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In this study, acetylcholine release is shown to reorganise hippocampal CA1 inhibitory networks resulting in prioritisation of entorhinal input over CA3 input. This is achieved by activation of a combination of M3 and M4 muscarinic receptors.

Convulsive seizures are known to cause severe cardiopulmonary changes and increased autonomic activity. Limited reports describe peri-ictal cardiac arrhythmias such as atrial fibrillation (AF) with generalized tonic–clonic seizures (GTCS). We present a unique case of a healthy 23-year-old male patient with new onset prolonged AF in the setting of new onset seizures, occurring on three independent occasions. Over two years, our patient had multiple hospitalizations for seizures with an electrocardiogram (ECG) diagnosis of AF made on three different occasions, occurring during his post-ictal state (all within 30 min of seizure onset). These seizures were never captured by electroencephalography (EEG) or witnessed by the medical staff, but were reported by family and/or reviewed on video provided by them. After his first GTCS, his AF persisted and was medically cardioverted. Two additional instances of AF after witnessed GTCS have been captured. After his second unprovoked seizure, an anti-seizure drug (ASD) was prescribed. A multi-disciplinary approach may be adopted to address comorbidities associated with seizures. Aggressive evaluation and treatment should be employed for newly diagnosed and refractory seizure patients associated with arrhythmias, in our case AF. Peri-ictal arrhythmias may be considered a potential marker for increased sudden unexpected death in epilepsy (SUDEP) risk. Keywords: Atrial fibrillation, Seizures, Epilepsy, Arrhythmias, EEG, ECG, SUDEP

A wooden house frame consists of many different lumber pieces, but because of the regularity of these building blocks, the structure can be designed using straightforward geometrical principles. The design of multicomponent protein assemblies, in comparison, has been much more complex, largely owing to the irregular shapes of protein structures1. Here we describe extendable linear, curved and angled protein building blocks, as well as inter-block interactions, that conform to specified geometric standards; assemblies designed using these blocks inherit their extendability and regular interaction surfaces, enabling them to be expanded or contracted by varying the number of modules, and reinforced with secondary struts. Using X-ray crystallography and electron microscopy, we validate nanomaterial designs ranging from simple polygonal and circular oligomers that can be concentrically nested, up to large polyhedral nanocages and unbounded straight 'train track' assemblies with reconfigurable sizes and geometries that can be readily blueprinted. Because of the complexity of protein structures and sequence-structure relationships, it has not previously been possible to build up large protein assemblies by deliberate placement of protein backbones onto a blank three-dimensional canvas; the simplicity and geometric regularity of our design platform now enables construction of protein nanomaterials according to 'back of an envelope' architectural blueprints.

Studying the role of social change, I investigated trends in approval for euthanasia between cohorts in the United States and how those trends are influenced by cohort replacement and religious attitudes. Using 16 waves from the General Social Survey (1985 to 2014; n = 6,638), I estimated differences in approval ratings between cohorts using logistic regression models. Models accounted for religious preference, religiosity, age, sex, race/ethnicity, socioeconomic status, marital status, and political ideology. Members of the baby boomer cohort are significantly more likely to approve of euthanasia than either their predecessors or successors, suggesting a cohort effect. Individuals who belong to more conservative religious groups and display higher levels of religiosity are less likely to approve. Cohort has a meaningful effect on approval of euthanasia, successors to the baby boomer cohort might increase their approval as their religiosity decreases and their parents and grandparents increasingly face end-of-life decisions.

Although the primary protein sequence of ubiquitin (Ub) is extremely stable over evolutionary time, it is highly tolerant to mutation during selection experiments performed in the laboratory. We have proposed that this discrepancy results from the difference between fitness under laboratory culture conditions and the selective pressures in changing environments over evolutionary timescales. Building on our previous work (Mavor et al., 2016), we used deep mutational scanning to determine how twelve new chemicals (3-Amino-1,2,4-triazole, 5-fluorocytosine, Amphotericin B, CaCl2, Cerulenin, Cobalt Acetate, Menadione, Nickel Chloride, p-Fluorophenylalanine, Rapamycin, Tamoxifen, and Tunicamycin) reveal novel mutational sensitivities of ubiquitin residues. Collectively, our experiments have identified eight new sensitizing conditions for Lys63 and uncovered a sensitizing condition for every position in Ub except Ser57 and Gln62. By determining the ubiquitin fitness landscape under different chemical constraints, our work helps to resolve the inconsistencies between deep mutational scanning experiments and sequence conservation over evolutionary timescales.

Although the primary protein sequence of ubiquitin (Ub) is extremely stable over evolutionary time, it is highly tolerant to mutation during selection experiments performed in the laboratory. We have proposed that this discrepancy results from the difference between fitness under laboratory culture conditions and the selective pressures in changing environments over evolutionary timescales. Building on our previous work (Mavor et al., 2016), we used deep mutational scanning to determine how twelve new chemicals (3-Amino-1,2,4-triazole, 5-fluorocytosine, Amphotericin B, CaCl2, Cerulenin, Cobalt Acetate, Menadione, Nickel Chloride, p-Fluorophenylalanine, Rapamycin, Tamoxifen, and Tunicamycin) reveal novel mutational sensitivities of ubiquitin residues. Collectively, our experiments have identified eight new sensitizing conditions for Lys63 and uncovered a sensitizing condition for every position in Ub except Ser57 and Gln62. By determining the ubiquitin fitness landscape under different chemical constraints, our work helps to resolve the inconsistencies between deep mutational scanning experiments and sequence conservation over evolutionary timescales.

Synthetic protein switches controlled with user-defined inputs are powerful tools for studying and controlling dynamic cellular processes. To date, these approaches have relied primarily on intermolecular regulation. Here we report a computationally guided framework for engineering intramolecular regulation of protein function. We utilize this framework to develop chemically inducible activator of RAS (CIAR), a single-component RAS rheostat that directly activates endogenous RAS in response to a small molecule. Using CIAR, we show that direct RAS activation elicits markedly different RAS-ERK signaling dynamics from growth factor stimulation, and that these dynamics differ among cell types. We also found that the clinically approved RAF inhibitor vemurafenib potently primes cells to respond to direct wild-type RAS activation. These results demonstrate the utility of CIAR for quantitatively interrogating RAS signaling. Finally, we demonstrate the general utility of our approach in design of intramolecularly regulated protein tools by applying it to the Rho family of guanine nucleotide exchange factors.

Background: In baseball, youth athletes play on smaller fields with shorter distances between bases, shorter pitching distances, and smaller mounds. Despite this, youth athletes use baseballs weighing the same amount as those used at the professional level, possibly predisposing youth baseball players to injuries. Purpose: (1) To determine the effects of throwing a smaller, lighter, and both smaller and lighter baseball on throwing arm stress in youth athletes and (2) to also investigate how changing the ball size and weight would affect elbow varus torque, shoulder distraction force, and throwing arm internal rotation velocity during the throwing motion. Study Design: Cross-sectional study; Level of evidence, 3. Methods: This cross-sectional cohort study analyzed the kinematics and kinetics of 38 youth baseball players (mean age, 8.3 ± 0.8 years) throwing a baseball modified in size and weight. Three-dimensional motion data were collected using a retroreflective marker set and a 12-camera motion analysis system. Full-body kinematics and kinetics were calculated using commercial software. Participants threw 5 different types of baseballs 3 times each, in random order, with full effort from a pitching mound to a target 14 m away. The balls used were a 5-oz regular baseball, 5-oz (0.142-kg) baseball with a 5% reduced circumference, 4-oz (0.113-kg) baseball, 4-oz baseball with a 5% reduced circumference, and 3-oz (0.085-kg) baseball. Analysis of variance was used to determine statistical differences in elbow varus torque, shoulder distraction force, and throwing arm internal rotation velocity among baseball types. The Tukey post hoc test was used to further investigate differences between the ball groups, considering P <.05 to be significant. Results: Analysis of variance detected a significant difference in elbow varus torque among ball groups (P =.024). The Tukey post hoc test revealed a moderate difference in elbow varus torque between the 5-oz baseball (4.73 ± 1.06 percentage body weight × height [%BW × H]) and 3-oz baseball (4.06 ± 0.83 %BW × H) (P =.017; d = 0.677 [95% CI, 0.08-1.27]). No significant differences were found in shoulder distraction force or throwing arm internal rotation velocity among ball groups. Conclusion: Compared with a 5-oz baseball, throwing a 3-oz baseball resulted in decreased elbow varus torque with a moderate effect size. [ABSTRACT FROM AUTHOR]