Miracle-dz/UniFAR-FTUs huggingface dataset:
Improved Cognitive Promotion through Accelerated Magnetic Stimulation

Abstract Noninvasive brain stimulation to enhance cognition is an area of increasing research interest. Theta burst stimulation (TBS) is a novel accelerated form of stimulation, which more closely mimics the brain’s natural firing patterns and may have greater effects on cognitive performance. We report here the comparative assessment of the effect of conventional high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) protocols and TBS protocols on cognition enhancement in healthy controls. Sixty healthy adults (34 males and 26 females) were randomized and counterbalanced and assigned to HF-rTMS (n = 20), TBS (n = 20), or sham (n = 20) groups. The promotion effects of different parameters of prefrontal stimulation on working memory and executive function were compared, as assessed by performance in N-back tasks and the Wisconsin Card Sorting Test (WCST). Both HF-rTMS and intermittent TBS (iTBS) groups displayed a significant improvement in N-back tasks, with an effect size of 0.79 and 1.50, respectively. Furthermore, the iTBS group displayed a significant improvement in the WCST, with an effect size of 0.84. The iTBS group demonstrated higher effect sizes than the HF-rTMS group (t = 2.68, p = 0.011), with an effect size of 0.85. However, no improvement in other tasks was observed (p > 0.05). Intermittent TBS has a stronger cognitive promoting effect than conventional rTMS. In summary, our findings provide direct evidence that iTBS may be a superior protocol for cognitive promotion.
Molecular Epidemiology of Enterovirus in Children with Central Nervous System Infections

Limited recent molecular epidemiology data are available for pediatric Central Nervous System (CNS) infections in Europe. The aim of this study was to investigate the molecular epidemiology of enterovirus (EV) involved in CNS infections in children. Cerebrospinal fluid (CSF) from children (0–16 years) with suspected meningitis–encephalitis (ME) who were hospitalized in the largest pediatric hospital of Greece from October 2017 to September 2020 was initially tested for 14 common pathogens using the multiplex PCR FilmArray® ME Panel (FA-ME). CSF samples positive for EV, as well as pharyngeal swabs and stools of the same children, were further genotyped employing Sanger sequencing. Of the 330 children tested with FA-ME, 75 (22.7%) were positive for EV and 50 different CSF samples were available for genotyping. The median age of children with EV CNS infection was 2 months (IQR: 1–60) and 44/75 (58.7%) of them were male. There was a seasonal distribution of EV CNS infections, with most cases detected between June and September (38/75, 50.7%). EV genotyping was successfully processed in 84/104 samples: CSF (n = 45/50), pharyngeal swabs (n = 15/29) and stools (n = 24/25). Predominant EV genotypes were CV-B5 (16/45, 35.6%), E30 (10/45, 22.2%), E16 (6/45, 13.3%) and E11 (5/45, 11.1%). However, significant phylogenetic differences from previous described isolates were detected. No unusual neurologic manifestations were observed, and all children recovered without obvious acute sequelae. Specific EV circulating genotypes are causing a significant number of pediatric CNS infections. Phylogenetic analysis of these predominant genotypes found genetic differences from already described EV isolates.
Strategies to Better Target Fungal Squalene Monooxygenase

Fungal pathogens present a challenge in medicine and agriculture. They also harm ecosystems and threaten biodiversity. The allylamine class of antimycotics targets the enzyme squalene monooxygenase. This enzyme occupies a key position in the sterol biosynthesis pathway in eukaryotes, catalyzing the rate-limiting reaction by introducing an oxygen atom to the squalene substrate converting it to 2,3-oxidosqualene. Currently, terbinafine—the most widely used allylamine—is mostly used for treating superficial fungal infections. The ability to better target this enzyme will have significant implications for human health in the treatment of fungal infections. The human orthologue can also be targeted for cholesterol-lowering therapeutics and in cancer therapies. This review will focus on the structural basis for improving the current therapeutics for fungal squalene monooxygenase.
Interplay between tau and α‐synuclein liquid–liquid phase separation

In Parkinson's disease with dementia, up to 50% of patients develop a high number of tau‐containing neurofibrillary tangles. Tau‐based pathologies may thus act synergistically with the α‐synuclein pathology to confer a worse prognosis. A better understanding of the relationship between the two distinct pathologies is therefore required. Liquid–liquid phase separation (LLPS) of proteins has recently been shown to be important for protein aggregation involved in amyotrophic lateral sclerosis, whereas tau phase separation has been linked to Alzheimer's disease. We therefore investigated the interaction of α‐synuclein with tau and its consequences on tau LLPS. We find α‐synuclein to have a low propensity for both, self‐coacervation and RNA‐mediated LLPS at pH 7.4. However, full‐length but not carboxy‐terminally truncated α‐synuclein efficiently partitions into tau/RNA droplets. We further demonstrate that Cdk2‐phosphorylation promotes the concentration of tau into RNA‐induced droplets, but at the same time decreases the amount of α‐synuclein inside the droplets. NMR spectroscopy reveals that the interaction of the carboxy‐terminal domain of α‐synuclein with the proline‐rich region P2 of tau is required for the recruitment of α‐synuclein into tau droplets. The combined data suggest that the concentration of α‐synuclein into tau‐associated condensates can contribute to synergistic aSyn/tau pathologies.
Structural and Biochemical Analysis Reveals a Distinct Catalytic Site of Salicylate 5-Monooxygenase NagGH from Rieske Dioxygenases

Rieske oxygenases are involved in the degradation of various aromatic compounds. These dioxygenases usually carry out hydroxylation of hydrophobic aromatic compounds and supply substrates with hydroxyl groups for extradiol/intradiol dioxygenases to cleave rings, and have been extensively studied. Salicylate 5-hydroxylase NagGH is a novel Rieske monooxygenase with high similarity to Rieske dioxygenases, and also shares reductase and ferredoxin similarity with a Rieske dioxygenase naphthalene 1,2-dioxygenase (NagAcAd) in Ralstonia sp. strain U2. ABSTRACT Rieske nonheme iron oxygenases (ROs) catalyze the oxidation of a wide variety of substrates and play important roles in aromatic compound degradation and polycyclic aromatic hydrocarbon degradation. Those Rieske dioxygenases that usually act on hydrophobic substrates have been extensively studied and structurally characterized. Here, we report the crystal structure of a novel Rieske monooxygenase, NagGH, the oxygenase component of a salicylate 5-monooxygenase from Ralstonia sp. strain U2 that catalyzes the hydroxylation of a hydrophilic substrate salicylate (2-hydroxybenzoate), forming gentisate (2, 5-dihydroxybenzoate). The large subunit NagG and small subunit NagH share the same fold as that for their counterparts of Rieske dioxygenases and assemble the same α3β3 hexamer, despite that they share low (or no identity for NagH) sequence identities with these dioxygenase counterparts. A potential substrate-binding pocket was observed in the vicinity of the nonheme iron site. It featured a positively charged residue Arg323 that was surrounded by hydrophobic residues. The shift of nonheme iron atom caused by residue Leu228 disrupted the usual substrate pocket observed in other ROs. Residue Asn218 at the usual substrate pocket observed in other ROs was likewise involved in substrate binding and oxidation, yet residues Gln316 and Ser367, away from the usual substrate pocket of other ROs, were shown to play a more important role in substrate oxidation than Asn218. The unique binding pocket and unusual substrate-protein hydrophilic interaction provide new insights into Rieske monooxygenases. IMPORTANCE Rieske oxygenases are involved in the degradation of various aromatic compounds. These dioxygenases usually carry out hydroxylation of hydrophobic aromatic compounds and supply substrates with hydroxyl groups for extradiol/intradiol dioxygenases to cleave rings, and have been extensively studied. Salicylate 5-hydroxylase NagGH is a novel Rieske monooxygenase with high similarity to Rieske dioxygenases, and also shares reductase and ferredoxin similarity with a Rieske dioxygenase naphthalene 1,2-dioxygenase (NagAcAd) in Ralstonia sp. strain U2. The structure of NagGH, the oxygenase component of salicylate 5-monooxygenase, gives a representative of those monooxygenases and will help us understand the mechanism of their substrate binding and product regio-selectivity.
Simulation of Pulse-Echo Radar for Vehicle Control and SLAM

Pulse-echo sensing is the driving principle behind biological echolocation as well as biologically-inspired sonar and radar sensors. In biological echolocation, a single emitter sends a self-generated pulse into the environment which reflects off objects. A fraction of these reflections are captured by two receivers as echoes, from which information about the objects, such as their position in 3D space, can be deduced by means of timing, intensity and spectral analysis. This is opposed to frequency-modulated continuous-wave radar, which analyses the shift in frequency of the returning signal to determine distance, and requires an array of antenna to obtain directional information. In this work, we present a novel simulator which can generate synthetic pulse-echo measurements for a simulated sensor in a virtual environment. The simulation is implemented by replicating the relevant physical processes underlying the pulse-echo sensing modality, while achieving high performance at update rates above 50 Hz. The system is built to perform design space exploration of sensor hardware and software, with the goals of rapid prototyping and preliminary safety testing in mind. We demonstrate the validity of the simulator by replicating real-world experiments from previous work. In the first case, a subsumption architecture vehicle controller is set to navigate an unknown environment using the virtual sensor. We see the same trajectory pattern emerge in the simulated environment rebuilt from the real experiment, as well as similar activation times for the high-priority behaviors (±1.9%), and low-priority behaviors (±0.2%). In a second experiment, the simulated signals are used as input to a biologically-inspired direct simultaneous mapping and localization (SLAM) algorithm. Using only path integration, 83% of the positional errors are larger than 10 m, while for the SLAM algorithm 95% of the errors are smaller than 3.2 m. Additionally, we perform design space exploration using the simulator. By creating a synthetic radiation pattern with increased spatiospectral variance, we are able to reduce the average localization error of the system by 11%. From these results, we conclude that the simulation is sufficiently accurate to be of use in developing vehicle controllers and SLAM algorithms for pulse-echo radar sensors.
Miniaturization: How many cells are needed to build a tooth?

Organs that develop early in life, and are replaced by a larger version as the animal grows, often represent a miniature version of the adult organ. Teeth constituting the first functional dentition in small‐sized teleost fish, such as medaka (Oryzias latipes), are examples of such miniature organs. With a dentin cone as small as the size of one human cell, or even smaller, these teeth raise the question how many dentin‐producing cells (odontoblasts) are required to build such a tooth, and whether this number can be as little as one.
Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes

PURPOSE Approximately 20% of patients with TP53-mutant myelodysplastic syndromes (MDS) achieve complete remission (CR) with hypomethylating agents. Eprenetapopt (APR-246) is a novel, first-in-class, small molecule that restores wild-type p53 functions in TP53-mutant cells. METHODS This was a phase Ib/II study to determine the safety, recommended phase II dose, and efficacy of eprenetapopt administered in combination with azacitidine in patients with TP53-mutant MDS or acute myeloid leukemia (AML) with 20%-30% marrow blasts (ClinicalTrials.gov identifier: NCT03072043). RESULTS Fifty-five patients (40 MDS, 11 AML, and four MDS/myeloproliferative neoplasms) with at least one TP53 mutation were treated. The overall response rate was 71% with 44% achieving CR. Of patients with MDS, 73% (n = 29) responded with 50% (n = 20) achieving CR and 58% (23/40) a cytogenetic response. The overall response rate and CR rate for patients with AML was 64% (n = 7) and 36% (n = 4), respectively. Patients with only TP53 mutations by next-generation sequencing had higher rates of CR (69% v 25%; P = .006). Responding patients had significant reductions in TP53 variant allele frequency and p53 expression by immunohistochemistry, with 21 (38%) achieving complete molecular remission (variant allele frequency < 5%). Median overall survival was 10.8 months with significant improvement in responding versus nonresponding patients by landmark analysis (14.6 v 7.5 months; P = .0005). Overall, 19/55 (35%) patients underwent allogeneic hematopoietic stem-cell transplant, with a median overall survival of 14.7 months. Adverse events were similar to those reported for azacitidine or eprenetapopt monotherapy, with the most common grade ≥ 3 adverse events being febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%). CONCLUSION Combination treatment with eprenetapopt and azacitidine is well-tolerated yielding high rates of clinical response and molecular remissions in patients with TP53-mutant MDS and oligoblastic AML.
In Vivo Inhibition of Marek’s Disease Virus in Transgenic Chickens Expressing Cas9 and gRNA against ICP4

Marek’s disease (MD), caused by MD herpesvirus (MDV), is an economically important disease in chickens. The efficacy of the existing vaccines against evolving virulent stains may become limited and necessitates the development of novel antiviral strategies to protect poultry from MDV strains with increased virulence. The CRISPR/Cas9 system has emerged as a powerful genome editing tool providing an opportunity to develop antiviral strategies for the control of MDV infection. Here, we characterized Tol2 transposon constructs encoding Cas9 and guide RNAs (gRNAs) specific to the immediate early infected-cell polypeptide-4 (ICP4) of MDV. We generated transgenic chickens that constitutively express Cas9 and ICP4-gRNAs (gICP4) and challenged them via intraabdominal injection of MDV-1 Woodlands strain passage-19 (p19). Transgenic chickens expressing both gRNA/Cas9 had a significantly reduced replication of MDV in comparison to either transgenic Cas9-only or the wild-type (WT) chickens. We further confirmed that the designed gRNAs exhibited sequence-specific virus interference in transgenic chicken embryo fibroblast (CEF) expressing Cas9/gICP4 when infected with MDV but not with herpesvirus of turkeys (HVT). These results suggest that CRISPR/Cas9 can be used as an antiviral approach to control MDV infection in chickens, allowing HVT to be used as a vector for recombinant vaccines.
Using the monocyte activation test as a stand-alone release test for medical devices.

Monocyte activation tests (MAT) are widely available but rarely used in place of animal-based pyrogen tests for safety assessment of medical devices. To address this issue, the National Toxicology Program Interagency Center for the Eval-uation of Alternative Toxicological Methods and the PETA International Science Consortium Ltd. convened a workshop at the National Institutes of Health on September 18-19, 2018. Participants included representatives from MAT testing laboratories, medical device manufacturers, the U.S. Food and Drug Administration's Center for Devices and Radio-logic Health (CDRH), the U.S. Pharmacopeia, the International Organization for Standardization, and experts in the development of MAT protocols. Discussions covered industry experiences with the MAT, remaining challenges, and how CDRH's Medical Device Development Tools (MDDT) Program, which qualifies tools for use in evaluating medical devices to streamline device development and regulatory evaluation, could be a pathway to qualify the use of MAT in place of the rabbit pyrogen test and the limulus amebocyte lysate test for medical device testing. Workshop outcomes and fol-low-up activities are discussed.
The Symptom Structure of Postdisaster Major Depression: Convergence of Evidence from 11 Disaster Studies Using Consistent Methods

Agreement has not been achieved across symptom factor studies of major depressive disorder, and no studies have identified characteristic postdisaster depressive symptom structures. This study examined the symptom structure of major depression across two databases of 1181 survivors of 11 disasters studied using consistent research methods and full diagnostic assessment, addressing limitations of prior self-report symptom-scale studies. The sample included 808 directly-exposed survivors of 10 disasters assessed 1–6 months post disaster and 373 employees of 8 organizations affected by the September 11, 2001 terrorist attacks assessed nearly 3 years after the attacks. Consistent symptom patterns identifying postdisaster major depression were not found across the 2 databases, and database factor analyses suggested a cohesive grouping of depression symptoms. In conclusion, this study did not find symptom clusters identifying postdisaster major depression to guide the construction and validation of screeners for this disorder. A full diagnostic assessment for identification of postdisaster major depressive disorder remains necessary.
A Study of Polydimethylsiloxane/Aromatic Polyamide Laminated Membranes for Separation of Acetic Acid/Water Mixtures by Pervaporation Process

Abstract Separation of acetic acid/water mixtures by pervaporation was attempted over a range of compositions using polydimethylsiloxane (PDMS), aromatic polyamide (PA), and laminated polydimethylsiloxane-aromatic polyamide membranes. PDMS membranes are hydrophobic and acetic acid selective, whereas PA membranes are hydrophilic and water selective. When PDMS and PA membranes were laminated, with PDMS on the top side and in contact with the feed, water selectivity of the bottom PA membrane was intensified. On the other hand, when the PA membrane was on the top side and in contact with the feed, the selectivity was lowered.
Probing negative ion density and temperature using a resonance hairpin probe

The sheath around the cylindrical pins of a resonance hairpin probe is modulated by applying a train of negative pulse voltages with respect to the grounded chamber. This phenomenon leads to the creation of a conjugate dielectric due to the electron-free sheath around the probe surface and the ambient plasma outside the sheath region. Synchronous measurement of electron density, ne, with respect to pulse waveform finds an overshoot in ne during the withdrawal of the negative pulses in the electronegative oxygen plasma. The physical reason behind this observation is presented together with a qualitative model for interpreting the density and temperature of negative ions based on this method.
Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD

PURPOSE Severe (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in particularly high mortality after HLA-mismatched transplantation. There are no approved agents for AGVHD prevention, underscoring the critical unmet need for novel therapeutics. ABA2 was a phase II trial to rigorously assess safety, efficacy, and immunologic effects of adding T-cell costimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, to test whether abatacept could decrease AGVHD. METHODS ABA2 enrolled adults and children with hematologic malignancies under two strata: a randomized, double-blind, placebo-controlled stratum (8/8-HLA-matched URD), comparing CNI/MTX plus abatacept with CNI/MTX plus placebo, and a single-arm stratum (7/8-HLA-mismatched URD) comparing CNI/MTX plus abatacept versus CNI/MTX CIBMTR controls. The primary end point was day +100 grade 3-4 AGVHD, with day +180 severe-AGVHD-free-survival (SGFS) a key secondary end point. Sample sizes were calculated using a higher type-1 error (0.2) as recommended for phase II trials, and were based on predicting that abatacept would reduce grade 3-4 AGVHD from 20% to 10% (8/8s) and 30% to 10% (7/8s). ABA2 enrolled 142 recipients (8/8s, median follow-up = 716 days) and 43 recipients (7/8s, median follow-up = 708 days). RESULTS In 8/8s, grade 3-4 AGVHD was 6.8% (abatacept) versus 14.8% (placebo) (P = .13, hazard ratio = 0.45). SGFS was 93.2% (CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo, P = .05). In the smaller 7/8 cohort, grade 3-4 AGVHD was 2.3% (CNI/MTX plus abatacept, intention-to-treat population), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%, P < .001), and the SGFS was better (97.7% v 58.7%, P < .001). Immunologic analysis revealed control of T-cell activation in abatacept-treated patients. CONCLUSION Adding abatacept to URD HCT was safe, reduced AGVHD, and improved SGFS. These results suggest that abatacept may substantially improve AGVHD-related transplant outcomes, with a particularly beneficial impact on HLA-mismatched HCT.
Defect engineering of room‐temperature ferromagnetism of carbon‐doped ZnO

This study investigates the role of carbon (C) in room‐temperature (RT) ferromagnetic C:ZnO films. RT ferromagnetism can be observed in air‐annealed C:ZnO samples. However, no feature that could be attributed to the incorporation of carbon at O sites (CO) was observed. An analysis of MCD spectra of the ferromagnetic C:ZnO sample included a non‐ferromagnetic peak and a ferromagnetic one. These are related to the loss of carbon and the creation of defects in an air‐annealed C:ZnO film by the reaction between C dopants and oxygen. We suggest even if the C dopants are not at CO sites, C is still a novel dopant to make ZnO ferromagnetic in controlling the defects in the structure formed by suitable post‐annealing. (© 2011 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Recent Advances in Nanomedicine for the Diagnosis and Treatment of Prostate Cancer Bone Metastasis

Patients with advanced prostate cancer can develop painful and debilitating bone metastases. Currently available interventions for prostate cancer bone metastases, including chemotherapy, bisphosphonates, and radiopharmaceuticals, are only palliative. They can relieve pain, reduce complications (e.g., bone fractures), and improve quality of life, but they do not significantly improve survival times. Therefore, additional strategies to enhance the diagnosis and treatment of prostate cancer bone metastases are needed. Nanotechnology is a versatile platform that has been used to increase the specificity and therapeutic efficacy of various treatments for prostate cancer bone metastases. In this review, we summarize preclinical research that utilizes nanotechnology to develop novel diagnostic imaging tools, translational models, and therapies to combat prostate cancer bone metastases.