Miracle-dz/UniFAR-FTUs huggingface dataset:
Overlap Arrhythmia Syndromes Resulting from Multiple Genetic Variations Studied in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for genetic models of cardiac diseases. We report an arrhythmia syndrome consisting of Early Repolarization Syndrome (ERS) and Short QT Syndrome (SQTS). The index patient (MMRL1215) developed arrhythmia-mediated syncope after electrocution and was found to carry six mutations. Functional alterations resulting from these mutations were examined in patient-derived hiPSC-CMs. Electrophysiological recordings were made in hiPSC-CMs from MMRL1215 and healthy controls. ECG analysis of the index patient showed slurring of the QRS complex and QTc = 326 ms. Action potential (AP) recordings from MMRL1215 myocytes showed slower spontaneous activity and AP duration was shorter. Field potential recordings from MMRL1215 hiPSC-CMs lack a “pseudo” QRS complex suggesting reduced inward current(s). Voltage clamp analysis of ICa showed no difference in the magnitude of current. Measurements of INa reveal a 60% reduction in INa density in MMRL1215 hiPSC-CMs. Steady inactivation and recovery of INa was unaffected. mRNA analysis revealed ANK2 and SCN5A are significantly reduced in hiPSC-CM derived from MMRL1215, consistent with electrophysiological recordings. The polygenic cause of ERS/SQTS phenotype is likely due to a loss of INa due to a mutation in PKP2 coupled with and a gain of function in IK,ATP due to a mutation in ABCC9.
In silico-driven analysis of the Glossina morsitans morsitans antennae transcriptome in response to repellent or attractant compounds

Background High-throughput sequencing generates large volumes of biological data that must be interpreted to make meaningful inference on the biological function. Problems arise due to the large number of characteristics p (dimensions) that describe each record [n] in the database. Feature selection using a subset of variables extracted from the large datasets is one of the approaches towards solving this problem. Methodology In this study we analyzed the transcriptome of Glossina morsitans morsitans (Tsetsefly) antennae after exposure to either a repellant (δ-nonalactone) or an attractant (ε-nonalactone). We identified 308 genes that were upregulated or downregulated due to exposure to a repellant (δ-nonalactone) or an attractant (ε-nonalactone) respectively. Weighted gene coexpression network analysis was used to cluster the genes into 12 modules and filter unconnected genes. Discretized and association rule mining was used to find association between genes thereby predicting the putative function of unannotated genes. Results and discussion Among the significantly expressed chemosensory genes (FDR < 0.05) in response to Ɛ-nonalactone were gustatory receptors (GrIA and Gr28b), ionotrophic receptors (Ir41a and Ir75a), odorant binding proteins (Obp99b, Obp99d, Obp59a and Obp28a) and the odorant receptor (Or67d). Several non-chemosensory genes with no assigned function in the NCBI database were co-expressed with the chemosensory genes. Exposure to a repellent (δ-nonalactone) did not show any significant change between the treatment and control samples. We generated a coexpression network with 276 edges and 130 nodes. Genes CAH3, Ahcy, Ir64a, Or67c, Ir8a and Or67a had node degree values above 11 and therefore could be regarded as the top hub genes in the network. Association rule mining showed a relation between various genes based on their appearance in the same itemsets as consequent and antecedent.
A Short-Term Medical Mission in Rural Nepal: Chief Complaints, Medications Dispensed, and Unmet Health Needs

Background Although Nepal is striving to expand primary health services for its citizens, many remote areas have limited access to basic health care. Short-term medical missions (STMMs) are one way of supplementing human resources for health in underserved areas. This article describes the chief complaints, medications dispensed, and unmet health needs during an STMM in rural Nepal. Methods This study is a retrospective analysis of data collected during an STMM that occurred in October 2017. Deidentified data from clinic intake forms were entered into an Excel spreadsheet, and formatted and cleaned. Demographics, chief complaints, medications, and unmet health needs were analyzed using descriptive statistics. Results During a two-day health camp, 443 patients were seen. The most common chief complaint was dental (33.4%) followed by musculoskeletal (28.2%) and gastrointestinal (21.2%). Medications were dispensed to 94.8% of patients, primarily analgesics, antibiotics, and ophthalmologic preparations. Of the patients, 21% had unmet health needs, including specialty care and labs or imaging that were beyond the scope of the STMM. One patient was referred urgently to a hospital for treatment of dyspnea and markedly elevated blood pressure. Conclusion While STMMs cannot replace access to primary health services, they can provide insight into acute care needs in a system that has limited surveillance. This information describing an acute care patient population should inform future development work.
Effects of Venlafaxine, Risperidone and Febuxostat on Cuprizone-Induced Demyelination, Behavioral Deficits and Oxidative Stress

Multiple sclerosis (MS) is a demyelinating, autoimmune disease that affects a large number of young adults. Novel therapies for MS are needed considering the efficiency and safety limitations of current treatments. In our study, we investigated the effects of venlafaxine (antidepressant, serotonin-norepinephrine reuptake inhibitor), risperidone (atypical antipsychotic) and febuxostat (gout medication, xanthine oxidase inhibitor) in the cuprizone mouse model of acute demyelination, hypothesizing an antagonistic effect on TRPA1 calcium channels. Cuprizone and drugs were administered to C57BL6/J mice for five weeks and locomotor activity, motor performance and cold sensitivity were assessed. Mice brains were harvested for histological staining and assessment of oxidative stress markers. Febuxostat and metabolites of venlafaxine (desvenlafaxine) and risperidone (paliperidone) were tested for TRPA1 antagonistic activity. Following treatment, venlafaxine and risperidone significantly improved motor performance and sensitivity to a cold stimulus. All administered drugs ameliorated the cuprizone-induced deficit of superoxide dismutase activity. Desvenlafaxine and paliperidone showed no activity on TRPA1, while febuxostat exhibited agonistic activity at high concentrations. Our findings indicated that all three drugs offered some protection against the effects of cuprizone-induced demyelination. The agonistic activity of febuxostat can be of potential use for discovering novel TRPA1 ligands.
Efficiency of Prolonged Prone Positioning for Mechanically Ventilated Patients Infected with COVID-19

Hypoxemia of the acute respiratory distress syndrome can be reduced by turning patients prone. Prone positioning (PP) is labor intensive, risks unplanned tracheal extubation, and can result in facial tissue injury. We retrospectively examined prolonged, repeated, and early versus later PP for 20 patients with COVID-19 respiratory failure. Blood gases and ventilator settings were collected before PP, at 1, 7, 12, 24, 32, and 39 h after PP, and 7 h after completion of PP. Analysis of variance was used for comparisons with baseline values at supine positions before turning prone. PP for >39 h maintained PaO2/FiO2 (P/F) ratios when turned supine; the P/F decrease at 7 h was not significant from the initial values when turned supine. Patients turned prone a second time, when again turned supine at 7 h, had significant decreased P/F. When PP started for an initial P/F ≤ 150 versus P/F > 150, the P/F increased throughout the PP and upon return to supine. Our results show that a single turn prone for >39 h is efficacious and saves the burden of multiple prone turns, and there is no significant advantage to initiating PP when P/F > 150 compared to P/F ≤ 150.
The complete chloroplast genome of Euphorbia hirta (Euphorbiaceae), a commonly used medicinal plant in China

Abstract Plants in the genus Euphorbia have been widely used as herbal medicine, and for ornamental horticulture and biofuel production. In this study, we report the complete chloroplast genome of Euphorbia hirta which is known as the ‘asthma-plant’ due to its medicinal use. The chloroplast genome of this species is 164,340 bp in length, including a pair of inverted repeat regions (IRs) (27,354 bp) that are divided by a large single-copy region (LSC) (91,373 bp) and a small single-copy region (SSC) (18,259 bp). The chloroplast genome of E. hirta contains 111 unique genes (77 protein-coding, 30 tRNA, and four rRNA), 19 of which are duplicated in the IR regions. The overall GC content is 35.4%. Phylogenetic analysis fully resolved E. hirta groups with other species of Euphorbia. The complete chloroplast genome of E. hirta provides useful information that can be used to distinguish related species and reconstruct evolutionary relationships.
Structural and Drug Targeting Insights on Mutant p53

Simple Summary The tumor suppressor protein p53 is frequently mutated in human cancers, and its reactivation represents an encouraging hope for precision anticancer therapy. Despite this, the clinical use of compounds capable of restoring the wild-type-like function to mutant p53 (mutp53) is not yet a reality. A more detailed understanding of the structural features of p53 mutations and the molecular mechanisms of mutp53 reactivators is critical to drive an efficient translation of these compounds into the clinic. In addition, this knowledge will provide insights into wild-type and mutp53 pharmacology at molecular levels, fostering the design and development of improved mutp53-targeted therapies to halt cancer. Abstract p53 is a transcription factor with a pivotal role in cell homeostasis and fate. Its impairment is a major event in tumor onset and development. In fact, about half of human cancers bear TP53 mutations that not only halt the normal function of p53, but also may acquire oncogenic gain of functions that favor tumorigenesis. Although considered undruggable for a long time, evidence has proven the capability of many compounds to restore a wild-type (wt)-like function to mutant p53 (mutp53). However, they have not reached the clinic to date. Structural studies have strongly contributed to the knowledge about p53 structure, stability, dynamics, function, and regulation. Importantly, they have afforded relevant insights into wt and mutp53 pharmacology at molecular levels, fostering the design and development of p53-targeted anticancer therapies. Herein, we provide an integrated view of mutp53 regulation, particularly focusing on mutp53 structural traits and on targeting agents capable of its reactivation, including their biological, biochemical and biophysical features. With this, we expect to pave the way for the development of improved small molecules that may advance precision cancer therapy by targeting p53.
Systematic Understanding of Recent Developments in Bacterial Cellulose Biosynthesis at Genetic, Bioprocess and Product Levels

Engineering biological processes has become a standard approach to produce various commercially valuable chemicals, therapeutics, and biomaterials. Among these products, bacterial cellulose represents major advances to biomedical and healthcare applications. In comparison to properties of plant cellulose, bacterial cellulose (BC) shows distinctive characteristics such as a high purity, high water retention, and biocompatibility. However, low product yield and extensive cultivation times have been the main challenges in the large-scale production of BC. For decades, studies focused on optimization of cellulose production through modification of culturing strategies and conditions. With an increasing demand for BC, researchers are now exploring to improve BC production and functionality at different categories: genetic, bioprocess, and product levels as well as model driven approaches targeting each of these categories. This comprehensive review discusses the progress in BC platforms categorizing the most recent advancements under different research focuses and provides systematic understanding of the progress in BC biosynthesis. The aim of this review is to present the potential of ‘modern genetic engineering tools’ and ‘model-driven approaches’ on improving the yield of BC, altering the properties, and adding new functionality. We also provide insights for the future perspectives and potential approaches to promote BC use in biomedical applications.
Stage-Specific Role of Amelx Activation in Stepwise Ameloblast Induction from Mouse Induced Pluripotent Stem Cells

Amelogenin comprises ~90% of enamel proteins; however, the involvement of Amelx transcriptional activation in regulating ameloblast differentiation from induced pluripotent stem cells (iPSCs) remains unknown. In this study, we generated doxycycline-inducible Amelx-expressing mouse iPSCs (Amelx-iPSCs). We then established a three-stage ameloblast induction strategy from Amelx-iPSCs, including induction of surface ectoderm (stage 1), dental epithelial cells (DECs; stage 2), and ameloblast lineage (stage 3) in sequence, by manipulating several signaling molecules. We found that adjunctive use of lithium chloride (LiCl) in addition to bone morphogenetic protein 4 and retinoic acid promoted concentration-dependent differentiation of DECs. The resulting cells had a cobblestone appearance and keratin14 positivity. Attenuation of LiCl at stage 3 together with transforming growth factor β1 and epidermal growth factor resulted in an ameloblast lineage with elongated cell morphology, positivity for ameloblast markers, and calcium deposition. Although stage-specific activation of Amelx did not produce noticeable phenotypic changes in ameloblast differentiation, Amelx activation at stage 3 significantly enhanced cell adhesion as well as decreased proliferation and migration. These results suggest that the combination of inducible Amelx transcription and stage-specific ameloblast induction for iPSCs represents a powerful tool to highlight underlying mechanisms in ameloblast differentiation and function in association with Amelx expression.
Static lattice energy minimization and lattice dynamics calculations on aluminosilicate minerals

Lattice energy minimization and lattice dynamics calculations for the minerals andalusite, sillimanite, kyanite, diopside, cordierite, gehlenite, leucite, orthozoisite, grossular, and pyrope are compared with experimental data and previous calculations. The potential models used in this study included bond-bending interactions, short-range Born-Mayer forces, effective dispersive interactions, long-range Coulomb interactions, and harmonic core-shell interactions for the 0 ions. Parameters for the potential models were generally taken from the literature, but the core-shell force constant was modified to give better agreement with experimental data for refractive indices. It was necessary to include bondbending interactions for AI-O polyhedra with coordination numbers even larger than four. A method for describing effective potentials with Al-Si disorder and solid-solution is presented. Modified Morse and Buckingham potentials were used to model O-H bonds. Relaxed energy-minimum structures were calculated, allowing cell parameters to change and treating atomic cores and shells as independent entities within the adiabatic approximation. Calculated phonon frequencies for the relaxed structures were used to construct thermodynamic functions. Elastic and dielectric constants were also calculated. Comparisons between calculated structures and other properties with experimental data have shown that the model is genuinely transferable and gives reasonable predictions of crystallographic, physical, and thermodynamic properties. Detailed analysis gives a measure of the reliability of the model.
Off-hour effect is not significant in endovascular treatment for anterior circulation large vessel occlusion in a multicentre registry

Background and purpose Whether the off-hour effect has an impact on workflow and outcomes of endovascular treatment (EVT) for anterior circulation large vessel occlusion (AC-LVO) remains uncertain. This study aimed to compare the characteristics and outcomes of patients who presented or were treated during off-hour versus on-hour in a multi-center registry. Methods AC-LVO patients from 21 centres were categorised into the off-hour group and the on-hour group. Off-hour (weekends, holidays, and 18:00–7:59 on weekdays) and on-hour (8:00–17:59 on weekdays except for holidays) were defined according to arrival and groin-puncture time points, respectively. Subgroup comparisons between patients both arrived and treated during off-hour (true off-hour) and on-hour (true on-hour) were performed. The primary outcome was the 90-day modified Rankin Scale (mRS) score. Secondary outcomes included favourable outcome (mRS 0–2 at 90 days), EVT-related time metrics, and other clinical outcomes. Ordinary and binary logistic regression and linear regression were taken to adjust for confounding factors. Results Of all 698 patients enrolled, 435 (62.3%) and 456 (65.3%) patients were categorised into the off-hour arrival and off-hour puncture group, respectively. Shorter onset to door time (adjusted ß coefficient: −21.56; 95% CI −39.96 to −3.16; p=0.022) was noted in the off-hour arrival group. Ordinal and dichotomous mRS scores at 90 days were comparable between the off-hour group and the on-hour group regardless of off-hour definitions. Other time metrics and outcomes were comparable between the two groups. Of 595 patients both presented and were treated during off-hour or on-hour, 394 patients were categorised into the true off-hour group and 201 into the true on-hour group. Time metrics and clinical outcomes were similar between the true off-hour and the true on-hour group. Conclusions The off-hour effect was not significant regarding clinical outcomes and in-hospital workflow in AC-LVO patients receiving EVT in this Chinese multicentre registry.
Strategic Distractor Suppression Improves Selective Control in Human Vision

Our visual environment is complicated, and our cognitive capacity is limited. As a result, we must strategically ignore some stimuli to prioritize others. Common sense suggests that foreknowledge of distractor characteristics, like location or color, might help us ignore these objects. But empirical studies have provided mixed evidence, often showing that knowing about a distractor before it appears counterintuitively leads to its attentional selection. What has looked like strategic distractor suppression in the past is now commonly explained as a product of prior experience and implicit statistical learning, and the long-standing notion the distractor suppression is reflected in α band oscillatory brain activity has been challenged by results appearing to link α to target resolution. Can we strategically, proactively suppress distractors? And, if so, does this involve α? Here, we use the concurrent recording of human EEG and eye movements in optimized experimental designs to identify behavior and brain activity associated with proactive distractor suppression. Results from three experiments show that knowing about distractors before they appear causes a reduction in electrophysiological indices of covert attentional selection of these objects and a reduction in the overt deployment of the eyes to the location of the objects. This control is established before the distractor appears and is predicted by the power of cue-elicited α activity over the visual cortex. Foreknowledge of distractor characteristics therefore leads to improved selective control, and α oscillations in visual cortex reflect the implementation of this strategic, proactive mechanism. SIGNIFICANCE STATEMENT To behave adaptively and achieve goals we often need to ignore visual distraction. Is it easier to ignore distracting objects when we know more about them? We recorded eye movements and electrical brain activity to determine whether foreknowledge of distractor characteristics can be used to limit processing of these objects. Results show that knowing the location or color of a distractor stops us from attentionally selecting it. A neural signature of this inhibition emerges in oscillatory alpha band brain activity, and when this signal is strong, selective processing of the distractor decreases. Knowing about the characteristics of task-irrelevant distractors therefore increases our ability to focus on task-relevant information, in this way gating information processing in the brain.
Optical Coherence Tomography and Glaucoma.

Early detection and monitoring are critical to the diagnosis and management of glaucoma, a progressive optic neuropathy that causes irreversible blindness. Optical coherence tomography (OCT) has become a commonly utilized imaging modality that aids in the detection and monitoring of structural glaucomatous damage. Since its inception in 1991, OCT has progressed through multiple iterations, from time-domain OCT, to spectral-domain OCT, to swept-source OCT, all of which have progressively improved the resolution and speed of scans. Even newer technological advancements and OCT applications, such as adaptive optics, visible-light OCT, and OCT-angiography, have enriched the use of OCT in the evaluation of glaucoma. This article reviews current commercial and state-of-the-art OCT technologies and analytic techniques in the context of their utility for glaucoma diagnosis and management, as well as promising future directions. Expected final online publication date for the Annual Review of Vision Science, Volume 7 is September 2021. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.