The purpose of this statement is to describe and define the phenotypic abnormalities that can be identified on visual and quantitative evaluation of computed tomographic (CT) images in subjects with ...chronic obstructive pulmonary disease (COPD), with the goal of contributing to a personalized approach to the treatment of patients with COPD. Quantitative CT is useful for identifying and sequentially evaluating the extent of emphysematous lung destruction, changes in airway walls, and expiratory air trapping. However, visual assessment of CT scans remains important to describe patterns of altered lung structure in COPD. The classification system proposed and illustrated in this article provides a structured approach to visual and quantitative assessment of COPD. Emphysema is classified as centrilobular (subclassified as trace, mild, moderate, confluent, and advanced destructive emphysema), panlobular, and paraseptal (subclassified as mild or substantial). Additional important visual features include airway wall thickening, inflammatory small airways disease, tracheal abnormalities, interstitial lung abnormalities, pulmonary arterial enlargement, and bronchiectasis.
Objective: To investigate whether intracranial pressure (ICP) waveform measurements obtained from extraventricular drainage (EVD) systems are suitable for the calculation of intracranial elastance ...(ICE) or cerebrovascular pressure autoregulation (PAR) indices. Methods: The transfer characteristic of an EVD system is investigated by its step and frequency responses with focus on the low frequency (LF) range from 0.02 to 0.065 Hz (important in PAR) and the location of the system's first resonance frequency (important for ICE). The effects of opening the distal end of the EVD for drainage of cerebrospinal fluid and the presence of trapped air bubbles are also investigated. Results: The EVD system exhibits a first resonant frequency below 4 Hz, resulting in significant distortion of the measured ICP waveform. The frequency response in the LF range only remains flat when the EVD is closed. Opening the drain results in drops in magnitude and phase along the entire frequency range above DC. Air bubbles close to the EVD catheter tip affect the LF range while an air bubble close to the pressure transducer further decreases the first resonant frequency. Tests with actual ICP waveforms confirmed EVD-induced waveform distortions that can lead to erroneous ICE estimation. Conclusion: EVD-based ICP measurements distort the waveform morphology. PAR indices based on LF information are only valid if the EVD is closed. EVD-based ICE estimation is to be avoided. Significance: ICP waveform analyses to derive information about ICE and PAR should be critically questioned if only EVD derived ICP signals are at hand.
Pancreatic cancer has the highest mortality rates of all cancer types. One potential explanation for the aggressiveness of this disease is that cancer cells have been found to communicate with one ...another using membrane-bound vesicles known as exosomes. These exosomes carry pro-survival molecules and increase the proliferation, survival, and metastatic potential of recipient cells, suggesting that tumor-derived exosomes are powerful drivers of tumor progression. Thus, to successfully address and eradicate pancreatic cancer, it is imperative to develop therapeutic strategies that neutralize cancer cells and exosomes simultaneously. Curcumin, a turmeric root derivative, has been shown to have potent anti-cancer and anti-inflammatory effects in vitro and in vivo. Recent studies have suggested that exosomal curcumin exerts anti-inflammatory properties on recipient cells. However, curcumin's effects on exosomal pro-tumor function have yet to be determined. We hypothesize that curcumin will alter the pro-survival role of exosomes from pancreatic cancer cells toward a pro-death role, resulting in reduced cell viability of recipient pancreatic cancer cells. The main objective of this study was to determine the functional alterations of exosomes released by pancreatic cancer cells exposed to curcumin compared to exosomes from untreated pancreatic cancer cells. We demonstrate, using an in vitro cell culture model involving pancreatic adenocarcinoma cell lines PANC-1 and MIA PaCa-2, that curcumin is incorporated into exosomes isolated from curcumin-treated pancreatic cancer cells as observed by spectral studies and fluorescence microscopy. Furthermore, curcumin is delivered to recipient pancreatic cancer cells via exosomes, promoting cytotoxicity as demonstrated by Hoffman modulation contrast microscopy as well as AlamarBlue and Trypan blue exclusion assays. Collectively, these data suggest that the efficacy of curcumin may be enhanced in pancreatic cancer cells through exosomal facilitation.
The small conducting airways are the major site of airflow obstruction in chronic obstructive pulmonary disease and may precede emphysema development.
We hypothesized a novel computed tomography (CT) ...biomarker of small airway disease predicts FEV1 decline.
We analyzed 1,508 current and former smokers from COPDGene with linear regression to assess predictors of change in FEV1 (ml/yr) over 5 years. Separate models for subjects without and with airflow obstruction were generated using baseline clinical and physiologic predictors in addition to two novel CT metrics created by parametric response mapping (PRM), a technique pairing inspiratory and expiratory CT images to define emphysema (PRM(emph)) and functional small airways disease (PRM(fSAD)), a measure of nonemphysematous air trapping.
Mean (SD) rate of FEV1 decline in ml/yr for GOLD (Global Initiative for Chronic Obstructive Lung Disease) 0-4 was as follows: 41.8 (47.7), 53.8 (57.1), 45.6 (61.1), 31.6 (43.6), and 5.1 (35.8), respectively (trend test for grades 1-4; P < 0.001). In multivariable linear regression, for participants without airflow obstruction, PRM(fSAD) but not PRM(emph) was associated with FEV1 decline (P < 0.001). In GOLD 1-4 participants, both PRM(fSAD) and PRM(emph) were associated with FEV1 decline (P < 0.001 and P = 0.001, respectively). Based on the model, the proportional contribution of the two CT metrics to FEV1 decline, relative to each other, was 87% versus 13% and 68% versus 32% for PRM(fSAD) and PRM(emph) in GOLD 1/2 and 3/4, respectively.
CT-assessed functional small airway disease and emphysema are associated with FEV1 decline, but the association with functional small airway disease has greatest importance in mild-to-moderate stage chronic obstructive pulmonary disease where the rate of FEV1 decline is the greatest. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).
Viral outbreaks remain a serious threat to human and animal populations and motivate the continued development of antiviral drugs and vaccines, which in turn benefits from a detailed understanding of ...both viral structure and dynamics. While great strides have been made in characterizing these systems experimentally, molecular simulations have proven to be an essential, complementary approach. In this work, we review the contributions of molecular simulations to the understanding of viral structure, functional dynamics, and processes related to the viral life cycle. Approaches ranging from coarse-grained to all-atom representations are discussed, including current efforts at modeling complete viral systems. Overall, this review demonstrates that computational virology plays an essential role in understanding these systems.
Accelerating sea-level rise and human impacts to the coast (e.g., altered sediment supply and hydrology, nutrient loading) influence the accumulation of sediment and organic matter, and thereby ...impact the ability of coastal tidal wetlands to maintain an elevation consistently within the vegetation growth range. Critical components of marsh sustainability are the marsh elevation within the vegetation growth range (elevation capital) and the rates of marsh surface elevation change and relative sea-level rise. The relationship among these factors and their combined influence on marsh integrity were evaluated by comparing trends in surface elevation change on five salt marsh sites located on three marsh islands in Jamaica Bay, NY, USA. All marsh sites were located in a similar physical setting (i.e., tidal range, sea-level rise rate, sediment supply). The structural integrity of the marshes ranged from densely vegetated (high integrity) to severely deteriorated (low integrity) with elevation capital ranging from high to low, respectively, and included a deteriorating marsh site that was partially restored. Two marshes with high elevation capital maintained their relative position high within the tidal range through a combination of surface sediment deposition and shallow subsurface expansion, and kept pace with local sea-level rise. A marsh with moderate elevation capital showed signs of flooding stress and was deteriorating, but managed to keep pace with local sea-level rise. The deteriorated marsh gained no elevation over the 14-year study and was located too low within the tidal range to support continuous coverage of salt marsh vegetation. Elevation gain in the restored marsh initially lagged behind sea-level rise for 8 years, but the elevation trend recovered and kept pace with sea-level rise for the last 5 years. A conceptual model is presented that describes the relationship among elevation capital, and rates of marsh elevation gain and sea-level rise. Note that a search for factors influencing wetland loss should focus on process changes to marsh vertical development (e.g., sediment supply, vegetation growth) and climate change effects (e.g., sea-level and temperature rise) that can cause elevation gain to lag behind sea-level rise, and these occur prior to the onset of marsh deterioration.
Doa10 (MARCHF6 in metazoans) is a large polytopic membrane-embedded E3 ubiquitin ligase in the endoplasmic reticulum (ER) that plays an important role in quality control of cytosolic and ER proteins. ...Although Doa10 is highly conserved across eukaryotes, it is not understood how Doa10 recognizes its substrates. Here, we define the substrate recognition mechanism of Doa10 by structural and functional analyses on Saccharomyces cerevisiae Doa10 and its model substrates. Cryo-EM analysis shows that Doa10 has unusual architecture with a large lipid-filled central cavity, and its conserved middle domain forms an additional water-filled lateral tunnel open to the cytosol. Our biochemical data and molecular dynamics simulations suggest that the entrance of the substrate's degron peptide into the lateral tunnel is required for efficient polyubiquitination. The N- and C-terminal membrane domains of Doa10 seem to form fence-like features to restrict polyubiquitination to those proteins that can access the central cavity and lateral tunnel. Our study reveals how extended hydrophobic sequences at the termini of substrate proteins are recognized by Doa10 as a signal for quality control.
HIV-1-neutralizing antibodies develop in most HIV-1-infected individuals, although highly effective antibodies are generally observed only after years of chronic infection. Here, we characterize the ...rate of maturation and extent of diversity for the lineage that produced the broadly neutralizing antibody VRC01 through longitudinal sampling of peripheral B cell transcripts over 15 years and co-crystal structures of lineage members. Next-generation sequencing identified VRC01-lineage transcripts, which encompassed diverse antibodies organized into distinct phylogenetic clades. Prevalent clades maintained characteristic features of antigen recognition, though each evolved binding loops and disulfides that formed distinct recognition surfaces. Over the course of the study period, VRC01-lineage clades showed continuous evolution, with rates of ∼2 substitutions per 100 nucleotides per year, comparable to that of HIV-1 evolution. This high rate of antibody evolution provides a mechanism by which antibody lineages can achieve extraordinary diversity and, over years of chronic infection, develop effective HIV-1 neutralization.
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