Yeast prions are self-perpetuating misfolded proteins that are infectious. In yeast, PSI+ is the prion form of the Sup35 protein. While the study of PSI+ has revealed important cellular mechanisms ...that contribute to prion propagation, the underlying cellular factors that influence prion formation are not well understood. Prion formation has been described as a multi-step process involving both the initial nucleation and growth of aggregates, followed by the subsequent transmission of prion particles to daughter cells. Prior evidence suggests that actin plays a role in this multi-step process, but actin’s precise role is unclear. Here, we investigate how actin influences the cell’s ability to manage newly formed visible aggregates and how actin influences the transmission of newly formed aggregates to future generations. At early steps, using 3D time-lapse microscopy, several actin mutants, and Markov modeling, we find that the movement of newly formed aggregates is random and actin independent. At later steps, our prion induction studies provide evidence that the transmission of newly formed prion particles to daughter cells is limited by the actin cytoskeletal network. We suspect that this limitation is because actin is used to possibly retain prion particles in the mother cell.
Abstract
A new analysis of the data set from the Pierre Auger Observatory provides evidence for anisotropy in the arrival directions of ultra-high-energy cosmic rays on an intermediate angular scale, ...which is indicative of excess arrivals from strong, nearby sources. The data consist of 5514 events above
with zenith angles up to 80° recorded before 2017 April 30. Sky models have been created for two distinct populations of extragalactic gamma-ray emitters: active galactic nuclei from the second catalog of hard
Fermi
-LAT sources (2FHL) and starburst galaxies from a sample that was examined with
Fermi
-LAT. Flux-limited samples, which include all types of galaxies from the
Swift
-BAT and 2MASS surveys, have been investigated for comparison. The sky model of cosmic-ray density constructed using each catalog has two free parameters, the fraction of events correlating with astrophysical objects, and an angular scale characterizing the clustering of cosmic rays around extragalactic sources. A maximum-likelihood ratio test is used to evaluate the best values of these parameters and to quantify the strength of each model by contrast with isotropy. It is found that the starburst model fits the data better than the hypothesis of isotropy with a statistical significance of 4.0
σ
, the highest value of the test statistic being for energies above
. The three alternative models are favored against isotropy with 2.7
σ
–3.2
σ
significance. The origin of the indicated deviation from isotropy is examined and prospects for more sensitive future studies are discussed.
Inoculation methods in pathogen inactivation studies ideally represent conditions that might occur in real-world scenarios. Surface contamination in or on low-moisture foods affects Salmonella ...thermal resistance, which is critically important for process validation applications. The objective of this study was to quantify the effect of inoculation protocol on the thermal resistance of Salmonella Enteritidis PT 30 in fabricated low-moisture foods. Almond meal, almond butter, wheat meal, wheat flour, and date paste were inoculated via prefabrication and postfabrication protocols. In the prefabrication protocol, kernels and fruits were surface inoculated and equilibrated to a target water activity (a
) (0.40 for almond and wheat products, 0.45 for date products) before fabricating meal, butter, flour, or paste and then reequilibrating the samples to the target a
. In the postfabrication protocol, meal, butter, flour, and paste were fabricated before inoculation and equilibration. All inoculated and equilibrated samples were subjected to isothermal treatment (80°C), pulled sequentially during processing, cooled, serially diluted, and plated to enumerate survivors. Log-linear and Weibull-type models were fit to the Salmonella survivor data and were compared via the corrected Akaike information criterion. Pre- and postfabrication protocols resulted in significant differences ( P < 0.05) in Salmonella thermal resistance in all products. Overall, the thermal resistance of Salmonella Enteritidis PT 30 in almond products was greater ( P < 0.05) than in wheat products, which was also greater ( P < 0.05) than in date paste. Additionally, Salmonella was more thermally resistant in almond products and date paste when inoculated pre- rather than postfabrication; however, the opposite was true for wheat products. These results indicate that the means of inoculation can significantly affect thermal resistance of Salmonella in low-moisture foods.
The bromodomain and extra terminal (BET) protein family recognizes acetylated lysines within histones and transcription factors using two N-terminal bromodomains, D1 and D2. The protein–protein ...interactions between BET bromodomains, acetylated histones, and transcription factors are therapeutic targets for BET-related diseases, including inflammatory disease and cancer. Prior work demonstrated that methylated-1,2,3-triazoles are suitable N-acetyl lysine mimetics for BET inhibition. Here we describe a structure–activity relationship study of triazole-based inhibitors that improve affinity, D1 selectivity, and microsomal stability. These outcomes were accomplished by targeting a nonconserved residue, Asp144 and a conserved residue, Met149, on BRD4 D1. The lead inhibitors DW34 and 26 have a BRD4 D1 K d of 12 and 6.4 nM, respectively. Cellular activity was demonstrated through suppression of c-Myc expression in MM.1S cells and downregulation of IL-8 in TNF-α-stimulated A549 cells. These data indicate that DW34 and 26 are new leads to investigate the anticancer and anti-inflammatory activity of BET proteins.
The aims of this retrospective cohort study were to 1) identify new alignment risk factors for proximal junctional kyphosis (PJK) in adult spinal deformity (ASD) patients with lower thoracic upper ...instrumented vertebra (UIV) and 2) determine the effect of junctional tethers on PJK and UIV alignment.
We analyzed consecutive ASD patients who underwent posterior instrumented fusion with lower thoracic UIV (T9-T11). Posteriorly anchored junctional tethers were used more recently for ligamentous augmentation to prevent PJK. In addition to regional and global parameters, upper segmental lumbar lordosis (ULL) versus lower segmental lumbar lordosis and UIV angle (measured from UIV inferior endplate to horizontal) were assessed. Primary outcome of PJK was defined as proximal junctional angle >10° and >10° greater than the corresponding preoperative measurement. Univariable and multivariable analyses were performed.
The study cohort comprised 120 ASD patients (mean age, 67 years) with minimum 1-year follow-up. Preoperative ULL (P = 0.034) and UIV angle (P = 0.026) were associated with PJK. No independent preoperative alignment risk factors of PJK were identified in multivariable analysis. Tether use was protective against PJK (odds ratio, 0.063 0.016–0.247; P < 0.001). PJK in tethered patients was more common with greater postoperative ULL (P = 0.047) and UIV angle (P = 0.026).
Junctional tethers significantly reduced PJK in ASD patients with lower thoracic UIV. In tethered patients, PJK was more common with greater postoperative lordosis of the upper lumbar spine and greater UIV angle. This finding suggests potential benefit of tethers to mitigate effects of segmental lumbar and focal UIV malalignment that may occur after deformity surgery.
•No preoperative alignment risk factors of PJK were identified in multivariable analysis.•Lower thoracic junctional tethers have a protective effect against PJK.•PJK in tethered patients was more common with greater postoperative ULL and UIV angle.•Tethers may mitigate effects of segmental and focal malalignment or overcorrection.
Secondary organic aerosol (SOA) impact climate by scattering and absorbing radiation and contributing to cloud formation. SOA models are based on studies of simplified chemical systems that do not ...account for the chemical complexity in the atmosphere. This study investigated SOA formation from a mixture of real Scots pine (Pinus sylvestris) emissions including a variety of monoterpenes and sesquiterpenes. SOA generation was characterized from different combinations of volatile compounds as the plant emissions were altered with an herbivore stress treatment. During active herbivore feeding, monoterpene and sesquiterpene emissions increased, but SOA mass yields decreased after accounting for absorption effects. SOA mass yields were controlled by sesquiterpene emissions in healthy plants. In contrast, SOA mass yields from stressed plant emissions were controlled by the specific blend of monoterpene emissions. Conservative estimates using a box model approach showed a 1.5- to 2.3-fold aerosol enhancement when the terpene complexity was taken into account. This enhancement was relative to the commonly used model monoterpene, "α-pinene". These results suggest that simplifying terpene complexity in SOA models could lead to underpredictions in aerosol mass loading.
Structural properties of amorphous In-based oxides, In - X - O with X = Zn, Ga, Sn, or Ge, are investigated using ab initio molecular dynamics liquid-quench simulations. The results reveal that ...indium retains its average coordination of 5.0 upon 20% X fractional substitution for In, whereas X cations satisfy their natural coordination with oxygen atoms. This finding suggests that the carrier generation is primarily governed by In atoms, in accord with the observed carrier concentration in amorphous In-O and In - X - O. At the same time, the presence of X affects the number of six-coordinated In atoms as well as the oxygen sharing between the InO sub(6) polyhedra. Based on the obtained interconnectivity and spatial distribution of the InO sub(6) and XO sub(x) polyhedra in amorphous In - X - O, composition-dependent structural models of the amorphous oxides are derived. The results help explain our Hall mobility measurements in In - X - O thin films grown by pulsed-laser deposition and highlight the importance of long-range structural correlations in the formation of amorphous oxides and their transport properties.
To evaluate, in the setting of breast cancer, the accuracy of registry radiation therapy (RT) coding compared with the gold standard of Medicare claims.
Using Surveillance, Epidemiology, and End ...Results (SEER)-Medicare data, we identified 73,077 patients aged ≥66 years diagnosed with breast cancer in the period 2001-2007. Underascertainment (1 - sensitivity), sensitivity, specificity, κ, and χ(2) were calculated for RT receipt determined by registry data versus claims. Multivariate logistic regression characterized patient, treatment, and geographic factors associated with underascertainment of RT. Findings in the SEER-Medicare registries were compared with three non-SEER registries (Florida, New York, and Texas).
In the SEER-Medicare registries, 41.6% (n=30,386) of patients received RT according to registry coding, versus 49.3% (n=36,047) according to Medicare claims (P<.001). Underascertainment of RT was more likely if patients resided in a newer SEER registry (odds ratio OR 1.70, 95% confidence interval CI 1.60-1.80; P<.001), rural county (OR 1.34, 95% CI 1.21-1.48; P<.001), or if RT was delayed (OR 1.006/day, 95% CI 1.006-1.007; P<.001). Underascertainment of RT receipt in SEER registries was 18.7% (95% CI 18.6-18.8%), compared with 44.3% (95% CI 44.0-44.5%) in non-SEER registries.
Population-based tumor registries are highly variable in ascertainment of RT receipt and should be augmented with other data sources when evaluating quality of breast cancer care. Future work should identify opportunities for the radiation oncology community to partner with registries to improve accuracy of treatment data.
Respiratory syncytial virus (RSV) infection is the major cause of bronchiolitis in young children. The factors that contribute to the increased propensity of RSV-induced distal airway disease ...compared with other commonly encountered respiratory viruses remain unclear. Here, we identified the RSV-encoded nonstructural 2 (NS2) protein as a viral genetic determinant for initiating RSV-induced distal airway obstruction. Infection of human cartilaginous airway epithelium (HAE) and a hamster model of disease with recombinant respiratory viruses revealed that NS2 promotes shedding of infected epithelial cells, resulting in two consequences of virus infection. First, epithelial cell shedding accelerated the reduction of virus titers, presumably by clearing virus-infected cells from airway mucosa. Second, epithelial cells shedding into the narrow-diameter bronchiolar airway lumens resulted in rapid accumulation of detached, pleomorphic epithelial cells, leading to acute distal airway obstruction. Together, these data indicate that RSV infection of the airway epithelium, via the action of NS2, promotes epithelial cell shedding, which not only accelerates viral clearance but also contributes to acute obstruction of the distal airways. Our results identify RSV NS2 as a contributing factor for the enhanced propensity of RSV to cause severe airway disease in young children and suggest NS2 as a potential therapeutic target for reducing the severity of distal airway disease.
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