Acute effects of alcohol on inhibition

This thesis set out to investigate whether individual differences in concentrations of the neurotransmitter γ-aminobutyric acid (GABA) could predict the extent of alcohol induced impairment to measures of behavioural inhibition. However, investigations in to the reliability of magnetic resonance spectroscopy (MRS) methods to measure GABA, and of the stop signal reaction time (SSRT) demonstrated that neither measure was sufficiently reliable to be used in correlational research. Instead, this thesis first investigated the effects of alcohol on neuronal oscillations measured by magnetoencephalography (MEG) in the gamma frequency band that are associated with GABA. In response to a visual stimulus alcohol was found to increase gamma power and decrease gamma frequency in the visual cortex. In response to a motor stimulus increases in gamma power were also observed over the motor cortex whilst intoxicated. During resting state recordings alcohol was found to increase power in central, parietal and occipital areas across a number of frequency bands and also to alter activity across functional resting state networks including the fronto-parietal, visual and motor networks. Secondly, alcohol was found to impair behavioural inhibition in line with previous literature. However, this effect was smaller than expected and did not extend from the manual response domain to saccadic responses. It was also found that the stop signal task was not exclusively measuring behavioural inhibition where alcohol also affected action-updating abilities. In the saccadic version of the stop signal task it was found that a saccadic inhibition effect was also present indicating top-down behavioural inhibition is aided by bottom-up automatic inhibition. Altogether this body of work provides a basis for future research wishing to investigate the relationship between acute effects of alcohol on GABAergic functioning and impulsivity in order to better inform intervention and prevention treatments

Cognitive control and automatic interference in mind and brain: A unified model of saccadic inhibition and countermanding

Countermanding behavior has long been seen as a cornerstone of executive control—the human ability to selectively inhibit undesirable responses and change plans. However, scattered evidence implies that stopping behavior is entangled with simpler automatic stimulus-response mechanisms. Here we operationalize this idea by merging the latest conceptualization of saccadic countermanding with a neural network model of visuo-oculomotor behavior that integrates bottom-up and top-down drives. This model accounts for all fundamental qualitative and quantitative features of saccadic countermanding, including neuronal activity. Importantly, it does so by using the same architecture and parameters as basic visually guided behavior and automatic stimulus-driven interference. Using simulations and new data, we compare the temporal dynamics of saccade countermanding with that of saccadic inhibition (SI), a hallmark effect thought to reflect automatic competition within saccade planning areas. We demonstrate how SI accounts for a large proportion of the saccade countermanding process when using visual signals. We conclude that top-down inhibition acts later, piggy-backing on the quicker automatic inhibition. This conceptualization fully accounts for the known effects of signal features and response modalities traditionally used across the countermanding literature. Moreover, it casts different light on the concept of top-down inhibition, its timing and neural underpinning, as well as the interpretation of stop-signal reaction time (RT), the main behavioral measure in the countermanding literature

The Grizzly, October 3, 2002

Students Show Parents Their Second Home: Family Day 2002 • Students Voice Opinions in Campus Terrorism Talk • Memory of Fountain Trickles Away • Davis Professor to Deliver Lectures for Students and Faculty • New Technical Director Brings Different View Behind the Scenes • Read All About it: Newspapers in the Bookstore • Opinions: Eminem: Good or Bad • Four Doors: A Memorial • Fun Historic Event: The Heritage Festival Held on the Wentz Farmstead • Women\u27s Rugby Score First try in Ursinus History • Dougherty Sprints to Second Place • Renovate Your Room by Swappin\u27 Suites • Comparative Pricing: Comfort Foodhttps://digitalcommons.ursinus.edu/grizzlynews/1521/thumbnail.jp

A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance.

K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV

The global abundance of tree palms

Aim Palms are an iconic, diverse and often abundant component of tropical ecosystems that provide many ecosystem services. Being monocots, tree palms are evolutionarily, morphologically and physiologically distinct from other trees, and these differences have important consequences for ecosystem services (e.g., carbon sequestration and storage) and in terms of responses to climate change. We quantified global patterns of tree palm relative abundance to help improve understanding of tropical forests and reduce uncertainty about these ecosystems under climate change. Location Tropical and subtropical moist forests. Time period Current. Major taxa studied Palms (Arecaceae). Methods We assembled a pantropical dataset of 2,548 forest plots (covering 1,191 ha) and quantified tree palm (i.e., ≥10 cm diameter at breast height) abundance relative to co‐occurring non‐palm trees. We compared the relative abundance of tree palms across biogeographical realms and tested for associations with palaeoclimate stability, current climate, edaphic conditions and metrics of forest structure. Results On average, the relative abundance of tree palms was more than five times larger between Neotropical locations and other biogeographical realms. Tree palms were absent in most locations outside the Neotropics but present in >80% of Neotropical locations. The relative abundance of tree palms was more strongly associated with local conditions (e.g., higher mean annual precipitation, lower soil fertility, shallower water table and lower plot mean wood density) than metrics of long‐term climate stability. Life‐form diversity also influenced the patterns; palm assemblages outside the Neotropics comprise many non‐tree (e.g., climbing) palms. Finally, we show that tree palms can influence estimates of above‐ground biomass, but the magnitude and direction of the effect require additional work. Conclusions Tree palms are not only quintessentially tropical, but they are also overwhelmingly Neotropical. Future work to understand the contributions of tree palms to biomass estimates and carbon cycling will be particularly crucial in Neotropical forests

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Source‐based morphometry reveals structural brain pattern abnormalities in 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1‐weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source‐based morphometry (SBM) pipeline (SS‐Detect) to generate structural brain patterns (SBPs) that capture co‐varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV‐SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel‐based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism