julilili42/papers huggingface dataset:
Mutations at a split codon in the GTPase-encoding domain of OPA1 cause dominant optic atrophy through different molecular mechanisms
2021-09-22

Abstract Exonic (i.e. coding) variants in genes associated with disease can exert pathogenic effects both at the protein and mRNA level, either by altering the amino acid sequence or by affecting pre-mRNA splicing. The latter is often neglected due to the lack of RNA analyses in genetic diagnostic testing. In this study we considered both pathomechanisms and performed a comprehensive analysis of nine exonic nucleotide changes in OPA1, which is the major gene underlying autosomal dominant optic atrophy (DOA) and is characterized by pronounced allelic heterogeneity. We focused on the GTPase-encoding domain of OPA1, which harbors most of the missense variants associated with DOA. Given that the consensus splice sites extend into the exons, we chose a split codon, namely codon 438, for our analyses. Variants at this codon are the second most common cause of disease in our large cohort of DOA patients harboring disease-causing variants in OPA1. In silico splice predictions, heterologous splice assays, analysis of patient’s RNA when available, and protein modeling revealed different molecular outcomes for variants at codon 438. The wildtype aspartate residue at amino acid position 438 is directly involved in the dimerization of OPA1 monomers. We found that six amino acid substitutions at codon 438 (i.e. all substitutions of the first and second nucleotide of the codon) destabilized dimerization while only substitutions of the first nucleotide of the codon caused exon skipping. Our study highlights the value of combining RNA analysis and protein modeling approaches to accurately assign patients to future precision therapies.
Time-dependent prediction of mortality and cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation using machine learning
2021-09-22

Abstract Allogeneic hematopoietic cell transplantation (HCT) effectively treats high-risk hematologic diseases but can entail HCT-specific complications, which may be minimized by appropriate patient management, supported by accurate, individual risk estimation. However, almost all HCT risk scores are limited to a single risk assessment before HCT without incorporation of additional data. We developed machine learning models which integrate both baseline patient data and time-dependent laboratory measurements to individually predict mortality and cytomegalovirus (CMV) reactivation after HCT at multiple time points per patient. These gradient boosting machine models provide well-calibrated, time-dependent risk predictions and achieved areas under the receiver-operating characteristic of 0.92 and 0.83 and areas under the precision-recall curve of 0.58 and 0.62 for prediction of mortality and CMV reactivation, respectively, in a 21-day time window. Both models were successfully validated in a prospective, non-interventional study and performed on par with expert hematologists in a pilot comparison.
Prospective Welfare Analysis—Extending Willingness-To-Pay Assessment to Embrace Sustainability
2021-09-22

Abstract In this paper, we outline how a future change in consumers’ willingness-to-pay can be accounted for in a consumer welfare effects analysis in antitrust. Key to our solution is the prediction of preferences of new consumers and changing preferences of existing consumers in the future. The dimension of time is inextricably linked with that of sustainability. Taking into account the welfare of future cohorts of consumers, concerns for sustainability can therefore be integrated into the consumer welfare paradigm to a greater extent. As we argue in this paper, it is expedient to consider changes in consumers’ willingness-to-pay, in particular if society undergoes profound changes in such preferences, for example, caused by an increase in generally available information on environmental effects of consumption, and a rising societal awareness about how consumption can have irreversible impacts on the environment. We offer suggestions on how to conceptionalize and operationalize the projection of such consumers’ changing preferences in a “prospective welfare analysis.” This increases the scope of the consumer welfare paradigm and can help to solve conceptual issues regarding the integration of sustainability into antitrust enforcement while keeping consumer surplus as a quantitative gauge.
An Activity Tracker–Guided Physical Activity Program for Patients Undergoing Radiotherapy: Protocol for a Prospective Phase III Trial (OnkoFit I and II Trials)
2021-09-22

Background The positive impact that physical activity has on patients with cancer has been shown in several studies over recent years. However, supervised physical activity programs have several limitations, including costs and availability. Therefore, our study proposes a novel approach for the implementation of a patient-executed, activity tracker–guided exercise program to bridge this gap. Objective Our trial aims to investigate the impact that an activity tracker–guided, patient-executed exercise program for patients undergoing radiotherapy has on cancer-related fatigue, health-related quality of life, and preoperative health status. Methods Patients receiving postoperative radiotherapy for breast cancer (OnkoFit I trial) or neoadjuvant, definitive, or postoperative treatment for other types of solid tumors (OnkoFit II trial) will be randomized (1:1:1) into 3-arm studies. Target accrual is 201 patients in each trial (50 patients per year). After providing informed consent, patients will be randomized into a standard care arm (arm A) or 1 of 2 interventional arms (arms B and C). Patients in arms B and C will wear an activity tracker and record their daily step count in a diary. Patients in arm C will receive personalized weekly targets for their physical activity. No further instructions will be given to patients in arm B. The target daily step goals for patients in arm C will be adjusted weekly and will be increased by 10% of the average daily step count of the past week until they reach a maximum of 6000 steps per day. Patients in arm A will not be provided with an activity tracker. The primary end point of the OnkoFit I trial is cancer-related fatigue at 3 months after the completion of radiotherapy. This will be measured by the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire. For the OnkoFit II trial, the primary end point is the overall quality of life, which will be assessed with the Functional Assessment of Cancer Therapy-General sum score at 6 months after treatment to allow for recovery after possible surgery. In parallel, blood samples from before, during, and after treatment will be collected in order to assess inflammatory markers. Results Recruitment for both trials started on August 1, 2020, and to date, 49 and 12 patients have been included in the OnkoFit I and OnkoFit II trials, respectively. Both trials were approved by the institutional review board prior to their initiation. Conclusions The OnkoFit trials test an innovative, personalized approach for the implementation of an activity tracker–guided training program for patients with cancer during radiotherapy. The program requires only a limited amount of resources. Trial Registration ClinicalTrials.gov NCT04506476; https://clinicaltrials.gov/ct2/show/NCT04506476. ClinicalTrials.gov NCT04517019; https://clinicaltrials.gov/ct2/show/NCT04517019. International Registered Report Identifier (IRRID) DERR1-10.2196/28524
Serum NfL in spinocerebellar ataxia type 1 is increased already at the preataxic stage, correlating with proximity to clinical onset
2021-09-22

Abstract Background and Objectives Neurofilament light (NfL) appears a promising fluid biomarker in repeat-expansion spinocerebellar ataxias (SCAs), with piloting studies in mixed SCA cohorts suggesting that NfL might be increased at the ataxic stage of spinocerebellar ataxia type 1 (SCA1). We here hypothesised that NfL is increased not only at the ataxic stage of SCA1, but also at its – likely most treatment-relevant – preataxic stage. Methods We assessed serum (sNfL) and cerebrospinal fluid (cNfL) levels of NfL in both preataxic and ataxic SCA1, leveraging a multicentric cohort of 40 SCA1 carriers (23 preataxic, 17 ataxic) and &gt;80 controls, and clinical follow-up data including actually observed (rather than only predicted) conversion to the ataxic stage (11 carriers). Results sNfL levels were increased with high age-corrected effect sizes at the preataxic (r=0.62) and ataxic stage (r=0.63), paralleling increases of cNfL levels. In preataxic subjects, sNfL levels increased with proximity to predicted ataxia onset, with significant sNfL elevations already 5 years before onset, and confirmed in preataxic subjects with actually observed ataxia onset. sNfL increases were detected already in preataxic SCA1 subjects without volumetric atrophy of cerebellum or pons, suggesting that sNfL might be more sensitive to early preataxic neurodegeneration than the currently known most change-sensitive regions in volumetric MRI. Using longitudinal sNfL measurements, we estimated sample sizes for clinical trials using the reduction of sNfL as endpoint. Conclusions sNfL levels might thus provide easily accessible peripheral biomarkers in both preataxic and ataxic SCA1, allowing stratification of preataxic subjects regarding proximity-to-onset, early detection of neurodegeneration even before volumetric MRI alterations, and potentially capture of treatment response in clinical trials.
BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity
2021-09-23

Activity of the NLRP3 inflammasome, a critical mediator of inflammation, is controlled by accessory proteins, posttranslational modifications, cellular localization, and oligomerization. How these factors relate is unclear. We show that a well-established drug target, Bruton’s tyrosine kinase (BTK), affects several levels of NLRP3 regulation. BTK directly interacts with NLRP3 in immune cells and phosphorylates four conserved tyrosine residues upon inflammasome activation, in vitro and in vivo. Furthermore, BTK promotes NLRP3 relocalization, oligomerization, ASC polymerization, and full inflammasome assembly, probably by charge neutralization, upon modification of a polybasic linker known to direct NLRP3 Golgi association and inflammasome nucleation. As NLRP3 tyrosine modification by BTK also positively regulates IL-1β release, we propose BTK as a multifunctional positive regulator of NLRP3 regulation and BTK phosphorylation of NLRP3 as a novel and therapeutically tractable step in the control of inflammation.
Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression
2021-09-23

Mouse models of non-alcoholic fatty liver disease (NAFLD) are required to define therapeutic targets, but detailed time-resolved studies to establish a sequence of events are lacking. Here, we fed male C57Bl/6N mice a Western or standard diet over 48 weeks. Multiscale time-resolved characterization was performed using RNA-seq, histopathology, immunohistochemistry, intravital imaging, and blood chemistry; the results were compared to human disease. Acetaminophen toxicity and ammonia metabolism were additionally analyzed as functional readouts. We identified a sequence of eight key events: formation of lipid droplets; inflammatory foci; lipogranulomas; zonal reorganization; cell death and replacement proliferation; ductular reaction; fibrogenesis; and hepatocellular cancer. Functional changes included resistance to acetaminophen and altered nitrogen metabolism. The transcriptomic landscape was characterized by two large clusters of monotonously increasing or decreasing genes, and a smaller number of ‘rest-and-jump genes’ that initially remained unaltered but became differentially expressed only at week 12 or later. Approximately 30% of the genes altered in human NAFLD are also altered in the present mouse model and an increasing overlap with genes altered in human HCC occurred at weeks 30–48. In conclusion, the observed sequence of events recapitulates many features of human disease and offers a basis for the identification of therapeutic targets.
Human iPSC-Derived Glia as a Tool for Neuropsychiatric Research and Drug Development
2021-09-23

Neuropsychiatric disorders such as schizophrenia or autism spectrum disorder represent a leading and growing burden on worldwide mental health. Fundamental lack in understanding the underlying pathobiology compromises efficient drug development despite the immense medical need. So far, antipsychotic drugs reduce symptom severity and enhance quality of life, but there is no cure available. On the molecular level, schizophrenia and autism spectrum disorders correlate with compromised neuronal phenotypes. There is increasing evidence that aberrant neuroinflammatory responses of glial cells account for synaptic pathologies through deregulated communication and reciprocal modulation. Consequently, microglia and astrocytes emerge as central targets for anti-inflammatory treatment to preserve organization and homeostasis of the central nervous system. Studying the impact of neuroinflammation in the context of neuropsychiatric disorders is, however, limited by the lack of relevant human cellular test systems that are able to represent the dynamic cellular processes and molecular changes observed in human tissue. Today, patient-derived induced pluripotent stem cells offer the opportunity to study neuroinflammatory mechanisms in vitro that comprise the genetic background of affected patients. In this review, we summarize the major findings of iPSC-based microglia and astrocyte research in the context of neuropsychiatric diseases and highlight the benefit of 2D and 3D co-culture models for the generation of efficient in vitro models for target screening and drug development.
Predicting motor behavior: an efficient EEG signal processing pipeline to detect brain states with potential therapeutic relevance for VR-based neurorehabilitation
2021-09-23

Abstract Virtual reality (VR)-based motor therapy is an emerging approach in neurorehabilitation. The combination of VR with electroencephalography (EEG) presents further opportunities to improve therapeutic efficacy by personalizing the paradigm. Specifically, the idea is to synchronize the choice and timing of stimuli in the perceived virtual world with fluctuating brain states relevant to motor behavior. Here, we present an open source EEG single-trial based classification pipeline that is designed to identify ongoing brain states predictive of the planning and execution of movements. 9 healthy volunteers each performed 1080 trials of a repetitive reaching task with an implicit two-alternative forced choice, i.e., use of the right or left hand, in response to the appearance of a visual target. The performance of the EEG decoding pipeline was assessed with respect to classification accuracy of right vs. left arm use, based on the EEG signal at the time of the stimulus. Different features, feature extraction methods, and classifiers were compared at different time windows; the number and location of informative EEG channels and the number of calibration trials needed were also quantified, as well as any benefits from individual-level optimization of pipeline parameters. This resulted in a set of recommended parameters that achieved an average 83.3% correct prediction on never-before-seen testing data, and a state-of-the-art 77.1% in a real-time simulation. Neurophysiological plausibility of the resulting classifiers was assessed by time–frequency and event-related potential analyses, as well as by Independent Component Analysis topographies and cortical source localization. We expect that this pipeline will facilitate the identification of relevant brain states as prospective therapeutic targets in closed-loop EEG-VR motor neurorehabilitation.
A Discriminative Lexicon Approach to Word Comprehension, Production and Processing: Maltese Plurals
2021-09-23

Comprehending and producing words is a natural process for human speakers. In linguistic theory, investigating this process formally and computationally is often done by focusing on forms only. By moving beyond the world of forms, we show in this study that the Discriminative Lexicon (DL) model operating with word comprehension as a mapping of form onto meaning and word production as a mapping of meaning onto form generates accurate predictions about what meanings listeners understand and what forms speakers produce. Furthermore, we show that measures derived from the computational model are predictive for human reaction times. Although mathematically very simple, the linear mappings betweenform and meaning posited by our model are powerful enough to capture the complexity and productivity of a Semitic language with a complex hybrid morphological system.
Volatility discovery in cryptocurrency markets
2021-09-23

Purpose Cryptocurrency markets are notoriously noisy, but not all markets might behave in the exact same way. Therefore, the aim of this paper is to investigate which one of the cryptocurrency markets contributes the most to the common volatility component inherent in the market. Design/methodology/approach The paper extracts each of the cryptocurrency's markets' latent volatility using a stochastic volatility model and, subsequently, models their dynamics in a fractionally cointegrated vector autoregressive model. The authors use the refinement of Lien and Shrestha (2009, J. Futures Mark) to come up with unique Hasbrouck (1995, J. Finance) information shares. Findings The authors’ findings indicate that Bitfinex is the leading market for Bitcoin and Ripple, while Bitstamp dominates for Ethereum and Litecoin. Based on the dominant market for each cryptocurrency, the authors find that the volatility of Bitcoin explains most of the volatility among the different cryptocurrencies. Research limitations/implications The authors’ findings are limited by the availability of the cryptocurrency data. Apart from Bitcoin, the data series for the other cryptocurrencies are not long enough to ensure the precision of the authors’ estimates. Originality/value To date, only price discovery in cryptocurrencies has been studied and identified. This paper extends the current literature into the realm of volatility discovery. In addition, the authors propose a discrete version for the evolution of a markets fundamental volatility, extending the work of Dias et al. (2018).
The effect of lamotrigine and other antiepileptic drugs on respiratory rhythm generation in the pre‐Bötzinger complex
2021-09-23

Abstract Objective Lamotrigine and other sodium‐channel blocking agents are among the most commonly used antiepileptic drugs (AEDs). Because other sodium channel blockers, such as riluzole, can severely alter respiratory rhythm generation during hypoxia, we wanted to investigate if AEDs can have similar effects. This is especially important in the context of sudden unexpected death in epilepsy (SUDEP), the major cause of death in patients suffering from therapy‐resistant epilepsy. Although the mechanism of action is not entirely understood, respiratory dysfunction after generalized tonic‐clonic seizures seems to play a major role. Methods We used transverse brainstem slice preparations from neonatal and juvenile mice containing the pre‐Bötzinger complex (PreBötC) and measured population as well as intracellular activity of the rhythm‐generating network under normoxia and hypoxia in the presence or absence of AEDs. Results We found a substantial inhibition of the gasping response induced by the application of sodium channel blockers (lamotrigine and carbamazepine). In contrast, levetiracetam, an AED‐modulating synaptic function, had a much smaller effect. The inhibition of gasping by lamotrigine was accompanied by a significant reduction of the persistent sodium current (INap) in PreBötC neurons. Surprisingly, the suppression of persistent sodium currents by lamotrigine did not affect the voltage‐dependent bursting activity in PreBötC pacemaker neurons, but led to a hypoxia‐dependent shift of the action potential rheobase in all measured PreBötC neurons. Significance Our results contribute to the understanding of the effects of AEDs on the vital respiratory functions of the central nervous system. Moreover, our study adds further insight into sodium‐dependent changes occurring during hypoxia and the contribution of cellular properties to the respiratory rhythm generation in the pre‐Bötzinger complex. It raises the question of whether sodium channel blocking AEDs could, in conditions of extreme hypoxia, contribute to SUDEP, an important issue that warrants further studies.
Characteristics of peripapillary retinal nerve fiber layer atrophy in glaucoma, optic nerve sheath meningioma, and sphenoid wing meningioma
2021-09-23

Abstract Background/objectives The correct classification of a slowly progressing optic atrophy can be challenging. The aim of this work was to find out if the characteristics of peripapillary retinal nerve fiber layer (RNFL) thickness loss differ between open angle glaucoma (POAG), optic nerve sheath meningioma (ONSM), and sphenoid wing meningioma (SWM). Methods A total of 45 patients with POAG, ONSM, and SWM were included in the retrospective study. The peripapillary RNFL thickness measured by spectral-domain optical coherence tomography was analyzed using the Heidelberg Engineering glaucoma module © . Results Each group consisted of 15 patients. The temporal sector of the RNFL thickness showed a median decrease of − 17 μm in glaucoma patients (range + 6/–34 μm), − 43 μm in ONSM (range − 19/ − 52 μm), and − 44 μm in SWM patients (range − 25/ − 52 μm). The RNFL thickness of the temporal sector of glaucoma patients differed significantly from the other groups ( p &lt; 0.001). All other sectors showed no significant difference between the 3 groups. Conclusion The peripapillary RNFL thickness of the temporal sector of patients with beginning to moderate POAG is usually inside normal limits or borderline. In contrast, patients with ONSM and SWM are much more likely to show a considerable reduction in RNFL thickness of the temporal sector. RNFL thickness of the temporal sector marked outside normal limits occurred exclusively in meningioma patients. Considering the presence of this condition as a predictor for meningioma, sensitivity and specificity were 0.8 and 1.0, respectively. In patients with significant reduction in RNFL thickness of the temporal sector, magnetic resonance imaging of the head should be considered to rule out compression of the optic nerves.
Health-Related Digital Autonomy. A Response to the Commentaries
2021-09-23

This article refers to:Artificial Intelligence, Social Media and Depression. A New Concept of Health-Related Digital AutonomyThe Coercive Potential of Digital Mental HealthA New Type of 'Greenwashing'? Social Media Companies Predicting Depression and Other Mental IllnessesIs Health-Related Digital Autonomy Setting the Autonomy Bar Too High?The Right to Contest AI Profiling Based on Social Media DataFour Stages in Social Media Network Analysis—Building Blocks for Health-Related Digital Autonomy in Artificial Intelligence, Social Media, and DepressionBlack Boxes and Bias in AI Challenge AutonomyError, Reliability and Health-Related Digital Autonomy in AI Diagnoses of Social Media AnalysisHealth-Related Digital Autonomy: An Important, But Unfinished StepConsultation with Doctor Twitter: Consent Fatigue, and the Role of Developers in Digital Medical EthicsArtificial Intelligence, Social Media, and Suicide Prevention: Principle of Beneficence Besides Respect for Autonomy