Richieri-Costa-Pereira syndrome is an autosomal-recessive acrofacial dysostosis characterized by mandibular median cleft associated with other craniofacial anomalies and severe limb defects. Learning ...and language disabilities are also prevalent. We mapped the mutated gene to a 122 kb region at 17q25.3 through identity-by-descent analysis in 17 genealogies. Sequencing strategies identified an expansion of a region with several repeats of 18- or 20-nucleotide motifs in the 5′ untranslated region (5′ UTR) of EIF4A3, which contained from 14 to 16 repeats in the affected individuals and from 3 to 12 repeats in 520 healthy individuals. A missense substitution of a highly conserved residue likely to affect the interaction of eIF4AIII with the UPF3B subunit of the exon junction complex in trans with an expanded allele was found in an unrelated individual with an atypical presentation, thus expanding mutational mechanisms and phenotypic diversity of RCPS. EIF4A3 transcript abundance was reduced in both white blood cells and mesenchymal cells of RCPS-affected individuals as compared to controls. Notably, targeting the orthologous eif4a3 in zebrafish led to underdevelopment of several craniofacial cartilage and bone structures, in agreement with the craniofacial alterations seen in RCPS. Our data thus suggest that RCPS is caused by mutations in EIF4A3 and show that EIF4A3, a gene involved in RNA metabolism, plays a role in mandible, laryngeal, and limb morphogenesis.
Cancer cell vascular invasion is a crucial step in the malignant progression toward metastasis. Here we used a genome-wide RNA interference screen with E0771 mammary cancer cells to uncover drivers ...of endothelial monolayer invasion. We identified keratin-associated protein 5-5 (Krtap5-5) as a candidate. Krtap5-5 belongs to a large protein family that is implicated in crosslinking keratin intermediate filaments during hair formation, yet these Krtaps have no reported role in cancer. Depletion of Krtap5-5 from cancer cells led to cell blebbing and a loss of keratins 14 and 18, in addition to the upregulation of vimentin intermediate filaments. This intermediate filament subtype switching induced dysregulation of the actin cytoskeleton and reduced the expression of hemidesmosomal α6/β4-integrins. We further demonstrate that knockdown of keratin 18 phenocopies the loss of Krtap5-5, suggesting that Krtap5-5 crosstalks with keratin 18 in E0771 cells. Disruption of the keratin cytoskeleton by perturbing Krtap5-5 function broadly altered the expression of cytoskeleton regulators and the localization of cell surface markers. Krtap5-5 depletion did not impact cell viability but reduced cell motility and extracellular matrix invasion, as well as extravasation of cancer cells into tissues in zebrafish and mice. We conclude that Krtap5-5 is a previously unknown regulator of cytoskeletal function in cancer cells that modulates motility and vascular invasion. Thus, in addition to its physiologic function, a Krtap can serve as a switch toward malignant progression.
The epidemiology of Mycobacterium tuberculosis (Mtb) and M. africanum (Maf) suggests differences in their virulence, but the host immune profile to better understand the pathogenesis of tuberculosis ...(TB) have not been studied. We compared the transcriptomic and metabolic profiles between Mtb- and Maf-infected TB cases to identify host biomarkers associated with lineages-specific pathogenesis and response to anti-TB chemotherapy. Venous blood samples from Mtb- and Maf-infected patients obtained before and after anti-TB treatment were analyzed for cell composition, gene expression and metabolic profiles. Prior to treatment, similar transcriptomic profiles were seen in Maf- and Mtb-infected patients. In contrast, post treatment, over 1600 genes related to immune responses and metabolic diseases were differentially expressed between the groups. Notably, the upstream regulator hepatocyte nuclear factor 4-alpha (HNF4α), which regulated 15% of these genes, was markedly enriched. Serum metabolic profiles were similar in both group pre-treatment, but the decline in pro-inflammatory metabolites post treatment were most pronounced in Mtb-infected patients. Together, the differences in both peripheral blood transcriptomic and serum metabolic profiles between Maf- and Mtb-infected patients observed over the treatment period, might be indicative of intrinsic host factors related to susceptibility to TB and/or differential efficacy of the standard anti-TB treatment on the two lineages.
N-acetylaspartate (NAA) in the medial temporal lobe (MTL) and parietal lobe gray matter (GM) is diminished in Alzheimer disease (AD). Because NAA is considered a marker of neuronal integrity, reduced ...medial temporal and parietal lobe NAA could be an early indication of dementia-related pathology in elderly individuals.
1) To determine whether cognitively impaired but nondemented (CIND) elderly individuals exhibit a similar pattern of reduced medial temporal and parietal lobe NAA as AD patients. 2) To compare regional NAA patterns, hippocampal and neocortical gray matter (GM) volumes in CIND patients who remained cognitively stable and those who became demented over 3.6 years of follow-up. 3) To examine the relationship between memory performance, medial temporal lobe NAA, and hippocampal volume.
Seventeen CIND, 24 AD, and 24 cognitively normal subjects were studied using MRSI and MRI.
Relative to controls, CIND patients had reduced MTL NAA (19 to 21%, p = 0.005), hippocampal (11 to 14%, p < or = 0.04), and neocortical GM (5%, p = 0.05) volumes. CIND patients who later became demented had less MTL NAA (26%, p = 0.01), hippocampal (17 to 23%, p < or = 0.05), and neocortical GM (13%, p = 0.02) volumes than controls, but there were no significant differences between stable CIND patients and controls. MTL NAA in combination with hippocampal volume improved discrimination of CIND and controls over hippocampal volume alone. In AD and CIND patients, decreased MTL NAA correlated significantly with impaired memory performance.
Reduced medial temporal lobe N-acetylaspartate, together with reduced hippocampal and neocortical gray matter volumes, may be early indications of dementia-related pathology in subjects at high risk for developing dementia.
ABSTRACT Between the beginning of its full-scale scientific operations in 2007 and 2012, the VERITAS Cherenkov telescope array observed more than 130 blazars; of these, 26 were detected as ...very-high-energy (VHE; E > 100 GeV) γ-ray sources. In this work, we present the analysis results of a sample of 114 undetected objects. The observations constitute a total live-time of ∼570 hr. The sample includes several unidentified Fermi-Large Area Telescope (LAT) sources (located at high Galactic latitude) as well as all the sources from the second Fermi-LAT catalog that are contained within the field of view of the VERITAS observations. We have also performed optical spectroscopy measurements in order to estimate the redshift of some of these blazars that do not have spectroscopic distance estimates. We present new optical spectra from the Kast instrument on the Shane telescope at the Lick observatory for 18 blazars included in this work, which allowed for the successful measurement or constraint on the redshift of four of them. For each of the blazars included in our sample, we provide the flux upper limit in the VERITAS energy band. We also study the properties of the significance distributions and we present the result of a stacked analysis of the data set, which shows a 4 excess.
We present a new measurement of the energy spectrum of iron nuclei in cosmic rays from 20 TeV to 500 TeV. The measurement makes use of a template-based analysis method, which, for the first time, is ...applied to the energy reconstruction of iron-induced air showers recorded by the VERITAS array of imaging atmospheric Cherenkov telescopes. The event selection makes use of the direct Cherenkov light which is emitted by charged particles before the first interaction, as well as other parameters related to the shape of the recorded air shower images. The measured spectrum is well described by a power law dFdE=f0·(EE0)−γ over the full energy range, with γ=2.82±0.30(stat)−0.27+0.24(syst) and f0=(4.82±0.98(stat)−2.70+2.12(syst))×10−7 m−2 s−1 TeV−1 sr−1 at E0=50 TeV, with no indication of a cutoff or spectral break. The measured differential flux is compatible with previous results, with improved statistical uncertainty at the highest energies.
HESS J1943+213 is a very high energy (VHE; >100 GeV) γ-ray source in the direction of the Galactic plane. Studies exploring the classification of the source are converging toward its identification ...as an extreme synchrotron BL Lac object. Here we present 38 hr of VERITAS observations of HESS J1943+213 taken over 2 yr. The source is detected with a significance of ∼20 standard deviations, showing a remarkably stable flux and spectrum in VHE γ-rays. Multifrequency Very Long Baseline Array (VLBA) observations of the source confirm the extended, jet-like structure previously found in the 1.6 GHz band with the European VLBI Network and detect this component in the 4.6 and 7.3 GHz bands. The radio spectral indices of the core and the jet and the level of polarization derived from the VLBA observations are in a range typical for blazars. Data from VERITAS, Fermi-LAT, Swift-XRT, the FLWO 48″ telescope, and archival infrared and hard X-ray observations are used to construct and model the spectral energy distribution (SED) of the source with a synchrotron self-Compton model. The well-measured γ-ray peak of the SED with VERITAS and Fermi-LAT provides constraining upper limits on the source redshift. Possible contribution of secondary γ-rays from ultra-high-energy cosmic-ray-initiated electromagnetic cascades to the γ-ray emission is explored, finding that only a segment of the VHE spectrum can be accommodated with this process. A variability search is performed across X-ray and γ-ray bands. No statistically significant flux or spectral variability is detected.
ABSTRACT The F-type star KIC 8462852 has recently been identified as an exceptional target for search for extraterrestrial intelligence (SETI) observations. We describe an analysis methodology for ...optical SETI, which we have used to analyze nine hours of serendipitous archival observations of KIC 8462852 made with the VERITAS gamma-ray observatory between 2009 and 2015. No evidence of pulsed optical beacons, above a pulse intensity at the Earth of approximately , is found. We also discuss the potential use of imaging atmospheric Cherenkov telescope arrays in searching for extremely short duration optical transients in general.
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