We questioned the significance of haplotype structure in gene regulation by testing whether individual single nucleotide polymorphisms (SNPs) within a gene promoter region interleukin-1-beta (IL1B) ...might affect promoter function and, if so, whether function was dependent on haplotype context. We sequenced genomic DNA from 25 individuals of diverse ethnicity, focusing on exons and upstream flanking regions of genes of the cluster. We identified four IL1B promoter region SNPs that were active in transient transfection reporter gene assays. To substantiate allelic differences found in reporter gene assays, we also examined nuclear protein binding to promoter sequence oligonucleotides containing different alleles of the SNPs. The effect of individual SNPs on reporter gene transcription varied according to which alleles of the three other SNPs were present in the promoter construct. The SNP patterns that influenced function reflected common haplotypes that occur in the population, suggesting functionally significant interactions between SNPs according to haplotype context. Of the haplotypes that include the four functional IL1B promoter SNPs (−3737, −1464, −511, −31), the four haplotypes that showed different contextual effects on SNP function accounted for >98% of the estimated haplotypes in Caucasian and African-American populations. This finding underlines the importance of understanding the haplotype structure of populations used for genetic studies and may be especially important in the functional analysis of genetic variation across gene regulatory regions.
Forty patients requiring one-lung ventilation (OLV) for thoracic surgery were randomly assigned to receive propofol (4-6 mg kg−1 h−1) or sevoflurane (1 MAC) for maintenance of anaesthesia. Three sets ...of measurements were taken: (i) after 30 min of two-lung ventilation (TLV), (ii) after 30 min of one-lung ventilation (OLV-1) in the supine position and (iii) during OLV in the lateral position (OLV-2) with the chest open and before surgical manipulation of the lung. There were no differences between groups in patient characteristics or preoperative condition. Increases in shunt fraction during OLV-1 were 17.4% and 17.2% (P=0.94), those during OLV-2 were 18.3% and 16.5% (P=0.59) for the propofol and sevoflurane group, respectively. Cardiac index and other haemodynamic and respiratory variables were similar for the two groups. We conclude that inhibition of hypoxic pulmonary vasoconstriction by sevoflurane may only account for small increases in shunt fraction and that much of the overall shunt fraction during OLV has other causes.
Following up on a suggestion that decay to a dark matter fermion might explain the 4σ discrepancy in the neutron lifetime, we consider the implications of such a fermion on neutron star structure. We ...find that including it reduces the maximum neutron star mass to well below the observed masses. In order to recover stars with the observed masses, the (repulsive) self-interactions of the dark fermion would have to be stronger than those of the nucleon-nucleon interaction.
We report on a detailed study of longitudinal strength in the nucleon resonance region, presenting new results from inclusive electron-proton cross sections measured at Jefferson Lab Hall C in the ...four-momentum transfer range 0.2
A newly obtained data sample of inclusive electron-nucleon scattering from both hydrogen and deuterium targets is analyzed. These JLab data span the nucleon resonance region up to four-momentum ...transfers of 5 (GeV/c)(2). The data are found to follow an average scaling curve. The inclusion of low-momentum transfer data yields a scaling curve resembling deep inelastic neutrino-nucleus scattering data, suggesting a sensitivity to valencelike structure only.
Abstract
BACKGROUND
The emergence of personalized therapy, which targets oncogenic drivers, has provided a novel adjunct to the standard-of-care therapy for glioblastoma, the most common central ...nervous system malignancy. Among the less frequently observed oncogenic drivers in glioblastoma are mutations in the proto-oncogene B-Raf. Although treatment options for BRAF-mutated malignancies have been extensively investigated, the implications of BRAF and MEK inhibition in gliomas remain ambiguous. In this study, we present a model system designed to predict cellular temporal trajectories, employing human neocortical slice models and patient-derived tumor cells, coupled with spatially resolved and single-cell transcriptomic analyses for comprehensive computational modeling.
MATERIAL AND METHODS
Non-neoplastic cortical tissue was procured from a BRAF(V600E) mutant glioblastoma patient during surgical intervention. The tissue was sectioned and inoculated with autologous glioblastoma cells to establish an ex-vivo personalized brain slice model. To facilitate adequate tumor growth, slices were cultured for seven days with clinically approved BRAF/MEK inhibitors and respective controls. For high-dimensional analysis, the tumor specimen and slices in all treatment conditions were profiled using live cell imaging, spatially resolved transcriptomics (Visium 10X) and single nucleus RNA-sequencing (10X). Advanced computational modeling techniques, encompassing graph neural networks and single-cell deconvolution, were employed to scrutinize the spatio-temporal evolution of the tumor and its microenvironment.
RESULTS
Live cell imaging showed varied treatment responses in tumor growth during culture. Immunofluorescence and immunohistochemistry analyses (using NeuN, GFAP, and Iba-1 cell markers) indicated no toxic effects from drug combinations on the tumor microenvironment. Single nucleus profiling revealed a tumoral trajectory towards induction of mesenchymal-like transcriptional programs under BRAF/MEK inhibition along with up-regulation of alternative receptor tyrosine kinases such as HER2/3 and EGFR. Spatial projection of single cell trajectories using cytospace confirmed the escape mechanism of BRAF/MEK inhibition due to acquisition of anti-inflammatory myeloid cells in close proximity to the tumor niches and enhancement of mesenchymal transcriptional programs. In line with the experimental set-up, we observed a rapid progression of the tumor und BRAF/MEK inhibition in the patient.
CONCLUSION
Our reported model system, employing high-dimensional readouts and advanced computational modeling, showcases a promising avenue to address uncertainties in personalized medicine, emphasizing that conventional oncological drivers may necessitate alternative treatment strategies in central nervous system malignancies.
Faraday tomography allows us to map diffuse polarized synchrotron emission from our Galaxy and use it to interpret the magnetic field in the interstellar medium (ISM). We have applied Faraday ...tomography to 60 observations from the LOFAR Two-meter Sky Survey (LOTSS) and produced a Faraday depth cube mosaic covering 568 square degrees at high Galactic latitudes, at 4.′3 angular resolution and 1 rad m−2 Faraday depth resolution, with a typical noise level of 50–100 μJy per point spread function (PSF) per rotation measure spread function (RMSF; 40–80 mK RMSF−1). While parts of the images are strongly affected by instrumental polarization, we observed diffuse polarized emission throughout most of the field, with typical brightness between 1 and 6 K RMSF−1, and Faraday depths between − 7 and +25 rad m−2. We observed many new polarization features, some up to 15° in length. These include two regions with very uniformly structured, linear gradients in the Faraday depth; we measured the steepness of these gradients as 2.6 and 13 rad m−2 deg−1. We also observed a relationship between one of the gradients and an H I filament in the local ISM. Other ISM tracers were also checked for correlations with our polarization data and none were found, but very little signal was seen in most tracers in this region. We conclude that the LOTSS data are very well suited for Faraday tomography, and that a full-scale survey with all the LOTSS data has the potential to reveal many new Galactic polarization features and map out diffuse Faraday depth structure across the entire northern hemisphere.
A newly obtained sample of inclusive electron-nucleon scattering data has been analyzed for precision tests of quark-hadron duality. The data are in the nucleon resonance region, and span the range ...0. 3<Q2<5.0 (GeV/c)(2). Duality is observed both in limited and extended regions around the prominent resonance enhancements. Higher twist contributions to the F2 structure function are found to be small on average, even in the low Q2 regime of approximately 0.5 (GeV/c)(2). Using duality, an average scaling curve is obtained. In all cases, duality appears to be a nontrivial property of the nucleon structure function.
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