Xeno nucleic acids (XNAs) are artificial genetic systems based on sugar-modified nucleotides. Herein, we investigate double-headed nucleotides as a new XNA. A new monomer, AT, is presented, and ...together with previous double-headed nucleotide monomers, new nucleic acid motifs consisting of up to five consecutive A·T base pairs have been obtained. Sections composed entirely of double-headed nucleotides are well-tolerated within a DNA duplex and can condense the genetic information. For instance, a 13-mer duplex is condensed to an 11-mer modified duplex containing four double-headed nucleotides while simultaneously improving duplex thermal stability with +14.0 °C. Also, the transfer of information from double-headed to natural nucleotides by DNA polymerases has been examined. The first double-headed nucleoside triphosphate was prepared but could not be recognized and incorporated by the tested DNA polymerases. On the other hand, it proved possible for Therminator DNA polymerase to transfer the information of a double-headed nucleotide in a template sequence to natural DNA under controlled conditions.
Esophageal, gastroesophageal junction, and gastric adenocarcinoma (herein gastroesophageal adenocarcinomas) are associated with poor prognosis and limited systemic treatment options. To further ...understand the genomic landscape of gastroesophageal cancers and its clinical correlations, circulating tumor DNA (ctDNA) from patients' plasma was evaluated using next-generation sequencing (NGS).
We analyzed genomic alterations of 55 patients (mostly advanced disease; 9, surgically resectable) with gastroesophageal adenocarcinomas using clinical-grade NGS performed on plasma-derived ctDNA (54-73 gene panel). The test detects single-nucleotide variants, as well as copy number amplifications, fusions, and indels in selected genes.
Seventy-six percent of patients (42/55) had ≥1 genomic alteration including variants of unknown significance (VUS) and 69.1% (38/55) had ≥1 characterized alteration (excluding VUSs). The median number of alterations per patient was 2 (range, 0-15).
(50.9%, 28/55),
(16.4%, 9/55),
(14.5%, 8/55), and
(14.5%, 8/55) genes were most frequently affected characterized alterations. Thirty-one patients also had tissue NGS. Concordance between tissue and ctDNA ranged from 61.3% (
alterations) to 87.1% (
alterations).
alterations were significantly associated with poor overall survival (HR, 14.06; 95% confidence interval, 2.44-81.03;
= 0.003 multivariate analysis). Among patients with ≥1 alteration, no 2 patients had identical molecular portfolios. All patients with ≥1 characterized alteration had theoretically targetable alterations by an FDA-approved agent (on- or off-label). Illustrative case treated with cognate agent is presented.
Evaluation of ctDNA by NGS among patients with gastroesophageal adenocarcinoma is feasible. Patients harbored heterogeneous patterns of genomics, with most having alterations that are potentially pharmacologically tractable.
Abstract
Massive star-forming regions exhibit an extremely rich and diverse chemistry, which in principle provides a wealth of molecular probes, as well as laboratories for interstellar prebiotic ...chemistry. Since the chemical structure of these sources displays substantial spatial variation among species on small scales (≲10
4
au), high-angular-resolution observations are needed to connect chemical structures to local environments and inform astrochemical models of massive star formation. To address this, we present ALMA 1.3 mm observations toward OB cluster-forming region G10.6-0.4 (hereafter “G10.6”) at a resolution of 014 (700 au). We find highly structured emission from complex organic molecules (COMs) throughout the central 20,000 au, including two hot molecular cores and several shells or filaments. We present spatially resolved maps of rotational temperature and column density for a large sample of COMs and warm gas tracers. These maps reveal a range of gas substructure in both O- and N-bearing species. We identify several spatial correlations that can be explained by existing models for the formation of COMs, including NH
2
CHO/HNCO and CH
3
OCHO/CH
3
OCH
3
, but also observe unexpected distributions and correlations that suggest that our current understanding of COM formation is far from complete. Importantly, complex chemistry is observed throughout G10.6, rather than being confined to hot cores. The COM composition appears to be different in the cores compared to the more extended structures, which illustrates the importance of high-spatial-resolution observations of molecular gas in elucidating the physical and chemical processes associated with massive star formation.
To understand the mechanism of cell-membrane compartmentalisation, we studied coarse-grained model systems consisting of lipid and cholesterol molecules. Cholesterol plays crucial role in lateral ...phase segregation in the bilayered lipid membrane to form cholesterol-rich liquid-ordered domains. In this NVT Molecular Dynamics simulation study, we have investigated the role of cholesterol in lipid bilayer destabilisation and domain formation. This study also reveals that the strength of cholesterol interaction is an important factor behind the phase segregation to form cholesterol-rich domains, whereas the relative dipolar strength of lipid and cholesterol molecules along with the concentration of cholesterol controls the formation of multi-bilayered stack.
Rapid voltage and temperature estimations with a Reduced Order Lumped Electrochemical-Thermal Model (TLM) was developed by applying a State Space Approach to transform partial differential equations ...(PDEs) into ordinary differential equations (ODEs). The TLM is attractive for Battery Management Systems (BMS) because of model restrictions that result in only four parameters: exchange current (i0S), diffusion time constant (τ), internal resistance (RIR), and the entropic heat coefficient (dUdT−1). The State Space approach is shown to be an effective method for reducing the computational time for the model by greater than 50% (~2s to less than 1s). This study also shows that the required model parameters (i0S, τ, RIR, dUdT−1) can be nondestructively extracted from real cells using the galvanostatic intermittent titration technique (GITT). This allows us to create cell-level temperature and state of charge (SOC) parameter surfaces that would be nearly impossible to develop experimentally. By confirming the extracted parameters with the model predicted parameters, future BMS models can further reduce computational time (approach millisecond predictions) by experimentally constraining the model. This means that the methodology reported in this paper can be ubiquitously implemented for other battery chemistries (e.g. cathodes, anodes), formats (e.g. 18650, pouch, prismatic), and properties (e.g. capacity ratios).
●Extracting exchange current, time constant, internal resistance, and entropic heat.●Novel reduced order methodology to an electrochemical-thermal lumped model.●Modeling parameters can be related to experimentally extracted quantities.●Reduction in computational time by greater than 50% (~2s to less than 1s).
•Human performance in aircraft maintenance is key to rank the organisations.•MRO management, infrastructure and many factors are identified and scaled.•A multi-criteria decision model is devised to ...rank the maintenance contractors.•The scientific approach is based on literature survey and data collection.•Provide a decision making tool for airlines, regulators, insurance firms.
Aircraft maintenance organisation is a complex socio-technical setup, where human factors influence the quality of aircraft maintenance service. Maintenance service quality is assessed based on the commitment of management and its ability to provide suitable facility, tools, spares and manpower supported with comfortable environment and maintenance procedures. Assessment of the service quality of the aircraft maintenance organisation is a complex process. Airlines, regulators, insurance companies and other agencies need decision support system, to assess the performance of a maintenance organisation. This paper provides criteria and scientific approach for assessing the maintenance organisation; it presents a methodology of applying Analytical Hierarchy Process to prioritise the key functions and to rank the maintenance organisations under study. The study has established that maintenance service quality in airline is directly correlated to its fleet size.
The Cancer Genome Atlas Network recently cataloged recurrent genomic abnormalities in glioblastoma multiforme (GBM). We describe a robust gene expression-based molecular classification of GBM into ...Proneural, Neural, Classical, and Mesenchymal subtypes and integrate multidimensional genomic data to establish patterns of somatic mutations and DNA copy number. Aberrations and gene expression of
EGFR,
NF1, and
PDGFRA/IDH1 each define the Classical, Mesenchymal, and Proneural subtypes, respectively. Gene signatures of normal brain cell types show a strong relationship between subtypes and different neural lineages. Additionally, response to aggressive therapy differs by subtype, with the greatest benefit in the Classical subtype and no benefit in the Proneural subtype. We provide a framework that unifies transcriptomic and genomic dimensions for GBM molecular stratification with important implications for future studies.
Four gene expression subtypes of GBM: Proneural, Neural, Classical, and Mesenchymal ► NF1 mutation and loss define Mesenchymal GBM ► Focal EGFR events define Classical GBM ► PGFRA\IDH1 events define Proneural GBM
Abstract
The Hyper Suprime-Cam (HSC) is an 870 megapixel prime focus optical imaging camera for the 8.2 m Subaru telescope. The wide-field corrector delivers sharp images of 0${^{\prime\prime}_{.}}$2 ...(FWHM) in the HSC-i band over the entire 1${^{\circ}_{.}}$5 diameter field of view. The collimation of the camera with respect to the optical axis of the primary mirror is done with hexapod actuators, the mechanical accuracy of which is a few microns. Analysis of the remaining wavefront error in off-focus stellar images reveals that the collimation of the optical components meets design specifications. While there is a flexure of mechanical components, it also is within the design specification. As a result, the camera achieves its seeing-limited imaging on Maunakea during most of the time; the median seeing over several years of observing is 0${^{\prime\prime}_{.}}$67 (FWHM) in the i band. The sensors use p-channel, fully depleted CCDs of 200 μm thickness (2048 × 4176 15 μm square pixels) and we employ 116 of them to pave the 50 cm diameter focal plane. The minimum interval between exposures is 34 s, including the time to read out arrays, to transfer data to the control computer, and to save them to the hard drive. HSC on Subaru uniquely features a combination of a large aperture, a wide field of view, sharp images and a high sensitivity especially at longer wavelengths, which makes the HSC one of the most powerful observing facilities in the world.
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