julilili42/papers huggingface dataset:
The STArgardt Remofuscin Treatment Trial (STARTT): design and baseline characteristics of enrolled Stargardt patients
2021-08-19

<ns4:p><ns4:bold>Background: </ns4:bold>This report describes the study design and baseline characteristics of patients with Stargardt disease (STGD1) enrolled in the STArgardt Remofuscin Treatment Trial (STARTT).</ns4:p><ns4:p> <ns4:bold>Methods: </ns4:bold>In total, 87 patients with genetically confirmed STGD1 were randomized in a double-masked, placebo-controlled proof of concept trial to evaluate the safety and efficacy of 20 milligram oral remofuscin for 24 months. The primary outcome measure is change in mean quantitative autofluorescence value of an 8-segment ring centred on the fovea (qAF<ns4:sub>8</ns4:sub>). Secondary efficacy variables are best corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), mesopic microperimetry (mMP), spectral domain optical coherence tomography (SD-OCT), reading speed on Radner reading charts, and patient-reported visual function as assessed by the National Eye Institute Visual Functioning Questionnaire 25 (NEI VFQ-25) and Functional Reading Independence (FRI) Index.</ns4:p><ns4:p> <ns4:bold>Results: </ns4:bold>Mean age of participants was 35±11 years with 49 (56%) female. Median qAF<ns4:sub>8</ns4:sub> value was 438 Units (range 210-729). Median BCVA and LLVA in decimal units were 0.50 (range 0.13-0.80) and 0.20 (range 0.06-0.63), respectively. The median of the mean retinal sensitivity with mMP was 20.4 dB (range 0.0-28.8). SD-OCT showed median central subfield retinal thickness of 142 μm (range 72-265) and median macular volume of 1.65 mm<ns4:sup>3</ns4:sup> (range 1.13-2.19). Compared to persons without vision impairment,<ns4:sup> </ns4:sup>both reading performance and patient-reported visual function were significantly lower (p&lt;0.001, one sample t-test). Mean reading speed was 108±39 words/minute with logRAD-score of 0.45±0.28. Mean VFQ-25 composite score was 72±13. Mean FRI Index score 2.8±0.6.</ns4:p><ns4:p> <ns4:bold>Conclusions: </ns4:bold>This trial design may serve as reference for future clinical trials as it explores the utility of qAF<ns4:sub>8</ns4:sub> as primary outcome measure. The baseline data represent the largest, multi-national, STGD1 cohort to date that underwent standardized qAF imaging, reading speed assessment and vision-related quality of life measures which all contribute to the characterization of STGD1.</ns4:p><ns4:p> <ns4:bold>EudraCT registration:</ns4:bold> 2018-001496-20 (09/05/2019)</ns4:p>
The flavin monooxygenase Bs3 triggers cell death in plants, impairs growth in yeast and produces H2O2 in vitro
2021-08-19

The pepper resistance gene Bs3 triggers a hypersensitive response (HR) upon transcriptional activation by the corresponding effector protein AvrBs3 from the bacterial pathogen Xanthomonas . Expression of Bs3 in yeast inhibited proliferation, demonstrating that Bs3 function is not restricted to the plant kingdom. The Bs3 sequence shows striking similarity to flavin monooxygenases (FMOs), an FAD- and NADPH-containing enzyme class that is known for the oxygenation of a wide range of substrates and their potential to produce H 2 O 2 . Since H 2 O 2 is a hallmark metabolite in plant immunity, we analyzed the role of H 2 O 2 during Bs3 HR. We purified recombinant Bs3 protein from E . coli and confirmed the FMO function of Bs3 with FAD binding and NADPH oxidase activity in vitro . Translational fusion of Bs3 to the redox reporter roGFP2 indicated that the Bs3-dependent HR induces an increase of the intracellular oxidation state in planta . To test if the NADPH oxidation and putative H 2 O 2 production of Bs3 is sufficient to induce HR, we adapted previous studies which have uncovered mutations in the NADPH binding site of FMOs that result in higher NADPH oxidase activity. In vitro studies demonstrated that recombinant Bs3 S211A protein has twofold higher NADPH oxidase activity than wildtype Bs3. Translational fusions to roGFP2 showed that Bs3 S211A also increased the intracellular oxidation state in planta . Interestingly, while the mutant derivative Bs3 S211A had an increase in NADPH oxidase capacity, it did not trigger HR in planta , ultimately revealing that H 2 O 2 produced by Bs3 on its own is not sufficient to trigger HR.
Combination of Pigment Epithelium Derived Factor (PEDF) With Anti- Vascular Endothelial Growth Factor (VEGF) Therapy Protects the Retina From Ischemic Damage
2021-08-19

Abstract BackgroundOcular ischemia is a vision-threatening disease, and is a medical condition associated with many ocular diseases. Anti-vascular endothelial growth factor (VEGF) therapy successfully prevents the progression of retinal neovascularization caused by ocular ischemia. Anti-VEGF therapy has limitations related to its side effects and suppression of physiological revascularization. Pigment epithelium derived factor (PEDF) has anti-angiogenesis and neurotrophic neuroprotective functions. It is a promising agent in the treatment of ischemia-induced retinal neurodegeneration. The purpose of this study is to investigate the effect of PEDF and anti-VEGF and the combined therapy on the ischemic rat eye model ex vivo .MethodsWe have previously established an ex vivo model of rat ocular ischemia by incubating the freshly enucleated eye in Dulbecco's modified eagle medium (DMEM) at 4 °C for 14 hours. This ex vivo eye model has already been confirmed as an ocular ischemia model. In this study, 36 eyes of 18 rats were used and each group included 6 eyes. The PEDF protein (10μg, 4μl), anti-VEGF drug (Avastin, 50μg, 4μl) or combined PEDF/Avastin (10μg PEDF + 50μg Avastin, 4μl) were intravitreally injected after eye enucleation. Fourteen hours later, eyes were fixed by formalin and immunohistochemical staining for VEGF, PEDF and glial fibrillary acidic protein (GFAP) was performed. The immunohistochemical staining intensity was analyzed for each group. Tunnel staining was used to determine the apoptosis of retinal neural cells.ResultsThe immunohistochemical staining intensity of VEGF and GFAP was significantly reduced in the neuroretina, the RPE cell layer and the choroidal vessels of the double treatment (PEDF/Anti-VEGF) eyes compared to the vehicle, PEDF, and anti-VEGF treatment alone. The intravitreally injected PEDF protein can penetrate the retina and locate in the neural retina, the RPE layer and the choroidal vessels. Compared to the vehicle-treated group, both the PEDF-treated and the double-treated groups showed significantly decreased number of TUNEL-positive nuclei, and the PEDF/Anti-VEGF treatment group had the least TUNEL-positive nuclei.Conclusions﻿PEDF/Anti-VEGF therapy shows a synergistic effect in the treatment of ischemic eye diseases. The combination of PEDF and anti-VEGF drug (Avastin) is a possible therapeutic strategy against ischemic retinal and choroidal diseases.
Eikonal quasinormal modes of black holes beyond general relativity. III. Scalar Gauss-Bonnet gravity
2021-08-20

In a recent series of papers we have shown how the eikonal/geometrical optics\\napproximation can be used to calculate analytically the fundamental quasinormal\\nmode frequencies associated with coupled systems of wave equations, which\\narise, for instance, in the study of perturbations of black holes in gravity\\ntheories beyond General Relativity. As a continuation to this series, we here\\nfocus on the quasinormal modes of nonrotating black holes in scalar\\nGauss-Bonnet gravity assuming a small-coupling expansion. We show that the\\naxial perturbations are purely tensorial and are described by a modified\\nRegge-Wheeler equation, while the polar perturbations are of mixed\\nscalar-tensor character and are described by a system of two coupled wave\\nequations. When applied to these equations, the eikonal machinery leads to\\naxial modes that deviate from the general relativistic results at quadratic\\norder in the Gauss-Bonnet coupling constant. We show that this result is in\\nagreement with an analysis of unstable circular null orbits around blackholes\\nin this theory, allowing us to establish the geometrical optics-null geodesic\\ncorrespondence for the axial modes. For the polar modes the small-coupling\\napproximation forces us to consider the ordering between eikonal and\\nsmall-coupling perturbative parameters; one of which we show, by explicit\\ncomparison against numerical data, yields the correct identification of the\\nquasinormal modes of the scalar-tensor coupled system of wave equations. These\\ncorrections lift the general relativistic degeneracy between scalar and\\ntensorial eikonal quasinormal modes at quadratic order in Gauss-Bonnet coupling\\nin a way reminiscent of the Zeeman effect. In general, our analytic, eikonal\\nquasinormal mode frequencies (normalized to the General Relativity ones) agree\\nwith numerical results with an error of in the regime of small\\ncoupling constant. (abridged)\\n
Clinical and molecular delineation of PUS3‐associated neurodevelopmental disorders
2021-08-20

Abstract Biallelic variants in PUS3 have recently been recognized as a rare cause of neurodevelopmental disorders. Pseudouridine synthase‐3 encoded by PUS3 is an enzyme important for modification of various RNAs, including transfer RNA (tRNA). Here we present the clinical and genetic features of 21 individuals with biallelic PUS3 variants: seven new and 14 previously reported individuals, where clinical features of two were updated. The clinical and genetic information were collected through collaborations or by literature search. All individuals were characterized by the local clinicians and the gene variants were identified by next generation sequencing (NGS) based methodologies. The clinical picture was dominated by global developmental delay, epilepsy, hypotonia and microcephaly. Gray sclera, which has previously been suggested to be a characteristic feature of PUS3 ‐associated phenotypes, was reported in only seven individuals. The patients had some dysmorphic facial features, but a recognizable gestalt was not observed. In conclusion, homozygous and compound heterozygous PUS3 variants lead to a rare neurodevelopmental disorder. Further functional studies are necessary to understand involvement of PUS3 and tRNA biogenesis in normal and abnormal brain development.
Strategies for feature extraction from structural brain imaging in lesion‐deficit modelling
2021-08-20

Abstract High‐dimensional modelling of post‐stroke deficits from structural brain imaging is highly relevant to basic cognitive neuroscience and bears the potential to be translationally used to guide individual rehabilitation measures. One strategy to optimise model performance is well‐informed feature selection and representation. However, different feature representation strategies were so far used, and it is not known what strategy is best for modelling purposes. The present study compared the three common main strategies: voxel‐wise representation, lesion‐anatomical componential feature reduction and region‐wise atlas‐based feature representation. We used multivariate, machine‐learning‐based lesion‐deficit models to predict post‐stroke deficits based on structural lesion data. Support vector regression was tuned by nested cross‐validation techniques and tested on held‐out validation data to estimate model performance. While we consistently found the numerically best models for lower‐dimensional, featurised data and almost always for principal components extracted from lesion maps, our results indicate only minor, non‐significant differences between different feature representation styles. Hence, our findings demonstrate the general suitability of all three commonly applied feature representations in lesion‐deficit modelling. Likewise, model performance between qualitatively different popular brain atlases was not significantly different. Our findings also highlight potential minor benefits in individual fine‐tuning of feature representations and the challenge posed by the high, multifaceted complexity of lesion data, where lesion‐anatomical and functional criteria might suggest opposing solutions to feature reduction.
Brain Computer Interfaces for Assisted Communication in Paralysis and Quality of Life
2021-08-20

The rapid evolution of Brain-Computer Interface (BCI) technology and the exponential growth of BCI literature during the past 20 years is a consequence of increasing computational power and the achievements of statistical learning theory and machine learning since the 1960s. Despite this rapid scientific progress, the range of successful clinical and societal applications remained limited, with some notable exceptions in the rehabilitation of chronic stroke and first steps towards BCI-based assisted verbal communication in paralysis. In this contribution, we focus on the effects of noninvasive and invasive BCI-based verbal communication on the quality of life (QoL) of patients with amyotrophic lateral sclerosis (ALS) in the locked-in state (LIS) and the completely locked-in state (CLIS). Despite a substantial lack of replicated scientific data, this paper complements the existing methodological knowledge and focuses future investigators’ attention on (1) Social determinants of QoL and (2) Brain reorganization and behavior. While it is not documented in controlled studies that the good QoL in these patients is a consequence of BCI-based neurorehabilitation, the proposed determinants of QoL might become the theoretical background needed to develop clinically more useful BCI systems and to evaluate the effects of BCI-based communication on QoL for advanced ALS patients and other forms of severe paralysis.
1.5 vs 3 Tesla Magnetic Resonance Imaging
2021-08-20

Abstract The second part of this review deals with experiences in neuroradiological and pediatric examinations using modern magnetic resonance imaging systems with 1.5 T and 3 T, with special attention paid to experiences in pediatric cardiac imaging. In addition, whole-body examinations, which are widely used for diagnostic purposes in systemic diseases, are compared with respect to the image quality obtained in different body parts at both field strengths. A systematic overview of the technical differences at 1.5 T and 3 T has been presented in part 1 of this review, as well as several organ-based magnetic resonance imaging applications including musculoskeletal imaging, abdominal imaging, and prostate diagnostics.
Aestivation as a response to climate change: the Great Banded Grayling Brintesia circe in Central Europe
2021-08-20

1. Climate change has forced species to shift distribution, alter migration behaviour, or change phenology. One of these adaptation strategies is aestivation to overcome hot, dry summers. For example, the abundance of the Great Banded Grayling Brintesia circe Fabricius (Lepidoptera, Nymphalidae) in Southern Germany used to show one flight peak between June and August, while now, a bimodal phenological record suggests 3–4 weeks of aestivation during the driest summer weeks. 2. To study this new phenomenon, a capture‐mark‐recapture study was performed in two nature reserves in Southern Germany during 92 days in 2019 and 2020. Gender, wing condition, and exact location of individuals of B. circe were recorded. These data show that in June (first flight period), 76%, 481 of 635 captured individuals were males, while in late August and September (second flight period), ≥95%, 452 of 462 were females. No individual marked during the first flight period was recaptured during the second flight period. 3. The results imply that mating takes place during the first flight period only, especially females aestivate, probably to avoid oviposition during the hottest and driest parts of the summer and that an unknown part of the population may disperse out or into the investigated habitats. This behaviour appears to have changed during the last decades probably as an adaptation to climate change. Females of B. circe are forced to oviposit later in summer as earlier eggs laid during hotter and drier times are less likely to develop successfully.
The Reaction of CO2 with a Borylnitrene: Formation of an 3‐Oxaziridinone
2021-08-20

Abstract The reaction of a borylnitrene with carbon dioxide is studied under cryogenic matrix isolation conditions. Photogenerated CatBN (Cat=catecholato) reacts with CO 2 under formation of the cycloaddition product CatBNCO 2 , a 3‐oxaziridinone derivative, after photoexcitation (&gt;550 nm). The product shows Fermi resonances between the CO stretching and ring deformation modes that cause unusual 13 C and 18 O isotopic shifts. A computational analysis of the 3‐oxaziridinone shows this cyclic carbamate to be less strained than an α‐lactone or an α‐lactame.
Mass Transfer Principles in Column Percolation Tests: Initial Conditions and Tailing in Heterogeneous Materials
2021-08-20

Initial conditions (pre-equilibrium or after the first flooding of the column), mass transfer mechanisms and sample composition (heterogeneity) have a strong impact on leaching of less and strongly sorbing compounds in column percolation tests. Mechanistic models as used in this study provide the necessary insight to understand the complexity of column leaching tests especially when heterogeneous samples are concerned. By means of numerical experiments, we illustrate the initial concentration distribution inside the column after the first flooding and how this impacts leaching concentrations. Steep concentration gradients close to the outlet of the column have to be expected for small distribution coefficients (Kd&lt;1 L kg−1) and longitudinal dispersion leads to smaller initial concentrations than expected under equilibrium conditions. In order to elucidate the impact of different mass transfer mechanisms, film diffusion across an external aqueous boundary layer (first order kinetics, FD) and intraparticle pore diffusion (IPD) are considered. The results show that IPD results in slow desorption kinetics due to retarded transport within the tortuous intragranular pores. Non-linear sorption has not much of an effect if compared to Kd values calculated for the appropriate concentration range (e.g., the initial equilibrium concentration). Sample heterogeneity in terms of grain size and different fractions of sorptive particles in the sample have a strong impact on leaching curves. A small fraction (&lt;1%) of strongly sorbing particles (high Kd) carrying the contaminant may lead to very slow desorption rates (because of less surface area)—especially if mass release is limited by IPD—and thus non-equilibrium. In contrast, mixtures of less sorbing fine material (“labile” contamination with low Kd), with a small fraction of coarse particles carrying the contaminant leads to leaching close to or at equilibrium showing a step-wise concentration decline in the column effluent.
The Structure of Cyclodecatriene Collinolactone, its Biosynthesis, and Semisynthetic Analogues: Effects of Monoastral Phenotype and Protection from Intracellular Oxidative Stress
2021-08-20

Abstract Recently described rhizolutin and collinolactone isolated from Streptomyces Gö 40/10 share the same novel carbon scaffold. Analyses by NMR and X‐Ray crystallography verify the structure of collinolactone and propose a revision of rhizolutin's stereochemistry. Isotope‐labeled precursor feeding shows that collinolactone is biosynthesized via type I polyketide synthase with Baeyer–Villiger oxidation. CRISPR‐based genetic strategies led to the identification of the biosynthetic gene cluster and a high‐production strain. Chemical semisyntheses yielded collinolactone analogues with inhibitory effects on L929 cell line. Fluorescence microscopy revealed that only particular analogues induce monopolar spindles impairing cell division in mitosis. Inspired by the Alzheimer‐protective activity of rhizolutin, we investigated the neuroprotective effects of collinolactone and its analogues on glutamate‐sensitive cells (HT22) and indeed, natural collinolactone displays distinct neuroprotection from intracellular oxidative stress.
Diminishing immune responses against variants of concern in dialysis patients four months after SARS-CoV-2 mRNA vaccination
2021-08-20

Abstract Patients undergoing chronic hemodialysis were among the first to receive SARS-CoV-2 vaccinations due to their increased risk for severe COVID-19 disease and high case fatality rates. To date, there have been minimal longitudinal studies in hemodialysis patients to ascertain whether protection offered by vaccination is long-lasting. To assess how surrogates for protection changed over time, we examined both the humoral and cellular response in a previously reported cohort of at-risk hemodialysis patients and healthy donors, four months after their second dose of Pfizer BNT162b2. Compared to three weeks post-second vaccination, both cellular and humoral responses against the original SARS-CoV-2 isolate as well as variants of concern were significantly reduced, with some dialyzed individuals having no B- or T-cell response. Our data strongly support the need for a third booster in hemodialysis patients and potentially other at-risk individuals.
SRG/ART-XC, Swift, NICER, and NuSTAR study of different states of the transient X-ray pulsar MAXI J0903–531
2021-08-20

The results of the broadband spectral and timing study of the recently discovered transient X-ray pulsar MAXI J0903–531 in a wide range of luminosities that differ by a factor of ~30 are reported. The observed X-ray spectrum in both states can be described as a classical pulsar-like spectrum consisting of a power law with a high-energy cutoff. We argue that the absence of the spectrum transformation to the two-hump structure that is expected at low fluxes indicates that the magnetic field of the neutron star is relatively weak below (2–3) × 10 12 G. This estimate is consistent with other indirect constraints and non-detection of any absorption features that might be interpreted as a cyclotron absorption line. The timing analysis of the NuSTAR data revealed only slight variations of a single-peaked pulse profile of the source as a function of the energy band and mass accretion rate. In both intensity states, the pulsed fraction increases from 40% to roughly 80% with the energy. Finally, we were also able to obtain the orbital solution for the binary system using data from the Fermi/GBM , NICER, and NuSTAR instruments.
Irony as a Test of the Presupposition-Denial Account: An ERP Study
2021-08-20

Abstract According to the Presupposition-Denial Account, complement set reference arises when focus is on the shortfall between the amount conveyed by a natural language quantifier and a larger, expected amount. Negative quantifiers imply a shortfall, through the denial of a presupposition, whereas positive quantifiers do not. An exception may be provided by irony. One function of irony is to highlight, through indirect negation, the shortfall between what is expected/desired, and what is observed. Thus, a positive quantifier used ironically should also lead to a shortfall and license complement set reference. Using ERPs, we examined whether reference to the complement set is more felicitous following a positive quantifier used ironically than one used non-ironically. ERPs during reading showed a smaller N400 for complement set reference following an ironic compared to a non-ironic context. The shortfall generated thorough irony is sufficient to allow focus on the complement set, supporting the Presupposition-Denial Account.