Alternative polyadenylation: Less than meets the eye

Abstract With the advances in deep-sequencing techniques over the last decade, the study of alternative cleavage and polyadenylation (APA) has shifted from individual gene to whole transcriptome analysis. Findings from such global studies have elevated APA to its currently accepted status as a major player in the regulation of eukaryotic gene expression. Although ∼70 % of human genes have been shown to contain multiple cleavage and polyadenylation sites, the extent of the consequences of APA and its role in regulating physiological processes are still largely unknown. The present review aims to summarize the experimental evidence that supports a physiological role of APA and highlights some of the shortcomings that need addressing to substantiate the widely proposed claim that APA is a key player in global gene regulation

Regional Image Perturbation Reduces LpL_p Norms of Adversarial Examples While Maintaining Model-to-model Transferability

Regional adversarial attacks often rely on complicated methods for generating adversarial perturbations, making it hard to compare their efficacy against well-known attacks. In this study, we show that effective regional perturbations can be generated without resorting to complex methods. We develop a very simple regional adversarial perturbation attack method using cross-entropy sign, one of the most commonly used losses in adversarial machine learning. Our experiments on ImageNet with multiple models reveal that, on average, $76\%$ of the generated adversarial examples maintain model-to-model transferability when the perturbation is applied to local image regions. Depending on the selected region, these localized adversarial examples require significantly less $L_p$ norm distortion (for $p \in \{0, 2, \infty\}$) compared to their non-local counterparts. These localized attacks therefore have the potential to undermine defenses that claim robustness under the aforementioned norms.Comment: Accepted for the ICML 2020, Workshop on Uncertainty and Robustness in Deep Learning (UDL

CDK9 and PP2A regulate RNA polymerase II transcription termination and coupled RNA maturation

CDK9 is a kinase critical for the productive transcription of protein-coding genes by RNA polymerase II (pol II). As part of P-TEFb, CDK9 phosphorylates the carboxyl-terminal domain (CTD) of pol II and elongation factors, which allows pol II to elongate past the early elongation checkpoint (EEC) encountered soon after initiation. We show that, in addition to halting pol II at the EEC, loss of CDK9 activity causes premature termination of transcription across the last exon, loss of polyadenylation factors from chromatin, and loss of polyadenylation of nascent transcripts. Inhibition of the phosphatase PP2A abrogates the premature termination and loss of polyadenylation caused by CDK9 inhibition, indicating that this kinase/phosphatase pair regulates transcription elongation and RNA processing at the end of protein-coding genes. We also confirm the splicing factor SF3B1 as a target of CDK9 and show that SF3B1 in complex with polyadenylation factors is lost from chromatin after CDK9 inhibition. These results emphasize the important roles that CDK9 plays in coupling transcription elongation and termination to RNA maturation downstream of the EEC

Arrestin recruitment to dopamine D2 receptor mediates locomotion but not incentive motivation

The dopamine (DA) D2 receptor (D2R) is an important target for the treatment of neuropsychiatric disorders such as schizophrenia and Parkinson's disease. However, the development of improved therapeutic strategies has been hampered by our incomplete understanding of this receptor's downstream signaling processes in vivo and how these relate to the desired and undesired effects of drugs. D2R is a G protein-coupled receptor (GPCR) that activates G protein-dependent as well as non-canonical arrestin-dependent signaling pathways. Whether these effector pathways act alone or in concert to facilitate specific D2R-dependent behaviors is unclear. Here, we report on the development of a D2R mutant that recruits arrestin but is devoid of G protein activity. When expressed virally in "indirect pathway" medium spiny neurons (iMSNs) in the ventral striatum of D2R knockout mice, this mutant restored basal locomotor activity and cocaine-induced locomotor activity in a manner indistinguishable from wild-type D2R, indicating that arrestin recruitment can drive locomotion in the absence of D2R-mediated G protein signaling. In contrast, incentive motivation was enhanced only by wild-type D2R, signifying a dissociation in the mechanisms that underlie distinct D2R-dependent behaviors, and opening the door to more targeted therapeutics

Aran, Galway Bay and Slyne Head Nephrops Grounds (FU17) 2023 UWTV Survey Report and catch scenarios for 2024

This report provides the main results and findings of the 21st annual underwater television survey on the Aran, Galway Bay and Slyne head Nephrops grounds, ICES assessment area; Functional Unit 17. The survey was multi-disciplinary in nature collecting UWTV, CTD and other ecosystem data. In 2023 a total of 44 UWTV stations were successfully completed, 34 on the Aran Grounds, 5 on Galway Bay and 5 on Slyne Head patches. The mean burrow density observed in 2023, adjusted for edge effect, was medium at 0.29 burrows/m². The final krigged burrow abundance estimate for the Aran Grounds was 356 million burrows with a CV (Coefficient of Variance; relative standard error) of 3%. The final abundance estimate for Galway Bay was 15 million and for Slyne Head was 5 million, with CVs of 7% and 4% respectively. The total abundance estimates have fluctuated considerably over the time series. The 2023 combined abundance estimate (375 million burrows) is 13% higher than in 2021, and it is below MSY Btrigger (540 million burrows). Using the 2023 estimate of abundance and updated stock data imply that catches in 2024 should be no more than 454 tonnes, according to the EU MAP and ICES MSY approach and assuming that discard rates and fishery selection patterns do not change from the average of 2020–2022. Virgularia mirabilis was the only sea-pen species observed on the UWTV footage. Trawl marks were present at 5% of the Aran stations surveyed.Marine Institut

FU19 Nephrops Grounds 2023 UWTV Survey Report and catch scenarios for 2024

This report provides the main results of the fourteenth underwater television survey of the various Nephrops patches in Functional Unit 19. The survey was multi disciplinary in nature collecting UWTV and other ecosystem data. In 2023 a total 42 UWTV stations were successfully completed. The mean density estimates varied considerably across the different patches. The 2023 raised abundance estimate showed a 15% decrease from the 2022 estimate and at 220 million burrows is below the MSY Btrigger reference point (430 million). Using the 2023 estimate of abundance and updated stock data implies catch in 2024 that correspond to the F ranges in the EU multi annual plan for Western Waters are between 224 and 248 tonnes (assuming that discard rates and fishery selection patterns do not change from the average of 2020–2022). One species of sea pen was observed; Virgularia mirabilis which has been observed on previous surveys of FU19. Trawl marks were observed at 10% of the stations surveyed.Marine Institut

Living Well with Diabetes: a randomized controlled trial of a telephone-delivered intervention for maintenance of weight loss, physical activity and glycaemic control in adults with type 2 diabetes

Background By 2025, it is estimated that approximately 1.8 million Australian adults (approximately 8.4% of the adult population) will have diabetes, with the majority having type 2 diabetes. Weight management via improved physical activity and diet is the cornerstone of type 2 diabetes management. However, the majority of weight loss trials in diabetes have evaluated short-term, intensive clinic-based interventions that, while producing short-term outcomes, have failed to address issues of maintenance and broad population reach. Telephone-delivered interventions have the potential to address these gaps. Methods/Design Using a two-arm randomised controlled design, this study will evaluate an 18-month, telephone-delivered, behavioural weight loss intervention focussing on physical activity, diet and behavioural therapy, versus usual care, with follow-up at 24 months. Three-hundred adult participants, aged 20-75 years, with type 2 diabetes, will be recruited from 10 general practices via electronic medical records search. The Social-Cognitive Theory driven intervention involves a six-month intensive phase (4 weekly calls and 11 fortnightly calls) and a 12-month maintenance phase (one call per month). Primary outcomes, assessed at 6, 18 and 24 months, are: weight loss, physical activity, and glycaemic control (HbA1c), with weight loss and physical activity also measured at 12 months. Incremental cost-effectiveness will also be examined. Study recruitment began in February 2009, with final data collection expected by February 2013. Discussion This is the first study to evaluate the telephone as the primary method of delivering a behavioural weight loss intervention in type 2 diabetes. The evaluation of maintenance outcomes (6 months following the end of intervention), the use of accelerometers to objectively measure physical activity, and the inclusion of a cost-effectiveness analysis will advance the science of broad reach approaches to weight control and health behaviour change, and will build the evidence base needed to advocate for the translation of this work into population health practice

Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.</p

Advances in the treatment of prolactinomas

Prolactinomas account for approximately 40% of all pituitary adenomas and are an important cause of hypogonadism and infertility. The ultimate goal of therapy for prolactinomas is restoration or achievement of eugonadism through the normalization of hyperprolactinemia and control of tumor mass. Medical therapy with dopamine agonists is highly effective in the majority of cases and represents the mainstay of therapy. Recent data indicating successful withdrawal of these agents in a subset of patients challenge the previously held concept that medical therapy is a lifelong requirement. Complicated situations, such as those encountered in resistance to dopamine agonists, pregnancy, and giant or malignant prolactinomas, may require multimodal therapy involving surgery, radiotherapy, or both. Progress in elucidating the mechanisms underlying the pathogenesis of prolactinomas may enable future development of novel molecular therapies for treatment-resistant cases. This review provides a critical analysis of the efficacy and safety of the various modes of therapy available for the treatment of patients with prolactinomas with an emphasis on challenging situations, a discussion of the data regarding withdrawal of medical therapy, and a foreshadowing of novel approaches to therapy that may become available in the future

Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals

We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12-16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI's magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57