Miracle-dz/UniFAR-FTUs huggingface dataset:
Genetic score omics regression and multi-trait meta-analysis detect widespread cis-regulatory effects shaping bovine complex traits

To complete the genome-to-phenome map, transcriptome-wide association studies (TWAS) are performed to correlate genetically predicted gene expression with observed phenotypic measurements. However, the relatively small training population assayed with gene expression could limit the accuracy of TWAS. We propose Genetic Score Omics Regression (GSOR) correlating observed gene expression with genetically predicted phenotype, i.e., genetic score. The score, calculated using variants near genes with assayed expression, provides a powerful association test between cis-effects on gene expression and the trait. In simulated and real data, GSOR outperforms TWAS in detecting causal/informative genes. Applying GSOR to transcriptomes of 16 tissue (N∼5000) and 37 traits in ∼120,000 cattle, multi-trait meta-analyses of omics-associations (MTAO) found that, on average, each significant gene expression and splicing mediates cis-genetic effects on 8∼10 traits. Supported by Mendelian Randomisation, MTAO prioritised genes/splicing show increased evolutionary constraints. Many newly discovered genes/splicing regions underlie previously thought single-gene loci to influence multiple traits.
Cortical Patterns Shift from Sequence Feature Separation during Planning to Integration during Motor Execution

Performing sequences of movements from memory and adapting them to changing task demands is a hallmark of skilled human behavior, from handwriting to playing a musical instrument. Prior studies showed a fine-grained tuning of cortical primary motor, premotor, and parietal regions to motor sequences: from the low-level specification of individual movements to high-level sequence features, such as sequence order and timing. However, it is not known how tuning in these regions unfolds dynamically across planning and execution. To address this, we trained 24 healthy right-handed human participants (14 females, 10 males) to produce four five-element finger press sequences with a particular finger order and timing structure in a delayed sequence production paradigm entirely from memory. Local cortical fMRI patterns during preparation and production phases were extracted from separate No-Go and Go trials, respectively, to tease out activity related to these perimovement phases. During sequence planning, premotor and parietal areas increased tuning to movement order or timing, regardless of their combinations. In contrast, patterns reflecting the unique integration of sequence features emerged in these regions during execution only, alongside timing-specific tuning in the ventral premotor, supplementary motor, and superior parietal areas. This was in line with the participants' behavioral transfer of trained timing, but not of order to new sequence feature combinations. Our findings suggest a general informational state shift from high-level feature separation to low-level feature integration within cortical regions for movement execution. Recompiling sequence features trial-by-trial during planning may enable flexible last-minute adjustment before movement initiation. SIGNIFICANCE STATEMENT Musicians and athletes can modify the timing and order of movements in a sequence trial-by-trial, allowing for a vast repertoire of flexible behaviors. How does the brain put together these high-level sequence features into an integrated whole? We found that, trial-by-trial, the control of sequence features undergoes a state shift from separation during planning to integration during execution across a network of motor-related cortical areas. These findings have implications for understanding the hierarchical control of skilled movement sequences, as well as how information in brain areas unfolds across planning and execution.
The fitness landscape of TEM-1 β-lactamase is stratified and inverted by sublethal concentrations of cefotaxime

Adaptive evolutionary processes are constrained by the availability of mutations which cause a fitness benefit – a concept that may be illustrated by ‘fitness landscapes’ which map the relationship of genotype space with fitness. Experimentally derived landscapes have demonstrated a predictability to evolution by identifying limited ‘mutational routes’ that evolution by natural selection may take between low and high-fitness genotypes. However, such studies often utilise indirect measures to determine fitness. We estimated the competitive fitness of each mutant relative to all of its single-mutation neighbours to describe the fitness landscape of three mutations in a β-lactamase enzyme at sub-lethal concentrations of the antibiotic cefotaxime in a structured and unstructured environment. We found that in the unstructured environment the antibiotic selected for higher-resistance types – but with an equivalent fitness for subsets of mutants, despite substantial variation in resistance – resulting in a stratified fitness landscape. In contrast, in a structured environment with low antibiotic concentration, antibiotic-susceptible genotypes had a relative fitness advantage, which was associated with antibiotic-induced filamentation. These results cast doubt that highly resistant genotypes have a unique selective advantage in environments with sub-inhibitory concentrations of antibiotics, and demonstrate that direct fitness measures are required for meaningful predictions of the accessibility of evolutionary routes. Importance The evolution of antibiotic resistant bacterial populations underpins the ongoing antibiotic-resistance crisis. We aim to understand how antibiotic-degrading enzymes can evolve to cause increased resistance, how this process is constrained and whether it can be predictable. To this end we performed competition experiments with a combinatorially-complete set of mutants of a β-lactamase gene subject to sub-inhibitory concentrations of the antibiotic cefotaxime. While some mutants confer their hosts with high resistance to cefotaxime, in competition these mutants do not always confer a selective advantage. Similarly, we identified conditions involving spatial structure where mutations causing high resistance result in a selective disadvantage. Together, this work suggests that the relationship between resistance level and fitness at sub-inhibitory concentrations is complex; predicting the evolution of antibiotic resistance requires knowledge of the conditions that select for resistant genotypes and the selective advantage evolved types have over their predecessors.
Morphological and sensorimotor phenotypes in a zebrafish CHARGE syndrome model are domain‐dependent

CHARGE syndrome is a rare disorder characterized by a spectrum of defects affecting multiple tissues and behavioral difficulties such as autism, attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, anxiety, and sensory deficits. Most CHARGE cases arise from de novo, loss-of-function mutations in a master transcriptional regulator, chromodomain-helicase-DNA-binding-protein-7 (CHD7). CHD7 regulates key neurodevelopmental factors and is required for neural processes including neuronal differentiation and neural crest cell migration, but how CHD7 affects neural circuit function to regulate behavior is unclear. To investigate the pathophysiology of behavioral symptoms in CHARGE, we established a mutant chd7 zebrafish line using CRISPR/Cas9 that recapitulates multiple CHARGE phenotypes. Using a panel of behavioral assays, we find that chd7 mutants have specific auditory and visually driven behavioral deficits that are independent of defects in sensory structures, implicating chd7 in the regulation of underlying brain circuits. Furthermore, by analyzing multiple chd7 alleles we show that the penetrance of morphological and behavioral phenotypes depends on the mutation location. These results provide novel insight into the heterogeneity of CHARGE syndrome and will inform future work to define mechanisms of CHD7-dependent neurobehavioral symptoms. Summary statement Mutation location within chd7 affects the expression of CHARGE Syndrome-related morphological and behavioral phenotypes in a larval zebrafish CHARGE model.
Hippocampal microstructure, but not macrostructure, mediates age differences in episodic memory

Separate unimodal magnetic resonance imaging (MRI) literatures have shown that hippocampal gray matter macrostructure (volume) and microstructure (diffusion) decline in aging and relate to episodic memory performance, with multimodal MRI studies reporting that episodic memory may be better explained by a combination of these metrics. However, these effects are often assessed independent of age or only within older adults and therefore do not address whether these distinct modalities mediate the effect of age on episodic memory. Here, we simultaneously examined the unique and joint contribution of hippocampal volume and diffusion to age-related differences in episodic memory in 83 younger and 61 older adults who underwent a T1-and diffusion-weighted MRI and completed the Rey Auditory Verbal Learning Test. As expected, older age was significantly related to smaller volume and higher diffusion (intracellular, dispersion, and free) in bilateral hippocampus and to worse episodic memory performance (immediate and delayed free recall, recognition). Structural equation modelling revealed that the age-memory relationship was significantly mediated by hippocampal diffusion, but not volume. A non-significant influential indirect effect further revealed that the structural metrics did not jointly mediate the age-memory relationship. Together, these findings indicate that hippocampal microstructure uniquely contributes to age-related differences in episodic memory and suggest that volume and diffusion capture distinct neurobiological properties of hippocampal gray matter.
Plan versus motion-referenced generalization of fast and slow processes in reach adaptation

Generalization in motor learning refers to the transfer of a learned compensation to other relevant contexts. The generalization function is typically assumed to be of Gaussian shape, centered on the planned motion, although more recent studies associate generalization with the actual motion. Because motor learning is thought to involve multiple adaptive processes with different time constants, we hypothesized that these processes have different time-dependent contributions to the generalization. Guided by a model-based approach, the objective of the present study was to experimentally examine these contributions. We first reformulated a validated two-state adaptation model as a combination of weighted motor primitives, each specified as a Gaussian-shaped tuning function. Adaptation in this model is achieved by updating individual weights of the primitives of the fast and slow adaptive process separately. Depending on whether updating occurred in a plan-referenced or a motion-referenced manner, the model predicted distinct contributions to the overall generalization by the slow and fast process. We tested 23 participants in a reach adaptation task, using a spontaneous recovery paradigm consisting of five successive blocks of a long adaptation phase to a viscous force field, a short adaptation phase with the opposite force, and an error-clamp phase. Generalization was assessed in eleven movement directions relative to the trained target direction. Results of our participant population fell within a continuum of evidence for plan-referenced to evidence for motion-referenced updating. This mixture may reflect the differential weighting of explicit and implicit compensation strategies among participants.
Familiarity of Background Music Modulates the Cortical Tracking of Target Speech at the “Cocktail Party”

The “cocktail party” problem – how a listener perceives speech in noisy environments – is typically studied using speech (multi-talker babble) or noise maskers. However, realistic cocktail party scenarios often include background music (e.g., coffee shops, concerts). Studies investigating music’s effects on concurrent speech perception have predominantly used highly controlled synthetic music or shaped noise which do not reflect naturalistic listening environments. Behaviorally, familiar background music and songs with vocals/lyrics inhibit concurrent speech recognition. Here, we investigated the neural bases of these effects. While recording multichannel EEG, participants listened to an audiobook while popular songs (or silence) played in the background at 0 dB signal-to-noise ratio. Songs were either familiar or unfamiliar to listeners and featured either vocals or isolated instrumentals from the original audio recordings. Comprehension questions probed task engagement. We used temporal response functions (TRFs) to isolate cortical tracking to the target speech envelope and analyzed neural responses around 100 ms (i.e., auditory N1 wave). We found that speech comprehension was, expectedly, impaired during background music(s) compared to silence. Target speech tracking was further hindered by the presence of vocals. When masked by familiar music, response latencies to speech were less susceptible to informational masking, suggesting concurrent neural tracking of speech was easier during music known to the listener. These differential effects of music familiarity were further exacerbated in listeners with less musical ability. Our neuroimaging results and their dependence on listening skills are consistent with early attentional gain mechanisms where familiar music is easier to tune out (listeners already know the song’s expectancies) and thus can allocate fewer attentional resources to the background music to better monitor concurrent speech material.
Computational model of the full-length TSH receptor

The receptor for thyroid stimulating hormone (TSHR), a GPCR, is of particular interest as the primary antigen in autoimmune hyperthyroidism (Graves’ disease) caused by stimulating TSHR antibodies. To date, only one domain of the extracellular region of the TSHR has been crystallized. We have now generated a model of the entire TSHR by merging the extracellular region of the receptor, obtained using artificial intelligence, with our recent homology model of the transmembrane domain, embedded it in a lipid membrane solvated it with water and counterions, and performed 1000ns Molecular Dynamic simulations on it. The simulations showed that the structure of the transmembrane and leucine-rich domains were remarkably constant while the linking region (LR), known more commonly as the “hinge region”, showed significant flexibility, forming several transient secondary structural elements. Furthermore, the relative orientation of the leucine-rich domain with the rest of the receptor was also seen to be variable. These data suggest that this linker region is an intrinsically disordered protein (IDP). Furthermore, preliminary data simulating the full TSHR model complexed with its ligand (TSH) showed that (a) there is a strong affinity between the linker region and TSH ligand and (b) the association of the linker region and the TSH ligand reduces the structural fluctuations in the linker region. This full-length model illustrates the importance of the linker region in responding to ligand binding and lays the foundation for studies of pathologic TSHR autoantibodies complexed with the TSHR to give further insight into their interaction with the flexible linker region.
Health professional student’s volunteering activities during the COVID-19 pandemic: A systematic literature review

Background The Coronavirus Disease 2019 (COVID-19) crisis has forced health and education services to use additional human resources, such as health professional students. Students in the health professions, particularly those in the medical field, can participate in a variety of voluntary activities, both directly and indirectly in health services. The aim of this review was to determine the affecting factors, types of activity, and benefits of undertaking a volunteering role by the health professional student. Methods A systematic review of health professional student volunteering during the COVID-19 pandemic was conducted using seven databases: Epistemonikos, ProQuest, Scopus, EBSCOhost, JSTOR, Cochrane Library, and PubMed. This literature search included published articles from March 2020 through to December 2021 using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines. Result We included 41 studies that met the selection criteria that assessed the factors and specific programs related to health profession students’ volunteering involvement during the COVID-19 pandemic era. The most frequently observed supporting factor of the eagerness to be a volunteer was the feeling of moral responsibility (such as social dedication, sense of duty, and care), potential learning opportunities, personal interest, and financial compensation. Factors that contributed to a person’s refusal to participate in a volunteer position were the fear of COVID-19 itself (such as transmission, risk of being infected, and personal identification as a risk group). Conclusion The review of available literature has shown that understanding the motivation and barriers to the willingness of health professional students to volunteer and the impact of volunteering activities on their future lives is a key for supporting them.
Assessing the Effect of Simultaneous Combining of Transcranial Direct Current Stimulation and Transcutaneous Auricular Vagus Nerve Stimulation on the Improvement of Working Memory Performance in Healthy Individuals

A previous study found that combining transcranial direct current stimulation (tDCS) and transcutaneous auricular vagus nerve stimulation (taVNS) could evoke significantly larger activation on a range of cortical and subcortical brain regions than the numerical summation of tDCS and taVNS effects. In this study, two within-subject experiments were employed to investigate its effects on working memory (WM). In experiment 1, the WM modulatory effects of tDCS over the left dorsolateral prefrontal cortex (DLPFC), taVNS, and simultaneous joint simulation of tDCS over the left DLPFC and taVNS (SJS-L) were compared among 60 healthy subjects. They received these three interventions between the baseline test and post-test in a random manner three times. In spatial 3-back task, there was a significant interaction between time and stimulations in the accuracy rate of matching trials (mACC, p=0.018). MACCs were significantly improved by SJS (p = 0.001) and taVNS (p = 0.045), but not by tDCS (p = 0.495). Moreover, 41 subjects in the SJS group showed improvement, which was significantly larger than that in the taVNS group (29 subjects) and tDCS group (26 subjects). To further investigate the generalization effects of SJS, 72 students were recruited in experiment 2. They received tDCS over the right DLPFC, taVNS, simultaneous joint simulation of tDCS over the right DLPFC and taVNS (SJS-R), and sham stimulation in a random manner four times. No significant results were found, but there was a tendency similar to experiment 1 in the spatial 3-back task. In conclusion, combining tDCS and taVNS might be a potential non-invasive neuromodulation technique which is worthy of study in future.
Factors Associated With HIV Testing Among MSM in Guilin, China: Results From a Cross-Sectional Study

Objectives: The objective of this study is to explore factors affecting the HIV testing behaviors among men who have sex with men (MSM) in China. Methods: A cross-sectional study was conducted in Guilin, China from April to June of 2021. Questionnaire data of 300 MSM were analyzed, and binary logistic regression models were used to examine the socio-demographic and sexual behavior characteristics associated with three HIV testing behaviors (self-testing, institutional testing, and regular testing). Results: The results showed that half of the respondents had the habit of regular HIV testing. Only 30.0% of MSM chose to do HIV testing after high-risk sexual behavior, and self-perceived luck was the main reason for not having HIV testing. Moreover, the influencing factors of three HIV testing behaviors after high-risk sexual behavior differ. Interestingly, income was not related to any of the three HIV testing behaviors among those MSM who participated. Conclusion: This research indicates insufficient health education on HIV testing behaviors among MSM in China. Health promotion practices targeting the MSM population to improve HIV-related knowledge, thus contributing to the HIV epidemic, are required.
A Comparison of Biophysical Conditions Between Sundanese Migrant and Non-Migrant Pekarangans in Indonesia

Pekarangan is a typical Indonesian home garden. This article aimed to look at biophysical conditions of pekarangan between Sundanese migrants and non-migrants. A total of 40 pekarangans in Selajambe and Ciomas Rahayu villages, West Java, were chosen as representative locations for the Sundanese non-migrant population (native Sundanese), and 40 pekarangans in Tegal Yoso and Tanjung Kesuma villages, Lampung, were chosen as representatives of the Sundanese migrant population. Research has been carried out in the period 2019–2021. To measure the biophysical conditions of pekarangans, we analyzed the pekarangan area, pekarangan size, number of species and individual of pekarangan plants, vertical diversity and horizontal diversity of plants, and the relationship between the pekarangan area and number of species and individual plants. The results showed that the difference in conditions of the pekarangan was indicated by the difference in the area and size but not by the diversity of the plants. Both types of pekarangans have the same level of diversity, as indicated by the number of individual plants that are almost the same in number per 100 m2. In addition, a strong and positive correlation (0.69–0.88) between the area of pekarangan and the number of individual plants indicated that the small to medium size or large pekarangan sizes had almost the same diversity of plants. The difference lied in the type of plant that is cultivated. Migrant pekarangans are dominant in cultivating food crops, while non-migrant pekarangans are dominant in cultivating ornamental plants. The selection of plants that have important and valuable functions can be a solution in maintaining the area of the pekarangan. Choosing plants with a variety of functions can be an option for a small to medium pekarangan size. To improve the biophysical conditions of the pekarangan was also inseparable from the involvement of economic, social, and cultural aspects in the pekarangan.