The polyunsaturated omega-6 fatty acid, arachidonic acid (AA 20:4n-6), is both the key of the immunoregulatory substances, prostaglandins, and leukotrienes, and an essential component of immune cell ...membrane phospholipids, providing stability and flexibility to ensure cellular function. To explore possible effects of the physiological burden of viral replication in chronic viral infections on AA availability, plasma total esterified fatty acid (FA) proportions were measured in the feline leukemia (FeLV) model. Plasma FA profiles of 12 specific-pathogen-free cats with chronic infections with Rickard strain feline leukemia virus (FeLV-R) were compared with 12 age- and sex-matched uninfected specific-pathogen-free cats at 4 months after infection. A significant decrease from normal of overage AA proportion was found in FeLV-R-infected cat plasma, while other major FA (palmitic, stearic, and oleic and omega-3 FA) normally remained present until near death. Since plasma FA content rapidly affects circulating immune cell membrane composition and since FeLV infection also targets immune cells, we compared FA profiles of feline T4-thymic lymphoma 3201 cell membranes that were infected with virulent FeLV-R or less virulent FeLV-A, at 20 days after viral inoculation with sham-inoculated uninfected 3201 cells. Significantly altered FA proportions and ratios of saturated to unsaturated FA found in infected cell membranes were similar to plasma FA changes and paralleled the virulence of the FeLV inoculum. Altered postinfection FA proportions may impart serious functional defects to the immune cells of chronic FeLV-infected cats, contributing to the inability of their immune systems to eliminate FeLV by depleted plasma AA stores and modified cell membrane composition. Decreased AA availability may be an important factor in the cachexia and fatal outcome of FeLV infection
In this paper, we present a review of how the various aspects of any study using an eye tracker (such as the instrument, methodology, environment, participant, etc.) affect the quality of the ...recorded eye-tracking data and the obtained eye-movement and gaze measures. We take this review to represent the empirical foundation for reporting guidelines of any study involving an eye tracker. We compare this empirical foundation to five existing reporting guidelines and to a database of 207 published eye-tracking studies. We find that reporting guidelines vary substantially and do not match with actual reporting practices. We end by deriving a minimal, flexible reporting guideline based on empirical research (Section "An empirically based minimal reporting guideline").
There are currently no reliable approaches for correctly identifying which patients with major depressive disorder (MDD) will respond well to antidepressant therapy. However, recent genetic advances ...suggest that Polygenic Risk Scores (PRS) could allow MDD patients to be stratified for antidepressant response. We used PRS for MDD and PRS for neuroticism as putative predictors of antidepressant response within three treatment cohorts: The Genome-based Therapeutic Drugs for Depression (GENDEP) cohort, and 2 sub-cohorts from the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study PRGN-AMPS (total patient number = 760). Results across cohorts were combined via meta-analysis within a random effects model. Overall, PRS for MDD and neuroticism did not significantly predict antidepressant response but there was a consistent direction of effect, whereby greater genetic loading for both MDD (best MDD result, p < 5*10-5 MDD-PRS at 4 weeks, β = -0.019, S.E = 0.008, p = 0.01) and neuroticism (best neuroticism result, p < 0.1 neuroticism-PRS at 8 weeks, β = -0.017, S.E = 0.008, p = 0.03) were associated with less favourable response. We conclude that the PRS approach may offer some promise for treatment stratification in MDD and should now be assessed within larger clinical cohorts.
The purpose of this project was to observe the amount of apical and mid‐curve transportation produced by a ranbge of nickel titanium (NiTi), titanium alloy and stainless steel (SS) files. Tests were ...carried out in simulated curved root canals produced in epoxy resin blocks. Seven commercially available file types were tested using sized 15 to 40. Instrumentation was carried out to 1 mm beyond the apex. Changes in canal dimensions were measured at 10X magnification under a shadowgraph.
There were substantial differences in the amount and the pattern of apical and mid‐curve transporation produced. The amount of transporation increased with each subsequent size of file. Under the same conditions, nickel titanium files produced significantly less transportation than stainless steel files. The least apical transportation was obtained with the NiTi Mity Turbo and the most by the SSK file and SS Hedstrom file. The least mid‐curve transportation was produced by the NiTi Mity Turbo and the most by the SS Hedstrom file.
Accurate ground‐based estimation of the carbon stored in terrestrial ecosystems is critical to quantifying the global carbon budget. Allometric models provide cost‐effective methods for biomass ...prediction. But do such models vary with ecoregion or plant functional type? We compiled 15 054 measurements of individual tree or shrub biomass from across Australia to examine the generality of allometric models for above‐ground biomass prediction. This provided a robust case study because Australia includes ecoregions ranging from arid shrublands to tropical rainforests, and has a rich history of biomass research, particularly in planted forests. Regardless of ecoregion, for five broad categories of plant functional type (shrubs; multistemmed trees; trees of the genus Eucalyptus and closely related genera; other trees of high wood density; and other trees of low wood density), relationships between biomass and stem diameter were generic. Simple power‐law models explained 84–95% of the variation in biomass, with little improvement in model performance when other plant variables (height, bole wood density), or site characteristics (climate, age, management) were included. Predictions of stand‐based biomass from allometric models of varying levels of generalization (species‐specific, plant functional type) were validated using whole‐plot harvest data from 17 contrasting stands (range: 9–356 Mg ha−1). Losses in efficiency of prediction were <1% if generalized models were used in place of species‐specific models. Furthermore, application of generalized multispecies models did not introduce significant bias in biomass prediction in 92% of the 53 species tested. Further, overall efficiency of stand‐level biomass prediction was 99%, with a mean absolute prediction error of only 13%. Hence, for cost‐effective prediction of biomass across a wide range of stands, we recommend use of generic allometric models based on plant functional types. Development of new species‐specific models is only warranted when gains in accuracy of stand‐based predictions are relatively high (e.g. high‐value monocultures).
Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified. To identify further genetic ...risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.
is one of the most frequently mutated oncogenes; the p110a protein it encodes plays a central role in tumor cell proliferation. Small-molecule inhibitors targeting the PI3K p110a catalytic subunit ...have entered clinical trials, with early-phase GDC-0077 studies showing antitumor activity and a manageable safety profile in patients with
-mutant breast cancer. However, preclinical studies have shown that PI3K pathway inhibition releases negative feedback and activates receptor tyrosine kinase signaling, reengaging the pathway and attenuating drug activity. Here we discover that GDC-0077 and taselisib more potently inhibit mutant PI3K pathway signaling and cell viability through unique HER2-dependent mutant p110a degradation. Both are more effective than other PI3K inhibitors at maintaining prolonged pathway suppression. This study establishes a new strategy for identifying inhibitors that specifically target mutant tumors by selective degradation of the mutant oncoprotein and provide a strong rationale for pursuing PI3Kα degraders in patients with HER2-positive breast cancer. SIGNIFICANCE: The PI3K inhibitors GDC-0077 and taselisib have a unique mechanism of action; both inhibitors lead to degradation of mutant p110a protein. The inhibitors that have the ability to trigger specific degradation of mutant p110a without significant change in wild-type p110a protein may result in improved therapeutic index in
-mutant tumors.
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Establishment of laboratory models of gynecologic neoplasms provides an important means of studying the biologic characteristics of these tumors. We report a previously uncharacterized human ...endometrial adenocarcinoma cell line that produces both intraperitoneal and subcutaneous growth in nude mice. The line was derived from a poorly differentiated endometrial cancer and has been carried in continuous tissue culture for greater than 100 passages. Doubling time in culture is approximately 48 hr. Antigenic phenotyping against a panel of murine monoclonal antibodies by rosetting cell surface assay on live cells or peroxidase assay on fixed cells has shown reactivity with a number of determinants, including MH99, MT334, MQ49, and the blood group antigens F3, 118, and 41-83. Cytogenetically, the line displays an aneuploid human karyotype with several chromosomal rearrangements and deletions. When injected intraperitoneally into nude mice, animals develop intraperitoneal nodules and ascites and succumb with wasting in 30-40 days. The intraperitoneal tumor has been passaged multiple times in nude mice by direct transfer of ascites. Subcutaneous injection of tumor cells produces nodules that grow at a reproducible rate. By light and electron microscopy, the nude mouse tumor is a poorly differentiated adenocarcinoma, similar to the original patient's tumor. It expresses both estrogen and progesterone receptors. CA 125 is not elevated in the serum of animals with tumor implants. The line appears to be cisplatin sensitive as determined by rates of growth of subcutaneous nodules. This cell line may be useful in studying the in vitro and in vivo properties of human endometrial carcinoma.
Understanding the movement of species’ ranges is a classic ecological problem that takes on urgency in this era of global change. Historically treated as a purely ecological process, range expansion ...is now understood to involve eco-evolutionary feedbacks due to spatial genetic structure that emerges as populations spread.We synthesize empirical and theoretical work on the eco-evolutionary dynamics of range expansion, with emphasis on bridging directional, deterministic processes that favor evolved increases in dispersal and demographic traits with stochastic processes that lead to the random fixation of alleles and traits. We develop a framework for understanding the joint influence of these processes in changing the mean and variance of expansion speed and its underlying traits. Our synthesis of recent laboratory experiments supports the consistent role of evolution in accelerating expansion speed on average, and highlights unexpected diversity in how evolution can influence variability in speed: results not well predicted by current theory. We discuss and evaluate support for three classes of modifiers of eco-evolutionary range dynamics (landscape context, trait genetics, and biotic interactions), identify emerging themes, and suggest new directions for future work in a field that stands to increase in relevance as populations move in response to global change.
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