Lung cancer is the number one cause of cancer‐related death worldwide with cigarette smoking as its major risk factor. Although the incidence of lung cancer in never smokers is rising, this subgroup ...of patients is underrepresented in genomic studies of lung cancer. Here, we assembled a prospective cohort of 46 never‐smoking, nonsmall cell lung cancer (NSCLC) patients and performed whole‐exome and low‐coverage whole‐genome sequencing on tumors and matched germline DNA. We observed fewer somatic mutations, genomic breakpoints and a smaller fraction of the genome with chromosomal instability in lung tumors from never smokers compared to smokers. The lower number of mutations, enabled us to identify TSC22D1 as a potential driver gene in NSCLC. On the other hand, the frequency of mutations in actionable genes such as EGFR and ERBB2 and of amplifications in MET were higher, while the mutation rate of TP53, which is a negative prognostic factor, was lower in never smokers compared to smokers. Together, these observations suggest a more favorable prognosis for never smokers with NSCLC. Classification of somatic mutations into six‐substitution type patterns or into 96‐substitution type signatures revealed distinct clusters between smokers and never smokers. Particularly, we identified in never smokers signatures related to aging, homologous recombination damage and APOBEC/AID activity as the most important underlying processes of NSCLC. This further indicates that second‐hand smoking is not driving NSCLC pathogenesis in never smokers.
What's new?
About 15 percent of lung cancers occur in people who never smoked but never smokers are usually underrepresented in genomic studies of lung cancer. Here the authors sequenced a unique cohort of 46 never smokers with non‐small cell lung carcinoma (NSCLC). They identified the transcription factor TSC22D1 as a new potential driver gene of NSCLC and observed higher mutation rates in receptor tyrosine‐protein kinases EGFR HER2 and MET in tumors of never smokers compared to smokers. Targeted agents against each of these 3 genes are available, underscoring the relevance of studying never smokers as a separate group.
Albedo reduction due to light-absorbing impurities can substantially enhance ice sheet surface melt by increasing surface absorption of solar energy. Glacier algae have been suggested to play a ...critical role in darkening the ablation zone in southwestern Greenland. It was very recently found that the Sentinel-3 Ocean and Land Colour Instrument (OLCI) band ratio R709 nm∕R673 nm can characterize the spatial patterns of glacier algal blooms. However, Sentinel-3 was launched in 2016, and current data are only available over three melting seasons (2016–2019). Here, we demonstrate the capability of the MEdium Resolution Imaging Spectrometer (MERIS) for mapping glacier algae from space and extend the quantification of glacier algal blooms over southwestern Greenland back to the period 2004–2011. Several band ratio indices (MERIS chlorophyll a indices and the impurity index) were computed and compared with each other. The results indicate that the MERIS two-band ratio index (2BDA) R709 nm∕R665 nm is very effective in capturing the spatial distribution and temporal dynamics of glacier algal growth on bare ice in July and August. We analyzed the interannual (2004–2011) and summer (July–August) trends of algal distribution and found significant seasonal and interannual increases in glacier algae close to the Jakobshavn Isbrae Glacier and along the middle dark zone between the altitudes of 1200 and 1400 m. Using broadband albedo data from the Moderate Resolution Imaging Spectroradiometer (MODIS), we quantified the impact of glacier algal growth on bare ice albedo, finding a significant correlation between algal development and albedo reduction over algae-abundant areas. Our analysis indicates the strong potential for the satellite algal index to be used to reduce bare ice albedo biases in regional climate model simulations.
Inverse problems are gaining more and more importance in the field of nondestructive testing (NDT). Magnetic imaging is an NDT method, which leads to an inverse problem if the underlying current ...density should be determined. With the current density, characteristics of an electrical conductor such as the geometry or the conductivity can be determined. In particular, for analyzing novel electrically conductive materials, the uniformity of the conductivity is a critical characteristic. A deconvolution-based method is presented to determine the current density distribution within an inhomogeneous electrical conductor from the resulting magnetic field measured with a state-of-the-art giant magnetoresistive magnetometer.
More than 8 million older people in Latin America depend on long-term care (LTC), accounting for 12% of people aged ≥ 60 years and almost 27% of those aged ≥ 80. It is crucial to develop sustainable ...strategies for providing LTC in the area, including institutional care. This special report aims to characterize institutional LTC in four countries (Brazil, Chile, Costa Rica and Mexico), using available information systems, and to identify the strategies adopted to support institutional care in these countries. This narrative review used nationwide, open-access, public data sources to gather demographic estimates and information about institutional LTC coverage and the availability of open-access data for the proportion of people with LTC needs, the number of LTC facilities and the number of residents living in them. These countries have a larger share of older people than the average in Latin America but fewer LTC facilities than required by the demand. National surveys lack standardization in defining disability, LTC and dependency on care. Information about institutional care is mainly fragmented and does not regularly include LTC facilities, their residents and workers. Data are crucial to inform evidence-based decisions to favor prioritization and to support advances in promoting policies around institutional LTC in Latin America. Although information about institutional care in the region is fragmented and insufficient, this paper profiles the four selected countries. It highlights the need for a better structure for data-driven LTC information systems. The lack of information emphasizes the urgency of the need to focus on and encourage research into this topic.
Contemporary climate warming over the Arctic is accelerating mass loss from the Greenland Ice Sheet through increasing surface melt, emphasizing the need to closely monitor its surface mass balance ...in order to improve sea-level rise predictions. Snow accumulation is the largest component of the ice sheet's surface mass balance, but in situ observations thereof are inherently sparse and models are difficult to evaluate at large scales. Here, we quantify recent Greenland accumulation rates using ultra-wideband (2-6.5 gigahertz) airborne snow radar data collected as part of NASA's Operation IceBridge between 2009 and 2012. We use a semi-automated method to trace the observed radiostratigraphy and then derive annual net accumulation rates for 2009-2012. The uncertainty in these radar-derived accumulation rates is on average 14 percent. A comparison of the radarderived accumulation rates and contemporaneous ice cores shows that snow radar captures both the annual and longterm mean accumulation rate accurately. A comparison with outputs from a regional climate model (MAR - Modele Atmospherique Regional for Greenland and vicinity) shows that this model matches radar-derived accumulation rates in the ice sheet interior but produces higher values over southeastern Greenland. Our results demonstrate that snow radar can efficiently and accurately map patterns of snow accumulation across an ice sheet and that it is valuable for evaluating the accuracy of surface mass balance models.
Mutations of ASXL1, encoding a component of the BAP1 histone H2A deubiquitinase complex, occur in human myeloid neoplasms and are uniformly associated with poor prognosis. However, the precise ...molecular mechanisms through which ASXL1 mutations alter BAP1 activity and drive leukemogenesis remain unclear. Here we demonstrate that cancer-associated frameshift mutations in ASXL1, which were originally proposed to act as destabilizing loss-of-function mutations, in fact encode stable truncated gain-of-function proteins. Truncated ASXL1 increases BAP1 protein stability, enhances BAP1 recruitment to chromatin and promotes the expression of a pro-leukemic transcriptional signature. Through a biochemical screen, we identified BAP1 catalytic inhibitors that inhibit truncated-ASXL1-driven leukemic gene expression and impair tumor progression in vivo. This study represents a breakthrough in our understanding of the molecular mechanisms of ASXL1 mutations in leukemia pathogenesis and identifies small-molecular catalytic inhibitors of BAP1 as a potential targeted therapy for leukemia.
Seven new peptaibols named tolypocladamides A–G have been isolated from an extract of the fungus Tolypocladium inflatum, which inhibits the interaction between Raf and oncogenic Ras in a cell-based ...high-throughput screening assay. Each peptaibol contains 11 amino acid residues, an octanoyl or decanoyl fatty acid chain at the N-terminus, and a leucinol moiety at the C-terminus. The peptaibol sequences were elucidated on the basis of 2D NMR and mass spectral fragmentation analyses. Amino acid configurations were determined by advanced Marfey’s analyses. Tolypocladamides A–G caused significant inhibition of Ras/Raf interactions with IC50 values ranging from 0.5 to 5.0 μM in a nanobioluminescence resonance energy transfer (NanoBRET) assay; however, no interactions were observed in a surface plasmon resonance assay for binding of the compounds to wild type or G12D mutant Ras constructs or to the Ras binding domain of Raf. NCI 60 cell line testing was also conducted, and little panel selectivity was observed.
Abstract
The US Southwest is in a drought crisis that has been developing over the past two decades, contributing to marked increases in burned forest areas and unprecedented efforts to reduce water ...consumption. Climate change has contributed to this ongoing decadal drought via warming that has increased evaporative demand and reduced snowpack and streamflows. However, on the supply side, precipitation has been low during the 21st century. Here, using simulations with an atmosphere model forced by imposed sea surface temperatures, we show that the 21st century shift to cooler tropical Pacific sea surface temperatures forced a decline in cool season precipitation that in turn drove a decline in spring to summer soil moisture in the southwest. We then project the near-term future out to 2040, accounting for plausible and realistic natural decadal variability of the Pacific and Atlantic Oceans and radiatively-forced change. The future evolution of decadal variability in the Pacific and Atlantic will strongly influence how wet or dry the southwest is in coming decades as a result of the influence on cool season precipitation. The worst-case scenario involves a continued cold state of the tropical Pacific and the development of a warm state of the Atlantic while the best case scenario would be a transition to a warm state of the tropical Pacific and the development of a cold state of the Atlantic. Radiatively-forced cool season precipitation reduction is strongest if future forced SST change continues the observed pattern of no warming in the equatorial Pacific cold tongue. Although this is a weaker influence on summer soil moisture than natural decadal variability, no combination of natural decadal variability and forced change ensures a return to winter precipitation or summer soil moisture levels as high as those in the final two decades of the 20th century.
How protein sequence codes for 3D structure remains a fundamental question in biology. One approach to understanding the folding code is to design a pair of proteins with maximal sequence identity ...but retaining different folds. Therefore, the nonidentities must be responsible for determining which fold topology prevails and constitute a fold-specific folding code. We recently designed two proteins, GA88 and GB88, with 88% sequence identity but different folds and functions Alexander et al. (2007) Proc Natl Acad Sci USA 104:11963-11968. Here, we describe the detailed 3D structures of these proteins determined in solution by NMR spectroscopy. Despite a large number of mutations taking the sequence identity level from 16 to 88%, GA88 and GB88 maintain their distinct wild-type 3-α and α/β folds, respectively. To our knowledge, the 3D-structure determination of two monomeric proteins with such high sequence identity but different fold topology is unprecedented. The geometries of the seven nonidentical residues (of 56 total) provide insights into the structural basis for switching between 3-α and α/β conformations. Further mutation of a subset of these nonidentities, guided by the GA88 and GB88 structures, leads to proteins with even higher levels of sequence identity (95%) and different folds. Thus, conformational switching to an alternative monomeric fold of comparable stability can be effected with just a handful of mutations in a small protein. This result has implications for understanding not only the folding code but also the evolution of new folds.
In this work, a strategy is proposed for the automatic diagnosis of failures in gearboxes using current signals from an induction motor. The stator currents were represented by the extended Park ...vector approach technique and decomposed by the wavelet packet transform. The calculation of the wavelet packet entropy promoted the distinction between broken tooth failures and the levels of severity of surface wear. The entropies of two wavelet details were used as inputs for a fuzzy inference for automatic classification of the gearbox condition. The experimental results presented a high rate of correctness in the fuzzy diagnosis, confirming the efficiency of the strategy for high rotation (60 Hz) and low rotation (20 Hz). The strategy presents simplicities related to the practical implementation and reduction of the amount of data analyzed.
PDF
