Miracle-dz/UniFAR-FTUs huggingface dataset:
Interaction of 2,4-Diaminopyrimidine–Containing Drugs Including Fedratinib and Trimethoprim with Thiamine Transporters

Inhibition of thiamine transporters has been proposed as a putative mechanism for the observation of Wernicke’s encephalopathy and subsequent termination of clinical development of fedratinib, a Janus kinase inhibitor (JAKi). This study aimed to determine the potential for other JAKi to inhibit thiamine transport using human epithelial colorectal adenocarcinoma (Caco-2) and thiamine transporter (THTR) overexpressing cells and to better elucidate the structural basis for interacting with THTR. Only JAKi containing a 2,4-diaminopyrimidine were observed to inhibit thiamine transporters. Fedratinib inhibited thiamine uptake into Caco-2 cells (IC50 = 0.940 µM) and THTR-2 (IC50 = 1.36 µM) and, to a lesser extent, THTR-1 (IC50 = 7.10 µM) overexpressing cells. Two other JAKi containing this moiety, AZD1480 and cerdulatinib, were weaker inhibitors of the thiamine transporters. Other JAKi—including monoaminopyrimidines, such as momelotinib, and nonaminopyrimidines, such as filgotinib—did not have any inhibitory effects on thiamine transport. A pharmacophore model derived from the minimized structure of thiamine suggests that 2,4-diaminopyrimidine–containing compounds can adopt a conformation matching several key features of thiamine. Further studies with drugs containing a 2,4-diaminopyrimidine resulted in the discovery that the antibiotic trimethoprim also potently inhibits thiamine uptake mediated by THTR-1 (IC50 = 6.84 µM) and THTR-2 (IC50 = 5.56 µM). Fedratinib and trimethoprim were also found to be substrates for THTR, a finding with important implications for their disposition in the body. In summary, our results show that not all JAKi have the potential to inhibit thiamine transport and further establish the interaction of these transporters with xenobiotics.
A Systems Biology Approach Provides Deeper Insights into Differentially Expressed Genes in Taxane-Anthracycline Chemoresistant and Non-Resistant Breast Cancers

Objective: To date, numerous studies have been conducted to search for reasons for chemoresistance and differences in survival rates of patients receiving chemotherapy. We have sought to identify differentially expressed genes (DEGs) between predicted chemotherapy resistance and sensitive phenotypes by a network as well as gene enrichment approach. Methods: Functional modules were explored with network analysis of DEGs in predicted neoadjuvant taxane-anthracycline resistance versus sensitive cases in the GSE25066 dataset, including 508 samples. A linear model was created by limma package in R to establish DEGs. Results: A gene set related to phagocytic vesicle membrane was found to be up-regulated in chemoresistance samples. Also, we found GO_CYTOKINE_ACTIVITY and GO_GROWTH_FACTOR BINDING to be up-regulated gene sets with the chemoresistance phenotype. Growth factors and cytokines are two groups of agents that induce the immune system to recruit APCs and promote tolerogenic phagocytosis. Some hub nodes like S100A8 were found to be important in the chemoresistant tumor cell network with associated high rank genes in GSEA. Conclusions: Functional gene sets and hub nodes could be considered as potential treatment targets. Moreover, by screening and enrichment analysis of a chemoresistance network, ligands and chemical agents have been found that could modify significant gene sets like the phagocytic vesicle membrane functional gene set as a key to chemoresistance. They could also impact on down- or up-regulated hub nodes.
Detecting malingering in traumatic brain injury: Combining response time with performance validity test accuracy

Abstract Objective: The present study examined the incremental utility of item-level response time (RT) variables on a traditional performance validity test in distinguishing adults with verified TBI from adults coached to feign neurocognitive impairment. Method: Participants were 45 adults with moderate to severe TBI, 45 healthy adults coached to feign neurocognitive impairment (SIM), and 61 healthy adult comparisons providing full effort (HC). All participants completed a computerized version of the Test of Memory Malingering (TOMM-C) in the context of a larger test battery. RT variables examined along with TOMM-C accuracy scores included mean RTs (Trial 1, Trial 2, correct and incorrect trials) and RT variability indices. Results: Several RT indices differed significantly across the groups. In general, SIM produced longer, more variable RTs than HC and TBI. Of the RT indices, average RT for Trial 1 and 2 were the best predictors of group membership; however, classification accuracies were greatly influenced by the groups being compared. Average RT for Trial 1 and 2 showed excellent discrimination of SIM and HC. All RT indices were less successful in discriminating SIM and TBI. Average RT for Trial 1 and 2 added incremental predictive value to TOMM-C accuracy in distinguishing SIM from TBI. Conclusion: Findings contribute to a limited body of research examining the incremental utility of combining RT with traditional PVTs in distinguishing feigned and bona fide TBI. Findings support the hypothesis that combining RT with TOMM-C accuracy can improve its diagnostic accuracy. Future research with other groups of clinical interest is recommended.
The mechanism of degradation of polyethylene in a high electrical field

A chemical analysis of LDPE (low-density polyethylene) applied above and below the luminescence inception voltage was performed. The authors also examined the time dependence of the luminescence intensity and the spectrum of the luminescence, considering the mechanism of degradation of LDPE in a high electric field. The luminescence inception stress is about 60kV/mm if the stress mitigating effect due to the space charge is disregarded. It was lower by about 200kV/mm than the electrical tree inception stress. When voltage above the luminescence inception voltage was applied to LDPE, a free radical and an oxide were detected by ESR (electron spin resonance) and XPS (X-ray photoelectron spectroscopy), respectively. The time dependence of the luminescence intensity under constant AC voltage was examined. The luminescence intensity is shown to be stable in the initial stage. However, an intense light was observed after a certain period of voltage application. <<ETX>>
An Electromagnetic Sensor Prototype to Assist Visually Impaired and Blind People in Autonomous Walking

The feasibility of an electromagnetic sensor to assist the autonomous walking of visually impaired and blind users is demonstrated in this paper. It is known that the people affected by visual diseases usually walk assisted by some supports, among which the white cane is the most common. Our idea consists in applying a microwave radar on the traditional white cane making aware the user about the presence of an obstacle in a wider and safer range. Compared to the already existing electronic travel aids devices, the proposed system exhibits better performance, noise tolerance, and reduced dimensions. In the following, the latest developments of this research activity are presented, with special concern for the miniaturization of circuit board and antennas. A laboratory prototype has been designed and realized and the first test results of obstacle detection are hereby shown to demonstrate the effectiveness of the system.
Pneumococcal neuraminidase activates TGF-β signalling

Neuraminidase A (NanA) is an important virulence factor that is anchored to the pneumococcal cell wall and cleaves sialic acid on host substrates. We noted that a secreted allele of NanA was over-represented in invasive pneumococcal isolates and promoted the development of meningitis when swapped into the genome of non-meningitis isolates replacing cell wall-anchored NanA. Both forms of recombinant NanA directly activated transforming growth factor (TGF)-β, increased SMAD signalling and promoted loss of endothelial tight junction ZO-1. However, in assays using whole bacteria, only the cell-bound NanA decreased expression of ZO-1 and showed NanA dependence of bacterial invasion of endothelial cells. We conclude that NanA secretion versus retention on the cell surface does not influence neurotropism of clinical isolates. However, we describe a new NanA-TGF-β signalling axis that leads to decreased blood-brain barrier integrity and enhances bacterial invasion.
Tolcapone-Enhanced Neurocognition in Healthy Adults: Neural Basis and Predictors

Abstract Background Failure of procognitive drug trials in schizophrenia may reflect the clinical heterogeneity of schizophrenia, underscoring the need to identify biomarkers of treatment sensitivity. We used an experimental medicine design to test the procognitive effects of a putative procognitive agent, tolcapone, using an electroencephalogram-based cognitive control task in healthy subjects. Methods Healthy men and women (n=27; ages 18–35 years), homozygous for either the Met/Met or Val/Val rs4680 genotype, received placebo and tolcapone 200 mg orally across 2 test days separated by 1 week in a double-blind, randomized, counterbalanced, within-subject design. On each test day, neurocognitive performance was assessed using the MATRICS Consensus Cognitive Battery and an electroencephalogram-based 5 Choice-Continuous Performance Test. Results Tolcapone enhanced visual learning in low-baseline MATRICS Consensus Cognitive Battery performers (d=0.35) and had an opposite effect in high performers (d=0.5), and enhanced verbal fluency across all subjects (P=.03) but had no effect on overall MATRICS Consensus Cognitive Battery performance. Tolcapone reduced false alarm rate (d=0.8) and enhanced frontal P200 amplitude during correctly identified nontarget trials (d=0.6) in low-baseline 5 Choice-Continuous Performance Test performers and had opposite effects in high performers (d=0.5 and d=0.25, respectively). Tolcapone’s effect on frontal P200 amplitude and false alarm rate was correlated (rs=-0.4, P=.05). All neurocognitive effects of tolcapone were independent of rs4680 genotype. Conclusion Tolcapone enhanced neurocognition and engaged electroencephalogram measures relevant to cognitive processes in specific subgroups of healthy individuals. These findings support an experimental medicine model for identifying procognitive treatments and provide a strong basis for future biomarker-informed procognitive studies in schizophrenia patients.
Dental anomalies in different growth and skeletal malocclusion patterns.

OBJECTIVES To evaluate prevalence, distribution, and sexual dimorphism of dental anomalies (DA) among different skeletal malocclusions (SM) and growth patterns (GP) under the hypothesis that specific clinical patterns exist and may indicate common etiological roots. MATERIALS AND METHODS A total of 1047 orthodontic records of patients older than 8 years were evaluated. The SN-GoGn angle was used to classify GP (hypodivergent, normal, and hyperdivergent), and the ANB angle was used to verify SM (Angle Classes I, II, and III). These assessments were done from lateral cephalometric radiographs. DA were diagnosed using panoramic radiographs by one calibrated investigator. Odds ratios, chi-square, and Student's t-tests were used. RESULTS Of the subjects, 56.7% were female, with mean age of 16.41 (±10.61) years. The prevalence of DA was 15.7%. Impaction and tooth agenesis were the most prevalent DA, with relative frequencies of 14.4% and 9.7%, respectively. DA were most prevalent in Class III SM (80.8%) and in hypodivergent GP (82.5%), although this was not statistically significant. Tooth agenesis ( P < .01) and microdontia ( P = .025) were significantly more common among hypodivergent GP and Class III SM, respectively. CONCLUSIONS The results of this study support the idea that DA are preferentially associated with certain patterns of malocclusion.
A Memory-Based FFT Processor Design With Generalized Efficient Conflict-Free Address Schemes

This paper presents the design and implementation of memory-based fast Fourier transform (FFT) processors with generalized efficient, conflict-free address schemes. We unified the conflict-free address schemes of three different FFT lengths, including the single-power points, the common nonsingle-power points, and the nonsingle-power points applied with a prime factor algorithm. Though the three cases differ in terms of decomposition, they are all compatible with memory-based architecture by the way of the proposed address schemes. Moreover, the decomposition algorithm utilizes a method, named high-radix–small-butterfly (HRSB), to decrease the computation cycles and eliminate the complexity of the processing engine. In addition, an efficient index generator, a simplified multipath delay commutator engine, and a unified Winograd Fourier transform algorithm butterfly core were also designed. We designed two FFT examples in long-term evolution system to verify the availability of the address scheme, including a 2n (128–2048)-point FFT unit and a 35 different point (12–1296) DFT unit. Compared with previous works with similar address schemes, this paper supports more generalized lengths and achieves more flexible throughput.
Pupillary Response and Phenotype in ASD: Latency to Constriction Discriminates ASD from Typically Developing Adolescents

Brain imaging data describe differences in the ASD brain, including amygdala overgrowth, neural interconnectivity, and a three‐phase model of neuroanatomical changes from early post‐natal development through late adolescence. The pupil reflex test (PRT), a noninvasive measure of brain function, may help improve early diagnosis and elucidate underlying physiology in expression of ASD endophenotype. Commonly observed characteristics of ASD include normal visual acuity but difficulty with eye gaze and photosensitivity, suggesting deficient neuromodulation of cranial nerves. Aims of this study were to confirm sensitivity of the PRT for identifying adolescents with ASD, determine if a phenotype for a subtype of ASD marked by pupil response is present in adolescence, and determine whether differences could be observed on a neurologic exam testing cranial nerves II and III (CNII; CNIII). Using pupillometry, constriction latency was measured serving as a proxy for recording neuromodulation of cranial nerves underlying the pupillary reflex. The swinging flashlight method, used to perform the PRT for measuring constriction latency and return to baseline, discriminated ASD participants from typically developing adolescents on 72.2% of trials. Results further confirmed this measure's sensitivity within a subtype of ASD in later stages of development, serving as a correlate of neural activity within the locus–coeruleus norepinephrine (LC–NE) system. A brainstem model of atypical PRT in ASD is examined in relation to modulation of cranial nerves and atypical arousal levels subserving the atypical pupillary reflex. Autism Res 2018, 11: 364–375. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.
Fast Bragg Grating Inscription in PMMA Polymer Optical Fibres: Impact of Thermal Pre-Treatment of Preforms

In this work, fibre Bragg gratings (FBGs) were inscribed in two different undoped poly- (methyl methacrylate) (PMMA) polymer optical fibres (POFs) using different types of UV lasers and their inscription times, temperature and strain sensitivities are investigated. The POF Bragg gratings (POFBGs) were inscribed using two UV lasers: a continuous UV HeCd @325 nm laser and a pulsed UV KrF @248 nm laser. Two PMMA POFs are used in which the primary and secondary preforms (during the two-step drawing process) have a different thermal treatment. The PMMA POFs drawn in which the primary or secondary preform is not specifically pre-treated need longer inscription time than the fibres drawn where both preforms have been pre-annealed at 80 °C for 2 weeks. Using both UV lasers, for the latter fibre much less inscription time is needed compared to another homemade POF. The properties of a POF fabricated with both preforms thermally well annealed are different from those in which just one preform step process is thermally treated, with the first POFs being much less sensitive to thermal treatment. The influence of annealing on the strain and temperature sensitivities of the fibres prior to FBG inscription is also discussed, where it is observed that the fibre produced from a two-step drawing process with well-defined pre-annealing of both preforms did not produce any significant difference in sensitivity. The results indicate the impact of preform thermal pre-treatment before the PMMA POFs drawing, which can be an essential characteristic in the view of developing POF sensors technology.
Ocular syphilis: an alarming infectious eye disease.

BACKGROUND To describe the clinical manifestations and ancillary examination outcomes of ocular syphilis in Southeast China. MATERIALS AND METHODS This is a retrospective, nonrandom case study. Demographic information, serum and cerebrospinal fluid (CSF) test results, and findings of fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA), and spectral domain optical coherence tomography (SD-OCT) were analyzed. RESULTS The study examined 21 eyes of 13 patients (average age 50.3 ± 5.9 (range 37-61) years). HIV co-infection was found in one patient. The most common manifestation was chorioretinitis (52.4%). Disc hyperfluorescence (66.7%) and persistent dark spots (91.7%) were the most common findings on FFA and ICGA, respectively. The inner segment/outer segment junction (IS/OS) loss was the most frequent manifestation (86.7%). Among the six patients with confirmed neurosyphilis, the average CSF protein level was 528.8 ± 327.1 mg/L. Visual acuity (VA) was improved in 8 of 13 eyes (61.5%) after treatment. CONCLUSIONS The manifestations of ocular syphilis can mimic any eye disease. Chorioretinitis was the most common finding in this case series. "Leopard spots" was the characteristic manifestation on FFA. IS/OS loss was the most common finding in patients with posterior uveitis on SD-OCT. Lumbar puncture can contribute to the diagnosis of neurosyphilis. Treatment for ocular syphilis was effective in these patients.
Autologous Conditioned Plasma Versus Placebo Injection Therapy in Lateral Epicondylitis of the Elbow: A Double Blind, Randomized Study

Abstract Introduction There are various therapeutic approaches to the treatment of lateral epicondylitis, a highly prevalent musculoskeletal disorder. Recently, injection therapy with autologous conditioned plasma (ACP) has shown promise as a new approach. Methods Set up as a prospective, double-blind, randomized controlled clinical trial, this study involved 50 patients with lateral epicondylitis. Following external randomization, 25 patients received one round of injection therapy with ACP (platelet rich plasma, PRP), while the remaining 25 patients received a placebo of 0.9 % NaCl. All patients were re-evaluated with respect to lateral epicondylitis of the elbow at four-weeks and six-months post-injection. Results Out of 50 patients, 36 qualified for reevaluation, 18 patients from the ACP therapy group and 18 from the placebo group. The initial Disability of the Arm, Shoulder and Hand (DASH) score for all reevaluated patients was 36.4 in the ACP group, and 41.0 in the placebo group; both groups exhibited decreased DASH scores at the four-week and six-month post-injection follow-up (6 months: ACP 30.1, placebo 25.8). The decrease of the DASH score after 4 weeks was greater and qualified as statistically significant in the placebo group (p = 0.041), compared to the DASH score decrease in the ACP treatment group, which was statistically non-significant. Additionally, the difference between the DASH scores of the treatment and placebo groups was statistically non-significant four weeks and six months after treatment. Discussion The results of this study suggest a therapeutic effect in both the ACP and placebo groups, with no evidence for a therapeutically significant difference between ACP and placebo treatments. It is hypothesized that, in accordance with the study protocols, injection with a local anaesthetic prior to ACP therapy may have an influence on the therapeutic effect of ACP. Future studies have to confirm recent findings that demonstrated a minimizing, or even inhibiting, action of local anaesthetics on the effects of ACP/PRP. Conclusion The effect of ACP/PRP injections needs to be investigated in future studies under standardized conditions.
Diisononyl phthalate aggravates allergic dermatitis by activation of NF-kB

Several epidemiological studies have suggested a possible link between exposure to Diisononyl phthalate (DINP) and the development of allergies. These findings remain controversial since there is insufficient scientific evidence to assess the ability of DINP to influence allergic immune responses. In addition, the mechanisms behind DINP-caused allergic diseases have not been fully elucidated. In this study, Balb/c mice were orally exposed to DINP for 3 weeks and were then sensitized with fluorescein isothiocyanate (FITC). We showed that oral exposure to DINP could aggravate allergic-dermatitis-like lesions, indicated by an increase in the number of mast cells, and in increased skin edema in FITC-induced contact hypersensitivity. This deterioration was concomitant with increased total serum immunoglobulin-E and Th2 cytokines. We determined the oxidative damage and the activation of nuclear factor-kb (NF-kB). The data demonstrated that DINP could promote oxidative damage and the activation of NF-kB in the skin. The expression of thymic stromal lymphopoietin and the activation of signal transducer and activator of transcriptions 3, 5 and 6 were enhanced concomitant with exacerbated allergic dermatitis effects and the activation of NF-kB induced by DINP. These effects were alleviated by pyrollidine dithiocarbamate, an inhibitor of NF-kB. The results suggest that oral exposure to DINP aggravated allergic contact dermatitis, which was positively regulated via NF-kB.
Food protein hydrolysates as a source of dipeptidyl peptidase IV inhibitory peptides for the management of type 2 diabetes

The prevalence of type 2 diabetes mellitus (T2DM) is increasing and it is estimated that by 2030 approximately 366 million people will be diagnosed with this condition. The use of dipeptidyl peptidase IV (DPP-IV) inhibitors is an emerging strategy for the treatment of T2DM. DPP-IV is a ubiquitous aminodipeptidase that cleaves incretins such as glucagon like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), resulting in a loss in their insulinotropic activity. Synthetic DPP-IV drug inhibitors are being used to increase the half-life of the active GLP-1 and GIP. Dietary intervention is accepted as a key component in the prevention and management of T2DM. Therefore, identification of natural food protein-derived DPP-IV inhibitors is desirable. Peptides with DPP-IV inhibitory activity have been identified in a variety of food proteins. This review aims to provide an overview of food protein hydrolysates as a source of the DPP-IV inhibitory peptides with particular focus on milk proteins. In addition, the proposed modes of inhibition and structure–activity relationship of peptide inhibitors are discussed. Milk proteins and associated peptides also display insulinotropic activity and help regulate blood glucose in healthy and diabetic subjects. Therefore, milk protein derived peptide inhibitors may be a unique multifunctional peptide approach for the management of T2DM.