Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacokinetic Models to Characterize the Absorption Phase and the Influence of a Proton Pump Inhibitor on the Overall Exposure of Dacomitinib

Introduction: Dacomitinib is an epidermal growth factor receptor (EGFR) inhibitor approved for the treatment of metastatic non-small cell lung cancer (NSCLC) in the first line in patients with EGFR activating mutations. Dacomitinib is taken orally once daily at 45 mg with or without food, until disease progression or unacceptable toxicity occurs. Oncology patients often can develop gastroesophageal reflux disease (GERD), which may require management with an acid-reducing agent. Proton pump inhibitors (PPIs), such as rabeprazole, inhibit sodium-potassium adenosine triphosphatase (H+/K+-ATPase) pumps that stimulate acid secretion in the stomach and have a prolonged pharmacodynamic effect that extends beyond 24 h post-administration. The aim of this work was to characterize the absorption of dacomitinib via modeling with a particular interest in quantifying the impact of rabeprazole on the pharmacokinetics (PK) of dacomitinib. Materials and Methods: The pooled dataset consisted of five clinical pharmacology healthy volunteer studies, which collected serial pharmacokinetic concentration-time profiles of dacomitinib. Non-linear mixed effects modeling was carried out to characterize dacomitinib pharmacokinetics in the presence and absence of the concomitant use of a PPI, rabeprazole. Several absorption models, some more empirical, and some more physiologically based, were tested: transit compartment, first-order absorption with and without lag time, and variations of combined zero- and first-order absorption kinetics models. Results: The presence of a PPI was a significant covariate affecting the extent (F) and rate (ka) of dacomitinib absorption, as previously reported in the dedicated clinical study. A transit compartment model was able to best describe the absorption phase of dacomitinib.
Synthesis, Characterization, and Histological Evaluation of Chitosan-Ruta Graveolens Essential Oil Films

The development of new biocompatible materials for application in the replacement of deteriorated tissues (due to accidents and diseases) has gained a lot of attention due to the high demand around the world. Tissue engineering offers multiple options from biocompatible materials with easy resorption. Chitosan (CS) is a biopolymer derived from chitin, the second most abundant polysaccharide in nature, which has been highly used for cell regeneration applications. In this work, CS films and Ruta graveolens essential oil (RGEO) were incorporated to obtain porous and resorbable materials, which did not generate allergic reactions. An oil-free formulation (F1: CS) and three different formulations containing R. graveolens essential oil were prepared (F2: CS-RGEO 0.5%; F3: CS+RGEO 1.0%; and F4: CS+RGEO 1.5%) to evaluate the effect of the RGEO incorporation in the mechanical and thermal stability of the films. Infrared spectroscopy (FTIR) analyses demonstrated the presence of RGEO. In contrast, X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analysis showed that the crystalline structure and percentage of CS were slightly affected by the RGEO incorporation. Interesting saturation phenomena were observed for mechanical and water permeability tests when RGEO was incorporated at higher than 0.5% (v/v). The results of subdermal implantation after 30 days in Wistar rats showed that increasing the amount of RGEO resulted in greater resorption of the material, but also more significant inflammation of the tissue surrounding the materials. On the other hand, the thermal analysis showed that the RGEO incorporation almost did not affect thermal degradation. However, mechanical properties demonstrated an understandable loss of tensile strength and Young’s modulus for F3 and F4. However, given the volatility of the RGEO, it was possible to generate a slightly porous structure, as can be seen in the microstructure analysis of the surface and the cross-section of the films. The cytotoxicity analysis of the CS+RGEO compositions by the hemolysis technique agreed with in vivo results of the low toxicity observed. All these results demonstrate that films including crude essential oil have great application potential in the biomedical field.
Disparities in parental awareness of children’s seasonal influenza vaccination recommendations and influencers of vaccination

Objective To determine parental awareness of influenza vaccination recommendations for children and explore associations with awareness. Design Cross-sectional survey. Setting/participants South Australian parents with a telephone listing in the Electronic White Pages were randomly selected. Methods Participants were interviewed using Computer Assisted Telephone Interviewing (CATI) during May–July 2016. Univariable and multivariable analyses explored characteristics associated with awareness; with the survey data weighted to reflect the population of SA and the probability of selection within a household. Results Of 539 parents, 33% were aware of the recommendation that all children (<5 years) should receive the influenza vaccine annually with 51.9% aware that children with special risk medical conditions (SRMC) should also receive the vaccine annually. Characteristics strongly associated with parental awareness of the recommendation for children aged < 5 years were knowledge of recommendation for children with a SRMC (adjusted Odds Ratio [aOR] 10.46, CI 4.44–24.63) or living in a metropolitan area (aOR 2.91, CI 1.19–7.09). There was lack of awareness in those not working (aOR 0.13, CI 0.04–0.47), with trade level education (compared with high school) (aOR 0.25 CI, 0.09–0.71) and in those born in the UK or Ireland (aOR 0.19, CI 0.04–0.85). Awareness of the recommendation for children with SRMC to receive the vaccine was strongly associated with knowledge of the influenza recommendation for children <5 years (aOR 10.22, CI 4.39–23.77) or not being born in Australia [UK/ Ireland (aOR 7.63, CI 1.86–31.31); other (aOR 3.93, CI 0.94–16.42)]. The most influential cues to future receipt were a general practitioner (GP) recommendation (63.8%) and providing influenza vaccine free for all children (37.6%). More parents who delayed or excluded vaccines believed that their children’s vaccinations (in general) were unnecessary, as other children were vaccinated (42.8%) compared to those with no or minor concerns (11.1%) (p<0.0001). Conclusions Parental awareness of children’s influenza vaccine recommendations is low. Targeted communication strategies and resources are required to establish broader community awareness of recommendations. Healthcare provider endorsement of the vaccine remains key and health care professionals, particularly GPs and paediatric specialists should be encouraged to discuss influenza vaccine with parents at every opportunity. Many parents have vaccine concerns and addressing concerns across the spectrum of hesitancy is crucial.
Electro-Osmotic Vortices Promote the Capture of Folded Proteins by PlyAB Nanopores

Biological nanopores are emerging as powerful tools for single-molecule analysis and sequencing. Here, we engineered the two-component pleurotolysin (PlyAB) toxin to assemble into 7.2 × 10.5 nm cylindrical nanopores with a low level of electrical noise in lipid bilayers, and we addressed the nanofluidic properties of the nanopore by continuum simulations. Surprisingly, proteins such as human albumin (66.5 kDa) and human transferrin (76–81 kDa) did not enter the nanopore. We found that the precise engineering of the inner surface charge of the PlyAB induced electro-osmotic vortices that allowed the electrophoretic capture of the proteins. Once inside the nanopore, two human plasma proteins could be distinguished by the characteristics of their current blockades. This fundamental understanding of the nanofluidic properties of nanopores provides a practical method to promote the capture and analysis of folded proteins by nanopores.
Mediating Factors for the Relationship between Stress and Work Ability over Time in Young Adults

Stress can affect work ability. The aim of this study was to identify how this pathway is mediated over time in young adults. Participants of the Work Ability in Young Adults cohort were selected. A theoretical framework was built, which lead to a statistical model. Selected dimensions of mediators were recovery, work demands affecting private life, feelings of control over private life, and physical activity in leisure time. A quadruple serial mediation model was built with four mediators. The total effect of stress on work ability was −0.3955, 95% CI [−0.4764, −0.3146]. The total indirect effect amounted to 81% with an effect of −0.3182, 95% CI [−0.3750, −0.2642]. The relationship between stress and Work Ability Score five years later in young adults was mediated by stress five years later, work demands affecting private life, feelings of control over private life and feeling well-rested upon waking. These results indicate that work demands affecting private life and feelings of control over private life are important mediators of the relationship between stress and work ability in young adults. A well-balanced relationship between work and private life can counteract the influence of stress on work ability in this age group.
A Relatively Small Gradient of Extracellular pH Directs Migration of MDA-MB-231 Cells In Vitro

Hematogenous tumor metastasis begins with the invasion and spread of primary tumor cells in the local tissue leading to intravasation. We hypothesized that tumor cells might actively migrate toward intratumor vessels with the extracellular metabolic gradient acting as a guiding cue. Here, we determined in vitro whether the extracellular gradient of pH can act as a cue for directional migration in MDA-MB-231 cells. Cell migration was determined by the wound-healing assay under gradients of extracellular pH (~0.2 units/mm) and oxygen concentration (~6% O2/mm) that were produced by a microfluidic device, gap cover glass (GCG). Without GCG, the migration of cells was spatially homogeneous; the same number of cells migrated to the rectangular wound space from the left and right boundaries. In contrast, when GCG generated pH/O2 gradients across the wound space, the number of cells migrating to the wound space from the boundary with higher pH/O2 values was considerably decreased, indicating a preferential movement of cells toward the region of higher pH/O2 in the gradient. The addition of hepes in the extracellular medium abolished both the extracellular pH gradient and the directional cell migration under GCG. We conclude that relatively small gradients of pH in the extracellular medium compared to those found in Na+/H+ exchanger-driven cell migration were sufficient to guide MDA-MB-231 cells. The directional cell migration as guided by the metabolic gradient could effectively elevate the probability of intravasation and, ultimately, hematogenous metastasis.
Crystal structure of adenylate kinase from an extremophilic archaeon Aeropyrum pernix with ATP and AMP.

The crystal structure of an adenylate kinase from an extremophilic archaeon Aeropyrum pernix was determined in complex with full ligands, ATP-Mg2+ and AMP, at a resolution of 2.0 Å. The protein forms a trimer as found for other adenylate kinases from archaea. Interestingly, the reacting three atoms, two phosphorus and one oxygen atoms, were located almost in line, supporting the SN2 nucleophilic substitution reaction mechanism. Based on the crystal structure obtained, the reaction coordinate was estimated by the quantum mechanics calculations combined with molecular dynamics. It was found that the reaction undergoes two energy barriers; the steps for breaking the bond between the oxygen and γ-phosphorus atoms of ATP to produce a phosphoryl fragment and creating the bond between the phosphoryl fragment and the oxygen atom of the β-phosphate group of ADP. The reaction coordinate analysis also suggested the role of amino acid residues for the catalysis of ADK.
Parent-child agreement in different domains of child behavior and health

Aim The present study aimed to investigate and compare parent-child agreement in different domains of child health and behavior. Methods Data were collected between 2011 and 2019 within the framework of the LIFE Child study (Germany). Different subgroups of 10- to 12-year-old children and their parents (n (max) = 692) completed questionnaires on several health behaviors (diet, media use, physical activity, sleep), parameters of health (behavioral strengths and difficulties, psychosomatic complaints), and school grades. Agreement between child and parent reports was evaluated using weighted kappa coefficients. Furthermore, the frequencies of different types of (dis)agreement (parent report > child report, same response, child report > parent report) were assessed and checked for associations with child or parent gender. Results Agreement between child and parent reports varied from low to almost perfect, with the greatest levels of agreement for school grades and organized physical activity, and the lowest for dizziness, sleep duration, and the consumption of potatoes. Child gender had no significant effect on parent-child agreement. In contrast, the findings suggest that parent gender had some effect on agreement levels, with higher agreement for certain psychosomatic complaints when parent reports were completed by the mother, and higher agreement for white bread consumption if they were completed by the father. For some of the questionnaire items (especially those relating to behavioral difficulties and psychosomatic complaints, but also to the consumption of individual food products and mobile phone use), the type of (dis)agreement differed depending on child or parent gender. Conclusions The findings suggest that the perceptions and reporting strategies of children and their parents can diverge considerably, in particular for behavior that is not easily observable or measurable.
Bacterial Quorum Sensing Signals Self-Assemble in Aqueous Media to Form Micelles and Vesicles: An Integrated Experimental and Molecular Dynamics Study.

Many species of common bacteria communicate and coordinate group behaviors, including toxin production and surface fouling, through a process known as quorum sensing (QS). In Gram-negative bacteria, QS is regulated by N-acyl L-homoserine lactones (AHLs) that possess a polar homoserine lactone head group and a nonpolar aliphatic tail. Past studies demonstrate that AHLs can aggregate in water or adsorb at interfaces, suggesting that molecular self-assembly could play a role in processes that govern bacterial communication. We used a combination of biophysical characterization and atomistic molecular dynamics (MD) simulations to characterize the self-assembly behaviors of 12 structurally related AHLs. We used static light scattering and measurements of surface tension to characterize the assembly of four naturally occurring AHLs (3-oxo-C8-AHL, 3-oxo-C12-AHL, C12-AHL, and C16-AHL) in aqueous media and determine their critical aggregation concentrations (CACs). MD simulations and alchemical free energy calculations were used to predict thermodynamically preferred aggregate structures for each AHL. Those calculations predicted that AHLs with 10 or 12 tail carbon atoms should form spherical micelles, and that AHLs with 14 or 16 tail carbon atoms should form vesicles in solution. Characterization of solutions of AHLs using negative stain transmission electron microscopy (TEM) and dynamic light scattering (DLS) revealed aggregates with sizes consistent with spherical micelles or small unilamellar vesicles for 3-oxo-C12-AHL and C12-AHL, and the formation of large vesicles (~250 nm) in solutions of C16-AHL. These experimental findings are in general agreement with our simulation predictions. Overall, our results provide insight into processes of self-assembly that can occur in this class of bacterial amphiphiles and, more broadly, provide a potential basis for understanding how AHL structure could influence processes that bacteria use to drive important group behaviors.
Similarly oriented objects appear more numerous

Several non-numerical factors influence the numerical estimation of visual arrays, including the spacing of items and whether they are arranged randomly or symmetrically. Here we report a novel numerosity illusion we term the coherence illusion. When items in an array have a coherent orientation (all pointing in the same direction) they seem to be more numerous than when items are oriented randomly. Participants show parametric effects of orientation coherence in three distinct numerical judgment tasks. These findings are not predicted by any current model of numerical estimation. We discuss array entropy as a possible framework for explaining both the coherence illusion and the previously reported regular-random illusion.
Adaptive responses of histone modifications to resistance exercise in human skeletal muscle

Exercise training causes epigenetic changes in skeletal muscle, although it is unclear how resistance exercise (RE) affects histone modifications. The present study was carried out to investigate the effects of acute RE and RE training on gene expression profiles and histone modifications in human skeletal muscle. Healthy male adults were assigned to acute RE (n = 9, age = 20.5±4.3yr, BMI = 28.0±6.8kg/m2) or RE training (n = 21, age = 23.7±2.5yr, BMI = 24.2±2.7kg/m2) groups. Biopsy samples were obtained from the vastus lateralis muscle before and three hours after a single bout of acute RE, or 3-days after 10 weeks of RE training. RNA sequencing analysis revealed that 153 genes with GO terms including muscle development, stress response, metabolism, cell death, and transcription factor were significantly up-regulated (+291% vs. pre-acute RE) upon acute RE. Expressions of these genes were also greater (+9.6% vs. pre-RE training, p<0.05) in RE trained subjects. Significant up-regulation of acetylated histone 3 (H3) (+235%) and H3 mono-methylated at lysine 4 (+290%) and tri-methylated at lysine 27 (+849%), whereas down-regulation of H3.3 variant (−39%) distributions relative to total H3 were observed at transcriptionally activated loci after acute RE compared to pre-acute RE levels. Interestingly, the distribution of acetylated H3 was found to be up-regulated as compared to the level of total H3 after RE training (+40%, p<0.05). These results indicate that a single bout of RE drastically alters both gene expressions and histone modifications in human skeletal muscle. It is also suggested that enhanced histone acetylation is closely related to up-regulation of gene expressions after RE training.
Molecular and epidemiological analysis of a Burkholderia cepacia sepsis outbreak from a tertiary care hospital in Bangladesh

Background Burkholderia cepacia complex (Bcc) is a group of serious pathogens in cystic fibrosis patients and causes life threatening infections in immunocompromised patients. Species within the Bcc are widely distributed within the environment, can survive in the presence of disinfectants and antiseptics, and are inherently multidrug resistant (MDR). Methods Dhaka Medical College Hospital (DMCH) patients with a B. cepacia positive blood culture between 20 October 2016 to 23rd September 2017 were considered as outbreak cases. Blood stream infections (BSIs) were detected using BacT/ALERT 3D at DMCH. B. cepacia was isolated on chromogenic UTI media followed by MALDI-TOF. Minimum inhibitory concentration (MIC) of clinically relevant antibiotics was determined by agar dilution. Whole genome sequencing was performed on an Illumina MiSeq platform. Patients’ demographic and clinical data were collected. Patients’ clinical history and genomic data of the outbreak strains were merged to investigate possible outbreaks. Ninety-one B. cepacia genomes were downloaded from ‘Burkholderia Genome Database’ and the genomic background of the global strains were compared with our outbreak strains. Results Among 236 BSIs, 6.35% (15/236) were B. cepacia. Outbreak cases were confined to the burn critical care unit and, to a lesser extent, the paediatrics department. There was a continuum of overlapping cases at DMCH between 23 October 2016 to 30 August 2017. Core genome SNPs showed that the outbreak strains were confined to a single clade, corresponded to a common clone (ST1578). The strains were shown to be MDR and associated with a mortality of 31% excluding discharge against medical advice. MIC profiles of the strains suggested that antibiotics deployed as empirical therapy were invariably inappropriate. The genetic background of the outbreak strains was very similar; however, a few variations were found regarding the presence of virulence genes. Compared to global strains from the Burkholderia Genome Database, the Bangladeshi strains were genetically distinct. Conclusions Environmental surveillance is required to investigate the aetiology and mode of transmission of the B. cepacia outbreak. Systematic management of nosocomial outbreaks, particularly in resource limited regions, will mitigate transmission and will improve patients’ outcomes.
End-to-End Deep Learning Fusion of Fingerprint and Electrocardiogram Signals for Presentation Attack Detection

Although fingerprint-based systems are the commonly used biometric systems, they suffer from a critical vulnerability to a presentation attack (PA). Therefore, several approaches based on a fingerprint biometrics have been developed to increase the robustness against a PA. We propose an alternative approach based on the combination of fingerprint and electrocardiogram (ECG) signals. An ECG signal has advantageous characteristics that prevent the replication. Combining a fingerprint with an ECG signal is a potentially interesting solution to reduce the impact of PAs in biometric systems. We also propose a novel end-to-end deep learning-based fusion neural architecture between a fingerprint and an ECG signal to improve PA detection in fingerprint biometrics. Our model uses state-of-the-art EfficientNets for generating a fingerprint feature representation. For the ECG, we investigate three different architectures based on fully-connected layers (FC), a 1D-convolutional neural network (1D-CNN), and a 2D-convolutional neural network (2D-CNN). The 2D-CNN converts the ECG signals into an image and uses inverted Mobilenet-v2 layers for feature generation. We evaluated the method on a multimodal dataset, that is, a customized fusion of the LivDet 2015 fingerprint dataset and ECG data from real subjects. Experimental results reveal that this architecture yields a better average classification accuracy compared to a single fingerprint modality.