess the intersite variability after harmonization of a high-angular-resolution 3T diffusion tensor imaging protocol across 13 scanners at the 11 academic medical centers participating in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury multisite study.
Diffusion MR imaging was acquired from a novel isotropic diffusion phantom developed at the National Institute of Standards and Technology and from the brain of a traveling volunteer on thirteen 3T MR imaging scanners representing 3 major vendors (GE Healthcare, Philips Healthcare, and Siemens). Means of the DTI parameters and their coefficients of variation across scanners were calculated for each DTI metric and white matter tract.
For the National Institute of Standards and Technology diffusion phantom, the coefficients of variation of the apparent diffusion coefficient across the 13 scanners was <3.8% for a range of diffusivities from 0.4 to 1.1 × 10
mm
/s. For the volunteer, the coefficients of variations across scanners of the 4 primary DTI metrics, each averaged over the entire white matter skeleton, were all <5%. In individual white matter tracts, large central pathways showed good reproducibility with the coefficients of variation consistently below 5%. However, smaller tracts showed more variability, with the coefficients of variation of some DTI metrics reaching 10%.
The results suggest the feasibility of standardizing DTI across 3T scanners from different MR imaging vendors in a large-scale neuroimaging research study.
We calculate the ac optical response to circularly polarized light of a Weyl semimetal (WSM) with varying amounts of tilt of the Dirac cones. Both type-I and -II (overtilted) WSMs are considered in a ...continuum model with broken time-reversal symmetry. The Weyl nodes appear in pairs of equal energies but of opposite momentum and chirality. For type I, the response of a particular node to right-hand polarized (RHP) and left-hand polarized (LHP) light is distinct only in a limited range of photon energy Ω, 21+C2/v<Ωμ<21−C2/v with μ the chemical potential and C2 the tilt associated with the positive chirality node assuming the two nodes are oppositely tilted. For the overtilted case (type II), the same lower bound applies but there is no upper bound. If the tilt is reversed, the RHP and LHP responses are also reversed. We present corresponding results for the Hall angle.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
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