A nuclear RNA degradation code for eukaryotic transcriptome surveillance.

The RNA exosome plays critical roles in eukaryotic RNA degradation, but it remains unclear how the exosome specifically recognizes its targets. The PAXT connection is an adaptor that recruits the exosome to polyadenylated RNAs in the nucleus, especially transcripts polyadenylated at intronic poly(A) sites. Here we show that PAXT-mediated RNA degradation is induced by the combination of a 5' splice site and a poly(A) junction, but not by either sequence alone.

SRC inhibition enables formation of a growth suppressive MAGI1-PP2A complex in isocitrate dehydrogenase-mutant cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive bile duct malignancy that frequently exhibits isocitrate dehydrogenase () mutations. Mutant IDH (IDHm) ICC is dependent on SRC kinase for growth and survival and is hypersensitive to inhibition by dasatinib, but the molecular mechanism underlying this sensitivity is unclear. We found that dasatinib reduced p70 S6 kinase (S6K) and ribosomal protein S6 (S6), leading to substantial reductions in cell size and de novo protein synthesis.

Attitudes Towards Conflicts of Interest in Medical Research: A Survey of US Medical Students.

Industry funds nearly two-thirds of US healthcare research, and industry-sponsorship may produce more favorable research results and conclusions. Medical students report feeling inadequately prepared to avoid negative industry influence. Research of educational interventions that educate students on the potential effects of industry influence is lacking, and no interventions have demonstrated long-term benefit.

Multiple and subject-specific roles of uncertainty in reward-guided decision-making.

Decision-making in noisy, changing, and partially observable environments entails a basic tradeoff between immediate reward and longer-term information gain, known as the exploration-exploitation dilemma. Computationally, an effective way to balance this tradeoff is by leveraging uncertainty to guide exploration. Yet, in humans, empirical findings are mixed, from suggesting uncertainty-seeking to indifference and avoidance.

The effect of pseudoknot base pairing on cotranscriptional structural switching of the fluoride riboswitch.

A central question in biology is how RNA sequence changes influence dynamic conformational changes during cotranscriptional folding. Here we investigated this question through the study of transcriptional fluoride riboswitches, non-coding RNAs that sense the fluoride anion through the coordinated folding and rearrangement of a pseudoknotted aptamer domain and a downstream intrinsic terminator expression platform. Using a combination of Escherichia coli RNA polymerase in vitro transcription and cellular gene expression assays, we characterized the function of mesophilic and thermophilic fluoride riboswitch variants.

The Effect of Pseudoknot Base Pairing on Cotranscriptional Structural Switching of the Fluoride Riboswitch.

A central question in biology is how RNA sequence changes influence dynamic conformational changes during cotranscriptional folding. Here we investigated this question through the study of transcriptional fluoride riboswitches, non-coding RNAs that sense the fluoride anion through the coordinated folding and rearrangement of a pseudoknotted aptamer domain and a downstream intrinsic terminator expression platform. Using a combination of RNA polymerase transcription and cellular gene expression assays, we characterized the function of mesophilic and thermophilic fluoride riboswitch variants.

The anticancer compound JTE-607 reveals hidden sequence specificity of the mRNA 3' processing machinery.

JTE-607 is an anticancer and anti-inflammatory compound and its active form, compound 2, directly binds to and inhibits CPSF73, the endonuclease for the cleavage step in pre-messenger RNA (pre-mRNA) 3' processing. Surprisingly, compound 2-mediated inhibition of pre-mRNA cleavage is sequence specific and the drug sensitivity is predominantly determined by sequences flanking the cleavage site (CS). Using massively parallel in vitro assays, we identified key sequence features that determine drug sensitivity.

Childhood infection burden, recent antibiotic exposure and vascular phenotypes in preschool children.

Background: Severe childhood infection has a dose-dependent association with adult cardiovascular events and with adverse cardiometabolic phenotypes. The relationship between cardiovascular outcomes and less severe childhood infections is unclear.

Aim: To investigate the relationship between common, non-hospitalised infections, antibiotic exposure, and preclinical vascular phenotypes in young children.

Both reactive and proactive control are deficient in children with ADHD and predictive of clinical symptoms.

Cognitive control deficits are a hallmark of attention deficit hyperactivity disorder (ADHD) in children. Theoretical models posit that cognitive control involves reactive and proactive control processes but their distinct roles and inter-relations in ADHD are not known, and the contributions of proactive control remain vastly understudied. Here, we investigate the dynamic dual cognitive control mechanisms associated with both proactive and reactive control in 50 children with ADHD (16F/34M) and 30 typically developing (TD) children (14F/16M) aged 9-12 years across two different cognitive controls tasks using a within-subject design.

Sirtuin 6 is required for the integrated stress response and resistance to inhibition of transcriptional cyclin-dependent kinases.

Pancreatic ductal adenocarcinoma (PDAC) is classified into two key subtypes, classical and basal, with basal PDAC predicting worse survival. Using in vitro drug assays, genetic manipulation experiments, and in vivo drug studies in human patient-derived xenografts (PDXs) of PDAC, we found that basal PDACs were uniquely sensitive to transcriptional inhibition by targeting cyclin-dependent kinase 7 (CDK7) and CDK9, and this sensitivity was recapitulated in the basal subtype of breast cancer. We showed in cell lines, PDXs, and publicly available patient datasets that basal PDAC was characterized by inactivation of the integrated stress response (ISR), which leads to a higher rate of global mRNA translation.

State-specific alterations in the neural computations underlying inhibitory control in women remitted from bulimia nervosa.

The neurocomputational processes underlying bulimia nervosa and its primary symptoms, out-of-control overeating and purging, are poorly understood. Research suggests that the brains of healthy individuals form a dynamic internal model to predict whether control is needed in each moment. This study tested the hypothesis that this computational process of inhibitory control is abnormally affected by metabolic state (being fasted or fed) in bulimia nervosa.

The anti-cancer compound JTE-607 reveals hidden sequence specificity of the mRNA 3' processing machinery.

JTE-607 is a small molecule compound with anti-inflammation and anti-cancer activities. Upon entering the cell, it is hydrolyzed to Compound 2, which directly binds to and inhibits CPSF73, the endonuclease for the cleavage step in pre-mRNA 3' processing. Although CPSF73 is universally required for mRNA 3' end formation, we have unexpectedly found that Compound 2- mediated inhibition of pre-mRNA 3' processing is sequence-specific and that the sequences flanking the cleavage site (CS) are a major determinant for drug sensitivity.

Identification of a Novel Keto Sugar Component in Streptococcus pneumoniae Serotype 12F Capsular Polysaccharide and Impact on Vaccine Immunogenicity.

Implementation of conjugate vaccine technology revolutionized the ability to effectively elicit long-lasting immune responses to bacterial capsular polysaccharides. Although expansion of conjugate vaccine serotype coverage is designed to target residual disease burden to pneumococcal serotypes not contained in earlier vaccine versions, details of polysaccharide Ag structure, heterogeneity, and epitope structure components contributing to vaccine-mediated immunity are not always clear. Analysis of Streptococcus pneumoniae serotype 12F polysaccharide by two-dimensional nuclear magnetic resonance spectroscopy and mass spectrometry revealed a partial substitution of N-acetyl-galactosamine by the keto sugar 2-acetamido-2,6-dideoxy-xylo-hexos-4-ulose (Sug) in up to 25% of the repeat units.

Cotranscriptional RNA strand exchange underlies the gene regulation mechanism in a purine-sensing transcriptional riboswitch.

RNA folds cotranscriptionally to traverse out-of-equilibrium intermediate structures that are important for RNA function in the context of gene regulation. To investigate this process, here we study the structure and function of the Bacillus subtilis yxjA purine riboswitch, a transcriptional riboswitch that downregulates a nucleoside transporter in response to binding guanine. Although the aptamer and expression platform domain sequences of the yxjA riboswitch do not completely overlap, we hypothesized that a strand exchange process triggers its structural switching in response to ligand binding.

Relative Validity and Reproducibility of a Semi-Quantitative Food Frequency Questionnaire for Determining Nutrient Intake in Older Adults in New Zealand: The REACH Study.

Dietary intake is an important predictor of health and disease outcomes. This cross-sectional study evaluated the relative validity and reproducibility of a semi-quantitative food frequency questionnaire (FFQ) for assessing energy and nutrient intake in older adults. Dietary data were collected 2018-2019 in Auckland, New Zealand from a convenience sample of community-dwelling adults (65-74 years, = 294, 37% male) using a 109-item self-administered FFQ at baseline (FFQ1) and four weeks later to assess reproducibility.

Epigenetic Therapies in Ovarian Cancer Alter Repetitive Element Expression in a -Dependent Manner.

Epithelial ovarian carcinomas are particularly deadly due to intratumoral heterogeneity, resistance to standard-of-care therapies, and poor response to alternative treatments such as immunotherapy. Targeting the ovarian carcinoma epigenome with DNA methyltransferase inhibitors (DNMTi) or histone deacetylase inhibitors (HDACi) increases immune signaling and recruits CD8 T cells and natural killer cells to fight ovarian carcinoma in murine models. This increased immune activity is caused by increased transcription of repetitive elements (RE) that form double-stranded RNA (dsRNA) and trigger an IFN response.

Revisiting the Role of Uncertainty-Driven Exploration in a (Perceived) Non-Stationary World.

Humans are often faced with an exploration-versus-exploitation trade-off. A commonly used paradigm, multi-armed bandit, has shown humans to exhibit an "uncertainty bonus", which combines with estimated reward to drive exploration. However, previous studies often modeled belief updating using either a Bayesian model that assumed the reward contingency to remain stationary, or a reinforcement learning model.

Devaluation of Unchosen Options: A Bayesian Account of the Provenance and Maintenance of Overly Optimistic Expectations.

Humans frequently overestimate the likelihood of desirable events while underestimating the likelihood of undesirable ones: a phenomenon known as . Previously, it was suggested that unrealistic optimism arises from asymmetric belief updating, with a relatively reduced coding of undesirable information. Prior studies have shown that a reinforcement learning (RL) model with asymmetric learning rates (greater for a positive prediction error than a negative prediction error) could account for unrealistic optimism in a bandit task, in particular the tendency of human subjects to persistently choosing a single option when there are multiple equally good options.

Leveraging Computer Vision Face Representation to Understand Human Face Representation.

Face processing plays a critical role in human social life, from differentiating friends from enemies to choosing a life mate. In this work, we leverage various computer vision techniques, combined with human assessments of similarity between pairs of faces, to investigate human face representation. We find that combining a shape- and texture-feature based model (Active Appearance Model) with a particular form of metric learning, not only achieves the best performance in predicting human similarity judgments on held-out data (both compared to other algorithms and to humans), but also performs better or comparable to alternative approaches in modeling human social trait judgment (e.

Distinct motivations to seek out information in healthy individuals and problem gamblers.

As massive amounts of information are becoming available to people, understanding the mechanisms underlying information-seeking is more pertinent today than ever. In this study, we investigate the underlying motivations to seek out information in healthy and addicted individuals. We developed a novel decision-making task and a novel computational model which allows dissociating the relative contribution of two motivating factors to seek out information: a desire for novelty and a general desire for knowledge.

Computationally reconstructing cotranscriptional RNA folding from experimental data reveals rearrangement of non-native folding intermediates.

The series of RNA folding events that occur during transcription can critically influence cellular RNA function. Here, we present reconstructing RNA dynamics from data (R2D2), a method to uncover details of cotranscriptional RNA folding. We model the folding of the Escherichia coli signal recognition particle (SRP) RNA and show that it requires specific local structural fluctuations within a key hairpin to engender efficient cotranscriptional conformational rearrangement into the functional structure.

Functional cooperativity between the trigger factor chaperone and the ClpXP proteolytic complex.

A functional association is uncovered between the ribosome-associated trigger factor (TF) chaperone and the ClpXP degradation complex. Bioinformatic analyses demonstrate conservation of the close proximity of tig, the gene coding for TF, and genes coding for ClpXP, suggesting a functional interaction. The effect of TF on ClpXP-dependent degradation varies based on the nature of substrate.

From likely to likable: The role of statistical typicality in human social assessment of faces.

Humans readily form social impressions, such as attractiveness and trustworthiness, from a stranger's facial features. Understanding the provenance of these impressions has clear scientific importance and societal implications. Motivated by the efficient coding hypothesis of brain representation, as well as Claude Shannon's theoretical result that maximally efficient representational systems assign shorter codes to statistically more typical data (quantified as log likelihood), we suggest that social "liking" of faces increases with statistical typicality.