Miracle-dz/UniFAR-FTUs huggingface dataset:
Exploring the Activation Mechanism of the mGlu5 Transmembrane Domain

As a class C GPCR and regulator of synaptic activity, mGlu5 is an attractive drug target, potentially offering treatment for several neurologic and psychiatric disorders. As little is known about the activation mechanism of mGlu5 at a structural level, potential of mean force calculations linked to molecular dynamics simulations were performed on the mGlu5 transmembrane domain crystal structure to explore various internal mechanisms responsible for its activation. Our results suggest that the hydrophilic interactions between intracellular loop 1 and the intracellular side of TM6 have to be disrupted to reach a theoretically active-like conformation. In addition, interactions between residues that are key for mGlu5 activation (Tyr6593.44 and Ile7515.51) and mGlu5 inactivation (Tyr6593.44 and Ser8097.39) have been identified. Inasmuch as mGlu5 receptor signaling is poorly understood, potentially showing a complex network of micro-switches and subtle structure-activity relationships, the present study represents a step forward in the understanding of mGlu5 transmembrane domain activation.
Effects of Ethanol Exposure During Adolescence or Adulthood on Locomotor Sensitization and Dopamine Levels in the Reward System

Behavioral sensitization is a process of neuroadaptation characterized by a gradual increase in motor behaviors. The major neural substrates involved in the behavioral sensitization lie on the dopaminergic mesocorticolimbic pathway, which is still under development during adolescence. To investigate age-differences in ethanol behavioral sensitization and dopamine levels in distinct brain regions of the reward system, adolescent and adult mice were repeatedly pretreated with saline or ethanol (2.0 g/kg i.p.) during 15 consecutive days and challenged with saline or ethanol 5 days after pretreatment. Dopamine and its metabolites were measured in tissue samples of the prefrontal cortex (PFC), nucleus accumbens (NAc) and striatum by HPLC analysis. While repeated ethanol administration resulted in the development of locomotor sensitization in both adult and adolescent mice, only the adults expressed sensitization to a subsequent ethanol challenge injection. Neurochemical results showed reduced dopamine levels in adolescents compared to adults. Specifically, mice pretreated with ethanol during adolescence displayed lower dopamine levels in the PFC compared to the respective adult group in response to an ethanol challenge injection, and preadolescent mice exhibited lower dopamine levels in the NAc following an acute ethanol treatment compared to adults. These findings suggest that adolescent mice are not only less sensitive to the expression of ethanol-induced sensitization than adults, but also show lower dopamine content after ethanol exposition in the PFC and NAc.
The Effect of Probabilistic Context on Implicit Temporal Expectations in Down Syndrome

One of the most important sources of predictability that human beings can exploit to create an internal representation of the external environment is the ability to implicitly build up subjective statistics of events’ temporal structure and, consequently, use this knowledge to prepare for future actions. Stimulus expectancy can be subjectively shaped by hierarchically nested sources of prediction, capitalizing on either local or global probabilistic rules. In order to better understand the nature of local-global proactive motor control in Down Syndrome, in the present study a group of participants with Down Syndrome (DS group; n = 28; mean age 29.5 ± 13 years; range 10–54) and a group of typically developing participants matched by either gender or mental age (TD-MA group; n = 28; 5.6 ± 1 years; range 4–8) were administered a novel motor preparation task, defined as the Dynamic Temporal Prediction (DTP) task. In the DTP, the temporal preparation to imperative stimuli is implicitly shaped by the local increase of expectancy. This is manipulated trial-by-trial as a function of the preparatory foreperiod interval (Stimulus-Onset Asynchrony or SOA). In addition, temporal preparation can be also implicitly adjusted as a function of global predictive context, so that a block-wise SOA-distribution bias toward a given preparatory interval might determine a high-order source of expectancy, with functional consequences on proactive motor control adjustment. Results showed that in both groups motor preparation was biased by temporal expectancy when this was locally manipulated within-trials. By contrast, only the TD-MA group was sensitive to global rule changes: only in this cohort was behavioral performance overall impacted by the SOA probabilistic distribution manipulated between-blocks. The evidence of a local-global dissociation in DS suggests that the use of flexible cognitive mechanisms to implicitly extract high-order probabilistic rules in order to build-up an internal model of the temporal properties of events is disrupted in this developmental disorder. Moreover, since the content of the information to be processed in the DTP task was neither verbal nor spatial, we suggest that atypical global processing in Down Syndrome is a domain-general rather than specific aspect characterizing the cognitive profile of this population.
A Neurovisceral Integrative Study on Cognition, Heart Rate Variability, and Fitness in the Elderly

The association between physical fitness and cognitive performance has been widely investigated in the literature. However, the neurophysiological mechanisms underlying this relationship are not yet clear. Here, we aim to evaluate the interactions between executive function measures, heart rate variability (HRV), and physical fitness in the context of the neurovisceral integration (NVI) theory. Twenty-eight healthy elderly subjects (>60 years) were submitted to evaluation of executive performance with three computerized tests: the N-back test measured working memory capacity, the Stroop Color test evaluated inhibitory control and selective attention, and the Wisconsin Card Sorting Test (WCST) evaluated abstract reasoning and cognitive flexibility. We also used the Physical Testing Battery for the Elderly to measure aerobic capacity, dynamic balance, upper body flexibility, and handgrip strength. Our results confirm the relationship between executive function and physical fitness, particularly between working memory, cardiorespiratory fitness, and dynamic balance. We also demonstrate an association between executive performance and HRV in older people, corroborating previous results from other groups obtained in young adults. However, our regression models did not indicate that HRV mediates the relationship between cognition and physical fitness in the elderly, suggesting that age-related degeneration of autonomic control can affect aspects of NVI in this population.
Students’ Evaluation of Teaching and Their Academic Achievement in a Higher Education Institution of Ecuador

This paper addresses the relationship between student evaluation of teaching (SET) and academic achievement in higher education. Meta-analytic studies on teaching effectiveness show a wide range of results, ranging from small to medium correlations between SET and student achievement, based on diverse methodological approaches, sample size studies, and contexts. This work aimed to relate SET, prior academic achievement, and academic achievement in a large sample of higher education students and teachers, using different methodological procedures, which consider as distinct units of analysis the group class and the individuals, the variability between students within classes, and the variability between group-class means, simultaneously. The data analysis included the calculation of group-class means and its relationship with the group-class mean academic achievement, through correlation and hierarchical regression techniques; additionally, a multilevel path analysis was applied to the relationship between prior academic achievement, SET, and their academic achievement, considering the variability among group classes. A multisection analysis was also carried out in those course disciplines in which there was more than one class group (section). The results of individual and group-class analysis revealed that SET was moderately low but related to academic achievement in a significant way once the effect of previous academic achievement was controlled. In addition, multilevel path analysis revealed the effect of SET on achievement, both within and between group-class levels. The results of the analysis carried out in the course disciplines with different sections, according to a multisection design, yielded similar results to the individual and aggregated data analyses. Taken together, the results revealed that SET was low related to academic achievement, once the effect of previous academic achievement was controlled. From these results, it follows that the use of SET as a measure of teachers’ effectiveness for making administrative decisions remains controversial.
Employee–Organization Relationships and Team Performance: Role of Team Collective Efficacy

Besides the previous social relationship perspective of employee–organization relationship (EOR) research, this study takes the social cognitive perspective to explore the role of team collective efficacy in mediating the relationship between EORs and team performance. This study further contends that team cohesion moderates the positive relationship between collective efficacy and team performance, thereby moderating the indirect relationship between EORs and team performance through collective efficacy. Data analyses of 231 teams in Study 1 and 63 teams in Study 2 support the hypotheses. Therefore, this study provides theoretical contributions to the EOR literature by introducing a new perspective at the team level and to the social cognitive literature by discussing a boundary condition of the effect of collective efficacy on team performance.
Secretion and Delivery of Intestinal Pathogenic Escherichia coli Virulence Factors via Outer Membrane Vesicles

Outer membrane vesicles (OMVs) are nanoscale proteoliposomes secreted from the cell envelope of all Gram-negative bacteria. Originally considered as an artifact of the cell wall, OMVs are now recognized as a general secretion system, which serves to improve the fitness of bacteria and facilitate bacterial interactions in polymicrobial communities as well as interactions between the microbe and the host. In general, OMVs are released in increased amounts from pathogenic bacteria and have been found to harbor much of the contents of the parental bacterium. They mainly encompass components of the outer membrane and the periplasm including various virulence factors such as toxins, adhesins, and immunomodulatory molecules. Numerous studies have clearly shown that the delivery of toxins and other virulence factors via OMVs essentially influences their interactions with host cells. Here, we review the OMV-mediated intracellular deployment of toxins and other virulence factors with a special focus on intestinal pathogenic Escherichia coli. Especially, OMVs ubiquitously produced and secreted by enterohemorrhagic E. coli (EHEC) appear as a highly advanced mechanism for secretion and simultaneous, coordinated and direct delivery of bacterial virulence factors into host cells. OMV-associated virulence factors are not only stabilized by the association with OMVs, but can also often target previously unknown target structures and perform novel activities. The toxins are released by OMVs in their active forms and are transported via cell sorting processes to their specific cell compartments, where they can develop their detrimental effects. OMVs can be considered as bacterial “long distance weapons” that attack host tissues and help bacterial pathogens to establish the colonization of their biological niche(s), impair host cell function, and modulate the defense of the host. Thus, OMVs contribute significantly to the virulence of the pathogenic bacteria.
Influence of Strength, Power, and Muscular Stiffness on Stroke Velocity in Junior Tennis Players

Objective The main aim of this study was to establish the relationship between strength, power characteristics, individual muscle stiffness, international tennis number (ITN), and stroke velocity (StV) in junior tennis players. Methods Twenty one junior male tennis players (mean ± SD; age, 17.0 ± 0.8 years; height, 1.8 ± 0.1 m; body mass, 72.3 ± 5.8 kg; BMI 22.1 ± 1.5 kg/m2), with an ITN ranging from 2 to 4, performed measurements regarding muscle stiffness of selected muscles involved in tennis strokes. StV (serve, forehand, and backhand), strength (maximum isometric strength) and power (medicine ball throws, squat jump, countermovement jump, and bench press) measurements were also performed (ICC = 0.803–0.998; CV = 0.3–6.4). Results Moderate inverse correlations were found between serve velocity (SV) and ITN (r = −0.43; p = 0.05), and large positive correlations were observed between pectoralis majoris stiffness (PMStiff) (r = 0.53; p = 0.01), isometric wrist flexion (r = 0.58; p = 0.006) and ITN, respectively. PMStiff was moderately inversely correlated to forehand velocity (FV) (r = −0.45; p = 0.03) and gastrocnemius (GStiff) and infraspinatus stiffness (IStiff) positively to SV (r = 0.45; p = 0.04; r = 0.42; p = 0.05). No significant correlations were found regarding strength and power measurements. Conclusion Greater stiffness values may enhance StV, especially when transferring power from lower to upper body. On the other hand, high scores could interfere in technical parameters that are key for velocity production in complex tennis strokes. Strength and power values proved to correlate poorly to StV in this particular sample of junior tennis players, possibly due to the multifactorial nature of tennis strokes and the possibility that they become more important as age and level increase.
Immunogenicity and Immune Silence in Human Cancer

Despite recent advances in cancer immunotherapy, the process of immunoediting early in tumorigenesis remains obscure. Here, we employ a mathematical model that utilizes the Cancer Genome Atlas (TCGA) data to elucidate the contribution of individual mutations and HLA alleles to the immunoediting process. We find that common cancer mutations including BRAF-V600E and KRAS-G12D are predicted to bind none of the common HLA alleles, and are thus “immunogenically silent” in the human population. We identify regions of proteins that are not presented by HLA at a population scale, coinciding with frequently mutated hotspots in cancer, and other protein regions broadly presented across the population in which few mutations occur. We also find that 9/29 common HLA alleles contribute disproportionately to the immunoediting of early oncogenic mutations. These data provide insights into immune evasion of common driver mutations and a molecular basis for the association of particular HLA genotypes with cancer susceptibility.
UGT1A1 Variants c.864+5G>T and c.996+2_996+5del of a Crigler-Najjar Patient Induce Aberrant Splicing in Minigene Assays

A large fraction of DNA variants impairs pre-mRNA splicing in human hereditary disorders. Crigler-Najjar syndrome (CNS) is characterized by a severe unconjugated hyperbilirubinemia caused by variants in the UGT1A1 gene. We previously reported one CNS-type II patient with two splice-site variants in trans (c.864+5G>T and c.996+2_996+5del). According to MaxEntScan, both disrupt their corresponding donor sites (c.864+5G>T: 6.99 → 2.28; c.996+2_996+5del: 5.96 → −11.02), so they were selected for subsequent functional tests. Given the unavailability of patient RNA, we constructed an UGT1A1 splicing-reporter minigene with exons 1–4 to characterize the underlying splicing anomaly. The variant c.996+2_996+5del generated two aberrant transcripts, Δ(E2) (exon 2 skipping/64%) and ▼(E2q135) (intron retention of 135-nt/36%), which lead to the loss of 18 conserved amino-acids and the gain of 45 new ones of a critical functional domain, respectively. The c.864+5G>T variant mainly produced the aberrant transcript Δ(E1q141) (141-nt deletion/70.4%) and the full-length isoform (29.6%). Δ(E1q141) would provoke the loss of 47 amino-acids of the N-terminal domain that encodes for substrate specificity. Thus, the three anomalous transcripts are likely to inactivate UGT1A1. Moreover, this patient is also homozygous for the promoter variant A(TA)7TAA that decreases UGT1A1 expression by 70%, so the full-length transcript produced by c.864+5G>T would be even more reduced (<9%), thus supporting the diagnosis of CNS-type II. Therefore, minigenes represent valuable tools for the functional and clinical classifications of genetic variants.
Examining the Phenomenon of Quarter-Life Crisis Through Artificial Intelligence and the Language of Twitter

Quarter-life crisis (QLC) is a popular term for developmental crisis episodes that occur during early adulthood (18–30). Our aim was to explore what linguistic themes are associated with this phenomenon as discussed on social media. We analyzed 1.5 million tweets written by over 1,400 users from the United Kingdom and United States that referred to QLC, comparing their posts to those used by a control set of users who were matched by age, gender and period of activity. Logistic regression was used to uncover significant associations between words, topics, and sentiments of users and QLC, controlling for demographics. Users who refer to a QLC were found to post more about feeling mixed emotions, feeling stuck, wanting change, career, illness, school, and family. Their language tended to be focused on the future. Of 20 terms selected according to early adult crisis theory, 16 were mentioned by the QLC group more than the control group. The insights from this study could be used by clinicians and coaches to better understand the developmental challenges faced by young adults and how these are portrayed naturalistically in the language of social media.
Habitat Use Patterns and Identification of Essential Habitat for an Endangered Coastal Shark With Vertebrae Microchemistry: The Case Study of Carcharhinus porosus

Sharks are among the most endangered and data poor vertebrates in the world. The lack of information regarding their habitat use is especially concerning since these are crucial for the establishment of priority areas for species conservation. Investigating the trace elements present in shark vertebrae has become an interesting tool to analyze species habitat use over individuals’ lifetimes. Therefore, we applied vertebrae microchemistry to investigate habitat use of Carcharhinus porosus in Brazil’s Northern Coast (BNC). We also discuss methodological issues that must be addressed in the future to make microchemistry studies with elasmobranchs at low latitudes more robust. Vertebrae from seventeen individuals sampled in the 1980s (n = 8), and in 2017 and 2018 (n = 9) were evaluated through laser ablation inductively coupled plasma mass spectrometry. We analyzed five elements known to reflect environmental characteristics (Ba, Ca, Mg, Mn, and Sr) by sex, seasons, decades of capture, and life stages. Since Ca is the most abundant element in the vertebrae, we calculated element:Ca ratios and employed these proportions for all statistical analysis. We also used fisheries-independent catch data from the 1980s to test if the BNC is a nursery area for C. porosus. We found significant differences in element concentrations between sexes in both multi and single-element analysis, while decades differed only in the multi-element and Sr:Ca. Furthermore, seasons differed in both multi-element and Mg:Ca and Ba:Ca ratios. We did not find differences between life stages. Neonate multi-element signatures yielded three major groups, thus suggesting that the species has at least three birthing grounds in the area. Despite the occurrence of individuals of all sizes, adults show a more distinct occurrence pattern. Our results point toward the hypothesis that the BNC is an essential habitat for this species since its whole life cycle occurs in this area. Therefore, the BNC is a critical area for its conservation. We reinforce that future studies with strictly tropical species should investigate the effects of metabolism, the species’ growth rate, and the validation of other elements capable of demonstrating fine-scale changes in habitat to reduce the inherent noise in microchemistry studies.
Contra-Directional Expression of Plasma Superoxide Dismutase with Lipoprotein Cholesterol and High-Sensitivity C-reactive Protein as Important Markers of Parkinson’s Disease Severity

Aim: Oxidative stress and inflammation play critical roles in the neuropathogenesis of PD. We aimed to evaluate oxidative stress and inflammation status by measuring serum superoxide dismutase (SOD) with lipoprotein cholesterol and high-sensitivity C-reactive protein (hsCRP) respectively in PD patients, and explore their correlation with the disease severity. Methods: We performed a cross-sectional study that included 204 PD patients and 204 age-matched healthy controls (HCs). Plasma levels of SOD, hsCRP, total cholesterol, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were measured. A series of neuropsychological assessments were performed to rate the severity of PD. Results: The plasma levels of SOD (135.7 ± 20.14 vs. 147.2 ± 24.34, P < 0.0001), total cholesterol, HDL-C and LDL-C in PD were significantly lower than those in HCs; the hsCRP level was remarkably increased in PD compared to HC (2.766 ± 3.242 vs. 1.637 ± 1.597, P < 0.0001). The plasma SOD was negatively correlated with the hsCRP, while positively correlated with total cholesterol, HDL-C, and LDL-C in PD patients. The plasma SOD were negatively correlated with H&Y, total UPDRS, UPDRS (I), UPDRS (II), and UPDRS (III) scores, but positively correlated with MoCA and MMSE scores. Besides, hsCRP was negatively correlated with MoCA; while total cholesterol, HDL-C and LDL-C were positively correlated with the MoCA, respectively. Conclusion: Our findings suggest that lower SOD along with cholesterol, HDL-C and LDL-C, and higher hsCRP levels might be important markers to assess the PD severity. A better understanding of SOD and hsCRP may yield insights into the pathogenesis of PD.
Heterogeneous Indicators of Cognitive Performance and Performance Variability Across the Lifespan

Reaction time (RT) and RT variability are core components of cognitive performance that can be captured through brief and easy-to-administer tasks of simple RT and choice RT. The current study aims to describe age-related differences in cognitive performance, toward better characterizing normative performance across the lifespan. We examined mean and variability of response times on a simple RT and choice RT tasks in a large and diverse web-based sample (10,060 visitors to TestMyBrain.org). We also examined lifespan-related differences in response time variability using multiple different approaches (raw variability, mean scaled variability, and mean residualized variability). These analyses revealed significant heterogeneity in the patterns of age-related differences in performance, across metrics and within different estimates of the same metric. Based on segmented regression analysis, age of peak performance differed significantly across metrics, with young adults having the best performance based on measures of median RT, middle age adults at peak on certain measures of RT variability (standard deviation and coefficient of variability), and older adults showing the best performance based on accuracy and mean-corrected RT variability. Our results indicate that no single measure of cognitive performance and performance variability produces the same findings with respect to age related change, with further work needed to establish the validity of particular metrics for different applications.