Miracle-dz/UniFAR-FTUs huggingface dataset:
Effects of Simulator Motion Feedback on Training of Skill-Based Control Behavior

This paper presents the results of a quasi-transfer-of-training experiment performed in the SIMONA Research Simulator at Delft University of Technology. The goal of the experiment was to quantify the effects of simulator motion feedback on the training of skill-based human operator control behavior using multimodal human operator modeling techniques. In the experiment, 24 task-naive participants, divided over two groups, were trained in performing a skill-based compensatory pitch tracking task. The first group was trained in a fixed-base setting and transferred to a moving-base condition; the second group trained with motion feedback and then transferred to the fixed-base condition. The group that received initial moving-base training showed quick adaptation of their control behavior upon transfer to the fixed-base setting and limited further learning. The group that trained in the fixed-base condition showed only limited transfer of their learned control strategy to the moving-base setting. After transfe.
QUANTIFICATION AND CLASSIFICATION OF MAGNETIC RESONANCE SPECTROSCOPY DATA AND APPLICATIONS TO BRAIN TUMOUR RECOGNITION

The medical diagnosis of brain tumours is one of the main applications of Magnetic Resonance. Magnetic Resonance consists of two main branches: Imaging and Spectroscopy. Magnetic Resonance Imaging is very well-known as the radiologic technique applied to produce high-quality images of tissues, such as the brain tissue, for diagnostic purposes. Magnetic Resonance Spectroscopy provides chemical information about all the molecules present in the brain, such as their concentrations. Both Imaging and Spectroscopy can be exploited for the grading and typing of brain tumours, also called the classification of brain tumours. As first topic, this thesis mainly studied the contribution of Spectroscopy for automated classification and the influence of several factors on the classification performance. It was found that a few preprocessing steps did not have a large impact on the classification results. This implies that several preprocessing steps can be ignored for diagnostic purposes and that acquisition schemes can be simplified. Furthermore, classification can be based on a restricted number of extracted parameters that cover the most characteristic information, which simplifies the computation and reduces the computation time. In addition, it was observed that spectroscopic and imaging parameters can provide complementary information for the typing of brain tumours. A second topic was the processing of experimental glycogen signals, which provides a better understanding of the biochemical processes involved in diseases such as diabetes. However, the spectral processing needs improvement. A common problem is that most methods assume the number of components present to be known exactly, but in practice this knowledge is lacking. Especially for so-called multi-exponential signals, in which different components occur at the same spectral frequency but with different linewidths. A framework was applied that determined the number of components for glycogen signals and that was able to confirm the presence of a multi-exponential pattern in glycogen signals.
Specific behaviors during auditory fear conditioning and postsynaptic expression of AMPA receptors in the basolateral amygdala predict interindividual differences in fear generalization in male rats

Auditory fear conditioning in rats is a widely used method to study learning, memory, and emotional responding. Despite procedural standardizations and optimizations, there is substantial interindividual variability in fear expression during test, notably in terms of fear expressed toward the testing context alone. To better understand which factors could explain this variation between subjects, we here explored whether behavior during training and expression of AMPA receptors (AMPARs) after long-term memory formation in the amygdala could predict freezing during test. We studied outbred male rats and found strong variation in fear generalization to a different context. Hierarchical clustering of these data identified two distinct groups of subjects that independently correlated with a specific pattern of behaviors expressed during initial training (i.e., rearing and freezing). The extent of fear generalization correlated positively with postsynaptic expression of GluA1-containing AMPA receptors in the basolateral nucleus of the amygdala. Our data thus identify candidate behavioral and molecular predictors of fear generalization that may inform our understanding of some anxiety-related disorders, such as posttraumatic stress disorder (PTSD), that are characterized by overgeneralized fear.
Elevated bile acids are associated with left ventricular structural changes in biliary atresia

Background: In children with biliary atresia (BA), pathologic structural changes within the heart, which define cirrhotic cardiomyopathy, are associated with adverse perioperative outcomes. Despite their clinical relevance, little is known about the pathogenesis and triggers of pathologic remodeling. Bile acid excess causes cardiomyopathy in experimental cirrhosis, but its role in BA is poorly understood. Methods: Echocardiographic parameters of left ventricular (LV) geometry [LV mass (LVM), LVM indexed to height, left atrial volume indexed to BSA (LAVI), and LV internal diameter (LVID)] were correlated with circulating serum bile acid concentrations in 40 children (52% female) with BA listed for transplantation. A receiver-operating characteristic curve was generated to determine optimal threshold values of bile acids to detect pathologic changes in LV geometry using Youden index. Paraffin-embedded human heart tissue was separately analyzed by immunohistochemistry for the presence of bile acid-sensing Takeda G-protein-coupled membrane receptor type 5. Results: In the cohort, 52% (21/40) of children had abnormal LV geometry; the optimal bile acid concentration to detect this abnormality with 70% sensitivity and 64% specificity was 152 µmol/L (C-statistics=0.68). Children with bile acid concentrations >152 µmol/L had ∼8-fold increased odds of detecting abnormalities in LVM, LVM index, left atrial volume index, and LV internal diameter. Serum bile acids positively correlated with LVM, LVM index, and LV internal diameter. Separately, Takeda G-protein-coupled membrane receptor type 5 protein was detected in myocardial vasculature and cardiomyocytes on immunohistochemistry. Conclusion: This association highlights the unique role of bile acids as one of the targetable potential triggers for myocardial structural changes in BA.
Population PK/PD model of tacrolimus for exploring the relationship between accumulated exposure and quantitative scores in myasthenia gravis patients

Tacrolimus is an important immunosuppressant used in the treatment of myasthenia gravis (MG). However, the population pharmacokinetic (PK) characteristics together with the exposure‐response of tacrolimus in the treatment of MG remain largely unknown. In this study, we aimed to develop a population PK/pharmacodynamic (PK/PD) model of tacrolimus in patients with MG, in order to explore the relationships among tacrolimus dose, exposure, and its therapeutic efficacy. The genotype of CYP3A5, Osserman's classification, and status of thymus, as well as demographic characteristics and other biomarkers from laboratory testing were tested as covariate, and simulations were performed based on the final model. The population PK model was described using a one‐compartment model with first‐order elimination and fixed absorption parameters. CYP3A5 genotype significantly influenced the apparent clearance, and total protein (TP) influenced the apparent volume of distribution as covariates. The quantitative MG scores were characterized by the cumulated area under curve of tacrolimus in a maximum effect function. Osserman's classification was a significant covariate on the initial score of patients with MG. The simulations demonstrated that tacrolimus showed an unsatisfying effect possibly due to insufficient exposure in some patients with MG. A starting dose of 2 mg/d and even higher dose for patients with CYP3A5 *1/*1 and *1/*3 and lower TP level were required for the rapid action of tacrolimus. The population PK/PD model quantitatively described the relationships among tacrolimus dose, exposure, and therapeutic efficacy in patients with MG, which could provide reference for the optimization of tacrolimus dosing regimen at the individual patient level.
Heterogeneous and anisotropic long-term concrete damage of the dez arch dam using thermal inverse analysis

Absract In this paper, an assumption used in the recent work of the author and his contributors considers the long-term concrete damage of the Dez arch dam as a homogeneous and isotropic process, was investigated in more detail and was adjusted. To this end, the vertical dam sections were divided into nine and six subsections along the thickness and height directions of the dam, respectively. In each subsection, a transversely isotropic damaged elastic constitutive law was considered for diagnostic analyses. Following the previous authors’ mentioned work, an optimization procedure (minimization of a certain error function) accompanied with an inverse thermal analysis was carried out. That analysis was performed within the framework of finite element (FE) method. Mentioned error function was defined as the sum of the squared residuals. Residuals were set as difference between nodal recorded displacements with inverse pendulums of the dam and the corresponding computed ones with the proposed model. Parameters considered as unknowns in the present inverse analysis, which have contributions in that above-mentioned error function, were the five independent elastic moduli presented in the formulation of the earlier mentioned transversely isotropic damaged elastic constitutive law: two Young’s moduli: one in the planes parallel to the up and down stream surfaces of the dam, called in-plane and the other in the perpendicular planes to those planes, named out-of-plane Young’s modulus; two Poisson’s ratios (in-plane and out-of-plane); and one shear modulus (out-of-plane). These parameters were identified performing numerous thermal inverse analyses. Obtained results revealed that the long-term damage of concrete of the Dez dam is a heterogeneous and anisotropic phenomenon because that the magnitude of the mentioned error function was obtained smaller than the corresponding value in the previous study which had been performed before based on the homogeneous and isotropic damage evolution assumption.
Comprehensive analysis reveals TSEN54 as a robust prognosis biomarker and promising immune-related therapeutic target for hepatocellular carcinoma

Background: Hepatocellular carcinoma represents the most common primary malignancy of all liver cancer types and its prognosis is usually unsatisfactory. TSEN54 encodes a protein constituting a subunit of the tRNA splicing endonuclease heterotetramer. Previous researches concentrated on the contribution of TSEN54 in pontocerebellar hypoplasia, but no studies have yet reported its role in HCC. Methods: TIMER, HCCDB, GEPIA, HPA, UALCAN, MEXPRESS, SMART, TargetScan, RNAinter, miRNet, starBase, Kaplan-Meier Plotter, cBioPortal, LinkedOmics, GSEA, TISCH, TISIDB, GeneMANIA, PDB, GSCALite were applied in this research. Results: We identified the upregulation of TSEN54 expression in HCC and related it to multiple clinicopathological features. Hypomethylation of TSEN54 was closely associated with its high expression. HCC sufferers who held high TSEN54 expression typically had shorter survival expectations. Enrichment analysis showed the involvement of TSEN54 in the cell cycle and metabolic processes. Afterward, we observed that TSEN54 expression level had a positive relationship to the infiltration level of multiple immune cells and the expression of several chemokines. We additionally identified that TSEN54 was related to the expression level of several immune checkpoints and TSEN54 was linked to several m6A-related regulators. Conclusions: TSEN54 is a prognostic marker of HCC. TSEN54 could become a prospective candidate for HCC diagnosis and therapy.
Comparing the emotional experiences of students in similar dissection‐ and prosection‐based medical gross anatomy courses: A mixed‐methods study

The anatomy laboratory can incite strong emotional reactions in students, which can in turn facilitate growth in empathy, care for vulnerable others, and professionalism. Despite this, little is known about the relative emotional impacts of different laboratory modalities. The response to the COVID‐19 pandemic created an opportunity to compare the emotional experiences of students in similar courses in which one group of students dissected donors and the other group learned from prosected donors. The courses were otherwise the same in content, length, instructional design, and assessment. Students in the dissection‐based (Fall 2019) and prosection‐based (Fall 2020) courses completed a previously validated survey that used quantitative and qualitative questions to assess their feelings about the donors and the anatomy laboratory experience. Students in both cohorts reported overall appreciation for having had the experience. Negative themes experienced by both groups included feeling anxiety, worries about depersonalizing donors, and physical discomfort in the laboratory. Students in the dissection course reported stronger connections with the donors and the donors' families but also more frequently felt negative feelings such as disgust, anxiety, and feeling alone. Students in the prosection course reported more consistently positive responses but worried about not using the donors to the fullest extent possible. Regardless of pedagogical design, students have complex emotional experiences in the anatomy laboratory and our results indicate that these feelings may be more intense in the context of dissection. Anatomists should foster educational settings that enable students to learn to process complex or challenging emotions.
Lack of Association between TWNK Rare Variants and Parkinson's Disease in a Chinese Cohort

Recently, six candidate monoallelic variants in twinkle mtDNA helicase (TWNK) were identified as potential disease causes for Parkinson’s disease (PD) in 263 patients of Italian ancestry. However, the presence of rare variants in patients was not enough to draw the conclusion that a novel gene is associated with the disease. Multiple replication studies were still necessary to establish the association. A subsequent study among 2943 patients with PD and 18,486 control subjects of European ancestry from the UK Biobank cohort and the Accelerating Medicines PartnershipParkinson’s Disease (AMP-PD) cohort debated the genetic role of TWNK rare variants in PD because of the appearance of TWNK rare variants in control subjects and no significant enrichment of TWNK rare variants in PD cases at the gene level. Therefore, the association between TWNK and PD still needs further clarification. Validations in independent cohorts from different ethnic backgrounds are truly essential and might provide additional insights. Moreover, we noted that in the six patients with PD with TWNK rare variants, four had early-onset PD (EOPD; age at onset, ≤45 years old), indicating rare variants of TWNK might be associated with EOPD. In this context, we explored the rare protein-coding variants of TWNK in a large Chinese PD cohort using whole-exome sequencing. In total, 1747 unrelated patients with PD were enrolled (mean age at onset SD, 47.92 12.24 years; males/ females, 892/855), including 897 patients with EOPD (mean age of onset SD, 38.51 6.74 years; males/females, 480/417) (Table S1). After filtering (see Supporting Information Methods), we identified 12 rare missense variants with minor allele frequency <0.01, among which 7 were detected only in the patients (Table S2). All the patients were negative for rare mutations in known PD causative genes. None of the TWNK rare variants reported in the original study were identified in our patients, suggesting genetic heterogeneity regarding TWNK variants in Chinese and European patients. Among the 16 patients with TWNK rare variants, 5 had EOPD (Table S3). No significant association was identified between these variants and PD with Fisher’s exact test (Table S4). Gene-level burden analysis using the optimized sequence kernel association test did not detect enrichment of rare variants or rare variants with high combined annotation-dependent depletion score (>20) in patients with PD, including patients with EOPD, compared with control subjects (Table 1). In summary, the current results do not support the genetic role of TWNK in PD. However, the results should be interpreted with caution because it is difficult to detect an association for rare variants in case–control designed studies with a small sample size. More robust independent replications with a larger sample size are still warranted.
PITAR, a DNA damage-inducible Cancer/Testis long noncoding RNA, inactivates p53 by binding and stabilizing TRIM28 mRNA

In tumors with WT p53, alternate mechanisms of p53 inactivation are reported. Here we have identified a long noncoding RNA, PITAR (p53 Inactivating TRIM28 associated RNA), as an inhibitor of p53. PITAR is highly expressed in glioblastoma (GBM) and glioma stem-like cells (GSC). We found that TRIM28 mRNA, which encodes a p53-specific E3 ubiquitin ligase, is a direct target of PITAR. PITAR interaction with TRIM28 RNA stabilized TRIM28 mRNA, which resulted in increased TRIM28 protein levels, enhanced p53 ubiquitination, and attenuated DNA damage response. While PITAR silencing inhibited the growth of WT p53 containing GSCs in vitro and reduced glioma tumor growth in vivo, its overexpression enhanced the tumor growth and promoted resistance to Temozolomide. DNA damage also activated PITAR, in addition to p53, thus creating an incoherent feedforward loop. Thus, we establish an alternate way of p53 inactivation and propose PITAR, an oncogenic Cancer/testis lncRNA, as a potential therapeutic target.
Intracranial electroencephalography reveals effector-independent evidence accumulation dynamics in multiple human brain regions

Neural representations of perceptual decision formation that are abstracted from specific motor requirements have previously been identified in humans using non-invasive electrophysiology, however, it is currently unclear where these originate in the brain. Here, we capitalized on the high spatiotemporal precision of intracranial EEG to localize such abstract decision signals. Presurgical epilepsy patients judged the direction of random-dot stimuli and responded either with a speeded button press (N=23), or vocally, after a randomized delay (N=11). We found a widely distributed motor-independent network of regions where high-frequency activity exhibited key characteristics consistent with evidence accumulation, including a gradual build-up that was modulated by the strength of the sensory evidence, and an amplitude that predicted subjects’ choice accuracy and response time. Our findings offer a new view on the brain networks governing human decision making.
Motor-targeted spinal stimulation promotes concurrent rebalancing of pathologic nociceptive transmission in chronic spinal cord injury

Electrical stimulation of spinal networks below a spinal cord injury (SCI) is a promising approach to restore functions compromised by inadequate excitatory neural drive. The most translationally successful examples are paradigms intended to increase neural transmission in weakened yet spared motor pathways and spinal motor networks rendered dormant after being severed from their inputs by lesion. Less well understood is whether spinal stimulation is also capable of reducing neural transmission in pathways made pathologically overactive by SCI. Debilitating spasms, spasticity, and neuropathic pain are all common manifestations of hyperexcitable spinal responses to sensory feedback. But whereas spasms and spasticity can often be managed pharmacologically, SCI-related neuropathic pain is notoriously medically refractory. Interestingly, however, spinal stimulation is a clinically available option for ameliorating neuropathic pain arising from etiologies other than SCI, and it has traditionally been assumed to modulate sensorimotor networks overlapping with those engaged by spinal stimulation for motor rehabilitation. Thus, we reasoned that spinal stimulation intended to increase transmission in motor pathways may simultaneously reduce transmission in spinal pain pathways. Using a well-validated pre-clinical model of SCI that results in severe bilateral motor impairments and SCI-related neuropathic pain, we show that the responsiveness of neurons integral to the development and persistence of the neuropathic pain state can be enduringly reduced by motor-targeted spinal stimulation while preserving spinal responses to non-pain-related sensory feedback. These results suggest that spinal stimulation paradigms could be intentionally designed to afford multi-modal therapeutic benefits, directly addressing the diverse, intersectional rehabilitation goals of people living with SCI.
Enhanced nonenzymatic RNA copying with in-situ activation of short oligonucleotides

The nonenzymatic copying of RNA is thought to have been necessary for the transition between prebiotic chemistry and ribozyme-catalyzed RNA replication in the RNA World. We have previously shown that a potentially prebiotic nucleotide activation pathway based on phospho-Passerini chemistry can lead to the efficient synthesis of 2-aminoimidazole activated mononucleotides when carried out under freeze-thaw cycling conditions. Such activated nucleotides react with each other to form 5′-5′ 2-aminoimidazolium bridged dinucleotides, enabling template-directed primer extension to occur within the same reaction mixture. However, mononucleotides linked to oligonucleotides by a 5′-5′ 2-aminoimidazolium bridge are superior substrates for nonenzymatic primer extension, due to their higher intrinsic reactivity and their higher template affinity. Here we show that eutectic phase phospho-Passerini chemistry efficiently activates short oligonucleotides and promotes the formation of monomer-bridged-oligonucleotide species during freeze-thaw cycles. We then demonstrate that in-situ generated monomer-bridged-oligonucleotides lead to efficient nonenzymatic template copying in the same reaction mixture. Our findings pave the way for future research into the activation of complex mixtures of mono- and oligonucleotides for the enhanced copying and potentially the replication of arbitrary RNA sequences.