Miracle-dz/UniFAR-FTUs huggingface dataset:
Pain-related opioidergic and dopaminergic neurotransmission: Dual meta-Analyses of PET radioligand studies

Molecular mechanisms of the interaction between pain and reward associated with pain relief processes in the human brain are still incompletely understood. This is partially due to the invasive nature of the available techniques to visualize and measure metabolic activity. Positron Emission Tomography (PET) radioligand studies using radioactive substances are still the only available modality to date that allows for the investigation of the molecular mechanisms in the human brain. For pain and reward studies, the most commonly studied PET radiotracers are [11C]-carfentanil (CFN) and [11C]- or [18F]-diprenorphine (DPN), which bind to opioid receptors, and [11C]-raclopride (RAC) and [18F]-fallypride (FAL) tracers, which bind to dopamine receptors. The current meta-analysis looks at 15 pain-related studies using opioid radioligands and 8 studies using dopamine radioligands in an effort to consolidate the available data into the most likely activated regions. Our primary goal was to identify regions of shared opioid/dopamine neurotransmission during pain-related experiences. SDM analysis of previously published voxel coordinate data showed that opioidergic activations were strongest in the bilateral caudate, thalamus, right putamen, cingulate gyrus, midbrain, inferior frontal gyrus, and left superior temporal gyrus. The dopaminergic studies showed that the bilateral caudate, thalamus, right putamen, cingulate gyrus, and left putamen had the highest activations. We were able to see a clear overlap between opioid and dopamine activations in a majority of the regions during pain-related processing, though there were some unique areas of dopaminergic activation such as the left putamen. Regions unique to opioidergic activation include the midbrain, inferior frontal gyrus, and left superior temporal gyrus. By investigating the regions of dopaminergic and opioidergic activation, we can potentially provide more targeted treatment to these sets of receptors in patients with pain conditions. These findings could eventually assist in the development of more targeted medication in order to help treat pain conditions and simultaneously prevent physical dependency.
Slow rhythmic eye motion predicts periodic alternation of bistable perception

Bistable perception is characterized by periodic alternation between two different perceptual interpretations, the mechanism of which is poorly understood. Herein, we show that perceptual decisions in bistable perception are strongly correlated with slow rhythmic eye motion, the frequency of which varies across individuals. From eye gaze trajectory measurements during three types of bistable tasks, we found that each subject’s gaze position oscillates slowly(less than 1Hz), and that this frequency matches that of bistable perceptual alternation. Notably, the motion of the eye apparently moves in opposite directions before two opposite perceptual decisions, and this enables the prediction of the timing and direction of perceptual alternation from eye motion. We also found that the correlation between eye movement and a perceptual decision is maintained during variations of the alternation frequency by the intentional switching or retaining of perceived states. This result suggests that periodic bistable perception is phase-locked with rhythmic eye motion.
MITOTIC SLIPPAGE IN NONCANCER CELLS INDUCED BY A MICROTUBULE DISRUPTOR, DISORAZOLE C1, AND THE NOVEL ROLE FOR GPIBA IN CYTOKINESIS AND TETRAPLOIDIZATION IN CANCER CELLS

Disorazole C1 (DZ) is a synthesized polyene macrodiolide, originally identified as a minor metabolite from the myxobacterium fermentation broth. I examined the cellular responses to DZ in noncancer and cancer cells, and compared the results to vinblastine and taxol. In noncancer cells, DZ induced a prolonged mitotic arrest, followed by mitotic slippage, which was associated with cyclin B degradation, but did not require p53. Four apoptosis detection assays, including examination of poly(ADP-ribose) polymerase cleavage, cytochrome C release, mitochondrial depolarization, and annexin V staining, were conducted and demonstrated little induction of apoptosis in noncancer cells treated with DZ. However, I observed an activated apoptotic pathway in cancer cells, suggesting that normal and malignant cells respond differently to DZ, and indicating a potential therapeutic application for this compound.GpIba is a transmembrane subunit of the von Willebrand factor receptor on platelet surfaces, functioning in platelet adhesion and activation. Recent research has revealed that GpIba also plays roles in transformation and genomic instability as an oncoprotein. In my studies, GpIba colocalized with F-actin and filamin A, an actin-binding protein, at the cleavage furrow in anaphase cells, suggesting a novel role for GpIba in cytokinesis. However, when GpIba was overexpressed in noncancer cells with p53 knockdown, GpIba, F-actin, and filamin A became mislocalized. RhoA, a cytokinesis regulator, was localized asymmetrically, although Aurora B, an important cytokinesis kinase, retained its correct localization. Additionally, anaphase bridges were observed in these GpIba-overexpressing cells, along with elevated percentages of cytokinesis failure and binucleation, indicating that GpIba overexpression led to cytokinesis defects/failure and tetraploidization. Conversely, in cancer cells that endogenously overexpress GpIba, I observed decreases in the percentages of binucleation and mitotic defects upon GpIba knockdown. Furthermore, down-regulation of Aurora B was demonstrated to mediate the mechanism through which GpIba overexpression led to cytokinesis failure, and the filamin A-binding domain and the signal peptide of GpIba were shown to be indispensible for this mechanism. These results add a new component of the existing cancer cell genetic instability pathways, by suggesting that overexpression of GpIba in cancer cells disrupts normal cytokinesis and causes tetraploidization through down-regulation of Aurora B.
Dorsal Anterior Cingulate Cortex Encodes the Subjective Motivational Value of Cognitive Task Performance

Humans can seamlessly combine value signals from diverse motivational incentives, yet it is not well-understood how these signals are “bundled” in the brain to modulate cognitive control. The dorsal anterior cingulate cortex (dACC) is theorized to integrate motivational value dimensions in the service of goal-directed action, though this hypothesis has yet to receive rigorous confirmation. Here, we examine the role of dACC in motivational integration using an experimental paradigm that quantifies combined effects of liquid (e.g., juice, neutral, saltwater) and monetary incentives on cognitive task performance. These incentives modulated dACC activity in both a trial-by-trial and block-wise fashion. Incentive-related dACC modulation predicted fluctuations in cognitive performance and self-report motivation ratings. Statistical mediation analyses indicate that dACC encodes incentives in terms of subjective motivational value, and that this value signal is associated with task performance. These results suggest dACC integrates motivational signals to compute the expected value of goal-directed cognitive control.
Life history covariation in intestinal nematodes of mammals

Using data on 66 species from 18 families and 6 orders, we examine patterns of interspecific covariation in female size, egg size, time from infection to production of infective stages (prepatency period), duration of reproduction (patency period), and fecundity in mammalian intestinal nematodes. Nematode species with shorter prepatency periods are smaller, have lower rates of somatic growth, lower fecundity and shorter reproductive periods; those with longer prepatency periods have the opposite suite of characters. These patterns are very different from that found in interspecific analyses of life history variation in other taxa. This may be a consequence of the energy-rich environment intestinal nematodes exploit, though comparable studies of free-living nematodes or other soft-bodied invertebrate phyla have not yet been done. The advantages of delaying reproduction, with the subsequent increase in fecundity and reproductive lifespan, depend on a number of factors, such as the relative importance of prepatency in the determination of parasite generation times, and adult mortality rates. Contrary to previous claims, nematode egg size is shown to be highly variable (as variable as female size), yet this variation is not associated with
A Program to Prepare Clinical Pharmacy Faculty Members to Use Entrustable Professional Activities in Experiential Education

Objective. To describe the design and evaluation of a program implemented to ready clinical faculty members to use entrustable professional activities (EPAs) for teaching and assessment in experiential education. Methods. The school adopted a set of EPAs for faculty members to implement in advanced pharmacy practice experiences (APPEs), and then delivered a two-session faculty development program to ensure faculty members’ readiness to implement the EPAs. To determine the success of the faculty development program, qualitative analysis of the moderated discussion held during the program was conducted, post-program and follow-up surveys were administered, and the results of the pilot implementation of EPAs were analyzed. Results. Eleven faculty members participated in the development program, and 10 of them completed the pilot implementation of EPAs and the follow-up survey after completing three APPE blocks. All faculty members responded that the program prepared them to apply what they learned about EPAs to their practice setting in both the post-program and follow-up surveys. In the follow-up survey, 80% of faculty members reported that they were confident in correctly applying what they learned from the program to the EPA pilot, and 100% answered a hypothetical application question correctly. Forty students participated in the pilot implementation of EPAs. Of these, 95% were directly observed by faculty members before making an entrustment decision, and 100% received feedback on their performance. Conclusion. The faculty development program was effective in preparing faculty members to implement the EPA framework in experiential teaching and use the entrustment rubric.
Complete Genome Sequence of Enterococcus faecium FS86, Used for Propagation of Bacteriophages with Therapeutic Potential

The Enterococcus faecium FS86 genome consists of a 2,685,395-bp chromosome and a 9,751-bp plasmid. The plasmid harbors mobilization-related genes. The pathogenicity factor genotype is cylA negative, aggA negative, gelE negative, sprE negative, esp negative, eep positive, and efaA positive. E. faecium FS86 belongs to multilocus sequence type 296, together with the probiotic strain E. faecium SF68. ABSTRACT The Enterococcus faecium FS86 genome consists of a 2,685,395-bp chromosome and a 9,751-bp plasmid. The plasmid harbors mobilization-related genes. The pathogenicity factor genotype is cylA negative, aggA negative, gelE negative, sprE negative, esp negative, eep positive, and efaA positive. E. faecium FS86 belongs to multilocus sequence type 296, together with the probiotic strain E. faecium SF68.
Insertions of codons encoding basic amino acids in H7 hemagglutinins of influenza A viruses occur by recombination with RNA at hotspots near snoRNA binding sites

The presence of multiple basic amino acids in the protease cleavage site of the hemagglutinin (HA) protein is the main molecular determinant of virulence of highly pathogenic avian influenza (HPAI) viruses. Recombination of HA RNA with other RNA molecules of host or virus origin is a dominant mechanism of multi basic cleavage site (MBCS) acquisition for H7 subtype HA. Using alignments of HA RNA sequences from documented cases of MBCS insertion due to recombination, we show that such recombination with host RNAs is most likely to occur at particular hotspots in ribosomal RNAs (rRNAs), transfer RNAs (tRNAs) and viral RNAs. The locations of these hotspots in highly abundant RNAs indicate that RNA recombination is facilitated by the binding of small nucleolar RNA (snoRNA) near the recombination points.
A digital 3D reference atlas reveals cellular growth patterns shaping the Arabidopsis ovule

A fundamental question in biology is how morphogenesis integrates the multitude of distinct processes that act at different scales, ranging from the molecular control of gene expression to cellular coordination in a tissue. Investigating morphogenesis of complex organs strongly benefits from three-dimensional representations of the organ under study. Here, we present a digital analysis of ovule development from Arabidopsis thaliana as a paradigm for a complex morphogenetic process. Using machine-learning-based image analysis we generated a three-dimensional atlas of ovule development with cellular resolution. It allows quantitative stage- and tissue-specific analysis of cellular patterns. Exploiting a fluorescent reporter enabled precise spatial determination of gene expression patterns, revealing subepidermal expression of WUSCHEL. Underlying the power of our approach, we found that primordium outgrowth progresses evenly, discovered a novel mode of forming a new cell layer, and detected a new function of INNER NO OUTER in restricting cell proliferation in the nucellus. Moreover, we identified two distinct subepidermal cell populations that make crucial contributions to ovule curvature. Our work demonstrates the expedience of a three-dimensional digital representation when studying the morphogenesis of an organ of complex cellular architecture and shape that eventually consists of 1,900 cells.
ORCESTRA: a platform for orchestrating and sharing high-throughput pharmacogenomic analyses

Reproducibility is essential to Open Science, as there is limited relevance for finding that cannot be reproduced by independent research groups, regardless of its validity. It is therefore crucial for scientists to describe their experiments in sufficient detail so they can be reproduced, challenged, and built upon. However, due to recent advances in the biological and computational sciences, it has become difficult to process, analyze, and share data with the community in a manner that is transparent. This has made reproducing research findings more challenging, with some researchers going as far as suggesting that the biomedical sciences are experiencing a “reproducibility crisis”. To overcome these issues, we created a cloud-based platform called ORCESTRA (www.orcestra.ca), which provides a flexible framework for the reproducible processing of multimodal biomedical data. The platform enables processing of genomic and pharmacological profiles of cancer samples through the use of automated processing pipelines that are user-customizable, which are executed through Pachyderm, a data versioning and orchestration tool. ORCESTRA creates an integrated and fully documented data object known as a PharmacoSet (PSet), with a persistent identifier (DOI), that can be used and shared for future analyses using the Bioconductor PharmacoGx package.
Origins of 1/f-like tissue oxygenation fluctuations in the murine cortex

The concentration of oxygen in the brain spontaneously fluctuates, and the power distribution in these fluctuations has 1/f-like dynamics. Though these oscillations have been interpreted as being driven by neural activity, the origins of these 1/f-like oscillations is not well understood. Here, to gain insight of the origin of the 1/f-like oxygen fluctuations, we investigated the dynamics of tissue oxygenation and neural activity in awake behaving mice. We found that oxygen signal recorded from the cortex of mice had 1/f-like spectra. However, band-limited power in the local field potential, did not show corresponding 1/f-like fluctuations. When local neural activity was suppressed, the 1/f-like fluctuations in oxygen concentration persisted. Two-photon measurements of erythrocyte spacing fluctuations (‘stalls’) and mathematical modelling show that stochastic fluctuations in erythrocyte flow and stalling could underlie 1/f-like dynamics in oxygenation. These results show discrete nature of erythrocytes and their irregular flow, rather than neural activity, could drive 1/f-like fluctuations in tissue oxygenation.
Orbitofrontal cortex and learning predictions of state transitions

Learning the transition structure of the environment – the probabilities of transitioning from one environmental state to another – is a key prerequisite for goal-directed planning and model-based decision making. To investigate the role of the orbitofrontal cortex (OFC) in goal-directed planning and decision making, we used fMRI to assess univariate and multivariate activity in the OFC while humans experienced state transitions that varied in degree of surprise. In convergence with recent evidence, we found that OFC activity was related to greater learning about transition structure, both across subjects and on a trial-by-trial basis. However, this relationship was inconsistent with a straightforward interpretation of OFC activity as representing a state prediction error that would facilitate learning of transitions via error-correcting mechanisms. The state prediction error hypothesis predicts that OFC activity at the time of observing an outcome should increase expectation of that observed outcome on subsequent trials. Instead, our results showed that OFC activity was associated with increased expectation of the more probable outcome; that is, with more optimal predictions. Our findings add to the evidence of OFC involvement in learning state-to-state transition structure, while providing new constraints for algorithmic hypotheses regarding how these transitions are learned. Significance Statement The orbitofrontal cortex (OFC) has been implicated in model-based decision making—the kind of decisions that result from planning using an “environment model” of how current actions affect our future states. However, the widely suggested role of the OFC in representing expected values of future states is not sufficient to explain why the OFC would be critical for planning in particular. A new line of evidence implicates the OFC in learning about transition structure of the environment – a key component of the “environment model” used for planning. We investigate this function, adding to the growing literature on the role of the OFC in learning and decision making, while unveiling new questions about the algorithmic role of OFC in goal-directed planning.
Engineering protein-specific proteases: targeting active RAS

We describe the design, kinetic properties, and structures of engineered subtilisin proteases that degrade the active form of RAS by cleaving a conserved sequence in switch 2. RAS is a signaling protein that, when mutated, drives a third of human cancers. To generate high specificity for the RAS target sequence, the active site was modified to be dependent on a cofactor (imidazole or nitrite) and protease sub-sites were engineered to create a linkage between substrate and cofactor binding. Selective proteolysis of active RAS arises from a 2-step process wherein sub-site interactions promote productive binding of the cofactor, enabling cleavage. Proteases engineered in this way specifically cleave active RAS in vitro, deplete the level of RAS in a bacterial reporter system, and also degrade RAS in human cell culture. Although these proteases target active RAS, the underlying design principles are fundamental and will be adaptable to many target proteins.
Comparative Transcriptional Profiling of Motor Neuron Disorder-Associated Genes in Various Human Cell Culture Models

Disease modeling requires appropriate cellular models that best mimic the underlying pathophysiology. Human origin and an adequate expression of the disease protein are pre-requisites that support information from a model to be meaningful. In this study we investigated expression profiles of (i) PBMCs and (ii) fibroblasts as patient derived cells as well as (iii) lymphoblasts and (iv) induced pluripotent stem cells (iPSC) as immortalized sources, and (v) iPSC-derived cortical neurons to assess their aptitude to model motor neuron diseases (MNDs) including hereditary spastic paraplegia (HSP), amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). We generated all five different cell types from two healthy donors and performed RNA sequencing to display expression patterns in MND-related genes. For the ten most common HSP genotypes we validated gene expression by qPCR. To verify the results on protein level, proteome analysis of fibroblasts, iPSCs and cortical neurons was performed. Depending on the specific MND gene we found largely different expression patterns. Out of 168 MND-related genes, 50 had their highest expression in iPSC-derived cortical neurons, 41 were most strongly expressed in fibroblasts, 26 in lymphoblasts, 22 in iPSCs, and 14 in PBMCs. Pathophysiologically related MNDs like HSPs associated with axonal transport deficits shared highest expression in cortical neurons. 15 MND-related genes were not detectable in any of the analyzed cell types. This may reflect the critical dependency of motor neurons on support of other cell types like oligodendrocytes which express myelin proteins like L1CAM (SPG1), PLP1 (SPG2) and MAG (SPG75) which are lacking in neurons but cause MNDs if mutated. This study provides comprehensive information on expression of genes associated with a large spectrum of MNDs. Expression profiles can be used to inform on appropriate cell models for genotype specific motor neuron research.
Identification and Investigation of miRNAs From Gastrodia elata Blume and Their Potential Function

Gastrodia elata Blume (G. elata) is a valuable traditional Chinese medicine with neuroprotection, anti-inflammatory, and immune regulatory functions. MicroRNAs (miRNA) is a kind of endogenous noncoding small RNAs that plays distinctly important roles for gene regulation of organisms. So far, the research on G. elata is mainly focused on the pharmacological functions of the natural chemical ingredients, and the function of G. elata miRNA remains unknown. In this study, 5,718 known miRNAs and 38 novel miRNAs were identified by high-throughput sequencing from G. elata. Based on GO and KEGG analysis, we found that the human genes possibly regulated by G. elata miRNAs were related to the cell cycle, immune regulation, intercellular communication, etc. Furthermore, two novel miRNAs as Gas-miR01 and Gas-miR02 have stable and high expression in the medicinal tissues of G. elata. Further bioinformatics prediction showed that both Gas-miR01 and Gas-miR02 could target Homo sapiens A20 gene, furthermore, the dual-luciferase reporter gene assay and Western Blotting verified the interaction of Gas-miR01 or Gas-miR02 with A20. These evidences suggested that G. elata-unique miRNAs might be involved in certain physiological processes. The animal experiment showed that Gas-miR01 and Gas-miR02 could be detected in some tissues of mice by intragastric administration; meanwhile, the A20 expression in some tissues of mice was downregulated. These results supported for the functional study of G. elata miRNAs.