Miracle-dz/UniFAR-FTUs huggingface dataset:
Clinical trial of ABCB5+ mesenchymal stem cells for recessive dystrophic epidermolysis bullosa

BACKGROUND Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating, and life-threatening inherited skin fragility disorder that comes about due to a lack of functional type VII collagen, for which no effective therapy exists. ABCB5+ dermal mesenchymal stem cells (ABCB5+ MSCs) possess immunomodulatory, inflammation-dampening, and tissue-healing capacities. In a Col7a1–/– mouse model of RDEB, treatment with ABCB5+ MSCs markedly extended the animals’ lifespans. METHODS In this international, multicentric, single-arm, phase I/IIa clinical trial, 16 patients (aged 4–36 years) enrolled into 4 age cohorts received 3 i.v. infusions of 2 × 106 ABCB5+ MSCs/kg on days 0, 17, and 35. Patients were followed up for 12 weeks regarding efficacy and 12 months regarding safety. RESULTS At 12 weeks, statistically significant median (IQR) reductions in the Epidermolysis Bullosa Disease Activity and Scarring Index activity (EBDASI activity) score of 13.0% (2.9%–30%; P = 0.049) and the Instrument for Scoring Clinical Outcome of Research for Epidermolysis Bullosa clinician (iscorEB‑c) score of 18.2% (1.9%–39.8%; P = 0.037) were observed. Reductions in itch and pain numerical rating scale scores were greatest on day 35, amounting to 37.5% (0.0%–42.9%; P = 0.033) and 25.0% (–8.4% to 46.4%; P = 0.168), respectively. Three adverse events were considered related to the cell product: 1 mild lymphadenopathy and 2 hypersensitivity reactions. The latter 2 were serious but resolved without sequelae shortly after withdrawal of treatment. CONCLUSION This trial demonstrates good tolerability, manageable safety, and potential efficacy of i.v. ABCB5+ MSCs as a readily available disease-modifying therapy for RDEB and provides a rationale for further clinical evaluation. TRIAL REGISTRATION Clinicaltrials.gov NCT03529877; EudraCT 2018-001009-98. FUNDING The trial was sponsored by RHEACELL GmbH & Co. KG. Contributions by NYF and MHF to this work were supported by the NIH/National Eye Institute (NEI) grants RO1EY025794 and R24EY028767.
Sudden sensorineural hearing loss: what can we learn from examining Reddit posts?

Abstract Background Many patients with sudden sensorineural hearing loss may seek hearing health information and social support online, although little is known about the online information seeking behaviour. Objective The present study aimed to examine the discussions around sudden sensorineural hearing loss in Reddit posts. Method A total of 526 Reddit posts about sudden sensorineural hearing loss were extracted and analysed using qualitative and quantitative methods. Results The content analysis identified eight main categories. Most of the posts were on topics of: sharing personal experiences (34 per cent), describing symptoms (31 per cent), discussing treatment options (36 per cent) and discussing possible causes (19 per cent) of sudden sensorineural hearing loss. The sudden sensorineural hearing loss Reddit posts varied significantly in terms of linguistic variables when compared to baseline Reddit posts. Reddit posts by individuals with sudden sensorineural hearing loss had significantly higher engagement, higher authenticity and made more references to their body when compared to other users. Conclusion The study results provide insights that can be helpful for professionals during clinical interactions.
A new regime of heme-dependent aromatic oxygenase superfamily

Two histidine-ligated heme-dependent monooxygenase proteins, TyrH and SfmD, have recently been found to resemble enzymes from the dioxygenase superfamily currently named after tryptophan 2,3-dioxygenase (TDO), that is, the TDO superfamily. These latest findings prompted us to revisit the structure and function of the superfamily. The enzymes in this superfamily share a similar core architecture and a histidine-ligated heme. Their primary functions are to promote O-atom transfer to an aromatic metabolite. TDO and indoleamine 2,3-dioxygenase (IDO), the founding members, promote dioxygenation through a two-step monooxygenation pathway. However, the new members of the superfamily, including PrnB, SfmD, TyrH, and MarE, expand its boundaries and mediate monooxygenation on a broader set of aromatic substrates. We found that the enlarged superfamily contains eight clades of proteins. Overall, this protein group is a more sizeable, structure-based, histidine-ligated heme-dependent, and functionally diverse superfamily for aromatics oxidation. The concept of TDO superfamily or heme-dependent dioxygenase superfamily is no longer appropriate for defining this growing superfamily. Hence, there is a pressing need to redefine it as a heme-dependent aromatic oxygenase (HDAO) superfamily. The revised concept puts HDAO in the context of thiol-ligated heme-based enzymes alongside cytochrome P450 and peroxygenase. It will update what we understand about the choice of heme axial ligand. Hemoproteins may not be as stringent about the type of axial ligand for oxygenation, although thiolate-ligated hemes (P450s and peroxygenases) more frequently catalyze oxygenation reactions. Histidine-ligated hemes found in HDAO enzymes can likewise mediate oxygenation when confronted with a proper substrate.
Influence of footwear, foot-strike pattern and step frequency on spatiotemporal parameters and lower-body stiffness in running

ABSTRACT This study aimed to determine the influence of footwear condition, foot-strike pattern and step frequency on running spatiotemporal parameters and lower-body stiffness during treadmill running. Thirty-one amateur endurance runners performed a two-session protocol (shod and barefoot). Each session consisted of two trials at 12 km · h−1 over 5 minutes altering step frequency every minute (150, 160, 170, 180 and 190 spm). First, participants were instructed to land with the heel first; after completion, the same protocol was repeated landing with the forefoot first. Repeated measures ANOVAs showed significant differences for footwear condition, foot-strike pattern and step frequency for each variable: percent contact time, percent flight time, vertical stiffness and leg stiffness (all p < 0.001). The results demonstrate greater estimated vertical and leg stiffness when running barefoot for both foot-strike patterns showing the largest values for barefoot+forefoot condition. Likewise, both vertical and leg stiffness became greater as step frequency increased. The proper manipulation of these variables facilitates our understanding of running performance and assist in training programmes design and injury management.
Surgical Treatment of an Innominate Artery Aneurysm Using Near-Infrared Spectroscopy for Cerebral Monitoring: A Case Report

Innominate artery aneurysms are challenging for surgeons to treat because of the requirement for brain protection during surgery. In innominate artery aneurysms, the endovascular approach does not require cardiopulmonary bypass, but patients who can be treated using this approach are limited in number, and the long-term results of endovascular treatment are unclear. Here, we report our experience of successfully treating a patient with an innominate artery aneurysm using near-infrared spectroscopy without cardiopulmonary bypass support or hypothermic circulatory arrest.
Self–regulatory learning theory as a lens on how undergraduate and postgraduate learners respond to feedback: A BEME scoping review: BEME Guide No. 66

Abstract Introduction Little is known of processes by which feedback affects learners to influence achievement. This review maps what is known of how learners interact with feedback, to better understand how feedback affects learning strategies, and to explore enhancing and inhibiting factors. Methods Pilot searching indicated a wide range of interpretations of feedback and study designs, prompting the use of scoping methodology. Inclusion criteria comprised: (i) learners (undergraduate, postgraduate, continuing education) who regularly receive feedback, and (ii) studies that associated feedback with subsequent learner reaction. The screening was performed independently in duplicate. Data extraction and synthesis occurred via an iterative consensus approach. Self-regulatory learning theory (SRL) was used as the conceptual framework. Results Of 4253 abstracts reviewed, 232 were included in the final synthesis. Understandings of feedback are diverse; a minority adopt recognised definitions. Distinct learner responses to feedback can be categorized as cognitive, behavioural, affective, and contextual with complex, overlapping interactions. Importantly emotional responses are commonplace; factors mediating them are pivotal in learner recipience. Conclusion Feedback benefits learners most when focussed on learner needs, via engagement in bi-directional dialogue. Learner emotions must be supported, with the construction of positive learner-teacher relationships. A developmental agenda is key to learner’s acceptance of feedback and enhancing future learning.
Can Remote Patient Monitoring Be the New Standard in Primary Care of Chronic Diseases, Post-COVID-19?

Background: One lesson from the current COVID-19 pandemic is the need to optimize health care provision outside of traditional settings, and potentially over longer periods of time. An important strategy is remote patient monitoring (RPM), allowing patients to remain at home, while they transmit health data and receive follow-up services. Materials and Methods: We conducted an overview of the latest systematic reviews that had included randomized controlled trials with adult patients with chronic diseases. We summarized results and displayed these in forest plots, and used GRADE (Grading of Recommendations Assessment, Development, and Evaluation) to assess our certainty of the evidence. Results: We included 4 systematic reviews that together reported on 11 trials that met our definition of RPM, each including patients with diabetes and/or hypertension. RPM probably makes little to no difference on HbA1c levels. RPM probably leads to a slight reduction in systolic blood pressure, with questionable clinical meaningfulness. RPM probably has a small negative effect on the physical component of health-related quality of life, but the clinical significance of this reduction is uncertain. We have low confidence in the finding that RPM makes no difference to the remaining five primary outcomes. Conclusion: Most of our findings are consistent with reviews of other, broader definitions of RPM. The type of RPM examined in this review is as effective as standard treatment for patients with diabetes/hypertension. If this or other types of RPM are to be used for "long covid" patients or for other chronic disease groups post-pandemic, we need to understand why RPM may negatively affect quality of life.
Windows of opportunity: Ocean warming shapes temperature‐sensitive epigenetic reprogramming and gene expression across gametogenesis and embryogenesis in marine stickleback

Rapid climate change is placing many marine species at risk of local extinction. Recent studies show that epigenetic mechanisms (e.g. DNA methylation, histone modifications) can facilitate both within and transgenerational plasticity to cope with changing environments. However, epigenetic reprogramming (erasure and re‐establishment of epigenetic marks) during gamete and early embryo development may hinder transgenerational epigenetic inheritance. Most of our knowledge about reprogramming stems from mammals and model organisms, whereas the prevalence and extent of reprogramming among non‐model species from wild populations is rarely investigated. Moreover, whether reprogramming dynamics are sensitive to changing environmental conditions is not well known, representing a key knowledge gap in the pursuit to identify mechanisms underlying links between parental exposure to changing climate patterns and environmentally adapted offspring phenotypes. Here, we investigated epigenetic reprogramming (DNA methylation/hydroxymethylation) and gene expression across gametogenesis and embryogenesis of marine stickleback (Gasterosteus aculeatus) under three ocean warming scenarios (ambient, +1.5 and +4°C). We found that parental acclimation to ocean warming led to dynamic and temperature‐sensitive reprogramming throughout offspring development. Both global methylation/hydroxymethylation and expression of genes involved in epigenetic modifications were strongly and differentially affected by the increased warming scenarios. Comparing transcriptomic profiles from gonads, mature gametes and early embryonic stages showed sex‐specific accumulation and temperature sensitivity of several epigenetic actors. DNA methyltransferase induction was primarily maternally inherited (suggesting maternal control of remethylation), whereas induction of several histone‐modifying enzymes was shaped by both parents. Importantly, massive, temperature‐specific changes to the epigenetic landscape occurred in blastula, a critical stage for successful embryo development, which could, thus, translate to substantial consequences for offspring phenotype resilience in warming environments. In summary, our study identified key stages during gamete and embryo development with temperature‐sensitive reprogramming and epigenetic gene regulation, reflecting potential ‘windows of opportunity’ for adaptive epigenetic responses under future climate change.
Ablation of arginyl‐tRNA‐protein transferase in oligodendrocytes impairs central nervous system myelination

Addition of arginine (Arg) from tRNA can cause major alterations of structure and function of protein substrates. This post‐translational modification, termed protein arginylation, is mediated by the enzyme arginyl‐tRNA‐protein transferase 1 (Ate1). Arginylation plays essential roles in a variety of cellular processes, including cell migration, apoptosis, and cytoskeletal organization. Ate1 is associated with neuronal functions such as neurogenesis and neurite growth. However, the role of Ate1 in glial development, including oligodendrocyte (OL) differentiation and myelination processes in the central nervous system, is poorly understood. The present study revealed a peak in Ate1 protein expression during myelination process in primary cultured OLs. Post‐transcriptional downregulation of Ate1 reduced the number of OL processes, and branching complexity, in vitro. We conditionally ablated Ate1 from OLs in mice using 2′,3′‐cyclic nucleotide 3′‐phosphodiesterase‐Cre promoter (“Ate1‐KO” mice), to assess the role of Ate1 in OL function and axonal myelination in vivo. Immunostaining for OL differentiation markers revealed a notable reduction of mature OLs in corpus callosum of 14‐day‐old Ate1‐KO, but no changes in spinal cord, in comparison with wild‐type controls. Local proliferation of OL precursor cells was elevated in corpus callosum of 21‐day‐old Ate1‐KO, but was unchanged in spinal cord. Five‐month‐old Ate1‐KO displayed reductions of mature OL number and myelin thickness, with alterations of motor behaviors. Our findings, taken together, demonstrate that Ate1 helps maintain proper OL differentiation and myelination in corpus callosum in vivo, and that protein arginylation plays an essential role in developmental myelination.
Differential expression and hypoxia‐mediated regulation of the N‐myc downstream regulated gene family

Many organisms rely on oxygen to generate cellular energy (adenosine triphosphate or ATP). During severe hypoxia, the production of ATP decreases, leading to cell damage or death. Conversely, excessive oxygen causes oxidative stress that is equally damaging to cells. To mitigate pathological outcomes, organisms have evolved mechanisms to adapt to fluctuations in oxygen levels. Zebrafish embryos are remarkably hypoxia‐tolerant, surviving anoxia (zero oxygen) for hours in a hypometabolic, energy‐conserving state. To begin to unravel underlying mechanisms, we analyze here the distribution of the N‐myc Downstream Regulated Gene (ndrg) family, ndrg1‐4, and their transcriptional response to hypoxia. These genes have been primarily studied in cancer cells and hence little is understood about their normal function and regulation. We show here using in situ hybridization that ndrgs are expressed in metabolically demanding organs of the zebrafish embryo, such as the brain, kidney, and heart. To investigate whether ndrgs are hypoxia‐responsive, we exposed embryos to different durations and severity of hypoxia and analyzed transcript levels. We observed that ndrgs are differentially regulated by hypoxia and that ndrg1a has the most robust response, with a ninefold increase following prolonged anoxia. We further show that this treatment resulted in de novo expression of ndrg1a in tissues where the transcript is not observed under normoxic conditions and changes in Ndrg1a protein expression post‐reoxygenation. These findings provide an entry point into understanding the role of this conserved gene family in the adaptation of normal cells to hypoxia and reoxygenation.
What motivates individual public service motivation and cooperation at the initial stage of the COVID‐19 outbreak: A cross‐sectional survey

Abstract Objectives This study assesses the status of public service motivation and explains it's the positive association with public cooperation during the initial stage of the COVID‐19 crisis. Moreover, potential causes of Chinese citizens' public service motivation have been explored. Methods A cross‐sectional survey of 30 provinces in China was conducted using an online questionnaire. The study was conducted in February 2020 during the initial stage of the COVID‐19 pandemic. Socio‐demographic factors, public service motivation, public satisfaction, public confidence, and public cooperation were assessed using questionnaires. Hierarchical multiple regression was used to identify clusters of interrelationships among public service motivation, public satisfaction, public confidence, and public cooperation among Chinese citizens. Results We found that participants' public satisfaction with COVID‐19‐related public services had a positive association with public confidence (B = 0.456, p < 0.001) and public service motivation (B = 0.177, p < 0.001). Moreover, public confidence regarding anti‐COVID‐19 measures had a positive influence on public service motivation (B = 0.308, p < 0.001) while mediating the relationship between public satisfaction and public service motivation. Public service motivation were positively associated with public cooperation with anti‐COVID‐19 measures during the initial stage of the COVID‐19 pandemic. Conclusion A considerably high level of public service motivation among Chinese citizens appeared during the initial stage of the COVID‐19 pandemic, resulting in an increase in public cooperation. Moreover, the findings prove that a high degree of satisfaction with the government's initiatives regarding anti‐COVID‐19 measures encouraged greater personal public service motivation in respondents by increasing confidence in governmental responses and performance.
Diffusion Tensor Imaging of the Lateral Pterygoid Muscle in Patients with Temporomandibular Joint Disorders and Healthy Volunteers

Objective This study aimed to explore the feasibility of functional evaluation of the lateral pterygoid muscle (LPM) using diffusion tensor imaging (DTI) in patients with temporomandibular joint disorders (TMDs). Materials and Methods A total of 119 patients with TMD (23 male and 96 female; mean age ± standard deviation, 41 ± 15 years; 58 bilateral and 61 unilateral involvements for a total of 177 joints) and 20 healthy volunteers (9 male and 11 female; 40 ± 13 years; 40 joints) were included in this prospective study. Based on DTI of the jaw in the resting state, the diffusion parameters, apparent diffusion coefficient (ADC), fractional anisotropy (FA), λ1, λ2, and λ3 of the superior and inferior heads of the LPM (SHLPM and IHLPM) were measured. Patients with TMD with normal disc position (ND), anterior disc displacement with reduction (ADWR), and anterior disc displacement without reduction (ADWOR) were compared. Results Patients with TMD overall, and ADWR and ADWOR subgroups had significantly higher ADC, λ1, λ2, and λ3 in both the SHLPM and IHLPM than those in volunteers (p < 0.05 for all), whereas the ND subgroup only had significantly higher ADC and λ1 (p < 0.001). Meanwhile, significant differences in FA in the SHLPM and IHLPM were found between volunteers and ADWOR (p = 0.014 and p = 0.037, respectively). Among the three TMD subgroups, except for λ3 and FA in the ADWR subgroup, ADWR and ADWOR subgroups had significantly higher ADC, λ1, λ2, and λ3 and lower FA than those in the ND group (p < 0.050). There was no significant difference in diffusion variables between ADWR and ADWOR. In ADWOR, the osteoarthritis group had significantly higher λ3 and lower FA values in the IHLPM than those in the non-osteoarthritis group. Conclusion DTI successfully detected functional changes in the LPM in patients with TMD. The unsynchronized diffusivity changes in the LPM in different subgroups of TMD signified the possibility of using diffusion parameters as indicators to identify the severity of LPM hyperfunction at various stages of TMD.
Construction of a multiepitope vaccine candidate against Fasciola hepatica: an in silico design using various immunogenic excretory/secretory antigens

ABSTRACT Background Fasciola hepatica is an important pathogen that causes liver fluke disease in definitive hosts such as livestock animals and humans. Various excretory/secretory products have been used in serological diagnosis and vaccination studies targeting fasciolosis. There are no commercial vaccines against fasciolosis yet. Bioinformatic analysis based on computational methods have lower cost and provide faster output compared to conventional vaccine antigen discovery techniques. The aim of this study was to predict B- and T-cell specific epitopes of four excretory/secretory antigens (Kunitz-type serine protease inhibitor, cathepsin L1, helminth defense molecule, and glutathione S-transferase) of Fasciola hepatica and to construct a multiepitope vaccine candidate against fasciolosis. Methods and Results Initially, nonallergic and the highest antigenic B- and T- cell epitopes were selected and then, physico-chemical parameters, secondary and tertiary structures of designed multiepitope vaccine candidate were predicted. Tertiary structure was refined and validated using online bioinformatic tools. Linear and discontinuous B-cell epitopes and disulfide bonds were determined. Finally, molecular docking analysis for MHC-I and MHC-II receptors was performed. Conclusion This multi-epitope vaccine candidate antigen, with high immunological properties, can be considered as a promising vaccine candidate for animal experiments and wet lab studies.
Lipid droplets diversity and functions in inflammation and immune response

ABSTRACT Introduction Lipid droplets (LDs) are dynamic and evolutionary conserved lipid-enriched organelles composed of a core of neutral lipids surrounded by a monolayer of phospholipids associated with a diverse array of proteins that are cell- and stimulus-regulated. Far beyond being simply a deposit of neutral lipids, accumulating evidence demonstrate that LDs act as spatial and temporal local for lipid and protein compartmentalization and signaling organization. Areas covered This review focuses on the progress in our understanding of LD protein diversity and LD functions in the context of cell signaling and immune responses, highlighting the relationship between LD composition with the multiple roles of this organelle in immunometabolism, inflammation and host-response to infection. Expert opinion LDs are essential platforms for various cellular processes, including metabolic regulation, cell signaling, and immune responses. The functions of LD in infection and inflammatory disease are associated with the dynamic and complexity of their proteome. Our contemporary view place LDs as critical regulators of different inflammatory and infectious diseases and key markers of leukocyte activation.