Miracle-dz/UniFAR-FTUs huggingface dataset:
Brain oscillatory activity as a biomarker of motor recovery in chronic stroke

In the present work, we investigated the relationship of oscillatory sensorimotor brain activity to motor recovery. The neurophysiological data of 30 chronic stroke patients with severe upper‐limb paralysis are the basis of the observational study presented here. These patients underwent an intervention including movement training based on combined brain–machine interfaces and physiotherapy of several weeks recorded in a double‐blinded randomized clinical trial. We analyzed the alpha oscillations over the motor cortex of 22 of these patients employing multilevel linear predictive modeling. We identified a significant correlation between the evolution of the alpha desynchronization during rehabilitative intervention and clinical improvement. Moreover, we observed that the initial alpha desynchronization conditions its modulation during intervention: Patients showing a strong alpha desynchronization at the beginning of the training improved if they increased their alpha desynchronization. Patients showing a small alpha desynchronization at initial training stages improved if they decreased it further on both hemispheres. In all patients, a progressive shift of desynchronization toward the ipsilesional hemisphere correlates significantly with clinical improvement regardless of lesion location. The results indicate that initial alpha desynchronization might be key for stratification of patients undergoing BMI interventions and that its interhemispheric balance plays an important role in motor recovery.
Advanced Polymers for Three-Dimensional (3D) Organ Bioprinting

Three-dimensional (3D) organ bioprinting is an attractive scientific area with huge commercial profit, which could solve all the serious bottleneck problems for allograft transplantation, high-throughput drug screening, and pathological analysis. Integrating multiple heterogeneous adult cell types and/or stem cells along with other biomaterials (e.g., polymers, bioactive agents, or biomolecules) to make 3D constructs functional is one of the core issues for 3D bioprinting of bioartificial organs. Both natural and synthetic polymers play essential and ubiquitous roles for hierarchical vascular and neural network formation in 3D printed constructs based on their specific physical, chemical, biological, and physiological properties. In this article, several advanced polymers with excellent biocompatibility, biodegradability, 3D printability, and structural stability are reviewed. The challenges and perspectives of polymers for rapid manufacturing of complex organs, such as the liver, heart, kidney, lung, breast, and brain, are outlined.
Mechanism of conditional partner selectivity in MITF/TFE family transcription factors with a conserved coiled coil stammer motif

Abstract Interrupted dimeric coiled coil segments are found in a broad range of proteins and generally confer selective functional properties such as binding to specific ligands. However, there is only one documented case of a basic-helix–loop–helix leucine zipper transcription factor—microphthalmia-associated transcription factor (MITF)—in which an insertion of a three-residue stammer serves as a determinant of conditional partner selectivity. To unravel the molecular principles of this selectivity, we have analyzed the high-resolution structures of stammer-containing MITF and an engineered stammer-less MITF variant, which comprises an uninterrupted symmetric coiled coil. Despite this fundamental difference, both MITF structures reveal identical flanking in-phase coiled coil arrangements, gained by helical over-winding and local asymmetry in wild-type MITF across the stammer region. These conserved structural properties allow the maintenance of a proper functional readout in terms of nuclear localization and binding to specific DNA-response motifs regardless of the presence of the stammer. By contrast, MITF heterodimer formation with other bHLH-Zip transcription factors is only permissive when both factors contain either the same type of inserted stammer or no insert. Our data illustrate a unique principle of conditional partner selectivity within the wide arsenal of transcription factors with specific partner-dependent functional readouts.
Ischemic Postconditioning Reduces Reperfusion Arrhythmias by Adenosine Receptors and Protein Kinase C Activation but Is Independent of KATP Channels or Connexin 43

Ischemic postconditioning (IPoC) reduces reperfusion arrhythmias but the antiarrhythmic mechanisms remain unknown. The aim of this study was to analyze IPoC electrophysiological effects and the role played by adenosine A1, A2A and A3 receptors, protein kinase C, ATP-dependent potassium (KATP) channels, and connexin 43. IPoC reduced reperfusion arrhythmias (mainly sustained ventricular fibrillation) in isolated rat hearts, an effect associated with a transient delay in epicardial electrical activation, and with action potential shortening. Electrical impedance measurements and Lucifer-Yellow diffusion assays agreed with such activation delay. However, this delay persisted during IPoC in isolated mouse hearts in which connexin 43 was replaced by connexin 32 and in mice with conditional deletion of connexin 43. Adenosine A1, A2A and A3 receptor blockade antagonized the antiarrhythmic effect of IPoC and the associated action potential shortening, whereas exogenous adenosine reduced reperfusion arrhythmias and shortened action potential duration. Protein kinase C inhibition by chelerythrine abolished the protective effect of IPoC but did not modify the effects on action potential duration. On the other hand, glibenclamide, a KATP inhibitor, antagonized the action potential shortening but did not interfere with the antiarrhythmic effect. The antiarrhythmic mechanisms of IPoC involve adenosine receptor activation and are associated with action potential shortening. However, this action potential shortening is not essential for protection, as it persisted during protein kinase C inhibition, a maneuver that abolished IPoC protection. Furthermore, glibenclamide induced the opposite effects. In addition, IPoC delays electrical activation and electrical impedance recovery during reperfusion, but these effects are independent of connexin 43.
Discovery of a new predominant cytosine DNA modification that is linked to gene expression in malaria parasites

Abstract DNA cytosine modifications are key epigenetic regulators of cellular processes in mammalian cells, with their misregulation leading to varied disease states. In the human malaria parasite Plasmodium falciparum, a unicellular eukaryotic pathogen, little is known about the predominant cytosine modifications, cytosine methylation (5mC) and hydroxymethylation (5hmC). Here, we report the first identification of a hydroxymethylcytosine-like (5hmC-like) modification in P. falciparum asexual blood stages using a suite of biochemical methods. In contrast to mammalian cells, we report 5hmC-like levels in the P. falciparum genome of 0.2–0.4%, which are significantly higher than the methylated cytosine (mC) levels of 0.01–0.05%. Immunoprecipitation of hydroxymethylated DNA followed by next generation sequencing (hmeDIP-seq) revealed that 5hmC-like modifications are enriched in gene bodies with minimal dynamic changes during asexual development. Moreover, levels of the 5hmC-like base in gene bodies positively correlated to transcript levels, with more than 2000 genes stably marked with this modification throughout asexual development. Our work highlights the existence of a new predominant cytosine DNA modification pathway in P. falciparum and opens up exciting avenues for gene regulation research and the development of antimalarials.
Arsenic and nutrient absorption characteristics and antioxidant response in different leaves of two ryegrass (Lolium perenne) species under arsenic stress

Arsenic (As), a heavy metal element, causes soil environmental concerns in many parts of the world, and ryegrass has been considered as an effective plant species for bioremediation of heavy metal pollution including As. This study was designed to investigate As content, nutrient absorption and antioxidant enzyme activity associated with As tolerance in the mature leaves, expanded leaves and emerging leaves of perennial ryegrass (Lolium perenne) and annual ryegrass (Lolium multiflorum) under 100 mg·kg-1 As treatment. The contents of As, calcium (Ca), magnesium (Mg), manganese (Mn) in the leaves of both ryegrass species were greatest in the mature leaves and least in the emerging leaves. The nitrogen (N), phosphorus (P), potassium (K) contents of both ryegrass species were greatest in the emerging leaves and least in the mature leaves. The As treatment reduced biomass more in the mature leaves and expanded leaves relative to the emerging leaves for annual ryegrass and reduced more in emerging leaves relative to the mature and expanded leaves for perennial ryegrass. Perennial ryegrass had higher As content than annual ryegrass in all three kinds of leaves. The As treatment increased hydrogen peroxide (H2O2) in expanded leaves of two ryegrass species, relative to the control. The As treatment increased the ascorbate peroxidase (APX) activity in the expanded leaves of perennial ryegrass and the mature leaves of annual ryegrass, the catalase (CAT) activity in the mature and expanded leaves of perennial ryegrass and the emerging leaves of annual ryegrass, relative to the control. The As treatment reduced peroxidase (POD) activity in all three kinds of leaves of annual ryegrass and superoxide dismutase (SOD) activity in expanded leaves of perennial ryegrass, relative to the control. The results of this study suggest that As tolerance may vary among different ages of leaf and reactive oxygen species (ROS) and antioxidant enzyme activity may be associated with As tolerance in the ryegrass.
Quality and utilization patterns of maternity waiting homes at referral facilities in rural Zambia: A mixed-methods multiple case analysis of intervention and standard of care sites

Introduction Maternity waiting homes, defined as residential lodging near a health facility, are recommended by the WHO. An improved MWH model, responsive to community standards for functionality and comfort, was implemented at two purposively selected health facilities in rural Zambia providing comprehensive emergency obstetric and neonatal care (CEmONC) services (intervention MWHs), and compared to three existing standard-of-care MWHs (comparison MWHs) at other CEmONC sites in the same districts. Methods We used a mixed-methods time-series design for this analysis. Quantitative data including MWH quality, MWH utilization, and demographics of women utilizing MWHs were collected from September 2016 through May 2018 to capture pre-post intervention trends. Qualitative data were obtained from two focus group discussions conducted with pregnant women at intervention MWHs in August 2017 and May 2018. The primary outcomes were quality scoring of the MWHs and maternal utilization of the MWHs. Results MWH quality was similar at all sites during the pre-intervention time period, with a significant change in overall quality scores between intervention (mean score 83.8, SD 12) and comparison (mean score 43.1, SD 10.2) sites after the intervention (p <0.0001). Women utilizing intervention and comparison MWHs at all time points had very similar demographics. After implementation of the intervention, there were marked increases in MWH utilization at both intervention and comparison sites, with a greater percentage increase at one of two intervention sites. Conclusions An improved MWH model can result in measurably improved quality scores for MWHs, and can result in increased utilization of MWHs at rural CEmONC facilities. MWHs are part of the infrastructure that might be needed for health systems to provide high quality “right place” maternal care in rural settings.
Sacroiliac Joint Ligaments and Sacroiliac Pain: A Case-Control Study on Micro- and Ultrastructural Findings on Morphologic Alterations.

BACKGROUND The sacroiliac joint (SIJ) is a common source of low back pain. SIJ pain has shown to have negative impact on patients' quality of life. Although clinically there is an increasing interest to treat SIJ-related pain both conservatively and surgically, the underlying mechanisms related to pathology in that region are poorly understood. One hypothesis is that the SIJ ligaments are structurally altered in SIJ pain. OBJECTIVES The given study investigated patient cases with different pain durations undergoing posterior distraction arthrodesis of the SIJ, with subsequent micro- and ultrastructural assessment of the interosseous and posterior SIJ ligaments compared with autopsy controls without known history of low back pain. STUDY DESIGN Case-control study. Morphologic-pathological analysis of tissue samples obtained during surgery with controls from legal medicine. SETTING Rural hospital setting in Halberstadt, Germany. METHODS SIJ ligaments were removed from 6 patients undergoing SIJ arthrodesis for histological and ultrastructural assessment in scanning and transmission electron microscopy, and compared with 6 controls without known history of SIJ pathology. RESULTS A number of alterations were observed in the ligaments of patients with SIJ, namely ligament disruption, collagen loosening and coiling, vascularization, and hemorrhage. In some areas, these changes were observed in proximity to healthy (structurally unaltered and intact tissues), indicative of a potential disease progression. Comparison to controls yielded a significant correlation between SIJ pathology and the level of collagen degeneration (Phi >/= 0.82; P < 0.001). LIMITATIONS Small sample size, method of tissue removal from patients may have influenced tissue integrity. CONCLUSIONS The combined clinical, histological, and ultrastructural analysis provided, to our knowledge, first-time evidence of morphologic SIJ ligament alteration of a nontraumatic and noninflammatory cause. Further research is necessary to elucidate these structural changes and to substantiate pain duration and patient-history-dependent changes at the ligaments of the posterior pelvis. KEY WORDS Collagen, electron microscopy, histological and ultrastructural assessment, interosseous sacroiliac ligament, low back pain, sacroiliac joint.
Evaluation of Microglia/Macrophage Cells from Rat Striatum and Prefrontal Cortex Reveals Differential Expression of Inflammatory-Related mRNA after Methamphetamine

RNA sequencing (RNAseq) can be a powerful tool in the identification of transcriptional changes after drug treatment. RNAseq was utilized to determine expression changes in Fluorescence-activated cell sorted (FACS) CD11b/c+ cells from the striatum (STR) and prefrontal cortex (PFC) of male Sprague-Dawley rats after a methamphetamine (METH) binge dosing regimen. Resident microglia and infiltrating macrophages were collected 2 h or 3 days after drug administration. Gene expression changes indicated there was an increase toward an overall pro-inflammatory state, or M1 polarization, along with what appears to be a subset of cells that differentiated toward the anti-inflammatory M2 polarization. In general, there were significantly more mRNA expression changes in the STR than the PFC and more at 2 h post-binge METH than at 3 days post-binge METH. Additionally, Ingenuity® Pathway Analysis along with details of RNA expression changes revealed cyclo-oxygenase 2 (COX2)-driven prostaglandin (PG) E2 synthesis, glutamine uptake, and the Nuclear factor erythroid2-related factor 2 (NRF2) canonical pathway in microglia were associated with the binge administration regimen of METH.
Structure of the RAD9-RAD1-HUS1 checkpoint clamp bound to RHINO sheds light on the other side of the DNA clamp

DNA clamp, a highly conserved ring-shaped protein, binds dsDNA within its central pore. Also, DNA clamp interacts with various nuclear proteins on its front, thereby stimulating their enzymatic activities and biological functions. It has been assumed that the DNA clamp is a functionally single-faced ring from bacteria to humans. Here, we report the crystal structure of the heterotrimeric RAD9-RAD1-HUS1 (9-1-1) checkpoint clamp bound to a peptide of RHINO, a recently identified cancer-related protein that interacts with 9-1-1 and promotes activation of the DNA damage checkpoint. This is the first structure of 9-1-1 bound to its partner. The structure reveals that RHINO is unexpectedly bound to the edge and around the back of the 9-1-1 ring through specific interactions with the RAD1 subunit of 9-1-1. Our finding indicates that 9-1-1 is a functionally double-faced DNA clamp.
Being there: A scoping review of grief support training in medical education

Introduction Medical education experts argue that grief support training for physicians would improve physician and patient and family wellness, and should therefore be mandatory. However, there is little evidence about the range of curricula interventions or the impact of grief training. The aim of this scoping review was to describe the current landscape of grief training worldwide in medical school, postgraduate residency and continuing professional development in the disciplines of pediatrics, family medicine and psychiatry. Methods Using Arksey and O’Malley’s scoping review principles, MEDLINE, EMBASE, ERIC, PsychInfo and Web of Science were searched by a librarian. Two levels of screening took place: a title and abstract review for articles that fit a predefined criteria and a full-text review of articles that met those criteria. Three investigators reviewed the articles and extracted data for analysis. To supplement the search, we also scanned the reference lists of included studies for possible inclusion. Results Thirty-seven articles published between 1979 and 2019 were analyzed. Most articles described short voluntary grief training workshops. At all training levels, the majority of these workshops focused on transmitting knowledge about the ethical and legal dimensions of death, dying and bereavement in medicine. The grief trainings described were characterized by the use of diverse pedagogical tools, including lectures, debriefing sessions, reflective writing exercises and simulation/role-play. Discussion Grief training was associated with increased self-assessed knowledge and expertise; however, few of the studies analyzed the impact of grief training on physician and patient and family wellness. Our synthesis of the literature indicates key gaps exist, specifically regarding the limited emphasis on improving physicians’ communication skills around death and dying and the limited use of interactive and self-reflexive learning tools. Most trainings also had an overly narrow focus on bereavement grief, rather than a more broadly defined definition of loss.
The Impact of Glucose on Corticospinal and Intracortical Excitability

Neurotransmission is highly dependent on the availability of glucose-derived energy, although it is unclear how glucose availability modulates corticospinal and intracortical excitability as assessed via transcranial magnetic stimulation (TMS). In this double-blinded placebo-controlled study, we tested the effect of acute glucose intake on motor-evoked potential (MEP) recruitment curves, short-interval intracortical inhibition (SICI), short-latency afferent inhibition (SAI) and long-latency afferent inhibition (LAI). Eighteen healthy males participated in four sessions. Session 1 involved acquisition of an individualized blood glucose response curve. This allowed measurements to be time-locked to an individualized glucose peak after consuming one of three drinks during the subsequent three sessions. Participants were administered a 300 mL concealed solution containing 75 g of glucose, sucralose, or water in separate sessions. Dependent measures were assessed at baseline and twice after drinking the solution. Secondary measures included blood glucose and mean arterial pressure. Corticospinal excitability and blood pressure increased following the drink across all treatments. No changes were observed in SICI, SAI or LAI. There was no rise in corticospinal excitability that was specific to the glucose drink, suggesting that acute changes in glucose levels do not necessarily alter TMS measures of corticospinal or intracortical excitability.
Development of a high yielding expression platform for the introduction of non-natural amino acids in protein sequences

ABSTRACT The ability to genetically encode non-natural amino acids (nnAAs) into proteins offers an expanded tool set for protein engineering. nnAAs containing unique functional moieties have enabled the study of post-translational modifications, protein interactions, and protein folding. In addition, nnAAs have been developed that enable a variety of biorthogonal conjugation chemistries that allow precise and efficient protein conjugations. These are being studied to create the next generation of antibody-drug conjugates with improved efficacy, potency, and stability for the treatment of cancer. However, the efficiency of nnAA incorporation, and the productive yields of cell-based expression systems, have limited the utility and widespread use of this technology. We developed a process to isolate stable cell lines expressing a pyrrolysyl-tRNA synthetase/tRNApyl pair capable of efficient nnAA incorporation. Two different platform cell lines generated by these methods were used to produce IgG-expressing cell lines with normalized antibody titers of 3 g/L using continuous perfusion. We show that the antibodies produced by these platform cells contain the nnAA functionality that enables facile conjugations. Characterization of these highly active and robust platform hosts identified key parameters that affect nnAA incorporation efficiency. These highly efficient host platforms may help overcome the expression challenges that have impeded the developability of this technology for manufacturing proteins with nnAAs and represents an important step in expanding its utility.
A daily diary study on maladaptive daydreaming, mind wandering, and sleep disturbances: Examining within-person and between-persons relations

Cross-sectional and experimental research have shown that task-unrelated thoughts (i.e., mind wandering) relate to sleep disturbances, but there is little research on whether this association generalizes to the day-level and other kinds of task-unrelated mentation. We employed a longitudinal daily diary design to examine the within-person and between-person associations between three self-report instruments measuring mind wandering, maladaptive daydreaming (a condition characterized by having elaborate fantasy daydreams so insistent that they interfere with daily functioning) and sleep disturbances. A final sample of 126 participants self-identified as experiencing maladaptive daydreaming completed up to 8 consecutive daily reports (in total 869 daily observations). The scales showed acceptable-to-excellent within-person reliability (i.e., systematic day-to-day change) and excellent between-person reliability. The proportion of between-person variance was 36% for sleep disturbances, 57% for mind wandering, and 75% for maladaptive daydreaming, respectively (the remaining being stochastic and systematic within-person variance). Contrary to our pre-registered hypothesis, maladaptive daydreaming did not significantly predict sleep disturbances the following night, B = -0.00 (SE = 0.04), p = . 956. Exploratory analyses indicated that while nightly sleep disturbances predicted mind wandering the following day, B = 0.20 (SE = 0.04), p < . 001, it did not significantly predict maladaptive daydreaming the following day, B = -0.04 (SE = 0.05), p = . 452. Moreover, daily mind wandering did not significantly predict sleep disturbances the following night, B = 0.02 (SE = 0.05), p = . 731. All variables correlated at the between-person level. We discuss the implications concerning the differences between maladaptive daydreaming and mind wandering and the possibility of targeting sleep for mind wandering interventions.