Mapping Netrin Signaling in \u3cem\u3eTetrahymena thermophila\u3c/em\u3e

The netrin family of proteins, found throughout the animal kingdom, are well known for their roles in developmental signaling. Netrin-1, the best-studied member of this family, signals through four receptor types in vertebrates: the UNC-5 family, DCC, neogenin, and DSCAM. We have previously characterized a netrin-1-like protein in the ciliated protozoan, Tetrahymena thermophila. This protein is secreted from Tetrahymena, and functions as a chemorepellent. Since a netrin-like protein is produced by this organism, we hypothesized that some components of the vertebrate netrin signaling pathway might also be present in Tetrahymena. Through immunolocalization on the plasma membrane of the cell, we have found that Tetrahymena appear to have a UNC-5 like protein, as well as proteins that are immunologically similar to neogenin. A homolog of src-1, a tyrosine kinase involved in vertebrate netrin-1, is also present in Tetrahymena. Future experiments will allow us to make more comparisons between netrin signaling in Tetrahymena with netrin signaling in the animal kingdom, and will allow us to determine the suitability of Tetrahymena as a model system for this particular pathway

Design of small molecule-responsive microRNAs based on structural requirements for Drosha processing

MicroRNAs (miRNAs) are prevalent regulatory RNAs that mediate gene silencing and play key roles in diverse cellular processes. While synthetic RNA-based regulatory systems that integrate regulatory and sensing functions have been demonstrated, the lack of detail on miRNA structure–function relationships has limited the development of integrated control systems based on miRNA silencing. Using an elucidated relationship between Drosha processing and the single-stranded nature of the miRNA basal segments, we developed a strategy for designing ligand-responsive miRNAs. We demonstrate that ligand binding to an aptamer integrated into the miRNA basal segments inhibits Drosha processing, resulting in titratable control over gene silencing. The generality of this control strategy was shown for three aptamer–small molecule ligand pairs. The platform can be extended to the design of synthetic miRNAs clusters, cis-acting miRNAs and self-targeting miRNAs that act both in cis and trans, enabling fine-tuning of the regulatory strength and dynamics. The ability of our ligand-responsive miRNA platform to respond to user-defined inputs, undergo regulatory performance tuning and display scalable combinatorial control schemes will help advance applications in biological research and applied medicine

Netrin-3 Avoidance and Mitotic Inhibition in \u3cem\u3eTetrahymena thermophila\u3c/em\u3e Involves Intracellular Calcium and Serine/Threonine Kinase Activity

Netrins are a family of signaling proteins ubiquitously expressed throughout the animal kingdom. While netrin-1 has been well characterized, other netrins, such as netrin-3, remain less well understood. In our current study, we characterize the behavior of two netrin-3 peptides, one derived from the N-terminal and one derived from the C-terminal of netrin-3. Both peptides cause avoidance behavior and mitotic inhibition in Tetrahymena thermophila at concentrations as low as 0.5 micrograms (μg) per milliliter. These effects can be reversed by addition of the calcium chelator, EGTA; the intracellular calcium chelator, BAPTA-AM, or the serine/threonine kinase inhibitor, apigenin. The broad spectrum tyrosine kinase inhibitor, genistein, has no effect on netrin-3 signaling, indicating that netrin-3 signaling in this organism uses a different pathway than the previously described netrin-1 pathway. Further studies will allow us to better describe the netrin-3 signaling pathway in this organism

Reducing bias in auditory duration reproduction by integrating the reproduced signal

Duration estimation is known to be far from veridical and to differ for sensory estimates and motor reproduction. To investigate how these differential estimates are integrated for estimating or reproducing a duration and to examine sensorimotor biases in duration comparison and reproduction tasks, we compared estimation biases and variances among three different duration estimation tasks: perceptual comparison, motor reproduction, and auditory reproduction (i.e. a combined perceptual-motor task). We found consistent overestimation in both motor and perceptual-motor auditory reproduction tasks, and the least overestimation in the comparison task. More interestingly, compared to pure motor reproduction, the overestimation bias was reduced in the auditory reproduction task, due to the additional reproduced auditory signal. We further manipulated the signal-to-noise ratio (SNR) in the feedback/comparison tones to examine the changes in estimation biases and variances. Considering perceptual and motor biases as two independent components, we applied the reliability-based model, which successfully predicted the biases in auditory reproduction. Our findings thus provide behavioral evidence of how the brain combines motor and perceptual information together to reduce duration estimation biases and improve estimation reliability

The ACER pollen and charcoal database: a global resource to document vegetation and fire response to abrupt climate changes during the last glacial period

Quaternary records provide an opportunity to examine the nature of the vegetation and fire responses to rapid past climate changes comparable in velocity and magnitude to those expected in the 21st-century. The best documented examples of rapid climate change in the past are the warming events associated with the Dansgaard–Oeschger (D–O) cycles during the last glacial period, which were sufficiently large to have had a potential feedback through changes in albedo and greenhouse gas emissions on climate. Previous reconstructions of vegetation and fire changes during the D–O cycles used independently constructed age models, making it difficult to compare the changes between different sites and regions. Here, we present the ACER (Abrupt Climate Changes and Environmental Responses) global database, which includes 93 pollen records from the last glacial period (73–15 ka) with a temporal resolution better than 1000 years, 32 of which also provide charcoal records. A harmonized and consistent chronology based on radiometric dating (14C, 234U∕230Th, optically stimulated luminescence (OSL), 40Ar∕39Ar-dated tephra layers) has been constructed for 86 of these records, although in some cases additional information was derived using common control points based on event stratigraphy. The ACER database compiles metadata including geospatial and dating information, pollen and charcoal counts, and pollen percentages of the characteristic biomes and is archived in Microsoft AccessTM at https://doi.org/10.1594/PANGAEA.870867

DNA methylation-based classification of central nervous system tumours.

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology

Seasonal-to-interannual prediction of North American coastal marine ecosystems: forecast methods, mechanisms of predictability, and priority developments

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Jacox, M. G., Alexander, M. A., Siedlecki, S., Chen, K., Kwon, Y., Brodie, S., Ortiz, I., Tommasi, D., Widlansky, M. J., Barrie, D., Capotondi, A., Cheng, W., Di Lorenzo, E., Edwards, C., Fiechter, J., Fratantoni, P., Hazen, E. L., Hermann, A. J., Kumar, A., Miller, A. J., Pirhalla, D., Buil, M. P., Ray, S., Sheridan, S. C., Subramanian, A., Thompson, P., Thorne, L., Annamalai, H., Aydin, K., Bograd, S. J., Griffis, R. B., Kearney, K., Kim, H., Mariotti, A., Merrifield, M., & Rykaczewski, R. Seasonal-to-interannual prediction of North American coastal marine ecosystems: forecast methods, mechanisms of predictability, and priority developments. Progress in Oceanography, 183, (2020): 102307, doi:10.1016/j.pocean.2020.102307.Marine ecosystem forecasting is an area of active research and rapid development. Promise has been shown for skillful prediction of physical, biogeochemical, and ecological variables on a range of timescales, suggesting potential for forecasts to aid in the management of living marine resources and coastal communities. However, the mechanisms underlying forecast skill in marine ecosystems are often poorly understood, and many forecasts, especially for biological variables, rely on empirical statistical relationships developed from historical observations. Here, we review statistical and dynamical marine ecosystem forecasting methods and highlight examples of their application along U.S. coastlines for seasonal-to-interannual (1–24 month) prediction of properties ranging from coastal sea level to marine top predator distributions. We then describe known mechanisms governing marine ecosystem predictability and how they have been used in forecasts to date. These mechanisms include physical atmospheric and oceanic processes, biogeochemical and ecological responses to physical forcing, and intrinsic characteristics of species themselves. In reviewing the state of the knowledge on forecasting techniques and mechanisms underlying marine ecosystem predictability, we aim to facilitate forecast development and uptake by (i) identifying methods and processes that can be exploited for development of skillful regional forecasts, (ii) informing priorities for forecast development and verification, and (iii) improving understanding of conditional forecast skill (i.e., a priori knowledge of whether a forecast is likely to be skillful). While we focus primarily on coastal marine ecosystems surrounding North America (and the U.S. in particular), we detail forecast methods, physical and biological mechanisms, and priority developments that are globally relevant.This study was supported by the NOAA Climate Program Office’s Modeling, Analysis, Predictions, and Projections (MAPP) program through grants NA17OAR4310108, NA17OAR4310112, NA17OAR4310111, NA17OAR4310110, NA17OAR4310109, NA17OAR4310104, NA17OAR4310106, and NA17OAR4310113. This paper is a product of the NOAA/MAPP Marine Prediction Task Force

Mendelian randomization of circulating polyunsaturated fatty acids and colorectal cancer risk

Background: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk. Methods: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined. Results: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [ORLA = 0.96; 95% confidence interval (CI) = 0.93-0.98; P = 5.2 × 10-4] and α-linolenic acid (ORALA = 0.95; 95% CI = 0.92-0.97; P = 5.4 × 10-5), whereas modest increased risks were observed for arachidonic (ORAA = 1.06; 95% CI = 1.03-1.08; P = 3.3 × 10-5), eicosapentaenoic (OREPA = 1.04; 95% CI = 1.01-1.07; P = 2.5 × 10-3), and docosapentaenoic acids (ORDPA = 1.03; 95% CI = 1.01-1.06; P = 1.2 × 10-2). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses. Conclusions: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk. Impact: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer

Maternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii F78

The pre- and postnatal environment may represent a window of opportunity for allergy and asthma prevention, and the hygiene hypothesis implies that microbial agents may play an important role in this regard. Using the cowshed-derived bacterium Acinetobacter lwoffii F78 together with a mouse model of experimental allergic airway inflammation, this study investigated the hygiene hypothesis, maternal (prenatal) microbial exposure, and the involvement of Toll-like receptor (TLR) signaling in prenatal protection from asthma. Maternal intranasal exposure to A. lwoffii F78 protected against the development of experimental asthma in the progeny. Maternally, A. lwoffii F78 exposure resulted in a transient increase in lung and serum proinflammatory cytokine production and up-regulation of lung TLR messenger RNA. Conversely, suppression of TLRs was observed in placental tissue. To investigate further, the functional relevance of maternal TLR signaling was tested in TLR2/3/4/7/9−/− knockout mice. The asthma-preventive effect was completely abolished in heterozygous offspring from A. lwoffii F78–treated TLR2/3/4/7/9−/− homozygous mother mice. Furthermore, the mild local and systemic inflammatory response was also absent in these A. lwoffii F78–exposed mothers. These data establish a direct relationship between maternal bacterial exposures, functional maternal TLR signaling, and asthma protection in the progeny