Miracle-dz/UniFAR-FTUs huggingface dataset:
The ectodomains determine ligand function in vivo and selectivity of DLL1 and DLL4 toward NOTCH1 and NOTCH2 in vitro

DLL1 and DLL4 are Notch ligands with high structural similarity but context-dependent functional differences. Here, we analyze their functional divergence using cellular co-culture assays, biochemical studies, and in vivo experiments. DLL1 and DLL4 activate NOTCH1 and NOTCH2 differently in cell-based assays and this discriminating potential lies in the region between the N-terminus and EGF repeat three. Mice expressing chimeric ligands indicate that the ectodomains dictate ligand function during somitogenesis, and that during myogenesis even regions C-terminal to EGF3 are interchangeable. Substitution of NOTCH1-interface residues in the MNNL and DSL domains of DLL1 with the corresponding amino acids of DLL4, however, does not disrupt DLL1 function in vivo. Collectively, our data show that DLL4 preferentially activates NOTCH1 over NOTCH2, whereas DLL1 is equally effective in activating NOTCH1 and NOTCH2, establishing that the ectodomains dictate selective ligand function in vivo, and that features outside the known binding interface contribute to their differences.
Meta‐analysis of amantadine efficacy for improving preclinical research reliability

Research Statistics, Pfizer Worldwide Research and Development, Cambridge, United Kingdom Internal Medicine Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA Motac Neuroscience, Manchester, United Kingdom Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, Institut des Maladies Neurodégénératives, Bordeaux, France
Machine Learning Suites for Online Toxicity Detection

To identify and classify toxic online commentary, the modern tools of data science transform raw text into key features from which either thresholding or learning algorithms can make predictions for monitoring offensive conversations. We systematically evaluate 62 classifiers representing 19 major algorithmic families against features extracted from the Jigsaw dataset of Wikipedia comments. We compare the classifiers based on statistically significant differences in accuracy and relative execution time. Among these classifiers for identifying toxic comments, tree-based algorithms provide the most transparently explainable rules and rank-order the predictive contribution of each feature. Among 28 features of syntax, sentiment, emotion and outlier word dictionaries, a simple bad word list proves most predictive of offensive commentary.
Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors: results from the prospective TEDDY study

Background Progression time from islet autoimmunity to clinical type 1 diabetes is highly variable and the extent that genetic factors contribute is unknown. Methods In 341 islet autoantibody-positive children with the human leucocyte antigen (HLA) DR3/DR4-DQ8 or the HLA DR4-DQ8/DR4-DQ8 genotype from the prospective TEDDY (The Environmental Determinants of Diabetes in the Young) study, we investigated whether a genetic risk score that had previously been shown to predict islet autoimmunity is also associated with disease progression. Results Islet autoantibody-positive children with a genetic risk score in the lowest quartile had a slower progression from single to multiple autoantibodies (p=0.018), from single autoantibodies to diabetes (p=0.004), and by trend from multiple islet autoantibodies to diabetes (p=0.06). In a Cox proportional hazards analysis, faster progression was associated with an increased genetic risk score independently of HLA genotype (HR for progression from multiple autoantibodies to type 1 diabetes, 1.27, 95% CI 1.02 to 1.58 per unit increase), an earlier age of islet autoantibody development (HR, 0.68, 95% CI 0.58 to 0.81 per year increase in age) and female sex (HR, 1.94, 95% CI 1.28 to 2.93). Conclusions Genetic risk scores may be used to identify islet autoantibody-positive children with high-risk HLA genotypes who have a slow rate of progression to subsequent stages of autoimmunity and type 1 diabetes.
Factors Influencing Lower Urinary Tract Symptoms in Advanced Cancer Patients With Chemotherapy-Induced Peripheral Neuropathy

Purpose This study aimed to investigate the severity of lower urinary tract symptoms (LUTS) and to identify factors that influenced LUTS in advanced cancer patients with chemotherapy-induced peripheral neuropathy (CIPN). Methods This cross-sectional study included a total of 158 advanced cancer patients with CIPN. A structured questionnaire including the International Prostate Symptom Score and the Functional Assessment of Cancer Therapy/Gynecology Oncology Group/Neurotoxicity scale was used. Data were analyzed using the Pearson correlation coefficient and multiple regression analysis. Results Nocturia was the most prevalent LUTS. A positive relationship was found between CIPN symptoms and LUTS. The duration of cancer diagnosis and the severity of CIPN were key factors that influenced LUTS. Conclusions The severity of CIPN symptoms was the most important predictor of LUTS. Nurses’ care for advanced cancer patients should incorporate a comprehensive health assessment, which includes a history of treatment and physical neuropathic symptoms, for any patient complaining of CIPN symptoms.
Impact of induced anxiety on neural responses to monetary incentives

Abstract Previous research demonstrates that aversive stimuli can interrupt appetitive processing and that brain regions involved with the processing of potential rewards, such as the ventral striatum (VS), also respond to threatening information. Potential losses can likewise activate the VS and, thus, the full extent to which threat can impact neural responses during incentive processing remains unclear. Here, unpredictable threat of shock was used to induce anxiety while participants performed the monetary incentive delay (MID) task during functional magnetic resonance imaging (fMRI). During anticipation, anxiety impacted neural responses within the bilateral VS and distributed regions of the occipital cortex. Anxiety enhanced activity within the VS to both gain and loss trials. Furthermore, anxiety enhanced activity to both gain and loss trials within dorsal areas of BA19. However, anxiety only enhanced activity during gain, but not loss trials, within ventral areas of BA19. These results suggest that during anticipation, induced anxiety enhanced VS activity to incentives generally, which might reflect changes in the subjective salience of gains and losses. Collectively, these results suggest that the impact of induced anxiety on responses to monetary incentives depend on the neural region, type of incentive, and stage of processing.
Reliability of X7R Multilayer Ceramic Capacitors During High Accelerated Life Testing (HALT)

Multilayer ceramic capacitors (MLCC) are essential components for determining the reliability of electronic components in terms of time to failure. It is known that the reliability of MLCCs depends on their composition, processing, and operating conditions. In this present work, we analyzed the lifetime of three similar X7R type MLCCs based on BaTiO3 by conducting High Accelerated Life Tests (HALT) at temperatures up to 200 °C at 400 V and 600 V. The results were adjusted to an Arrhenius equation, which is a function of the activation energy (Ea) and a voltage stress exponent (n), in order to predict their time to failure. The values of Ea are in the range of 1–1.45 eV, which has been reported for the thermal failure and dielectric wear out of BaTiO3-based dielectric capacitors. The stress voltage exponent value was in the range of 4–5. Although the Ea can be associated with a failure mechanism, n only gives an indication of the effect of voltage in the tests. It was possible to associate those values with each type of tested MLCC so that their expected life could be estimated in the range of 400–600 V.
A prediction tool for hospital‐acquired pressure ulcers among surgical patients: Surgical pressure ulcer risk score

Surgical patients are prone to developing hospital‐acquired pressure ulcers (HAPU). Therefore, a better prediction tool is needed to predict risk using preoperative data. This study aimed to determine, from previously published HAPU risk factors, which factors are significant among our surgical population and to develop a prediction tool that identifies pressure ulcer risk before the operation. A literature review was first performed to elicit all the published HAPU risk factors before conducting a retrospective case‐control study using medical records. The known HAPU risks were compared between patients with HAPU and without HAPU who underwent operations during the same period (July 2015‐December 2016). A total of 80 HAPU cases and 189 controls were analysed. Multivariate logistic regression analyses identified eight significant risk factors: age ≥ 75 years, female gender, American Society of Anaesthesiologists ≥ 3, body mass index < 23, preoperative Braden score ≤ 14, anaemia, respiratory disease, and hypertension. The model had bootstrap‐corrected c‐statistic 0.78 indicating good discrimination. A cut‐off score of ≥6 is strongly predictive, with a positive predictive value of 73.2% (confidence interval [CI]: 59.7%‐84.2%) and a negative predictive value of 80.7% (CI: 74.3%‐86.1%). SPURS contributes to the preoperative identification of pressure ulcer risk that could help nurses implement preventive measures earlier.
Neural Correlates of Familiarity in Music Listening: A Systematic Review and a Neuroimaging Meta-Analysis

Familiarity in music has been reported as an important factor modulating emotional and hedonic responses in the brain. Familiarity and repetition may increase the liking of a piece of music, thus inducing positive emotions. Neuroimaging studies have focused on identifying the brain regions involved in the processing of familiar and unfamiliar musical stimuli. However, the use of different modalities and experimental designs has led to discrepant results and it is not clear which areas of the brain are most reliably engaged when listening to familiar and unfamiliar musical excerpts. In the present study, we conducted a systematic review from three databases (Medline, PsychoINFO, and Embase) using the keywords (recognition OR familiar OR familiarity OR exposure effect OR repetition) AND (music OR song) AND (brain OR brains OR neuroimaging OR functional Magnetic Resonance Imaging OR Position Emission Tomography OR Electroencephalography OR Event Related Potential OR Magnetoencephalography). Of the 704 titles identified, 23 neuroimaging studies met our inclusion criteria for the systematic review. After removing studies providing insufficient information or contrasts, 11 studies (involving 212 participants) qualified for the meta-analysis using the activation likelihood estimation (ALE) approach. Our results did not find significant peak activations consistently across included studies. Using a less conservative approach (p < 0.001, uncorrected for multiple comparisons) we found that the left superior frontal gyrus, the ventral lateral (VL) nucleus of the left thalamus, and the left medial surface of the superior frontal gyrus had the highest likelihood of being activated by familiar music. On the other hand, the left insula, and the right anterior cingulate cortex had the highest likelihood of being activated by unfamiliar music. We had expected limbic structures as top clusters when listening to familiar music. But, instead, music familiarity had a motor pattern of activation. This could reflect an audio-motor synchronization to the rhythm which is more engaging for familiar tunes, and/or a sing-along response in one's mind, anticipating melodic, harmonic progressions, rhythms, timbres, and lyric events in the familiar songs. These data provide evidence for the need for larger neuroimaging studies to understand the neural correlates of music familiarity.
A qualitative study of parent perspectives on barriers, facilitators and expectations for school asthma care among urban, African-American children

Abstract Objectives: Minority children experience the disproportionate burden of asthma and its consequences. Studies suggest ethnic groups may experience asthma differently with varied perceptions and expectations among parents of African-American and Latino children. Because parents coordinate asthma care with the school, where children spend a significant amount of their day, this study’s goal was to determine parents’ perspectives on school asthma management. Methods: Focus groups were conducted with parents of children with asthma at four urban schools whose student population is predominantly African-American. A semi-structured guide was utilized focusing on barriers, facilitators and expectations for asthma care at school. Grounded theory principles were applied in this study. Results: Twenty-two parents (91% females) representing 13 elementary and 10 middle school children with asthma (61% boys) participated in four focus groups. Most children (87%) had persistent asthma. The identified barriers to effective school-based asthma care included limited awareness of children with asthma by teachers/staff, communication issues (e.g. school/parent, within school), inadequate education and lack of management plans or systems in place. In contrast, the identified facilitators included steps that fostered education, communication and awareness, as supported by management plans and parent initiative. Parents described their expectations for increased communication and education about asthma, better systems for identifying children with asthma, and a trained asthma point person for school-based asthma care. Conclusions: Parents of children with asthma identified important barriers, facilitators and expectations that must be considered to advance school asthma management. Improved school-based asthma care could lead to better health and academic outcomes.
Mitochondrial Heat Shock Protein 60s Interact with What’s This Factor 9 to Regulate RNA Splicing of ccmFC and rpl2

Mitochondrial intron splicing is a plant-specific feature that was acquired during the co-evolution of eukaryotic host cells and a-proteobacteria. The elimination of these introns is facilitated by mitochondrial-targeted proteins encoded by its host, nucleus. What's this factor 9 (WTF9), a nuclear-encoded plant organelle RNA recognition (PORR) protein, is involved in the splicing of the mitochondrial group II introns rpl2 and ccmFC. Disruption of WTF9 causes developmental defects associated with the loss of Cyt c and Cyt c1 in Arabidopsis. In the present study, using a co-immunoprecipitation assay, we found that HSP60s interacted with WTF9, which was further confirmed by a pull-down assay. HSP60s are molecular chaperones that assist with protein folding in both eukaryotic and prokaryotic cells. However, accumulating evidence suggests that HSP60s also participate in other biological functions such as RNA metabolism and RNA protection. In this study, we found that consistently with their interaction with WTF9, HSP60s interacted with 48 nucleotides of the ccmFC intron. In mutant studies, the double mutant hsp60-3a1hsp60-3b1 exhibited a small stature phenotype and reduced splicing efficiency for rpl2 and ccmFC. These observations were similar to those in wtf9 mutants and suggest that HSP60s are involved in the RNA splicing of rpl2 and ccmFC introns in mitochondria. Our findings suggest that HSP60s participate in mitochondrial RNA splicing through their RNA-binding ability.
Assessing the function of pneumococcal neuraminidases NanA, NanB and NanC in in vitro and in vivo lung infection models using monoclonal antibodies

ABSTRACT Streptococcus pneumoniae isolates express up to three neuraminidases (sialidases), NanA, NanB and NanC, all of which cleave the terminal sialic acid of glycan-structures that decorate host cell surfaces. Most research has focused on the role of NanA with limited investigations evaluating the roles of all three neuraminidases in host-pathogen interactions. We generated two highly potent monoclonal antibodies (mAbs), one that blocks the enzymatic activity of NanA and one cross-neutralizing NanB and NanC. Total neuraminidase activity of clinical S. pneumoniae isolates could be inhibited by this mAb combination in enzymatic assays. To detect desialylation of cell surfaces by pneumococcal neuraminidases, primary human tracheal/bronchial mucocilial epithelial tissues were infected with S. pneumoniae and stained with peanut lectin. Simultaneous targeting of the neuraminidases was required to prevent desialylation, suggesting that inhibition of NanA alone is not sufficient to preserve terminal lung glycans. Importantly, we also found that all three neuraminidases increased the interaction of S. pneumoniae with human airway epithelial cells. Lectin-staining of lung tissues of mice pre-treated with mAbs before intranasal challenge with S. pneumoniae confirmed that both anti-NanA and anti-NanBC mAbs were required to effectively block desialylation of the respiratory epithelium in vivo. Despite this, no effect on survival, reduction in pulmonary bacterial load, or significant changes in cytokine responses were observed. This suggests that neuraminidases have no pivotal role in this murine pneumonia model that is induced by high bacterial challenge inocula and does not progress from colonization as it happens in the human host.
Use of bone-modifying agents among breast cancer patients with bone metastasis: evidence from oncology practices in the US

Purpose Bone-modifying agents (BMAs) are recommended for women with bone metastasis from breast cancer to prevent skeletal-related events. We examined the usage patterns and identified the factors associated with the use of BMAs (denosumab and intravenous bisphosphonates) among women in the US. Patients and methods Electronic health records from oncology clinics were used to identify women diagnosed with bone metastasis from breast cancer between 2013 and 2014. Patients were excluded if they had recently used a BMA or had concurrent cancer at an additional primary site. The incidence of BMA initiation, interruption, and reinitiation were estimated using competing risk regression models. A generalized linear model was used to estimate risk factors for treatment initiation and interruption. Results There were 589 women diagnosed with bone metastasis from breast cancer. By 1 year, 68% of these patients (95% CI: 64%, 71%) had initiated treatment with a BMA. Denosumab and zoledronic acid were the most commonly used agents, whereas pamidronate was used infrequently. Young women were more likely to initiate a BMA than older women (adjusted risk difference: 6.4 [95% CI: 1.5, 10.9]). Of the 412 patients who initiated a BMA, 46% (95% CI: 41%, 51%) experienced an interruption within 1 year. Seventy-four percent (95% CI: 68%, 79%) of patients who interrupted their treatment had reinitiated therapy within 1 year of interruption. Conclusion The majority of women diagnosed with bone metastasis from breast cancer initiate a BMA within 1 year of diagnosis, but a large proportion, particularly among the elderly, do not use these therapies.
Prospective bi-directional associations between sedentary time and physical activity with cognitive performance: a cohort study

ABSTRACT This prospective study determined whether: (1) objective physical activity (PA) and sedentary (SED) time at 9 years was associated with cognition at 15 years, (2) cognition at 9 years was associated with PA and SED at 15 years, and (3) the change in PA and SED from 9 to 15 years was associated with the change in cognition. Cognitive performance was assessed from picture vocabulary, verbal analogy, passage comprehension, and applied problem tasks. Regression models were used to explore each aim while adjusting for covariates. Among the combined sample, SED (min· day−1) at 9 years was unrelated with cognitive performance at 15 years, whereas participating in ≥ 60 min· day−1 of moderate-to-vigorous PA (MVPA) at 9 years predicted lower cognitive scores at 15 years. In the reverse direction, cognitive performance at 9 years was unrelated with SED and MVPA (min· day−1) at 15 years. Over 6 years, increased SED (min· day−1) predicted lower improvement to verbal analogy scores (B = −0.01, p = 0.028). In comparison, an increase (or relatively smaller decline) in MVPA (min· day−1) predicted greater improvement in applied problem scores (B = 0.06, p = 0.007). Contextual information regarding SED and MVPA behavior would help understand bi-directional associations of activity and cognition.
Polish Validation of the SarQoL®, a Quality of Life Questionnaire Specific to Sarcopenia

Recently, SarQoL® (Sarcopenia and Quality of Life), a quality of life (QoL) questionnaire specific to sarcopenia, was successfully developed. For practical reasons, there is a great interest in validating this questionnaire in other populations. The aim of this cross-sectional study was to translate and adjust the SarQoL® into Polish and to standardize the validity of this method for the assessment of sarcopenic individuals in Poland with regard to psychometric properties. The English version was used for the translation process. A total of 106 community-dwelling Caucasian subjects aged 73.3 ± 5.94 years (65.1% females) were studied, with 60 participants being diagnosed sarcopenic. The translation and cross-cultural adaptation was carried out in five phases according to specific standard guidelines. There were no major linguistic issues in the translation process. The data confirmed a good discriminant validity, i.e., significantly lower scores for all domains (reduced global QoL in sarcopenic subjects compared to non-sarcopenic ones; 54.9 ± 16.5 vs. 63.3 ± 17.1, p = 0.013), and high internal consistency (Cronbach’s alpha coefficient was 0.92). The significant correlation of the SarQoL® scores with those of other questionnaires (SF-36v2® Health Survey and EuroQoL-5-Dimension) that are supposed to have similar dimensions indicated the consistent construct validity of the SarQoL®-PL questionnaire. No floor/ceiling effects were found. An excellent agreement was found between the test and the re-test (intraclass coefficient correlation (ICC): 0.99). The first Polish version of the SarQoL® questionnaire is valid and consistent and therefore may be used with reliability for clinical and research purposes regarding QoL assessment of sarcopenic individuals. However, further research, in particular prospective studies, is needed to determine potential limitations and the suitability of the new tool for the Polish scenario and specificity.