Miracle-dz/UniFAR-FTUs huggingface dataset:
Robust Wnt signaling is maintained by a Wg protein gradient and Fz2 receptor activity in the developing Drosophila wing

ABSTRACT Wnts are secreted proteins that regulate cell fate during development of all metazoans. Wnt proteins were proposed to spread over several cells to activate signaling directly at a distance. In the Drosophila wing epithelium, an extracellular gradient of the Wnt1 homolog Wingless (Wg) was observed extending over several cells away from producing cells. Surprisingly, however, it was also shown that a membrane-tethered Neurotactin-Wg fusion protein (NRT-Wg) can largely replace endogenous Wg, leading to proper patterning of the wing. Therefore, the functional range of Wg and whether Wg spreading is required for correct tissue patterning remains controversial. Here, by capturing secreted Wg on cells away from the source, we show that Wg acts over a distance of up to 11 cell diameters to induce signaling. Furthermore, cells located outside the reach of extracellular Wg depend on the Frizzled2 receptor to maintain signaling. Frizzled2 expression is increased in the absence of Wg secretion and is required to maintain signaling and cell survival in NRT-wg wing discs. Together, these results provide insight into the mechanisms by which robust Wnt signaling is achieved in proliferating tissues. Highlighted Article: Measuring the direct range of action of the Wg gradient reveals that Wg morphogen signaling in the growing epithelia is regulated by both long-range gradient-dependent and gradient-independent mechanisms.
HIST1H1E heterozygous protein‐truncating variants cause a recognizable syndrome with intellectual disability and distinctive facial gestalt: A study to clarify the HIST1H1E syndrome phenotype in 30 individuals

Histone Gene Cluster 1 Member E, HIST1H1E, encodes Histone H1.4, is one of a family of epigenetic regulator genes, acts as a linker histone protein, and is responsible for higher order chromatin structure. HIST1H1E syndrome (also known as Rahman syndrome, OMIM #617537) is a recently described intellectual disability (ID) syndrome. Since the initial description of five unrelated individuals with three different heterozygous protein‐truncating variants (PTVs) in the HIST1H1E gene in 2017, we have recruited 30 patients, all with HIST1H1E PTVs that result in the same shift in frame and that cluster to a 94‐base pair region in the HIST1H1E carboxy terminal domain. The identification of 30 patients with HIST1H1E variants has allowed the clarification of the HIST1H1E syndrome phenotype. Major findings include an ID and a recognizable facial appearance. ID was reported in all patients and is most frequently of moderate severity. The facial gestalt consists of a high frontal hairline and full lower cheeks in early childhood and, in later childhood and adulthood, affected individuals have a strikingly high frontal hairline, frontal bossing, and deep‐set eyes. Other associated clinical features include hypothyroidism, abnormal dentition, behavioral issues, cryptorchidism, skeletal anomalies, and cardiac anomalies. Brain magnetic resonance imaging (MRI) is frequently abnormal with a slender corpus callosum a frequent finding.
Omega-3 polyunsaturated fatty acids impinge on CD4+ T cell motility and adipose tissue distribution via direct and lipid mediator-dependent effects.

AIMS Adaptive immunity contributes to the pathogenesis of cardiovascular metabolic disorders (CVMD). The omega-3 polyunsaturated fatty acids (n-3PUFA) are beneficial for cardiovascular health, with potential to improve the dysregulated adaptive immune responses associated with metabolic imbalance. We aimed to explore the mechanisms through which n-3PUFA may alter T cell motility and tissue distribution to promote a less inflammatory environment and improve lymphocyte function in CVMD. METHODS AND RESULTS Using mass spectrometry lipidomics, cellular, biochemical, and in vivo and ex vivo analyses, we investigated how eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the main n-3PUFA, modify the trafficking patterns of activated CD4+ T cells. In mice subjected to allogeneic immunization, a 3-week n-3PUFA-enriched diet reduced the number of effector memory CD4+ T cells found in adipose tissue, and changed the profiles of eicosanoids, octadecanoids, docosanoids, endocannabinoids, 2-monoacylglycerols, N-acyl ethanolamines and ceramides, in plasma, lymphoid organs and fat tissues. These bioactive lipids exhibited differing chemotactic properties when tested in chemotaxis assays with activated CD4+ T cells in vitro. Furthermore, CD4+ T cells treated with EPA and DHA showed a significant reduction in chemokinesis, as assessed by trans-endothelial migration assays, and, when implanted in recipient mice, demonstrated less efficient migration to the inflamed peritoneum. Finally, EPA and DHA treatments reduced the number of polarised CD4+ T cells in vitro, altered the phospholipid composition of membrane microdomains and decreased the activity of small Rho GTPases, Rhoα and Rac1 instrumental in cytoskeletal dynamics. CONCLUSIONS Our findings suggest that EPA and DHA affect the motility of CD4+ T cells and modify their ability to reach target tissues by interfering with the cytoskeletal rearrangements required for cell migration. This can explain, at least in part, the anti-inflammatory effects of n-3PUFA supporting their potential use in interventions aiming to address adipocyte low grade inflammation associated with cardiovascular metabolic disease.
Halogen and Hydrogen Bonding in Halogenabenzene/NH3 Complexes Compared Using Next-Generation QTAIM

Next-generation quantum theory of atoms in molecules (QTAIM) was used to investigate the competition between hydrogen bonding and halogen bonding for the recently proposed (Y = Br, I, At)/halogenabenzene/NH3 complex. Differences between using the SR-ZORA Hamiltonian and effective core potentials (ECPs) to account for relativistic effects with increased atomic mass demonstrated that next-generation QTAIM is a much more responsive tool than conventional QTAIM. Subtle details of the competition between halogen bonding and hydrogen bonding were observed, indicating a mixed chemical character shown in the 3-D paths constructed from the bond-path framework set B. In addition, the use of SR-ZORA reduced or entirely removed spurious features of B on the site of the halogen atoms.
Neural Pattern Similarity Differentially Relates to Memory Performance in Younger and Older Adults

Age-related memory decline is associated with changes in neural functioning, but little is known about how aging affects the quality of information representation in the brain. Whereas a long-standing hypothesis of the aging literature links cognitive impairments to less distinct neural representations in old age (“neural dedifferentiation”), memory studies have shown that overlapping neural representations of different studied items are beneficial for memory performance. In an electroencephalography (EEG) study, we addressed the question whether distinctiveness or similarity between patterns of neural activity supports memory differentially in younger and older adults. We analyzed between-item neural pattern similarity in 50 younger (19–27 years old) and 63 older (63–75 years old) male and female human adults who repeatedly studied and recalled scene–word associations using a mnemonic imagery strategy. We compared the similarity of spatiotemporal EEG frequency patterns during initial encoding in relation to subsequent recall performance. The within-person association between memory success and pattern similarity differed between age groups: For older adults, better memory performance was linked to higher similarity early in the encoding trials, whereas young adults benefited from lower similarity between earlier and later periods during encoding, which might reflect their better success in forming unique memorable mental images of the joint picture–word pairs. Our results advance the understanding of the representational properties that give rise to subsequent memory, as well as how these properties may change in the course of aging. SIGNIFICANCE STATEMENT Declining memory abilities are one of the most evident limitations for humans when growing older. Despite recent advances of our understanding of how the brain represents and stores information in distributed activation patterns, little is known about how the quality of information representation changes during aging and thus affects memory performance. We investigated how the similarity between neural representations relates to subsequent memory in younger and older adults. We present novel evidence that the interaction of pattern similarity and memory performance differs between age groups: Older adults benefited from higher similarity during early encoding, whereas young adults benefited from lower similarity between early and later encoding. These results provide insights into the nature of memory and age-related memory deficits.
Postoperative pain and comfort scores: Do they correlate?

Research on the nocebo effect has shown that some words can hurt. Pain is defined as ‘unpleasant’ and ‘associated with actual or potential tissue damage’. So, a sensation described as ‘pain’ may function as a negative suggestion or nocebo communication. This can lead to pain being experienced or exacerbated where it would not have been otherwise. The nocebo effect has also been implicated as adversely affecting the pain experience during the assessment of pain postoperatively. Words that avoid this potential nocebo effect such as ‘comfort’ may represent a more satisfactory alternative. We therefore aimed to determine whether ‘comfort’ and ‘pain’ scores correlate when assessing patients postoperatively at the same timepoint. Patients were questioned before routine post-anaesthesia rounds to rate their pain and comfort levels, with the sequence of questions randomised. Patients were asked to rate pain and comfort on a 0–10 verbal numerical rating scale, where 0 represents ‘no pain’ or ‘no comfort’ and 10 ‘worst pain’ or ‘most comfort’ imaginable, respectively. To provide a clinically relevant correlation of approximately 0.7 between pain and inverted comfort scores, a sample size of 100 would provide adequate precision (95% confidence interval (CI) 0.58–0.79). A P-value of <0.05 was considered significant. We recruited 100 patients. A positive correlation of 0.62 was found between pain and inverted comfort scores (95% CI 0.47–0.72; P<0.0001). The question sequence of asking about pain or comfort did not affect either score. Comfort and pain scores are moderately correlated. This finding represents a first step in validating comfort scores and suggests that they could be considered a suitable alternative to pain scores when assessing patients postoperatively. As comfort is not an exact antonym to pain, caution is required when using these measures interchangeably.
Does the beauty premium effect always exist? — an ERP study of the facial attractiveness stereotype in public’s attitudes toward in-Service Chinese civil servant

Abstract Objectives: Civil servants image is one of the most important representatives of government image. Therefore, it is of great significance to study the factors affecting the public’s attitudes toward in-service civil servants. The current study aims to learn whether female facial attractiveness would affect the male public’s attitudes toward in-service civil servants using event-related potentials. Methods: Participants were recruited to view attractive/unattractive faces followed by positive/negative adjectives. We observed that positive adjectives after unattractive faces elicited smaller N400 amplitudes than negative adjectives, and the N400 amplitude elicited by attractive faces after negative adjectives was significantly smaller than that elicited by unattractive faces. What’s more, we found that the voltage of N400 was negative correlated with reaction time. Results: It showed that the incongruity of physically appearance and in-service civil servant positions lead to longer reaction time. The unattractive civil servant is more congruent with positive adjectives than the attractive one in the public’s mind. Conclusion: We explain these findings from two aspects. First, the public is more rational for in-service civil servants, and factors that are unrelated to governing capacity, such as physical attractiveness, do not influence their attitudes. Second, civil servants are the position that requires technical ability to serve the public rather than communication ability, which was represented by physically attractive.
Graphical Nash Equilibria and Replicator Dynamics on Complex Networks

Pairwise-interaction graphical games have been widely used in the study and design of strategic interaction in multiagent systems. With regard to this issue, one entitative problem is actually to understand how the interaction structure of agents affects the strategy configuration of Nash equilibria. This paper intends to study the effect of interaction networks on Nash equilibria in pairwise-interaction graphical games. We first show that interaction networks may induce new strategy equilibria in pairwise-interaction graphical games and then provide graphical conditions for the existence of these network-induced equilibria. Furthermore, to determine Nash equilibria of pairwise-interaction graphical games, a graphical replicator dynamics model is formulated, and its connection with graphical games is established. In detail, it is shown that every Nash equilibrium of the graphical games corresponds to a fixed point of the graphical replicator dynamics and that every asymptotically stable fixed point of the graphical replicator dynamics corresponds to a strict pure Nash equilibrium of the graphical games. The obtained results are applied in understanding coordination in complex networks and determination of structural conflicts in signed graphs. This work may provide new insights into understanding and designing strategy equilibria and dynamics in games on networks.
Event-Related Potential Evidence of Implicit Metric Structure during Silent Reading

Under the Implicit Prosody Hypothesis, readers generate prosodic structures during silent reading that can direct their real-time interpretations of the text. In the current study, we investigated the processing of implicit meter by recording event-related potentials (ERPs) while participants read a series of 160 rhyming couplets, where the rhyme target was always a stress-alternating noun–verb homograph (e.g., permit, which is pronounced PERmit as a noun and perMIT as a verb). The target had a strong–weak or weak–strong stress pattern, which was either consistent or inconsistent with the stress expectation generated by the couplet. Inconsistent strong–weak targets elicited negativities between 80–155 ms and 325–375 ms relative to consistent strong–weak targets; inconsistent weak–strong targets elicited a positivity between 365–435 ms relative to consistent weak–strong targets. These results are largely consistent with effects of metric violations during listening, demonstrating that implicit prosodic representations are similar to explicit prosodic representations.
Prediction of Gait Freezing in Parkinsonian Patients: A Binary Classification Augmented With Time Series Prediction

This paper presents a novel technique to predict freezing of gait in advanced stage Parkinsonian patients using movement data from wearable sensors. A two-class approach is presented which consists of autoregressive predictive models to project the feature time series, followed by machine learning based classifiers to discriminate freezing from nonfreezing based on the predicted features. To implement and validate our technique a set of time domain and frequency domain features were extracted from the 3D acceleration data, which was then analyzed using information theoretic and feature selection approaches to determine the most discriminative features. Predictive models were trained to predict the features from their past values, then fed into binary classifiers based on support vector machines and probabilistic neural networks which were rigorously cross validated. We compared the results of this approach with a three-class classification approach proposed in previous literature, in which a pre-freezing class was introduced and the problem of prediction of the gait freezing incident was reduced to solving a three-class classification problem. The two-class approach resulted in a sensitivity of 93±4%, specificity of 91±6%, with an expected prediction horizon of 1.72 s. Our subject-specific gait freezing prediction algorithm outperformed existing algorithms, yields consistent results across different subjects and is robust against the choice of classifier, with slight variations in the selected features. In addition, we analyzed the merits and limitations of different families of features to predict gait freezing.
Ligand-Free Estrogen Receptor α (ESR1) as Master Regulator for the Expression of CYP3A4 and Other Cytochrome P450 Enzymes in the Human Liver

Cytochrome P450 3A4 isoform (CYP3A4) transcription is controlled by hepatic transcription factors (TFs), but how TFs dynamically interact remains uncertain. We hypothesize that several TFs form a regulatory network with nonlinear, dynamic, and hierarchical interactions. To resolve complex interactions, we have applied a computational approach for estimating Sobol’s sensitivity indices (SSI) under generalized linear models to existing liver RNA expression microarray data (GSE9588) and RNA-seq data from genotype-tissue expression (GTEx), generating robust importance ranking of TF effects and interactions. The SSI-based analysis identified TFs and interacting TF pairs, triplets, and quadruplets involved in CYP3A4 expression. In addition to known CYP3A4 TFs, estrogen receptor α (ESR1) emerges as key TF with the strongest main effect and as the most frequently included TF interacting partner. Model predictions were validated using small interfering RNA (siRNA)/short hairpin RNA (shRNA) gene knockdown and clustered regularly interspaced short palindromic repeats (CRISPR)–mediated transcriptional activation of ESR1 in biliary epithelial Huh7 cells and human hepatocytes in the absence of estrogen. Moreover, ESR1 and known CYP3A4 TFs mutually regulate each other. Detectable in both male and female hepatocytes without added estrogen, the results demonstrate a role for unliganded ESR1 in CYP3A4 expression consistent with unliganded ESR1 signaling reported in other cell types. Added estrogen further enhances ESR1 effects. We propose a hierarchical regulatory network for CYP3A4 expression directed by ESR1 through self-regulation, cross regulation, and TF-TF interactions. We also demonstrate that ESR1 regulates the expression of other P450 enzymes, suggesting broad influence of ESR1 on xenobiotics metabolism in human liver. Further studies are required to understand the mechanisms underlying role of ESR1 in P450 regulation. SIGNIFICANCE STATEMENT This study focuses on identifying key transcription factors and regulatory networks for CYP3A4, the main drug metabolizing enzymes in liver. We applied a new computational approach (Sobol’s sensitivity analysis) to existing hepatic gene expression data to determine the role of transcription factors in regulating CYP3A4 expression, and used molecular genetics methods (siRNA/shRNA gene knockdown and CRISPR-mediated transcriptional activation) to test these interactions in life cells. This approach reveals a robust network of TFs, including their putative interactions and the relative impact of each interaction. We find that ESR1 serves as a key transcription factor function in regulating CYP3A4, and it appears to be acting at least in part in a ligand-free fashion.
Specificity of MYB interactions relies on motifs in ordered and disordered contexts

Abstract Physical interactions between members of the MYB and bHLH transcription factor (TF) families regulate many important biological processes in plants. Not all reported MYB–bHLH interactions can be explained by the known binding sites in the R3 repeat of the MYB DNA-binding domain. Noteworthy, most of the sequence diversity of MYB TFs lies in their non-MYB regions, which contain orphan small subgroup-defining motifs not yet linked to molecular functions. Here, we identified the motif mediating interaction between MYB TFs from subgroup 12 and their bHLH partners. Unlike other known MYB–bHLH interactions, the motif locates to the centre of the predicted disordered non-MYB region. We characterised the core motif, which enabled accurate prediction of previously unknown bHLH-interacting MYB TFs in Arabidopsis thaliana, and we confirmed its functional importance in planta. Our results indicate a correlation between the MYB–bHLH interaction affinity and the phenotypic output controlled by the TF complex. The identification of an interaction motif outside R3 indicates that MYB–bHLH interactions must have arisen multiple times, independently and suggests many more motifs of functional relevance to be harvested from subgroup-specific studies.
The Voicemail Elicitation Task: Functional Workplace Language Assessment for Persons With Traumatic Brain Injury.

Purpose Politeness markers (PMs) are words that enhance cooperativity in dialogue and are an essential component of professional/work communication. Persons with moderate/severe traumatic brain injury (TBI) underuse PMs in connected speech and have employment stability issues. The voicemail elicitation task (VET) is a standardized computerized language sampling procedure measuring PM rate in role-play tasks. Our purpose is to provide preliminary data establishing the potential of a screening assessment tool for professional/work communication. Method We measured VET performance using spoken PMs per minute (PMpM). We present data from 63 persons. Forty-three participants with TBI (22-65 years old, ≥ 1-year postinjury) worked in midlevel jobs before their injury and attempted work return after injury at the same job level. Twenty participants with TBI did not maintain work > 1 year (unstably employed), and 23 did maintain work for ≥ 1 year (stably employed). Twenty controls without history of neurological impairment working at the same job level also completed the VET protocol. We analyzed the data using between-group comparison with 1-way analysis of variance and post hoc analysis. We used receiver operating characteristic curve analysis to calculate sensitivity and specificity, as well as an optimal cutoff value for a screening measure. Results Group differences, F(2, 60) = 19.59, p = . 0001, η2 = . 376, were identified between unstably employed persons with TBI performing with lower PMpM scores than the stably employed TBI group and the control group. Receiver operating characteristic curve analysis indicated a cutoff score of 11.55 PMpM. There was acceptable specificity (0.700, 95% CI [0.499, 0.901]) and sensitivity (0.696, 95% CI [0.508, 0.883]) for a screening tool indicating further assessment of social communication. Conclusion The VET holds promise as a clinical screening tool to identify persons at risk for social communication-related job instability after TBI and the need for a more comprehensive social communication assessment.