Phase separation of intrinsically disordered proteins (IDPs) commonly underlies the formation of membraneless organelles, which compartmentalize molecules intracellularly in the absence of a lipid ...membrane. Identifying the protein sequence features responsible for IDP phase separation is critical for understanding physiological roles and pathological consequences of biomolecular condensation, as well as for harnessing phase separation for applications in bioinspired materials design. To expand our knowledge of sequence determinants of IDP phase separation, we characterized variants of the intrinsically disordered RGG domain from LAF-1, a model protein involved in phase separation and a key component of P granules. Based on a predictive coarse-grained IDP model, we identified a region of the RGG domain that has high contact probability and is highly conserved between species; deletion of this region significantly disrupts phase separation in vitro and in vivo. We determined the effects of charge patterning on phase behavior through sequence shuffling. We designed sequences with significantly increased phase separation propensity by shuffling the wild-type sequence, which contains well-mixed charged residues, to increase charge segregation. This result indicates the natural sequence is under negative selection to moderate this mode of interaction. We measured the contributions of tyrosine and arginine residues to phase separation experimentally through mutagenesis studies and computationally through direct interrogation of different modes of interaction using all-atom simulations. Finally, we show that despite these sequence perturbations, the RGG-derived condensates remain liquid-like. Together, these studies advance our fundamental understanding of key biophysical principles and sequence features important to phase separation.
This study constitutes an investigation into the acoustic variability of intervocalic alveolar taps in a corpus of spontaneous speech from Madrid, Spain. Substantial variability was documented in ...this segment, with highly reduced variants constituting roughly half of all tokens during spectrographic inspection. In addition to qualitative documentation, the intensity difference between the tap and surrounding vowels was measured. Changes in this intensity difference were statistically modeled using Bayesian finite mixture models containing lexical and phonetic predictors. Model comparisons indicate predictive performance is improved when we assume two latent categories, interpreted as two pronunciation variants for the Spanish tap. In interpreting the model, predictors were more often related to categorical changes in which pronunciation variant was produced than to gradient intensity changes within each tap type. Variability in tap production was found according to lexical frequency, speech rate, and phonetic environment. These results underscore the importance of evaluating model fit to the data as well as what researchers modeling phonetic variability can gain in moving past linear models when they do not adequately fit the observed data.
The REWIND trial demonstrated cardiovascular (CV) benefits to patients with type 2 diabetes and multiple CV risk factors or established CV disease. This exploratory analysis evaluated the degree to ...which the effect of dulaglutide on CV risk factors could statistically account for its effects on major adverse cardiovascular events (MACE) in the REWIND trial.
Potential mediators of established CV risk factors that were significantly reduced by dulaglutide were assessed in a post hoc analysis using repeated measures mixed models and included glycated hemoglobin (HbA1c), body weight, waist-to-hip ratio, systolic blood pressure, low-density lipoprotein (LDL), and urine albumin/creatinine ratio (UACR). These factors, for which the change in level during follow-up was significantly associated with incident MACE, were identified using Cox regression modeling. Each identified variable was then included as a covariate in the Cox model assessing the effect of dulaglutide on MACE to estimate the degree to which the hazard ratio of dulaglutide vs placebo was attenuated. The combined effect of the variables associated with attenuation was assessed by including all variables in an additional Cox model.
Although all evaluated variables were significantly improved by treatment, only changes in HbA1c and UACR were associated with MACE and a reduction in the effect of dulaglutide on this outcome was observed. The observed hazard ratio for MACE for dulaglutide vs placebo reduced by 36.1% by the updated mean HbA1c, and by 28.5% by the updated mean UACR. A similar pattern was observed for change from baseline in HbA1c and UACR and a reduction of 16.7% and 25.4%, respectively in the hazard ratio for MACE with dulaglutide vs placebo was observed. When HbA1c and UACR were both included, the observed hazard ratio reduced by 65.4% for the updated mean and 41.7% for the change from baseline with no HbA1c-UACR interaction (P interaction = 0.75 and 0.15, respectively).
Treatment-induced improvement in HbA1c and UACR, but not changes in weight, systolic blood pressure, or LDL cholesterol, appear to partly mediate the beneficial effects of dulaglutide on MACE outcomes. These observations suggest that the proven effects of dulaglutide on cardiovascular disease benefit are partially related to changes in glycemic control and albuminuria, with residual unexplained benefit. Clinicaltrials.gov; Trial registration number: NCT01394952. URL: https://clinicaltrials.gov/ct2/show/NCT01394952.
Using phonological neighborhood density has been a common method to quantify lexical competition. It is useful and convenient but has shortcomings that are worth reconsidering. The present study ...quantifies the effects of lexical competition during spoken word recognition using acoustic distance and acoustic absement rather than phonological neighborhood density. The indication of a word's lexical competition is given by what is termed to be its acoustic distinctiveness, which is taken as its average acoustic absement to all words in the lexicon. A variety of acoustic representations for items in the lexicon are analyzed. Statistical modeling shows that acoustic distinctiveness has a similar effect trend as that of phonological neighborhood density. Additionally, acoustic distinctiveness consistently increases model fitness more than phonological neighborhood density regardless of which kind of acoustic representation is used. However, acoustic distinctiveness does not seem to explain all of the same things as phonological neighborhood density. The different areas that these two predictors explain are discussed in addition to the potential theoretical implications of the usefulness of acoustic distinctiveness in the models. The present paper concludes with some reasons why a researcher may want to use acoustic distinctiveness over phonological neighborhood density in future experiments.
The breadth and complexity of natural behaviors inspires awe. Understanding how our perceptions, actions, and internal thoughts arise from evolved circuits in the brain has motivated neuroscientists ...for generations. Researchers have traditionally approached this question by focusing on stereotyped behaviors, either natural or trained, in a limited number of model species. This approach has allowed for the isolation and systematic study of specific brain operations, which has greatly advanced our understanding of the circuits involved. At the same time, the emphasis on experimental reductionism has left most aspects of the natural behaviors that have shaped the evolution of the brain largely unexplored. However, emerging technologies and analytical tools make it possible to comprehensively link natural behaviors to neural activity across a broad range of ethological contexts and timescales, heralding new modes of neuroscience focused on natural behaviors. Here we describe a three-part roadmap that aims to leverage the wealth of behaviors in their naturally occurring distributions, linking their variance with that of underlying neural processes to understand how the brain is able to successfully navigate the everyday challenges of animals’ social and ecological landscapes. To achieve this aim, experimenters must harness one challenge faced by all neurobiological systems, namely variability, in order to gain new insights into the language of the brain.
Miller et al. argue that natural behavior can serve as a powerful lens into the full range of computations that brains perform by leveraging the dynamic covariance between behavior and neural activity.
The Massive Auditory Lexical Decision (MALD) database is an end-to-end, freely available auditory and production data set for speech and psycholinguistic research, providing time-aligned stimulus ...recordings for 26,793 words and 9592 pseudowords, and response data for 227,179 auditory lexical decisions from 231 unique monolingual English listeners. In addition to the experimental data, we provide many precompiled listener- and item-level descriptor variables. This data set makes it easy to explore responses, build and test theories, and compare a wide range of models. We present summary statistics and analyses.
While known to influence visual lexical processing, the semantic information we associate with words has recently been found to influence auditory lexical processing as well. The present work ...explored the influence of semantic richness in auditory lexical decision. Study 1 recreated an experiment investigating semantic richness effects in concrete nouns (Goh et al., 2016). In Study 2, we expanded the stimulus set from 442 to 8,626 items, exploring the robustness of effects observed in Study 1 against a larger data set with increased diversity in both word class and other characteristics of interest. We also utilized generalized additive mixed models to investigate potential nonlinear effects. Results indicate that semantic richness effects become more nuanced and detectable when a wider set of items belonging to different parts of speech is examined. Findings are discussed in the context of models of spoken word recognition.
To evaluate the technical feasibility and clinical efficacy of osteoid osteoma (OO) cryoablation in a large, pediatric/adolescent cohort.
An electronic medical record and imaging archive review was ...performed to identify all cryoablations performed for OOs between 2011 and 2015 at a single tertiary care pediatric hospital. The subsequent analysis included 29 patients with suspected OOs treated by cryoablation (age range, 3-18 y; mean age, 11.3 y; 17 boys; 12 girls). Conventional CT guidance was used in 22 procedures; cone-beam CT guidance was used in 7 procedures. Follow-up data were obtained via a standardized telephone questionnaire (23/29 patients; 79.3%) and clinical notes (5/29 patients; 17.2%). One patient was lost to follow-up.
Technical success was achieved in 100% of patients (29/29). Immediate clinical success (cessation of pain and nonsteroidal antiinflammatory drug NSAID use within 1 mo after the procedure) was achieved in 27/28 patients (96.4%). Short-term clinical success (cessation of pain and NSAID use for > 3 mo after the procedure) was achieved in 24/25 patients (96%). Long-term clinical success (cessation of pain and NSAID use for > 12 mo after the procedure) was achieved in 19/21 patients (90.5%). Median pain scale score before the procedure was 10 (range, 5-10); median pain scale score after the procedure was 0 (range, 0-8; P < .0001). There were 6 minor complications (21%) and no major complications.
Image-guided cryoablation is a technically feasible, clinically efficacious therapeutic option for children and adolescents with symptomatic OO.
The recognition of spoken pseudowords Kelley, Matthew C.; Tucker, Benjamin V.
Language, cognition and neuroscience,
10/2022, Letnik:
37, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Pseudowords are used as stimuli in many psycholinguistic experiments, yet they remain largely under-researched. To better understand the cognitive processing of pseudowords, we analysed the ...pseudoword responses in the Massive Auditory Lexical Decision megastudy data set. Linguistic characteristics that influence the processing of real English words - namely, phonotactic probability, phonological neighbourhood density, uniqueness point, and morphological complexity - were also found to influence the processing time of spoken pseudowords. Subsequently, we analysed how the linguistic characteristics of non-unique portions of pseudowords influenced processing time. We again found that the named linguistic characteristics affected processing time, highlighting the dynamicity of activation and competition. We argue these findings also speak to learning new words and spoken word recognition generally. We then discuss what aspects of pseudoword recognition a full model of spoken word recognition must account for. We finish with a re-description of the auditory lexical decision task in light of our results.
People with chronic ankle instability (CAI) exhibit less weight-bearing dorsiflexion range of motion (ROM) and less knee flexion during landing than people with stable ankles. Examining the ...relationship between dorsiflexion ROM and landing biomechanics may identify a modifiable factor associated with altered kinematics and kinetics during landing tasks.
To examine the relationship between weight-bearing dorsiflexion ROM and single-legged landing biomechanics in persons with CAI.
Cross-sectional study.
Laboratory.
Fifteen physically active persons with CAI (5 men, 10 women; age = 21.9 ± 2.1 years, height = 168.7 ± 9.0 cm, mass = 69.4 ± 13.3 kg) participated.
Participants performed dorsiflexion ROM and single-legged landings from a 40-cm height. Sagittal-plane kinematics of the lower extremity and ground reaction forces (GRFs) were captured during landing.
Static dorsiflexion was measured using the weight-bearing-lunge test. Kinematics of the ankle, knee, and hip were observed at initial contact, maximum angle, and sagittal displacement. Sagittal displacements of the ankle, knee, and hip were summed to examine overall sagittal displacement. Kinetic variables were maximum posterior and vertical GRFs normalized to body weight. We used Pearson product moment correlations to evaluate the relationships between dorsiflexion ROM and landing biomechanics. Correlations (r) were interpreted as weak (0.00-0.40), moderate (0.41-0.69), or strong (0.70-1.00). The coefficient of determination (r(2)) was used to determine the amount of explained variance among variables.
Static dorsiflexion ROM was moderately correlated with maximum dorsiflexion (r = 0.49, r(2) = 0.24), ankle displacement (r = 0.47, r(2) = 0.22), and total displacement (r = 0.67, r(2) = 0.45) during landing. Dorsiflexion ROM measured statically and during landing demonstrated moderate to strong correlations with maximum knee (r = 0.69-0.74, r(2) = 0.47-0.55) and hip (r = 0.50-0.64, r(2) = 0.25-0.40) flexion, hip (r = 0.53-0.55, r(2) = 0.28-0.30) and knee (r = 0.53-0.70, r(2) = 0.28-0.49) displacement, and vertical GRF (-0.47- -0.50, r(2) = 0.22-0.25).
Dorsiflexion ROM was moderately to strongly related to sagittal-plane kinematics and maximum vertical GRF during single-legged landing in persons with CAI. Persons with less dorsiflexion ROM demonstrated a more erect landing posture and greater GRF.
PDF
