Miracle-dz/UniFAR-FTUs huggingface dataset:
QTc interval and ventricular action potential prolongation in the Mecp2 Null/+ murine model of Rett syndrome

Rett Syndrome (RTT) is a congenital, X‐chromosome‐linked developmental disorder characterized by developmental delay, dysautonomia, and breathing irregularities. RTT is also associated with sudden death and QT intervals are prolonged in some RTT patients. Most individuals with RTT have mutations in the MECP2 gene. Whilst there is some evidence for QT prolongation in mouse models of RTT, there is comparatively little information on how loss of Mecp2 function affects ventricular action potentials (APs) and, to‐date, none on ventricular APs from female RTT mice. Accordingly, the present study was conducted to determine ECG and ventricular AP characteristics of Mecp2Null/+ female mice. ECG recordings from 12–13 month old female Mecp2Null/+ mice showed prolonged rate corrected QT (QTc) intervals compared to wild‐type (WT) controls. Although Mecp2Null/+ animals exhibited longer periods of apnoea than did controls, no correlation between apnoea length and QTc interval was observed. Action potentials (APs) from Mecp2Null/+ myocytes had longer APD90 values than those from WT myocytes and showed augmented triangulation. Application of the investigational INa,Late inhibitor GS‐6615 (eleclazine; 10 μM) reduced both APD90 and AP triangulation in Mecp2Null/+ and WT myocytes. These results constitute the first direct demonstration of delayed repolarization in Mecp2Null/+ myocytes and provide further evidence that GS‐6615 may have potential as an intervention against QT prolongation in RTT.
On axionic dark matter in Type IIA string theory

We investigate viable scenarios with various axions in the context of supersymmetric field theory and in globally consistent D‐brane models. The Peccei‐Quinn symmetry is associated with an anomalous U(1) symmetry, which acquires mass at the string scale but remains as a perturbative global symmetry at low energies. The origin of the scalar Higgs‐axion potential from F‐, D‐ and soft breaking terms is derived, and two Standard Model examples of global intersecting D6‐brane models in Type II orientifolds are presented, which differ in the realisation of the Higgs sector and in the hidden sector, the latter of which is of particluar importance for the soft supersymmetry breaking terms.
Flipped teaching transition to online teaching by STEM educators during the COVID-19 pandemic

COVID-19 necessitated online teaching (OT) during the second half of the spring 2020 semester. The perceptions of science, technology, engineering, and math (STEM) faculty of OT at a two-year (2-YI) and a four-year (4-YI) institution were examined during this sudden switchover. One group of educators had received flipped teaching (FT) training (FTEs, n = 23), whereas the other group was practicing traditional teaching (TTEs, n = 18). There were two cohorts of FTEs: cohort 1 were implementing FT for the third time in their classrooms, and cohort 2 had started for the first time. The survey results suggested that FTEs were more confident with OT than TTEs (P < 0.05). It was interesting to note that 62.5% of the FTEs, whether they were from cohort 1 or cohort 2, chose an asynchronous approach, whereas 37.5% delivered synchronous OT during the sudden transition. It was found that FT experience helped cohort 1 adjust to OT compared with cohort 2. Overall, these results suggest that FTEs were confident and their resources for FT eased the transition to OT. NEW & NOTEWORTHY COVID-19 necessitated online teaching (OT). The perceptions of STEM faculty of OT at two-year and four-year institutions were examined. One group had received flipped teaching (FT) training (FTEs), whereas the others practiced traditional teaching (TTEs). Among two cohorts of FTEs, cohort 1 had been practicing FT but not cohort 2. FTEs were more confident with OT than TTEs. FT experience helped cohort 1 adjust to OT more than cohort 2. Overall, FT eased the transition to OT.
CARM1-mediated methylation of ASXL2 impairs tumor-suppressive function of MLL3/COMPASS

An imbalance in the activities of the Polycomb and Trithorax complexes underlies numerous human pathologies, including cancer. The BRCA1 associated protein-1 (BAP1) deubiquitinase negatively regulates Polycomb activity and recruits the Trithorax histone H3K4 methyltransferase, mixed-lineage leukemia protein 3 (MLL3) within Complex Proteins Associated with Set1 (COMPASS), to the enhancers of tumor suppressor genes. We previously demonstrated that the BAP1-MLL3 pathway is mutated in several cancers, yet how BAP1 recruits MLL3 to its target loci remains an important unanswered question. We demonstrate that the ASXL2 subunit of the BAP1 complex mediates a direct interaction with MLL3/COMPASS. ASXL2 loss results in decreased MLL3 occupancy at enhancers and reduced BAP1-MLL3 target gene expression. Interaction between ASXL2 and MLL3 is negatively regulated by protein arginine methyltransferase 4 (PRMT4/CARM1), which methylates ASXL2 at R639/R641. ASXL2 methylation blocks binding to MLL3 and impairs the expression of MLL3/COMPASS-dependent genes. This previously unidentified transcriptional repressive function of CARM1 provides insight into the BAP1/MLL3-COMPASS axis and reveals a potential cancer therapeutic target.
Metabolic modulation of synaptic failure and thalamocortical hypersynchronization with preserved consciousness in Glut1 deficiency

Individuals with glucose transporter type I deficiency (G1D) habitually experience nutrient-responsive epilepsy associated with decreased brain glucose. However, the mechanistic association between blood glucose concentration and brain excitability in the context of G1D remains to be elucidated. Electroencephalography (EEG) in G1D individuals revealed nutrition time-dependent seizure oscillations often associated with preserved volition despite electrographic generalization and uniform average oscillation duration and periodicity, suggesting increased facilitation of an underlying neural loop circuit. Nonlinear EEG ictal source localization analysis and simultaneous EEG/functional magnetic resonance imaging converged on the thalamus-sensorimotor cortex as one potential circuit, and 18F-deoxyglucose positron emission tomography (18F-DG-PET) illustrated decreased glucose accumulation in this circuit. This pattern, reflected in a decreased thalamic to striatal 18F signal ratio, can aid with the PET imaging diagnosis of the disorder, whereas the absence of noticeable ictal behavioral changes challenges the postulated requirement for normal thalamocortical activity during consciousness. In G1D mice, 18F-DG-PET and mass spectrometry also revealed decreased brain glucose and glycogen, but preserved tricarboxylic acid cycle intermediates, indicating no overall energy metabolism failure. In brain slices from these animals, synaptic inhibition of cortical pyramidal neurons and thalamic relay neurons was decreased, and neuronal disinhibition was mitigated by metabolic sources of carbon; tonic-clonic seizures were also suppressed by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition. These results pose G1D as a thalamocortical synaptic disinhibition disease associated with increased glucose-dependent neuronal excitability, possibly in relation to reduced glycogen. Together with findings in other metabolic defects, inhibitory neuron dysfunction is emerging as a modulable mechanism of hyperexcitability. Description Decreased astrocyte-neuron glucose flux in G1D causes epileptogenic oscillations that are modulable by metabolic intervention. Fuel-dependent inhibition Glucose transporter type I deficiency (G1D) is characterized by reduced brain glucose and development of treatment-resistant epilepsy. Here, Rajasekaran et al. use electroencephalography and imaging data from individuals with G1D and showed that the thalamus/sensorimotor cortex circuit might be a critical area involved in the increased brain excitability and the development of seizures. In a mouse model of G1D, the authors showed no energy metabolism impairments, whereas synaptic inhibition of cortical pyramidal and thalamic cells was reduced. Switch in carbon source restored inhibitory activity, and inhibition of AMPA receptor reduced seizures in mice, suggesting that failure of the inhibitory synapses of the circuit might be the main cause of seizure activity in G1D.
Malignancies among newly diagnosed systemic lupus erythematosus patients and their survival

The objective of this study was to evaluate the incidence of malignancies among newly diagnosed systemic lupus erythematosus (SLE) patients compared to reference individuals. Another aim was to assess the survival of SLE patients with malignancy compared to references with malignancy. Finnish adult (>17 years) newly diagnosed SLE patients were identified by their drug reimbursement decisions made during 1.1. 2000–31.12. 2014 from the register of the Social Insurance Institution. For each case, three population controls were individually selected by age, sex and place of residence. Overall, 1006 SLE patients (women 84%), with a mean age of 45.5 years (SD 16 years) and 3005 population controls were linked to Finnish Cancer Registry, and the information about incident malignancies was retrieved from the day the special reimbursement decision for SLE medication was accepted (index day, ID) until 31.12. 2018 or until death. The patients diagnosed with malignancy were followed up until 31.12. 2019 considering survival. During the follow-up, 85 SLE patients (women 78%) and 192 controls (women 78%) had developed one or more malignancy after the ID. The incidence rate ratio for any malignancy was 1.41 (95% CI 1.08–1.85). The most common malignancy in SLE patients was non-Hodgkin lymphoma, with twelve cases. SLE patients with malignancy had a lower adjusted 15-year survival than controls with malignancy, 27.1% versus 52.4%, and the adjusted hazard ratio for death was 1.68 (95% CI 1.17–2.43). Our results confirm that SLE patients have a higher risk for overall malignancy. The results also suggest that SLE patients with malignancy have lower survival than their references with malignancy.
Dizziness After Traumatic Brain Injury: A Prospective TRACK-TBI Analysis of Risk Factors, Quality of Life, and Neurocognitive Effects

Objective To determine the longitudinal incidence of dizziness and its association with demographic factors, neurocognitive effects, functionality, and quality of life. Study Design Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) is a prospective, longitudinal cohort study in which TBI patients were assessed at the emergency department and 2-week, 3-month, 6-month, and 12-month follow-up via telephone and/or in-person visits. Setting Multicenter study in emergency departments of 18 academic medical centers in the United States. Patients A total of 1,514 patients 17 years or older with a diagnosis of TBI, injury occurrence within 24 hours of admission, fluency in English or Spanish, and completed Rivermead Post-Concussion Symptoms Questionnaire (RPQ) at 12 months were enrolled between February 2014 and August 2018. Main Outcome Measure RPQ, Short Form-12 Version 2, Wechsler Adult Intelligence Scale IV, Trail Making Test, Patient Health Questionnaire-9, PROMIS-PAIN, and Glasgow Outcome Scale–Extended Revised. The primary outcome measure was a self-report of “feelings of dizziness” on RPQ at 12 months post-TBI. Results Of the 1,514 participants, 1,002 (66%) were male and 512 (34%) were female. The mean age was 41.6 (SD, 17.4) years. At 12 months, 26% experienced dizziness, with 9% experiencing moderate or severe dizziness. Dizziness was strongly associated with headache (odds ratio [OR], 3.45; 95% confidence interval [CI], 2.92–4.07; p < 0.001), nausea (OR, 4.43; 95% CI, 3.45–5.69; p < 0.001), worse hearing (OR, 3.57; 95% CI, 2.64–4.82; p < 0.001), noise sensitivity (OR, 3.02; 95% CI, 2.54–3.59; p < 0.001), and light sensitivity (OR, 3.51; 95% CI, 2.91–4.23; p < 0.001). In multivariable regression models, participants with severe dizziness demonstrated lower performance compared with those without new or worse dizziness on the Wechsler Adult Intelligence Scale IV (−6.64; p < 0.001), Trail Making Test part A (7.90; p = 0.003) and part B (19.77; p = 0.028), and Short Form-12 physical (−13.60; p < 0.001) and mental health (−11.17; p < 0.001), after controlling for age, sex, education, and TBI severity. Conclusion Dizziness is common among TBI patients and relates to quality of life and neurocognitive performance.
Bacterial Transcription Factors Bind to Coding Regions and Regulate Internal Cryptic Promoters

Although bacterial TFs regulate transcription by binding to specific sequences at the promoter region, little is known about the mechanisms and functions of TFs binding within the CDS. In this study, we show that bacterial TFs have same binding pattern in both CDS and promoter regions, and we reveal three regulatory mechanisms of CDS-bound TF that together demonstrate the complexity of the regulatory mechanisms of bacterial TFs and the wide spread of internal cryptic promoters in CDS. ABSTRACT Transcription factors (TFs) regulate transcription by binding to the specific sequences at the promoter region. However, the mechanisms and functions of TFs binding within the coding sequences (CDS) remain largely elusive in prokaryotes. To this end, we collected 409 data sets for bacterial TFs, including 104 chromatin immunoprecipitation sequencing (ChIP-seq) assays and 305 data sets from the systematic evolution of ligands by exponential enrichment (SELEX) in seven model bacteria. Interestingly, these TFs displayed the same binding capabilities for both coding and intergenic regions. Subsequent biochemical and genetic experiments demonstrated that several TFs bound to the coding regions and regulated the transcription of the binding or adjacent genes. Strand-specific RNA sequencing revealed that these CDS-binding TFs regulated the activity of the cryptic promoters, resulting in the altered transcription of the corresponding antisense RNA. TF RhpR hindered the transcriptional elongation of a subgenic transcript within a CDS. A ChIP-seq and Ribo-seq coanalysis revealed that RhpR influenced the translational efficiency of binding genes. Taken together, the present study reveals three regulatory mechanisms of CDS-bound TFs within individual genes, operons, and antisense RNAs, which demonstrate the variability of the regulatory mechanisms of TFs and expand upon the complexity of bacterial transcriptomes. IMPORTANCE Although bacterial TFs regulate transcription by binding to specific sequences at the promoter region, little is known about the mechanisms and functions of TFs binding within the CDS. In this study, we show that bacterial TFs have same binding pattern in both CDS and promoter regions, and we reveal three regulatory mechanisms of CDS-bound TF that together demonstrate the complexity of the regulatory mechanisms of bacterial TFs and the wide spread of internal cryptic promoters in CDS.
“Jumping into the COVID‐19 arena”: The professional transition into clinical practice of new graduate nurses in Italy at time of COVID‐19

Abstract Aims and Objectives To evaluate the impact of the professional transition of new graduate nurses during the COVID‐19 pandemic. Background The transition from the role of student to the professional role can be challenging for new graduate nurses for the acquisition of higher autonomy and responsibility. The COVID‐19 pandemic impacted the quality of the professional transition. Design This was a cross‐sectional observational study following the Strengthening and Reporting of Observational Studies in Epidemiology checklist. Methods One hundred and two nurses who graduated in three consecutive sessions (November 2019—pre‐pandemic, March 2020—pandemic outbreak, and November 2020—2nd wave) in a north Italian university located in the most affected Italian region by the COVID‐19 pandemic, completed an online survey assessing well‐being, risk of burnout, resilience, perceived stigma, strengths and limitations and quality of the professional transition. The study was performed between March and May 2021. Results 81.4% of participants described the professional transition as worse than expected, and new graduate nurses who worked in COVID‐19 settings reported a more difficult transition to professional life. No differences emerged in burnout, mental well‐being and perceived stigma between new graduate nurses who worked in COVID‐19 settings and those who did not. Similarly, no differences emerged amongst the three graduated cohort sessions. The most commonly mentioned challenges faced during the transition were organisational aspects, suddenly acquired autonomy and lack of suitable coaching. Conclusion New graduate nurses reported a challenging academic‐professional transition, in particular, those who worked in COVID‐19 settings. The mid‐ and long‐term impact of experiencing an academic‐professional transition in COVID‐19 settings should be assessed and monitored. Relevance to clinical practice The professional transition of new graduate students should be adequately planned and monitored, new graduates should be assisted to develop realistic expectations about the transition, and an adequate coaching period should be guaranteed all the more during health emergencies.
On the migration of two planets in a disc and the formation of mean motion resonances

We study the dynamics of a system of two super-Earths embedded in a protoplanetary disc. We build a simple model of an irradiated viscous disc and use analytical prescriptions for the planet-disc interactions which lead to migration. We show that depending on the disc parameters, planets' masses and their positions in the disc, the migration of each planet can be inward or outward and the migration of a two-planet system can be convergent (which may lead to formation of a first order mean motion resonance, MMR) or divergent (a system moves away from MMR). We performed $3500$ simulations of the migration of two-planet systems with various masses and initial orbits. Almost all of them end up as resonant configurations, although the period ratios may be very distant from the nominal values of a given MMR. We found that almost all the systems resulting from the migration are periodic configurations.
The role of the efflux transporter, P‐glycoprotein, at the blood–brain barrier in drug discovery

The blood–brain barrier (BBB) expresses a high abundance of transporters, particularly P‐glycoprotein (P‐gp), that regulate endogenous and exogenous molecule uptake and removal of waste. This review discusses key drug metabolism and pharmacokinetic considerations for the efflux transporter P‐gp at the BBB in drug discovery and development. We highlight the differences in P‐gp expression and protein levels across species but the limited observations of species‐specific substrates. Given the impact of age and disease on BBB biology, we summarise the modulation of P‐gp for several neurological disorders and ageing and exemplify several disease‐specific hurdles or opportunities for drug exposure in the brain. Furthermore, the review includes observations of CNS‐related drug‐drug interactions due to the inhibition or induction of P‐gp at the BBB in animal studies and humans and the need for continued evaluation especially for compounds with a narrow therapeutic window. This review focusses primarily on small molecules but also considers the impact of new chemical entities, particularly beyond Ro5 molecules and their potential to be recognised as P‐gp substrates as well as advanced drug delivery systems which offer an alternative approach to achieve and sustain central nervous system exposure.
Synthesis and Use of the Bifunctional Sulfenic Acid Probe BCN‐E‐BCN for In Vitro and Cell‐Based Assays of Protein Oxidation

The reversible oxidation of cysteine thiol groups to sulfenic acid by reactive oxygen species (ROS) such as hydrogen peroxide can impact protein function, activity, and localization. As a consequence, ROS have profound effects on cell functions including proliferation, differentiation, and survival. Furthermore, there are clear associations between the effects of ROS on cells and the etiology of several diseases including cancer and neurodegeneration. In spite of the importance of cysteine sulfenylation as a validated post‐translational modification, its labile nature impedes efficient and reproducible detection of proteins with cysteine sulfenic acid residues. To overcome this challenge, we developed a novel cell‐permeable bifunctional reagent, consisting of two linked bicyclo[6.1. 0]nonyne (BCN) moieties coupled with a short ethylenediamine‐derived linker (BCN‐E‐BCN) that enables the detection of sulfenylated proteins in vitro and in intact cells. The two symmetrical BCN groups allow protein sulfenic acids to be selectively tagged with a BCN at one end while allowing for copper‐free click chemistry with azide‐tagged reagents of the opposite BCN. In this protocol, the synthesis of BCN‐E‐BCN and its use to detect cysteine sulfenic acids will be detailed. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC.
RADIATIVELY INEFFICIENT ACCRETION FLOWS INDUCED BY GRAVITATIONAL-WAVE EMISSION BEFORE MASSIVE BLACK HOLE COALESCENCE

We study an accretion flow during the gravitational-wave driven evolution of binary massive black holes. After the binary orbit decays due to an interaction with a massive circumbinary disk, the binary is decoupled from the circumbinary disk because the orbital-decay timescale due to emission of gravitational wave becomes shorter than the viscous timescale evaluated at the inner edge of circumbinary disk. During the subsequent evolution, the accretion disk, which is truncated at the tidal radius because of the tidal torque, also shrinks as the orbital decay. Assuming that the disk mass changed by this process is all accreted, the disk becomes radiatively inefficient when the semimajor axis is several hundred Schwarzschild radii. The high-energy radiations, in spite of a low bolometric luminosity, are emitted from an accretion disk around each black hole long before the black hole coalescence, as well as the gravitational wave signals. The synchrotron process can notably produce potentially observable radio emissions at large distances if there is a strong magnetic field with an equipartition value. By the addition of the assumption of a dipole magnetic field, step-like light variations are seen in the observed light curve because the luminosity is higher and its duration time is shorter in the radio emission by the disk around the secondary black hole than that of the primary black hole. Such a precursor would be unique to not a single black hole system but a binary black hole system, and implies that binary black holes finally merge without accretion disks.