Miracle-dz/UniFAR-FTUs huggingface dataset:
Validating the Xerostomia Inventory in a radiation-induced xerostomia population in German language.

OBJECTIVES Though xerostomia is a frequent oral symptom, there is no validated disease-specific questionnaire in German. The purpose of this study was to translate and validate versions of the Xerostomia Inventory and the Summated Xerostomia Inventory in a German speaking population. PARTICIPANTS AND METHODS Thirty-nine patients including 18 patients suffering from radiation-induced xerostomia enrolled in this study. Both questionnaires were translated into German language according to international accepted guidelines. For validation, we evaluated reliability, validity and responsiveness using the COSMIN manual for cross-cultural adaptation. RESULTS Cronbach's α was 0.92 for XI and 0.91 for SXI, showing both high internal consistency. Patients suffering from xerostomia showed significantly higher average scores demonstrating its discriminant validity. Confirmatory factor analysis showed excellent "goodness of fit" values for SXI and good to moderate values for XI, confirming the assumed factor structures. The Xerostomia Inventory and its summated version both showed excellent test-retest-reliability in the non-xerostomia group (ICC=0.85 and 0.84). CONCLUSIONS The XI and SXI in their cross-cultural adapted versions are the first validated self-report assessments for xerostomia in German language. They are characterized by practical design and can be easily interpreted by the treating physician. This article is protected by copyright. All rights reserved.
An EFL Flipped Learning Course Design: Utilizing Students' Mobile Online Devices.

This paper reports on a research project in a university English as Foreign Language (EFL) program in Japan which explored ways to sustain active participation in e-learning tasks. The tasks were intended to improve students’ scores on the Test of English for International Communication (TOEIC), a test used by businesses to make hiring decisions. The research adopted a Flipped Learning (FL) approach to Blended Learning (BL). A web-based courseware, ATR CALL BRIX (http://www.atr-lt.jp/products/brix/index.html), which featured e-learning materials for the TOEIC Test, was used. The students used mobile devices to access the courseware before class in order to prepare for in-class teacher-student analysis of their performance on the learning tasks. The teaching methodology integrated the online and in-class tasks in a single learning environment by means of an e-mentoring system used in conjunction with an in-class student self-evaluation task. The findings of preand post-TOEIC testing showed a significant degree of TOEIC score improvement in the experimental group. Post-course evaluations revealed that the combination of e-mentoring and the in-class self-evaluation system had encouraged sustained engagement in outside-of-class learning activities.
Heat Stress Negatively Affects the Transcriptome Related to Overall Metabolism and Milk Protein Synthesis in Mammary Tissue of Mid-Lactating Dairy Cows.

Inadequate dry matter intake (DMI) only partially accounts for the decrease in milk protein synthesis during heat stress (HS) in dairy cows. Our hypothesis is that reduced milk protein synthesis during HS in dairy cows is also caused by biological changes within the mammary gland. The objective of this study was to assess the hypothesis via RNAseq analysis of mammary tissue. Herein, four dairy cows were used in a crossover design where HS was induced for 9 days using environmental chambers. There was a 30 d washout between periods. Mammary tissue was collected via biopsy at the end of each environmental period [HS or pair-fed and thermal neutral (PFTN)] for transcriptomic analysis. RNAseq analysis revealed HS affected >2,777 genes (FDR-adjusted P-value<0.05) in mammary tissue. Expression of main milk protein encoding genes and several key genes related to regulation of protein synthesis and amino acid and glucose transport were downregulated by HS. Bioinformatics analysis revealed an overall decrease of mammary tissue metabolic activity by HS (especially carbohydrate and lipid metabolism) and an increase in immune activation and inflammation. Network analysis revealed a major role of TNF, IFNG, S100A8, S100A9, and IGF-1 in inducing/controlling the inflammatory response, with a central role of NF-κB in the process of immunoactivation. The same analysis indicated an overall inhibition of PPARg. Collectively, these data suggest HS directly controls milk protein synthesis via reducing the transcription of metabolic-related genes and increasing inflammation-related genes.
Long-term Weight Loss Maintenance in the Continuation of a Randomized Diabetes Prevention Translational Study: The Healthy Living Partnerships to Prevent Diabetes (HELP PD) Continuation Trial

OBJECTIVE HELP PD was a clinical trial of 301 adults with prediabetes. Participants were randomized to enhanced usual care (EUC) or to a lifestyle weight loss (LWL) intervention led by community health workers that consisted of a 6-month intensive phase (phase 1) and 18 months of maintenance (phase 2). At 24 months, participants were asked to enroll in phase 3 to assess whether continued group maintenance (GM) sessions would maintain improvements realized in phases 1 and 2 compared with self-directed maintenance (SM) or EUC. RESEARCH DESIGN AND METHODS In phase 3, LWL participants were randomly assigned to GM or SM. EUC participants remained in the EUC arm and, along with participants in SM, received monthly newsletters. All participants received semiannual dietitian sessions. Anthropometrics and biomarkers were assessed every 6 months. Mixed-effects models were used to assess changes in outcomes over time. RESULTS Eighty-two of the 151 intervention participants (54%) agreed to participate in phase 3; 41 were randomized to GM and 41 to SM. Of the 150 EUC participants, 107 (71%) continued. Ninety percent of clinic visits were completed. Over 48 months of additional follow-up, outcomes remained relatively stable in the EUC participants; the GM group was able to maintain body weight, BMI, and waist circumference; and these measures all increased significantly (P < 0.001) in the SM group. CONCLUSIONS Participants in the GM arm maintained weight loss achieved in phases 1 and 2, while those in the SM arm regained weight. Because group session attendance by the participants in the GM arm was low, it is unclear what intervention components led to successful weight maintenance.
Visual Analog Scale Ratings and Orthographic Transcription Measures of Sentence Intelligibility in Parkinson's Disease With Variable Listener Exposure.

Purpose While orthographic transcription (OT) is the gold standard for measures of intelligibility, it is relatively inaccessible to clinicians. This study investigates the relationship between visual analog scale (VAS) ratings and OT measures of intelligibility for speakers with Parkinson's disease (PD), with the eventual goal of developing more clinically feasible assessments of intelligibility. Method Twenty speakers with PD and 5 controls read 11 sentences. First, 33 listeners completed an OT task using 1 sentence from each speaker. An additional 33 listeners rated the intelligibility of 1 sentence from each speaker using a VAS, reflecting a minimized exposure VAS (MEV) task. Lastly, 14 additional listeners each rated the intelligibility of all 11 sentences produced by all speakers using a VAS, reflecting an extended exposure VAS (EEV) task. Smaller listener groups were simulated from each VAS task for comparison to scores from the OT task. Results There was a strong relationship between OT and both MEV and EEV. This relationship remained strong ( R 2 ≥ .82) even when only 1 listener in MEV and 2 listeners in EEV were simulated per sentence. Conclusions VAS ratings may be a suitable alternative to OT measures of sentence intelligibility for PD using listeners with both minimal and extended exposure to the stimuli.
Differentiation of human olfactory system‐derived stem cells into dopaminergic neuron‐like cells: A comparison between olfactory bulb and mucosa as two sources of stem cells

Cell transplantation has become a possible therapeutic approach in the treatment of neurodegenerative diseases of the nervous system by replacing lost cells. The current study aimed to make a comparison between the differentiation capacity of the olfactory bulb neural stem cells (OB‐NSCs) and olfactory ectomesenchymal stem cells (OE‐MSCs) into dopaminergic‐like neurons under the inductive effect of transforming growth factor β (TGF‐β). After culturing and treating with TGF‐β, the differentiation capacities of both types of stem cells into dopaminergic neuron‐like cells were evaluated. Quantitative real‐time polymerase chain reaction analysis 3 weeks after induction demonstrated that the mRNA expression of the dopaminergic activity markers tyrosine hydroxylase (TH), dopamine transporter (DAT), paired box gene 2 (PAX2), and PAX5 in the neuron‐like cells derived from OB‐NSCs was significantly higher than those derived from OE‐MSCs. These findings were further supported by the immunocytochemistry staining showing that the expression of the tyrosine hydroxylase, DAT, PAX2, and paired like homeodomain 3 seemed to be slightly higher in OB‐NSCs compared with OE‐MSCs. Despite the lower differentiation capacity of OE‐MSCs, other considerations such as a noninvasive and easier harvesting process, faster proliferation attributes, longer life span, autologous transplantability, and also the easier and inexpensive cultural process of the OE‐MSCs, cumulatively make these cells the more appropriate alternative in the case of autologous transplantation during the treatment process of neurodegenerative disorders like Parkinson's disease.
Reversal of Factor Xa Inhibitors by Andexanet Alfa May Increase Thrombogenesis Compared to Pretreatment Values

Recombinant coagulation factor Xa (FXa), inactivated Zh-zo, also known as andexanet alfa (AA), is a modified version of human FXa that has been developed to neutralize FXa inhibitors. We studied the reversal effect of AA for these inhibitors in various anticoagulant and thrombin generation (TG) assays. Individual aliquots of normal human plasma containing 1 µg/mL of apixaban, betrixaban, edoxaban, and rivaroxaban, were supplemented with saline or AA at a concentration of 100 µg/mL. Clotting profiles include prothrombinase-induced clotting time, activated partial thromboplastin time, and prothrombin time. Factor Xa activity was measured using an amidolytic method. Thrombin generation was measured using a calibrated automated thrombogram. Differential neutralization of all 4 anticoagulants was noted in the activated clotting time and other clotting tests. The FXa activity reversal profile varied with an observed decrease in apixaban (22%), betrixaban (56%), edoxaban (28%), and rivaroxaban (49%). Andexanet alfa also led to an increased TG in comparison to saline. The peak thrombin was higher (40%), area under the curve (AUC) increased (15%), whereas the lag time (LT) decreased (17%). Andexanet alfa added at 100 µg/mL to various FXa supplemented systems resulted in reversal of the inhibitory effects, restoring the TG profile; AUC, LT, and peak thrombin levels were comparable to those of unsupplemented samples. Andexanet alfa is capable of reversing anti-Xa activity of different oral FXa inhibitors but overshoots thrombogenesis in both the saline and FXa inhibitor supplemented systems. The degree of neutralization of Xa inhibitor is specific to each agent.
Insight into the Microstructure and Ionic Conductivity of Cold Sintered NASICON Solid Electrolyte for Solid-State Batteries.

Li1.3Al0. 3Ti1.7 (PO4)3 (LATP) is a popular solid electrolyte used in solid-state lithium batteries due to its high ionic conductivity. Traditionally, the densification of LATP is achieved by a high temperature sintering process (about 1000 ºC). Herein, we report the compaction of LATP by a newly developed cold sintering process and post-annealing. LATP pellets are first densified at 120 ºC and then annealed at 650 ºC, yielding an ionic conductivity of 8.04x10-5 S cm-1 at room temperature and a relative density of 93% with a low activation energy of 0.37 eV. High resolution transmission electron microscopy of the cold-sintered pellets are investigated as well, showing that the particles are interconnected with some nano-precipitates at the grain boundaries. Such nano-crystalline enriched grain boundaries are beneficial for lithium ion transportation, which leads to higher ionic conductivity of cold sintered sample. This new sintering process can direct new horizons for development of all solid- state batteries due to its simplicity.
Analysis of Beamforming Antenna for Practical Indoor Location-Tracking Application

The single antenna used in conventional ultra-wideband radar has difficulty tracking targets over a wide range because of a relatively narrow beamwidth. Herein, we propose a beamforming antenna that can track targets over a wide range by electronically controlling the main beam of the antenna. The proposed beamforming antenna was fabricated by connecting a 1 × 4 linear array antenna and a 4 × 4 Butler matrix. The Butler matrix was fabricated in a laminated substrate using two TRF-45 substrates. Furthermore, the input Ports 1–4 generate a phase difference at regular intervals in each output port, and the output phase is fed to the array antenna. The proposed tapered-slot antenna was fabricated on a Taconic TLY substrate, and the impedance bandwidth of the antenna was achieved within a wide bandwidth of 4.32 GHz by satisfying a VSWR (Voltage Standing Wave Ratio) ≤2 within the 1.45–5.78 GHz band. Furthermore, the fabricated antenna has directional radiation patterns, which was found to be a suitable characsteristic for location tracking in a certain direction. Finally, the beamforming antenna has four beamforming angles, and to verify the performance for an indoor location tracking application of impulse-radio ultra-wideband radar, it was connected to an NVA-R661 module.
Drug‐drug interactions between feminizing hormone therapy and pre‐exposure prophylaxis among transgender women: the iFACT study

Concerns over potential drug‐drug interactions (DDI) between feminizing hormone therapy (FHT) and pre‐exposure prophylaxis (PrEP) have hampered uptake and adherence of PrEP among transgender women (TGW). To determine DDI between FHT and PrEP, we measured the pharmacokinetic (PK) parameters of blood plasma estradiol (E2) and tenofovir (TFV) in Thai TGW.
Functional divergence caused by mutations in an energetic hotspot in ERK2

Significance Extracellular signal-regulated kinases 1/2 (ERK1/2; mitogen-activated protein kinases) regulate physiological processes, including development and proliferation, and are overactive in many cancers. A conserved binding site docks effector proteins. Two adjacent negatively charged residues, one facing inward and the other into solvent, are required for docking, and have cancer-associated mutations. Mutation of the inward-facing residue disrupts ERK2 structure and decreases stability, while the outward-facing residue stabilizes the wild-type conformation. Both mutants cause similar changes in activities in vitro, yet drastically different Drosophila phenotypes, implying unanticipated functional differences. The clustered negative charges and stability differences suggest that the docking site is energetically strained by charge repulsion and provides energy to drive docking-induced conformational changes. Stability and energetic differences likely impact phenotypes. The most frequent extracellular signal-regulated kinase 2 (ERK2) mutation occurring in cancers is E322K (E-K). ERK2 E-K reverses a buried charge in the ERK2 common docking (CD) site, a region that binds activators, inhibitors, and substrates. Little is known about the cellular consequences associated with this mutation, other than apparent increases in tumor resistance to pathway inhibitors. ERK2 E-K, like the mutation of the preceding aspartate (ERK2 D321N [D-N]) known as the sevenmaker mutation, causes increased activity in cells and evades inactivation by dual-specificity phosphatases. As opposed to findings in cancer cells, in developmental assays in Drosophila, only ERK2 D-N displays a significant gain of function, revealing mutation-specific phenotypes. The crystal structure of ERK2 D-N is indistinguishable from that of wild-type protein, yet this mutant displays increased thermal stability. In contrast, the crystal structure of ERK2 E-K reveals profound structural changes, including disorder in the CD site and exposure of the activation loop phosphorylation sites, which likely account for the decreased thermal stability of the protein. These contiguous mutations in the CD site of ERK2 are both required for docking interactions but lead to unpredictably different functional outcomes. Our results suggest that the CD site is in an energetically strained configuration, and this helps drive conformational changes at distal sites on ERK2 during docking interactions.
On adaptive random testing

Adaptive random testing (ART) has been proposed as an enhancement to random testing for situations where failure-causing inputs are clustered together. The basic idea of ART is to evenly spread test cases throughout the input domain. It has been shown by simulations and empirical analysis that ART frequently outperforms random testing. However, there are some outstanding issues on the cost-effectiveness and practicality of ART, which are the main foci of this thesis. Firstly, this thesis examines the basic factors that have an impact on the faultdetection effectiveness of adaptive random testing, and identifies favourable and unfavourable conditions for ART. Our study concludes that favourable conditions for ART occur more frequently than unfavourable conditions. Secondly, since all previous studies allow duplicate test cases, there has been a concern whether adaptive random testing performs better than random testing because ART uses fewer duplicate test cases. This thesis confirms that it is the even spread rather than less duplication of test cases which makes ART perform better than RT. Given that the even spread is the main pillar of the success of ART, an investigation has been conducted to study the relevance and appropriateness of several existing metrics of even spreading. Thirdly, the practicality of ART has been challenged for nonnumeric or high dimensional input domains. This thesis provides solutions that address these concerns. Finally, a new problem solving technique, namely, mirroring, has been developed. The integration of mirroring with adaptive random testing has been empirically shown to significantly increase the cost-effectiveness of ART. In summary, this thesis significantly contributes to both the foundation and the practical applications of adaptive random testing.
Discovery of receptor‐ligand interfaces in the immunoglobulin superfamily

Cell‐surface‐anchored immunoglobulin superfamily (IgSF) proteins are widespread throughout the human proteome, forming crucial components of diverse biological processes including immunity, cell‐cell adhesion, and carcinogenesis. IgSF proteins generally function through protein‐protein interactions carried out between extracellular, membrane‐bound proteins on adjacent cells, known as trans‐binding interfaces. These protein‐protein interactions constitute a class of pharmaceutical targets important in the treatment of autoimmune diseases, chronic infections, and cancer. A molecular‐level understanding of IgSF protein‐protein interactions would greatly benefit further drug development. A critical step toward this goal is the reliable identification of IgSF trans‐binding interfaces. We propose a novel combination of structure and sequence information to identify trans‐binding interfaces in IgSF proteins. We developed a structure‐based binding interface prediction approach that can identify broad regions of the protein surface that encompass the binding interfaces and suggests that IgSF proteins possess binding supersites. These interfaces could theoretically be pinpointed using sequence‐based conservation analysis, with performance approaching the theoretical upper limit of binding interface prediction accuracy, but achieving this in practice is limited by the current ability to identify an appropriate multiple sequence alignment for conservation analysis. However, an important contribution of combining the two orthogonal methods is that agreement between these approaches can estimate the reliability of the predictions. This approach was benchmarked on the set of 22 IgSF proteins with experimentally solved structures in complex with their ligands. Additionally, we provide structure‐based predictions and reliability scores for the 62 IgSF proteins with known structure but yet uncharacterized binding interfaces.
Models and treatments for traumatic optic neuropathy and demyelinating optic neuritis

Pathologies of the optic nerve could result as primary insults in the visual tract or as secondary deficits due to inflammation, demyelination, or compressing effects of the surrounding tissue. The extent of damage may vary from mild to severe, differently affecting patient vision, with the most severe forms leading to complete uni‐ or bilateral visual loss. The aim of researchers and clinicians in the field is to alleviate the symptoms of these, yet uncurable pathologies, taking advantage of known and novel potential therapeutic approaches, alone or in combinations, and applying them in a limited time window after the insult. In this review, we discuss the epidemiological and clinical profile as well as the pathophysiological mechanisms of two main categories of optic nerve pathologies, namely traumatic optic neuropathy and optic neuritis, focusing on the demyelinating form of the latter. Moreover, we report on the main rodent models mimicking these pathologies or some of their clinical aspects. The current treatment options will also be reviewed and novel approaches will be discussed.
Physiologically-based pharmacokinetic modeling of benzo(a)pyrene and the metabolite in humans of different ages

ABSTRACT Age-specific differences in the pharmacokinetics of benzo(a)pyrene (BaP) and its metabolite 3-hydroxybenzo(a)pyrene (3-OHBaP) potentially affect time courses of tissue concentration; however, the quantitative impact of these differences is not well characterized. Our objective was to quantify the effect of age-specific differences in physiological and biochemical parameters on the pharmacokinetics of BaP and 3-OHBaP from newborn at birth to adulthood following inhalation exposure. The time courses of BaP and 3-OHBaP were simulated by using a physiologically based pharmacokinetic model with Advanced Continuous Simulation Language (ACSLX). The concentrations of BaP increased with age in the liver but decreased with age in most tissues, urine, and blood. The concentrations of 3-OHBaP were the highest in the newborns. Our results also showed that the concentration of BaP has almost reached a steady state in the kidney, liver, lung, rapidly perfused tissues, slowly perfused tissues, and skin except for adipose tissues. However, the concentration of 3-OHBaP has reached a steady state in all tissues. This study suggests that age-specific parameters have an effect on the pharmacokinetics of BaP and 3-OHBaP. In particular, tissue concentration in the newborns is higher than other age groups, which indicates that the newborns are susceptible to environmental BaP exposure.