Miracle-dz/UniFAR-FTUs huggingface dataset:
University of Groningen Construction and benchmarking of a multi-ethnic reference panel for the imputation of HLA class I and II alleles

Genotype imputation of the human leukocyte antigen (HLA) region is a cost-effective means to infer classical HLA alleles from inexpensive and dense SNP array data. In the research setting, imputation helps avoid costs for wet lab-based HLA typing and thus renders association analyses of the HLA in large cohorts feasible. Yet, most HLA imputation reference panels target Caucasian ethnicities and multi-ethnic panels are scarce. We compiled a high-quality multi-ethnic reference panel based on genotypes measured with Illumina’s Immunochip genotyping array and HLA types established using a high-resolution next generation sequencing approach. Our reference panel includes more than 1,300 samples from Germany, Malta, China, India, Iran, Japan and Korea and samples of African American ancestry for all classical HLA class I and II alleles including HLA-DRB3/4/5. Applying extensive cross-validation, we benchmarked the imputation using the HLA imputation tool HIBAG, our multi-ethnic reference and an independent, previously published data set compiled of subpopulations of the 1000 Genomes project. We achieved average imputation accuracies higher than 0.924 for the commonly studied HLA-A, -B, -C, -DQB1 and -DRB1 genes across all ethnicities. We investigated allele-specific imputation challenges in regard to geographic origin of the samples using sensitivity and specificity measurements as well as allele frequencies and identified HLA alleles that are challenging to impute for each of the populations separately. In conclusion, our new multi-ethnic reference data set allows for high resolution HLA imputation of genotypes at all classical HLA class I and II genes including the HLA-DRB3/4/5 loci based on diverse ancestry populations.
Measuring Treatment Response in Pharmacological and Lifestyle Interventions Using Electroencephalography in ADHD: A Review

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and/or impulsivity with associations to short- and long-term aversive life events. The exact etiology of the disorder is still unknown. ADHD is heterogeneous in symptomology and a single consistent, reliable biomarker has not been found. Quantitative electroencephalography (EEG) has been proposed as a potential way to differentiate those with ADHD from typically developing controls; however, the data on the diagnostic utility of this approach have been variable. Quantitative EEG has been employed in prognostic ways to assess differences in baseline spectral power profiles and pharmacological and nonpharmacological treatment effects on electrocortical activity within the ADHD population. The aim of this review is to summarize the literature investigating the degree of normalization of resting-state EEG profiles in individuals with ADHD through various interventions, including stimulant and nonstimulant medication, exercise, and diet.
Neuroimaging Biomarkers of Experimental Epileptogenesis and Refractory Epilepsy

This article provides an overview of neuroimaging biomarkers in experimental epileptogenesis and refractory epilepsy. Neuroimaging represents a gold standard and clinically translatable technique to identify neuropathological changes in epileptogenesis and longitudinally monitor its progression after a precipitating injury. Neuroimaging studies, along with molecular studies from animal models, have greatly improved our understanding of the neuropathology of epilepsy, such as the hallmark hippocampus sclerosis. Animal models are effective for differentiating the different stages of epileptogenesis. Neuroimaging in experimental epilepsy provides unique information about anatomic, functional, and metabolic alterations linked to epileptogenesis. Recently, several in vivo biomarkers for epileptogenesis have been investigated for characterizing neuronal loss, inflammation, blood-brain barrier alterations, changes in neurotransmitter density, neurovascular coupling, cerebral blood flow and volume, network connectivity, and metabolic activity in the brain. Magnetic resonance imaging (MRI) is a sensitive method for detecting structural and functional changes in the brain, especially to identify region-specific neuronal damage patterns in epilepsy. Positron emission tomography (PET) and single-photon emission computerized tomography are helpful to elucidate key functional alterations, especially in areas of brain metabolism and molecular patterns, and can help monitor pathology of epileptic disorders. Multimodal procedures such as PET-MRI integrated systems are desired for refractory epilepsy. Validated biomarkers are warranted for early identification of people at risk for epilepsy and monitoring of the progression of medical interventions.
Exercise adherence: beliefs of adults with knee osteoarthritis over 2 years

ABSTRACT Exercise is an established treatment to alleviate pain and improve function among adults with knee osteoarthritis (KOA). However, long-term adherence to exercise is poor and effective approaches to support adherence are limited. Here, we report on an ancillary study to a randomized controlled trial (RCT) where the primary outcome was 2-year adherence to a home based strength-training program. The aims of this current study were to (i) explore experiences, feelings, and perspectives related to long-term adherence to exercise among adults with painful KOA participating in a 2-year RCT, and (ii) identify factors that influenced long-term adherence to exercise. Methods: We purposively recruited 25 subjects and conducted in-depth interviews at the 2-year RCT assessment. In the RCT participants completed a 6-week group exercise program followed by automated telephone calls. Findings: Three conceptual categories describing beliefs about exercise were identified: (1) monitoring; (2) knowledge of how to manage their exercise behaviors; and (3) benefits of exercise. Monitoring provided by peers and instructors during group exercise, and telephone technology were valued by participants. Participants who reported low adherence expressed ambivalence about the benefits of exercise and a desire for more social support. Those who reported high adherence exhibited self-determination and self-efficacy. Conclusions: A novel finding is the conceptual link of self-determination to high adherence to strength-training exercises over 2 years among adults with KOA. Implications for physical therapists include identifying patients’ autonomy, competence, and relatedness needs to foster intrinsic control for exercise behavior.
Cumulative mitochondrial activity correlates with ototoxin susceptibility in zebrafish mechanosensory hair cells

Mitochondria play a prominent role in mechanosensory hair cell damage and death. Although hair cells are thought to be energetically demanding cells, how mitochondria respond to these demands and how this might relate to cell death is largely unexplored. Using genetically encoded indicators, we found that mitochondrial calcium flux and oxidation are regulated by mechanotransduction and demonstrate that hair cell activity has both acute and long-term consequences on mitochondrial function. We tested whether variation in mitochondrial activity reflected differences in the vulnerability of hair cells to the toxic drug neomycin. We observed that susceptibility did not correspond to the acute level of mitochondrial activity but rather to the cumulative history of that activity.
Does Intrinsic Disorder in Proteins Favor Their Interaction with Lipids?

Intrinsically disordered proteins (IDPs) are implicated in a range of human diseases, some of which are associated with the ability to bind to lipids. Although the presence of solvent‐exposed hydrophobic regions in IDPs should favor their interactions with low‐molecular‐weight hydrophobic/amphiphilic compounds, this hypothesis has not been systematically explored as of yet. In this study, the analysis of the DisProt database with regard to the presence of lipid‐binding IDPs (LBIDPs) reveals that they comprise, at least, 15% of DisProt entries. LBIDPs are classified into four groups by ligand type, functional categories, domain structure, and conformational state. 57% of LBIDPs are classified as ordered according to the CH‐CDF analysis, and 70% of LBIDPs possess lengths of disordered regions below 50%. To investigate the lipid‐binding properties of IDPs for which lipid binding is not reported, three proteins from different conformational groups are rationally selected. They all are shown to bind linoleic (LA) and oleic (OA) acids with capacities ranging from 9 to 34 LA/OA molecules per protein molecule. The association with LA/OA causes the formation of high‐molecular‐weight lipid–protein complexes. These findings suggest that lipid binding is common among IDPs, which can favor their involvement in lipid metabolism.
Safety Evaluation of the MiniMed 670G System in Children 7–13 Years of Age with Type 1 Diabetes

Abstract Objective: To evaluate the safety of in-home use of the MiniMed™ 670G system with SmartGuard™ technology in children with type 1 diabetes (T1D). Methods: Participants (N = 105, ages 7–13 years, mean age 10.8 ± 1.8 years) were enrolled at nine centers (eight in the United States and one in Israel) and completed a 2-week baseline run-in phase in Manual Mode followed by a 3-month study phase with Auto Mode enabled. Sensor glucose (SG), glycated hemoglobin (HbA1c), percentage of SG values across glucose ranges, and SG variability, during the run-in and study phases were compared. Participants underwent frequent sample testing with i-STAT® venous reference measurement during a hotel period (6 days/5 nights) to evaluate the system's continuous glucose monitoring performance. Results: Auto Mode was used a median of 81% of the time. From baseline to end of study, overall SG dropped by 6.9 ± 17.2 mg/dL (P < 0.001), HbA1c decreased from 7.9% ± 0.8% to 7.5% ± 0.6% (P < 0.001), percentage of time in target glucose range (70–180 mg/dL) increased from 56.2% ± 11.4% to 65.0% ± 7.7% (P < 0.001), and the SG coefficient of variation decreased from 39.6% ± 5.4% to 38.5% ± 3.8% (P = 0.009). The percentage of SG values within target glucose range was 68.2% ± 9.1% and that of i-STAT reference values was 65.6% ± 17.7%. The percentage of values within 20%/20 of the i-STAT reference was 85.2%. There were no episodes of severe hypoglycemia or diabetic ketoacidosis during the study phase. Conclusion: In-home use of MiniMed 670G system Auto Mode for 3 months by children with T1D, similar to MiniMed 670G system use by adolescents and adults with T1D, was safe and associated with reduced HbA1c levels and increased time in target glucose range, compared with baseline.
Cost-effectiveness of Financial Incentives for Patients and Physicians to Manage Low-Density Lipoprotein Cholesterol Levels

Key Points Question Are reductions in cardiovascular disease risk produced by financial incentives placed on patients, physicians, or both to control low-density lipoprotein cholesterol levels worth the costs needed to achieve these health benefits? Findings In this model-based economic evaluation, incentives shared between patients and physicians had an incremental cost-effectiveness ratio of $60 000/quality-adjusted life-year. However, this result was sensitive to assumptions around the durations of low-density lipoprotein cholesterol level reductions and incentive payments. Meaning Shared incentives between patients and physicians appear to provide reasonable value (<$100 000/quality-adjusted life-year) for the health gains that they produce, although longer-term demonstrations are needed to show how long these low-density lipoprotein cholesterol level reductions persist.
成人早期前体T细胞急性淋巴细胞白血病的临床特征和预后分析

目的 分析成人早期前体T细胞急性淋巴细胞白血病（ETP-ALL）的临床、实验室特征及预后情况。 方法 回顾性分析2009年1月至2017年3月确诊的13例ETP-ALL患者的临床和实验室资料，并与非ETP的T-ALL（Non-ETP ALL）患者进行比较。 结果 75例T-ALL患者中，符合ETP-ALL诊断标准患者13例（17.3%），其中男10例（76.9%），女3例（23.1%），诊断时中位年龄为35（15~49）岁。 与62例Non-ETP ALL患者相比，ETP-ALL患者的WBC、LDH、外周血原始细胞计数较低，胸腺肿物发生率更低，PLT水平更高。 ETP-ALL与Non-ETP ALL患者1个疗程CR率分别为33. 3%和90. 1%，差异具有统计学意义（χ2=26.521，P<0.001）。 两组患者的中位总生存（OS）时间分别为11. 33（95%CI 0~28.46）和25. 69（95% CI 11.98~39.41）个月，3年OS率分别为41. 7%和40. 7%（P=0.699）。 两组患者的中位无事件生存（EFS）时间分别为1. 51（95% CI 1.23~1.79）和21. 36（95% CI 4.67~38.04）个月，3年EFS率分别为16. 7%和39. 5%（P=0.002），3年无复发生存（RFS）率分别为53. 0%和52. 0%（P=0.797）。 多因素分析显示是否为ETP-ALL并不是影响T-ALL总体预后的独立因素，而是否合并中枢神经系统白血病、是否行异基因造血干细胞移植为T-ALL的独立预后因素。 结论 该研究为国内首次关于成人ETP-ALL特征以及预后分析的报道。 在成人T-ALL患者中，ETP-ALL占17.3%，具有起病时肿瘤负荷不高，但1个疗程化疗CR率较低的临床特点。 异基因造血干细胞移植有可能克服ETP-ALL的不良预后。
Analysis and Design of SCMA-Based Hybrid Unicast-Multicast Relay-Assisted Networks

This paper studies a multi-user network model based on sparse code multiple access (SCMA), where both unicast and multicast services are considered. In the direct transmission scheme, the communication between the base station (BS) and the users is completed with one stage, in which the relay is inexistent. In the two-stage cooperative transmission scheme, any number of relays are placed to improve the reliability of wireless communication system. The BS broadcasts the requested message to users and relays in the first stage, and the successful relays forward the message to unsuccessful users in the second stage. To characterize the performance of these two schemes, we derive the exact and approximate expressions of average outage probability. Furthermore, to take full advantage of the cooperative diversity, an optimal power allocation and relay location strategy in the high signal-to-noise ratio (SNR) regime is studied. The outage probability reaches the minimum value when the first stage occupies half of the total energy consumed. Simulation and analysis results are presented to demonstrate the performance of these two schemes. The results show that the two-stage cooperative scheme effectively reduce the average outage probability in SCMA network, especially in the high SNR region.
Probing the Meaning of Persistent Propeptide Release in Type 1 Diabetes

Type 1 diabetes is well recognized to be immune mediated, resulting in destruction of β-cells. That this eradication is not always complete was evident in an early report from the Diabetes Control and Complications Trial (DCCT) showing that 11% of adult participants with type 1 diabetes for more than 5 years had measurable C-peptide in the fasting state and following mixed-meal stimulation, while no adolescents had evidence of such (1). Further, in participants with measurable C-peptide responses, C-peptide declined in all after a year of randomized therapy, with this decline being less in those who received intensive insulin therapy. Subsequently, it was shown in adolescents that 2 weeks of intensive insulin therapy, compared with conventional therapy, resulted in improved β-cell function a year later along with superior glucose control (2). In addition to C-peptide, proinsulin has also been shown to be circulating in individuals with type 1 diabetes at the time of diagnosis and to be still measurable 30 months later (3,4). Thus, there is long-standing evidence that at the time of diagnosis and subsequently, individuals with type 1 diabetes have β-cells still capable of synthesizing proinsulin, and many can process it to C-peptide and insulin. In the current issue of Diabetes Care , Sims et al. (5) report longitudinal findings on proinsulin secretion in type 1 diabetes using a large number of samples from the T1D Exchange. They divided their subjects into three groups based on stimulated C-peptide responses to a mixed meal. We have categorized these groups as having absent, intermediate, and high C-peptide responses, although the latter are a great deal lower than what is observed in healthy people. Individuals in the absent group had C-peptide responses that were below the reliable lower detection limit of the assay, and they were not studied further. These …
Growth, Bone Health, and Cognition: Nutritional Evaluation of a Sustainable Ocean-Based Advance Protein Powder (APP)

ABSTRACT This study evaluated an alternative ocean-based fish protein, Advanced Protein Powder (APP) as a feasible, environmentally sustainable protein source to reduce childhood malnutrition. We completed a rodent feeding study to evaluate growth and development in young growing mice on a purified diet containing APP as compared to mice-fed diets using other common protein sources – casein, whey, and soy. Results suggested APP to be an effective and safe protein source and ensured normal body growth, bone development, and brain function in APP diet-fed mice. Evidence provided in this study supports considering the use of APP to reduce malnutrition among children worldwide.
Phytochemical Constituents and the Evaluation Biological Effect of Cinnamomum yabunikkei H.Ohba Leaf

Cinnamomum yabunikkei H.Ohba leaf is known as a traditional medicinal material in Korea. However, no scientific identification of the components or efficacy of C.yabunikkei H.Ohba leaf has been reported. In the present study, we prepared various solvent extracts of C.yabunikkei H.Ohba leaf to understand its basic properties and evaluated the antioxidant, xanthine oxidase inhibitory, and elastase inhibitory activities of hexane, ethyl acetate, acetone, methanol, ethanol, and water extracts for the first time. The antioxidant properties were evaluated based on 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity, reducing power, and total phenolic contents. The hot water extract showed the highest DPPH radical scavenging activity and total phenolic contents, and the reducing power was the highest in the water extract. The hexane extract showed an excellent elastase inhibitory effect compared to control (phosphoramidone) and the highest xanthine oxidase inhibitory activity. These results present basic information for the possible uses of the hot water and hexane extracts from C. yabunikkei leaf for the treatment of diseases caused by oxidative imbalance. In the present study, individual extracts exhibited different effects. Therefore, it is hypothesized that the applicability of C. yabunikkei will depend on the extraction method and nature of the extract. The hot water and hexane extracts could be used as antioxidants, and as anti-gout and anti-wrinkle materials respectively. Several biologically active substances present in hexane extract of C. yabunikkei have been analyzed by GCMS and demonstrated to possess antioxidant and xanthine oxidase inhibitory activity. To the best of our knowledge, this is the first study that reports the chemical profiling and biological effects of various C. yabunikkei leaf extracts, suggesting their potential use in food therapy, cosmetics or alternative medicine.
A Conflicted Tale of Two Novel AR Antagonists In Vitro and In Vivo: Pyrifluquinazon Versus Bisphenol C

Chemicals that disrupt androgen receptor (AR) function in utero induce a cascade of adverse effects in male rats including reduced anogenital distance, retained nipples, and reproductive tract malformations. The objective of this study was to compare the in vitro and in utero activities of two novel AR antagonists, bisphenol C (BPC) and pyrifluquinazon (PFQ). In vitro, BPC was as potent an AR antagonist as hydroxyflutamide. Furthermore, BPC inhibited fetal testis testosterone production and testis gene expression ex vivo. However, when BPC was administered at 100 and 200 mg/kg/d in utero, the reproductive tract of the male offspring was minimally affected. None of the males displayed reproductive malformations. For comparison, in utero administration of flutamide has been shown to induce malformations in 100% of males at 6 mg/kg/d. In vitro, PFQ was several orders of magnitude less potent than BPC, vinclozolin, or procymidone. However, in utero administration of 12.5, 25, 50, and 100 mg PFQ/kg/d on GD 14-18 induced antiandrogenic effects at all dosage levels and 91% of the males displayed reproductive malformation in the high dose group. Overall, BPC was ∼380-fold more potent than PFQ in vitro, whereas PFQ was far more potent than BPC in utero. Incorporating toxicokinetic and toxicodynamic data into in vitro to in vivo extrapolations would reduce the discordance between the in vitro and in utero effects of PFQ and BPC and combining in vitro results with a short-term Hershberger assay would reduce the uncertainty in predicting the in utero effects of antiandrogenic chemicals.
Characterization of advanced glycation end products and their receptor (RAGE) in an animal model of myocardial infarction

Circulating advanced glycation end products (AGE) and their receptor, RAGE, are increased after a myocardial infarction (MI) episode and seem to be associated with worse prognosis in patients. Despite the increasing importance of these molecules in the course of cardiac diseases, they have never been characterized in an animal model of MI. Thus, the aim of this study was to characterize AGE formation and RAGE expression in plasma and cardiac tissue during cardiac remodeling after MI in rats. Adult male Wistar rats were randomized to receive sham surgery (n = 15) or MI induction (n = 14) by left anterior descending coronary artery ligation. The MI group was stratified into two subgroups based on postoperative left ventricular ejection fraction: low (MIlowEF) and intermediate (MIintermEF). Echocardiography findings and plasma levels of AGEs, protein carbonyl, and free amines were assessed at baseline and 2, 30, and 120 days postoperatively. At the end of follow-up, the heart was harvested for AGE and RAGE evaluation. No differences were observed in AGE formation in plasma, except for a decrease in absorbance in MIlowEF at the end of follow-up. A decrease in yellowish-brown AGEs in heart homogenate was found, which was confirmed by immunodetection of N-ε-carboxymethyl-lysine. No differences could be seen in plasma RAGE levels among the groups, despite an increase in MI groups over the time. However, MI animals presented an increase of 50% in heart RAGE at the end of the follow-up. Despite the inflammatory and oxidative profile of experimental MI in rats, there was no increase in plasma AGE or RAGE levels. However, AGE levels in cardiac tissue declined. Thus, we suggest that the rat MI model should be employed with caution when studying the AGE-RAGE signaling axis or anti-AGE drugs for not reflecting previous clinical findings.
Larval Pollen Stress Increases Adult Susceptibility to Clothianidin in Honey Bees

Neonicotinoid insecticides have come under scrutiny for their potential role in honey bee declines. Additionally, reduced access to forage in agricultural areas creates the potential for risk interactions with these pesticides in regions critical for honey production. In this study, we sought to determine whether sufficient access to pollen during larval development could mitigate stress associated with oral clothianidin exposure in honey bee adults. An apiary was established where pollen traps deprived half of the colonies of pollen, which was then supplemented to the others. Adults were fed 0, 10, 40, 200, or 400 µg/L clothianidin in the laboratory, and larval and adult lipids and superoxide dismutase (SOD) activities were compared between feeding treatments. Survival at sublethal concentrations of clothianidin was significantly reduced for adult bees reared in pollen deprived colonies. Adult SOD activity was affected by clothianidin dose but not larval feeding treatment, though within the pollen-deprived cohort, SOD was greater in controls than those fed clothianidin. Larval SOD differed between field replicates, with supplemented colonies having slightly higher activity levels during a period of pollen dearth, indicating that supplementation during these periods is particularly important for mitigating oxidative stress within the hive. Larval lipids were significantly higher in supplemented colonies during a substantial pollen flow, though adult lipids were unaffected by feeding treatment. These results suggest that during periods of pollen dearth, oxidative stress and adult worker longevity will be improved by supplementing colonies with locally collected pollen.