Prefrontal signals precede striatal signals for biased credit assignment in motivational learning biases

Actions are biased by the outcomes they can produce: Humans are more likely to show action under reward prospect, but hold back under punishment prospect. Such motivational biases derive not only from biased response selection, but also from biased learning: humans tend to attribute rewards to their own actions, but are reluctant to attribute punishments to having held back. The neural origin of these biases is unclear. Specifically, it remains open whether motivational biases arise primarily from the architecture of subcortical regions or also reflect cortical influences, the latter being typically associated with increased behavioral flexibility and control beyond stereotyped behaviors. Simultaneous EEG-fMRI allowed us to track which regions encoded biased prediction errors in which order. Biased prediction errors occurred in cortical regions (dorsal anterior and posterior cingulate cortices) before subcortical regions (striatum). These results highlight that biased learning is not a mere feature of the basal ganglia, but arises through prefrontal cortical contributions, revealing motivational biases to be a potentially flexible, sophisticated mechanism

Application of Paleoclimatology to Coral Reef Monitoring and Management

The skeletons of reef-building corals are valuable archives of climatic and environmental information. Paleoclimatic data chiefly have been generated in areas most sensitive to global or regional climatic variability. However, these records also provide valuable information on anthropogenic influences – guidance of value to resource managers. NOAA’s Coral Reef Watch targets observations of current and past coral reef health in or near marine protected areas through satellites, in situ sensor platforms, and paleoclimatic analyses. Paleoclimatic data provide retrospective monitoring through multi-century environmental reconstructions that improve our understanding of past stress to coral reefs. Two sites in the Florida Keys National Marine Sanctuary were the first to benefit from Coral Reef Watch Program paleoenvironmental analyses. Coral cores yielded direct measurements of δ18O, δ13C, Sr/Ca, and coral skeletal growth (extension, density, and calcification) and reconstructions of reef temperatures. Temperature reconstructions were compared with instrumental data from nearby stations and global data sets, while skeletal growth was used to infer responses to changing climatic and environmental conditions. Differences between paleoclimatic data and gridded datasets demonstrated that paleodata provide more accurate estimates of reef temperatures as they sample subsurface temperatures where the corals live. Because of relatively high thermal variability, at least 12 samples per year are needed at these sites. Further work will extend these records back in time, to new locations, and expand on the data reconstructed from the skeletal archives

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Catecholaminergic modulation of meta-learning

The remarkable expedience of human learning is thought to be underpinned by meta-learning, whereby slow accumulative learning processes are rapidly adjusted to the current learning environment. To date, the neurobiological implementation of meta-learning remains unclear. A burgeoning literature argues for an important role for the catecholamines dopamine and noradrenaline in meta-learning. Here, we tested the hypothesis that enhancing catecholamine function modulates the ability to optimise a meta-learning parameter (learning rate) as a function of environmental volatility. 102 participants completed a task which required learning in stable phases, where the probability of reinforcement was constant, and volatile phases, where probabilities changed every 10–30 trials. The catecholamine transporter blocker methylphenidate enhanced participants’ ability to adapt learning rate: Under methylphenidate, compared with placebo, participants exhibited higher learning rates in volatile relative to stable phases. Furthermore, this effect was significant only with respect to direct learning based on the participants’ own experience, there was no significant effect on inferred-value learning where stimulus values had to be inferred. These data demonstrate a causal link between catecholaminergic modulation and the adjustment of the meta-learning parameter learning rate

Paraffin-related injury in low-income South African communities: knowledge, practice and perceived risk

OBJECTIVE: To explore what individuals at risk of injury from using paraffin (also known as kerosene) know about paraffin safety, what they do to protect themselves and their families from paraffin-related injury, and how they perceive their risk for such injury. Also, to explore interrelations between these factors and age, sex, education and income. METHODS: A sample of 238 individuals was randomly recruited from low-income housing districts near Cape Town, South Africa in 2007. Trained research assistants interviewed participants to explore their knowledge about paraffin-related safety and their perceived risk of injury from using paraffin. Researchers inspected participants' homes to evaluate paraffin safety practices. Descriptive and correlational analyses were conducted. FINDINGS: Participants had relatively low levels of knowledge about paraffin-related safety. They had high levels of unsafe practice and their perceived risk of injury was moderate. Knowledge of paraffin safety and safe practices were positively correlated with each other. Greater knowledge showed a negative correlation with the perception of being at risk for injury, but safe practices showed no correlation with perceived risk of injury. Formal education, the number of children in the home and frequency of paraffin use were positively correlated with knowledge but not with safe practices. The only significant correlate to safe practices was greater income, perhaps a reflection of the impact of financial resources on paraffin safety practices. CONCLUSION: To develop successful paraffin safety interventions, it is necessary to understand baseline levels of knowledge, practice and perceived risk of injury among at-risk populations. Our findings could be of value for designing interventions that will increase knowledge, improve safe practices and lead to the accurate perception of the risk of injury from using paraffin