Miracle-dz/UniFAR-FTUs huggingface dataset:
A Nonmechanistic Parametric Modeling Approach for Benchmark Dose Estimation of Event‐Time Data

We propose benchmark dose estimation for event‐time data, using a two‐step approach. This approach avoids estimation of complex models and has been previously shown to give robust results for summarizing relevant parameters for risk assessment. In the first step, the probability of the event of interest to occur (in a certain time interval) is described as a function of time, resulting in an event‐time model; such a model is fitted allowing an individual curve for each dose, and relevant estimates are extracted. In the second step, a dose–response model is fitted to the estimates of t50 obtained from the event‐time model in the first step. Given a predefined benchmark response, the benchmark dose is then estimated from the resulting model. This novel approach is demonstrated in two examples. Our application of the time‐to‐event model showed a gain in power compared to the traditional analysis of end‐of‐study summary data.
Molecular dynamics simulation of a polymer chain in solution

Results of a molecular dynamics simulation of a single polymer chain in a good solvent are presented. The latter is modeled explicitly as a bath of particles. This system provides a first‐principles microscopic test of the hydrodynamic Kirkwood–Zimm theory of the chain’s Brownian motion. A 30 monomer chain is studied in 4066 solvent particles as well as 40/4056 and 60/7940 systems. The density was chosen rather high, in order to come close to the ideal situation of incompressible flow, and to ensure that diffusive momentum transport is much faster than particle motions. In order to cope with the numerical instability of microcanonical algorithms, we generate starting states by a Langevin simulation that includes a coupling to a heat bath, which is switched off for the analysis of the dynamics. The long range of the hydrodynamic interaction induces a large effect of finite box size on the diffusive properties, which is observable for the diffusion constants of both the chain and the solvent particles. The .
Antimicrobial Testings and Gas Chromatographic Analyses of Aroma Chemicals

Abstract In continuation of our scientific work in the field of combined and sytematical investigation of antimicrobial activities (by means of agar dilution and agar diffusion methods) and structural properties (using gas chromatographic analyses: GC and GC/MS with chiral and achiral columns) of different aroma compounds in various samples (pure chemicals, essential oils, extracts, etc.), further odor-active hydrocarbons (2-carene, 3-carene, limonene and β-caryophyllene) and oxygenated mono- and sesquiterpenes (1,8-cineole, linalool, carvone, camphor and linalyl acetate as well as santalol) were used. Only in the case of (+)-3-carene, (+)-carvone, (-)-linalool and racemic linalool antimicrobial activities were found against all used strains (Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsielle pneumonia and Candida albicans). Detailed results of both, antimicrobial activities and structural properties of the investigated aroma compounds will be presented in this paper.
Affordance-Based Grasping Point Detection Using Graph Convolutional Networks for Industrial Bin-Picking Applications

Grasping point detection has traditionally been a core robotic and computer vision problem. In recent years, deep learning based methods have been widely used to predict grasping points, and have shown strong generalization capabilities under uncertainty. Particularly, approaches that aim at predicting object affordances without relying on the object identity, have obtained promising results in random bin-picking applications. However, most of them rely on RGB/RGB-D images, and it is not clear up to what extent 3D spatial information is used. Graph Convolutional Networks (GCNs) have been successfully used for object classification and scene segmentation in point clouds, and also to predict grasping points in simple laboratory experimentation. In the present proposal, we adapted the Deep Graph Convolutional Network model with the intuition that learning from n-dimensional point clouds would lead to a performance boost to predict object affordances. To the best of our knowledge, this is the first time that GCNs are applied to predict affordances for suction and gripper end effectors in an industrial bin-picking environment. Additionally, we designed a bin-picking oriented data preprocessing pipeline which contributes to ease the learning process and to create a flexible solution for any bin-picking application. To train our models, we created a highly accurate RGB-D/3D dataset which is openly available on demand. Finally, we benchmarked our method against a 2D Fully Convolutional Network based method, improving the top-1 precision score by 1.8% and 1.7% for suction and gripper respectively.
RUNX3 Transcript Variants Have Distinct Roles in Ovarian Carcinoma and Differently Influence Platinum Sensitivity and Angiogenesis

Simple Summary Epithelial ovarian cancer treatment is limited by missing predictive markers, frequent chemotherapy resistance and an incomplete understanding of the biology of tumors. Earlier work proved that hypermethylation of the gene RUNX3 coding for a transcription factor has prognostic value, and RUNX3 transcript variant overexpression, regulated by this epigenetic mechanism, influences cisplatin sensitivity and malignant properties of cells contrary. The present data validate RUNX3 transcript variant-specific effects for high-grade serous ovarian cancer and identify RUNX3-regulated genes and processes. Specifically, DNA damage repair and angiogenesis are influenced by RUNX3, and transcript variant 1 mediates stronger carcinogenic properties. Abstract The prognosis of late-stage epithelial ovarian cancer (EOC) patients is affected by chemotherapy response and the malignant potential of the tumor cells. In earlier work, we identified hypermethylation of the runt-related transcription factor 3 gene (RUNX3) as a prognostic biomarker and contrary functions of transcript variants (TV1 and TV2) in A2780 and SKOV3 cells. The aim of the study was to further validate these results and to increase the knowledge about RUNX3 function in EOC. New RUNX3 overexpression models of high-grade serous ovarian cancer (HGSOC) were established and analyzed for phenotypic (IC50 determination, migration, proliferation and angiogenesis assay, DNA damage analysis) and transcriptomic consequences (NGS) of RUNX3 TV1 and TV2 overexpression. Platinum sensitivity was affected by a specific transcript variant depending on BRCA background. RUNX3 TV2 induced an increased sensitivity in BRCA1wt cells (OVCAR3), whereas TV1 increased the sensitivity and induced a G2/M arrest under treatment in BRCA1mut cells (A13-2-12). These different phenotypes relate to differences in DNA repair: homologous recombination deficient A13-2-12 cells show less γH2AX foci despite higher levels of Pt-DNA adducts. RNA-Seq analyses prove transcript variant and cell-line-specific RUNX3 effects. Pathway analyses revealed another clinically important function of RUNX3—regulation of angiogenesis. This was confirmed by thrombospondin1 analyses, HUVEC spheroid sprouting assays and proteomic profiling. Importantly, conditioned media (CM) from RUNX3 TV1 overexpressing A13-2-12 cells induced an increased HUVEC sprouting. Altogether, the presented data support the hypothesis of different functions of RUNX3 transcript variants related to the clinically relevant processes—platinum resistance and angiogenesis.
Structural and Energetic Characterization of the Denatured State from the Perspectives of Peptides, the Coil Library, and Intrinsically Disordered Proteins

The α and polyproline II (PPII) basins are the two most populated regions of the Ramachandran map when constructed from the protein coil library, a widely used denatured state model built from the segments of irregular structure found in the Protein Data Bank. This indicates the α and PPII conformations are dominant components of the ensembles of denatured structures that exist in solution for biological proteins, an observation supported in part by structural studies of short, and thus unfolded, peptides. Although intrinsic conformational propensities have been determined experimentally for the common amino acids in short peptides, and estimated from surveys of the protein coil library, the ability of these intrinsic conformational propensities to quantitatively reproduce structural behavior in intrinsically disordered proteins (IDPs), an increasingly important class of proteins in cell function, has thus far proven elusive to establish. Recently, we demonstrated that the sequence dependence of the mean hydrodynamic size of IDPs in water and the impact of heat on the coil dimensions, provide access to both the sequence dependence and thermodynamic energies that are associated with biases for the α and PPII backbone conformations. Here, we compare results from peptide-based studies of intrinsic conformational propensities and surveys of the protein coil library to those of the sequence-based analysis of heat effects on IDP hydrodynamic size, showing that a common structural and thermodynamic description of the protein denatured state is obtained.
Viral Evasion of RIG-I-Like Receptor-Mediated Immunity through Dysregulation of Ubiquitination and ISGylation

Viral dysregulation or suppression of innate immune responses is a key determinant of virus-induced pathogenesis. Important sensors for the detection of virus infection are the RIG-I-like receptors (RLRs), which, in turn, are antagonized by many RNA viruses and DNA viruses. Among the different escape strategies are viral mechanisms to dysregulate the post-translational modifications (PTMs) that play pivotal roles in RLR regulation. In this review, we present the current knowledge of immune evasion by viral pathogens that manipulate ubiquitin- or ISG15-dependent mechanisms of RLR activation. Key viral strategies to evade RLR signaling include direct targeting of ubiquitin E3 ligases, active deubiquitination using viral deubiquitinating enzymes (DUBs), and the upregulation of cellular DUBs that regulate RLR signaling. Additionally, we summarize emerging new evidence that shows that enzymes of certain coronaviruses such as SARS-CoV-2, the causative agent of the current COVID-19 pandemic, actively deISGylate key molecules in the RLR pathway to escape type I interferon (IFN)-mediated antiviral responses. Finally, we discuss the possibility of targeting virally-encoded proteins that manipulate ubiquitin- or ISG15-mediated innate immune responses for the development of new antivirals and vaccines.
Spatio-Temporal Dynamics of Plasmodium falciparum and Plasmodium vivax in French Guiana: 2005–2019

Aims: This study examines the dynamics of malaria as influenced by meteorological factors in French Guiana from 2005 to 2019. It explores spatial hotspots of malaria transmission and aims to determine the factors associated with variation of hotspots with time. Methods: Data for individual malaria cases came from the surveillance system of the Delocalized Centers for Prevention and Care (CDPS) (n = 17) from 2005–2019. Meteorological data was acquired from the NASA Goddard Earth Sciences Data and Information Services Center (GES DISC) database. The Box–Jenkins autoregressive integrated moving average (ARIMA) model tested stationarity of the time series, and the impact of meteorological indices (issued from principal component analysis—PCA) on malaria incidence was determined with a general additive model. Hotspot characterization was performed using spatial scan statistics. Results: The current sample includes 7050 eligible Plasmodium vivax (n = 4111) and Plasmodium falciparum (n = 2939) cases from health centers across French Guiana. The first and second PCA-derived meteorological components (maximum/minimum temperature/minimum humidity and maximum humidity, respectively) were significantly negatively correlated with total malaria incidence with a lag of one week and 10 days, respectively. Overall malaria incidence decreased across the time series until 2017 when incidence began to trend upwards. Hotspot characterization revealed a few health centers that exhibited spatial stability across the entire time series: Saint Georges de l’Oyapock and Antecume Pata for P. falciparum, and Saint Georges de l’Oyapock, Antecume Pata, Régina and Camopi for P. vivax. Conclusions: This study highlighted changing malaria incidence in French Guiana and the influences of meteorological factors on transmission. Many health centers showed spatial stability in transmission, albeit not temporal. Knowledge of the areas of high transmission as well as how and why transmission has changed over time can inform strategies to reduce the transmission of malaria in French Guiana. Hotspots should be further investigated to understand other influences on local transmission, which will help to facilitate elimination.
Pedestrian Crossing Decisions in Virtual Environments: Behavioral Validity in CAVEs and Head-Mounted Displays

Objective To contribute to the validation of virtual reality (VR) as a tool for analyzing pedestrian behavior, we compared two types of high-fidelity pedestrian simulators to a test track. Background While VR has become a popular tool in pedestrian research, it is uncertain to what extent simulator studies evoke the same behavior as nonvirtual environments. Method An identical experimental procedure was replicated in a CAVE automatic virtual environment (CAVE), a head-mounted display (HMD), and on a test track. In each group, 30 participants were instructed to step forward whenever they felt the gap between two approaching vehicles was adequate for crossing. Results Our analyses revealed distinct effects for the three environments. Overall acceptance was highest on the test track. In both simulators, crossings were initiated later, but a relationship between gap size and crossing initiation was apparent only in the CAVE. In contrast to the test track, vehicle speed significantly affected acceptance rates and safety margins in both simulators. Conclusion For a common decision task, the results obtained in virtual environments deviate from those in a nonvirtual test bed. The consistency of differences indicates that restrictions apply when predicting real-world behavior based on VR studies. In particular, the higher susceptibility to speed effects warrants further investigation, since it implies that differences in perceptual processing alter experimental outcomes. Application Our observations should inform the conclusions drawn from future research in pedestrian simulators, for example by accounting for a higher sensitivity to speed variations and a greater uncertainty associated with crossing decisions.
Long-Term Bacterial and Fungal Dynamics following Oral Lyophilized Fecal Microbiota Transplantation in Clostridioides difficile Infection

Clostridioides difficile infection (CDI) is a substantial health concern worldwide, complicated by patterns of increasing antibiotic resistance that may impact primary treatment. Orally administered fecal microbiota transplantation (FMT) is efficacious in the management of recurrent CDI, with specific bacterial species known to influence clinical outcomes. ABSTRACT Oral lyophilized fecal microbiota transplantation (FMT) is effective in recurrent Clostridioides difficile infection (CDI); however, limited data exist on its efficacy in primary CDI and long-term microbial engraftment. Patients with primary or recurrent CDI were prospectively enrolled to receive oral FMT. Changes in the bacterial and fungal communities were characterized prior to and up to 6 months following treatment. A total of 37 patients with CDI (15 primary, 22 recurrent) were treated with 6 capsules each containing 0.35-g lyophilized stool extract. A total of 33 patients (89%) had sustained CDI cure, of whom 3 required a second course. There were no safety signals identified. FMT significantly increased bacterial diversity and shifted composition toward donor profiles in responders but not in nonresponders, with robust donor contribution observed to 6 months following FMT (P < 0.001). Responders showed consistent decreases in Enterobacteriaceae and increases in Faecalibacterium sp. to levels seen in donors. Mycobiome profiling revealed an association with FMT failure and increases in one Penicillium taxon, as well as coexclusion relationships between Candida sp. and bacterial taxa enriched in both donors and responders. Primary CDI was associated with more robust changes in the bacterial community than those with recurrent disease. Oral FMT leads to durable microbial engraftment in patients with primary and recurrent CDI, with several microbial taxa being associated with therapy outcome. Novel coexclusion relationships between bacterial and fungal species support the clinical relevance of transkingdom dynamics. IMPORTANCE Clostridioides difficile infection (CDI) is a substantial health concern worldwide, complicated by patterns of increasing antibiotic resistance that may impact primary treatment. Orally administered fecal microbiota transplantation (FMT) is efficacious in the management of recurrent CDI, with specific bacterial species known to influence clinical outcomes. To date, little is known about the efficacy of FMT in primary CDI and the impact of the mycobiome on therapeutic outcomes. We performed matched bacterial and fungal sequencing on longitudinal samples from a cohort of patients treated with oral FMT for primary and recurrent CDI. We validated many bacterial signatures following oral therapy, confirmed engraftment of donor microbiome out to 6 months following therapy, and demonstrated coexclusion relationships between Candida albicans and two bacterial species in the gut microbiota, which has potential significance beyond CDI, including in the control of gut colonization by this fungal species.
Medical Student Ultrasound-Guided Intravenous Catheter Education

Introduction Simulation-based mastery learning (SBML) improves skill transfer to humans. However, limited data exist to support the practice of performing additional training attempts once mastery has been achieved. We explored whether implementing this concept in an SBML model improves skill transfer in ultrasound-guided peripheral intravenous (USGPIV) catheter placement from simulator to humans. Methods Forty-eight first- and second-year medical students underwent SBML for USGPIV placement to mastery standards on a simulator once to achieve minimum passing standard based on a 19-item checklist. Next, they completed either 0, 4, or 8 additional mastery level simulated performances in nonconsecutive order before attempting USGPIV placement on a human. An unplanned post hoc retention phase occurred 6 months later where participants' USGPIV skills were reassessed on a second human volunteer using the same checklist. Results In this sample, the success rate among the 3 training cohorts did not improve as the number of additional training sessions increased (exact P = 0.60) and were comparable among the 3 cohorts (exact P = 0.82). The overall checklist performance was also comparable among the 3 cohorts (exact P = 0.57). In an unplanned (small) sample of returning participants, the USGPIV retention rate exceeded 80% for those originally assigned to 4 or 8 sessions, whereas the retention rate fell less than 50% for those originally assigned to control. Among these returning participants, the overall success rate was 58% on the initial assessment and was 68% on retention. Conclusions In this sample of novices, we were unable to show that up to 8 additional mastery level performances of USGPIV placement on a simulator following SBML training improve skill transfer for both USGPIV placement success and total checklist performance.
Ethics of emerging infectious disease outbreak responses: Using Ebola virus disease as a case study of limited resource allocation

Emerging infectious diseases such as Ebola Virus Disease (EVD), Nipah Virus Encephalitis and Lassa fever pose significant epidemic threats. Responses to emerging infectious disease outbreaks frequently occur in resource-constrained regions and under high pressure to quickly contain the outbreak prior to potential spread. As seen in the 2020 EVD outbreaks in the Democratic Republic of Congo and the current COVID-19 pandemic, there is a continued need to evaluate and address the ethical challenges that arise in the high stakes environment of an emerging infectious disease outbreak response. The research presented here provides analysis of the ethical challenges with regard to allocation of limited resources, particularly experimental therapeutics, using the 2013–2016 EVD outbreak in West Africa as a case study. In-depth semi-structured interviews were conducted with senior healthcare personnel (n = 16) from international humanitarian aid organizations intimately engaged in the 2013–2016 EVD outbreak response in West Africa. Interviews were recorded in private setting, transcribed, and iteratively coded using grounded theory methodology. A majority of respondents indicated a clear propensity to adopt an ethical framework of guiding principles for international responses to emerging infectious disease outbreaks. Respondents agreed that prioritization of frontline workers’ access to experimental therapeutics was warranted based on a principle of reciprocity. There was widespread acceptance of adaptive trial designs and greater trial transparency in providing access to experimental therapeutics. Many respondents also emphasized the importance of community engagement in limited resource allocation scheme design and culturally appropriate informed consent procedures. The study results inform a potential ethical framework of guiding principles based on the interview participants’ insights to be adopted by international response organizations and their healthcare workers in the face of allocating limited resources such as experimental therapeutics in future emerging infectious disease outbreaks to ease the moral burden of individual healthcare providers.
Flapless application of enamel matrix derivative in periodontal retreatment: A multicenter randomized feasibility trial.

AIM To investigate the potential benefit of enamel matrix derivative (EMD) as adjunct to re-instrumentation of residual pockets persisting after steps 1 and 2 of periodontal therapy. MATERIAL & METHODS 44 adult patients participated in a multicenter feasibility randomized clinical trial with split-mouth design. They had presented at re-evaluation after initial non-surgical periodontal therapy (steps 1 and 2 of periodontal therapy) for generalized periodontitis with at least 2 teeth with residual probing pocket depths (PPD) ≥ 5 and ≤ 8 mm, with bleeding on probing (BOP). Two teeth with similar PPD were randomized to receive re-instrumentation either with (test) or without (control) adjunctive flapless administration of EMD. Differences in the changes of PPD and BOP from baseline to 6 and 12 months were analyzed, and the frequencies of pocket closure (PPD ≤ 4 mm and no BOP) compared. RESULTS For the primary outcome "change of mean PPD after 6 months" a significant additional benefit of 0.79 ± 1.3 mm (p < 0.0001) could be observed for the test group. At 12 months, this difference could be maintained (0.85 ± 1.1 mm; p < 0.0001). The frequency of pocket closure in the test group was 69% at 6 and 80% at 12 months and significantly higher than in the control group with 34% and 42%, respectively (p < 0.01). CONCLUSION The results of the present feasibility study indicate a benefit of adjunctive EMD during non-surgical retreatment (step 3 of periodontal therapy) of residual deep pockets.