Work minimization accounts for footfall phasing in slow quadrupedal gaits

Quadrupeds, like most bipeds, tend to walk with an even left/right footfall timing. However, the phasing between hind and forelimbs shows considerable variation. Here, we account for this variation by modeling and explaining the influence of hind-fore limb phasing on mechanical work requirements. These mechanics account for the different strategies used by: (1) slow animals (a group including crocodile, tortoise, hippopotamus and some babies); (2) normal medium to large mammals; and (3) (with an appropriate minus sign) sloths undertaking suspended locomotion across a range of speeds. While the unusual hind-fore phasing of primates does not match global work minimizing predictions, it does approach an only slightly more costly local minimum. Phases predicted to be particularly costly have not been reported in nature

The scaling or ontogeny of human gait kinetics and walk-run transition: The implications of work vs. peak power minimization

A simple model is developed to find vertical force profiles and stance durations that minimize either limb mechanical work or peak power demands during bipedal locomotion. The model predicts that work minimization is achieved with a symmetrical vertical force profile, consistent with previous models and observations of adult humans, and data for 487 participants (predominantly 11–18 years old) required to walk at a range of speeds at a Science Fair. Work minimization also predicts the discrete walk-run transition, familiar for adult humans. In contrast, modeled peak limb mechanical power demands are minimized with an early skew in vertical ground reaction force that increases with speed, and stance durations that decrease steadily with speed across the work minimizing walk-run transition speed. The peak power minimization model therefore predicts a continuous walk-run gait transition that is quantitatively consistent with measurements of younger children (1.1–4.7 years) required to locomote at a range of speeds but free to select their own gaits

On the linear stability of solitons and hairy black holes with a negative cosmological constant: the odd-parity sector

Using a recently developed perturbation formalism based on curvature quantities, we investigate the linear stability of black holes and solitons with Yang-Mills hair and a negative cosmological constant. We show that those solutions which have no linear instabilities under odd- and even- parity spherically symmetric perturbations remain stable under odd-parity, linear, non-spherically symmetric perturbations.Comment: 26 pages, 1 figur

Characterization of variational quantum algorithms using free fermions

We study variational quantum algorithms from the perspective of free fermions. By deriving the explicit structure of the associated Lie algebras, we show that the Quantum Approximate Optimization Algorithm (QAOA) on a one-dimensional lattice -- with and without decoupled angles -- is able to prepare all fermionic Gaussian states respecting the symmetries of the circuit. Leveraging these results, we numerically study the interplay between these symmetries and the locality of the target state, and find that an absence of symmetries makes nonlocal states easier to prepare. An efficient classical simulation of Gaussian states, with system sizes up to $80$ and deep circuits, is employed to study the behavior of the circuit when it is overparameterized. In this regime of optimization, we find that the number of iterations to converge to the solution scales linearly with system size. Moreover, we observe that the number of iterations to converge to the solution decreases exponentially with the depth of the circuit, until it saturates at a depth which is quadratic in system size. Finally, we conclude that the improvement in the optimization can be explained in terms of of better local linear approximations provided by the gradients

Modifying the m6A brain methylome by ALKBH5-mediated demethylation: a new contender for synaptic tagging

Synaptic plasticity processes, which underlie learning and memory formation, require RNA to be translated local to synapses. The synaptic tagging hypothesis has previously been proposed to explain how mRNAs are available at specific activated synapses. However how RNA is regulated, and which transcripts are silenced or processed as part of the tagging process is still unknown. Modification of RNA by N6-methyladenosine (m6A/m) influences the cellular fate of mRNA. Here, by advanced microscopy, we showed that m6A demethylation by the eraser protein ALKBH5 occurs at active synaptic ribosomes and at synapses during short term plasticity. We demonstrated that at activated glutamatergic post-synaptic sites, both the YTHDF1 and YTHDF3 reader and the ALKBH5 eraser proteins increase in co-localisation to m6A-modified RNAs; but only the readers showed high co-localisation to modified RNAs during late-stage plasticity. The YTHDF1 and YTHFDF3 readers also exhibited differential roles during synaptic maturation suggesting that temporal and subcellular abundance may determine specific function. m6A-sequencing of human parahippocampus brain tissue revealed distinct white and grey matter m6A methylome profiles indicating that cellular context is a fundamental factor dictating regulated pathways. However, in both neuronal and glial cell-rich tissue, m6A effector proteins are themselves modified and m6A epitranscriptional and posttranslational modification processes coregulate protein cascades. We hypothesise that the availability m6A effector protein machinery in conjunction with RNA modification, may be important in the formation of condensed synaptic nanodomain assemblies through liquid-liquid phase separation. Our findings support that m6A demethylation by ALKBH5 is an intrinsic component of the synaptic tagging hypothesis and a molecular switch which leads to alterations in the RNA methylome, synaptic dysfunction and potentially reversible disease states

A global experiment on motivating social distancing during the COVID-19 pandemic

Finding communication strategies that effectively motivate social distancing continues to be a global public health priority during the COVID-19 pandemic. This cross-country, preregistered experiment (n = 25,718 from 89 countries) tested hypotheses concerning generalizable positive and negative outcomes of social distancing messages that promoted personal agency and reflective choices (i.e., an autonomy-supportive message) or were restrictive and shaming (i.e. a controlling message) compared to no message at all. Results partially supported experimental hypotheses in that the controlling message increased controlled motivation (a poorly-internalized form of motivation relying on shame, guilt, and fear of social consequences) relative to no message. On the other hand, the autonomy-supportive message lowered feelings of defiance compared to the controlling message, but the controlling message did not differ from receiving no message at all. Unexpectedly, messages did not influence autonomous motivation (a highly-internalized form of motivation relying on one’s core values) or behavioral intentions. Results supported hypothesized associations between people’s existing autonomous and controlled motivations and self-reported behavioral intentions to engage in social distancing: Controlled motivation was associated with more defiance and less long-term behavioral intentions to engage in social distancing, whereas autonomous motivation was associated with less defiance and more short- and long-term intentions to social distance. Overall, this work highlights the potential harm of using shaming and pressuring language in public health communication, with implications for the current and future global health challenges.info:eu-repo/semantics/publishedVersio

Adaptive Evolution of the Myo6 Gene in Old World Fruit Bats (Family: Pteropodidae)

PMCID: PMC3631194This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Estimation and testing for the effect of a genetic pathway on a disease outcome using logistic kernel machine regression via logistic mixed models

<p>Abstract</p> <p>Background</p> <p>Growing interest on biological pathways has called for new statistical methods for modeling and testing a genetic pathway effect on a health outcome. The fact that genes within a pathway tend to interact with each other and relate to the outcome in a complicated way makes nonparametric methods more desirable. The kernel machine method provides a convenient, powerful and unified method for multi-dimensional parametric and nonparametric modeling of the pathway effect.</p> <p>Results</p> <p>In this paper we propose a logistic kernel machine regression model for binary outcomes. This model relates the disease risk to covariates parametrically, and to genes within a genetic pathway parametrically or nonparametrically using kernel machines. The nonparametric genetic pathway effect allows for possible interactions among the genes within the same pathway and a complicated relationship of the genetic pathway and the outcome. We show that kernel machine estimation of the model components can be formulated using a logistic mixed model. Estimation hence can proceed within a mixed model framework using standard statistical software. A score test based on a Gaussian process approximation is developed to test for the genetic pathway effect. The methods are illustrated using a prostate cancer data set and evaluated using simulations. An extension to continuous and discrete outcomes using generalized kernel machine models and its connection with generalized linear mixed models is discussed.</p> <p>Conclusion</p> <p>Logistic kernel machine regression and its extension generalized kernel machine regression provide a novel and flexible statistical tool for modeling pathway effects on discrete and continuous outcomes. Their close connection to mixed models and attractive performance make them have promising wide applications in bioinformatics and other biomedical areas.</p

Regression of Moral Reasoning during Medical Education: Combined Design Study to Evaluate the Effect of Clinical Study Years

BACKGROUND: Moral reasoning is important for developing medical professionalism but current evidence for the relationship between education and moral reasoning does not clearly apply to medical students. We used a combined study design to test the effect of clinical teaching on moral reasoning. METHODS: We used the Defining Issues Test-2 as a measure of moral judgment, with 3 general moral schemas: Personal Interest, Maintaining Norms, and Postconventional Schema. The test was applied to 3 consecutive cohorts of second year students in 2002 (n = 207), 2003 (n = 192), and 2004 (n = 139), and to 707 students of all 6 study years in 2004 cross-sectional study. We also tested 298 age-matched controls without university education. RESULTS: In the cross-sectional study, there was significant main effect of the study year for Postconventional (F(5,679) = 3.67, P = 0.003) and Personal Interest scores (F(5,679) = 3.38, P = 0.005). There was no effect of the study year for Maintaining Norms scores. 3(rd) year medical students scored higher on Postconventional schema score than all other study years (p<0.001). There were no statistically significant differences among 3 cohorts of 2(nd) year medical students, demonstrating the absence of cohort or point-of-measurement effects. Longitudinal study of 3 cohorts demonstrated that students regressed from Postconventional to Maintaining Norms schema-based reasoning after entering the clinical part of the curriculum. INTERPRETATION: Our study demonstrated direct causative relationship between the regression in moral reasoning development and clinical teaching during medical curriculum. The reasons may include hierarchical organization of clinical practice, specific nature of moral dilemmas faced by medical students, and hidden medical curriculum

Targeting HIV-1 Env gp140 to LOX-1 Elicits Immune Responses in Rhesus Macaques.

Improved antigenicity against HIV-1 envelope (Env) protein is needed to elicit vaccine-induced protective immunity in humans. Here we describe the first tests in non-human primates (NHPs) of Env gp140 protein fused to a humanized anti-LOX-1 recombinant antibody for delivering Env directly to LOX-1-bearing antigen presenting cells, especially dendritic cells (DC). LOX-1, or 1ectin-like oxidized low-density lipoprotein (LDL) receptor-1, is expressed on various antigen presenting cells and endothelial cells, and is involved in promoting humoral immune responses. The anti-LOX-1 Env gp140 fusion protein was tested for priming immune responses and boosting responses in animals primed with replication competent NYVAC-KC Env gp140 vaccinia virus. Anti-LOX-1 Env gp140 vaccination elicited robust cellular and humoral responses when used for either priming or boosting immunity. Co-administration with Poly ICLC, a TLR3 agonist, was superior to GLA, a TLR4 agonist. Both CD4+ and CD8+ Env-specific T cell responses were elicited by anti-LOX-1 Env gp140, but in particular the CD4+ T cells were multifunctional and directed to multiple epitopes. Serum IgG and IgA antibody responses induced by anti-LOX-1 Env gp140 against various gp140 domains were cross-reactive across HIV-1 clades; however, the sera neutralized only HIV-1 bearing sequences most similar to the clade C 96ZM651 Env gp140 carried by the anti-LOX-1 vehicle. These data, as well as the safety of this protein vaccine, justify further exploration of this DC-targeting vaccine approach for protective immunity against HIV-1