Miracle-dz/UniFAR-FTUs huggingface dataset:
Two apples a day lower serum cholesterol and improve cardiometabolic biomarkers in mildly hypercholesterolemic adults: a randomized, controlled, crossover trial

ABSTRACT BACKGROUND Apples are rich in bioactive polyphenols and fiber. Evidence suggests that consumption of apples or their bioactive components is associated with beneficial effects on lipid metabolism and other markers of cardiovascular disease (CVD). However, adequately powered randomized controlled trials are necessary to confirm these data and explore the mechanisms. OBJECTIVE We aimed to determine the effects of apple consumption on circulating lipids, vascular function, and other CVD risk markers. METHODS The trial was a randomized, controlled, crossover, intervention study. Healthy mildly hypercholesterolemic volunteers (23 women, 17 men), with a mean ± SD BMI 25.3 ± 3.7 kg/m2 and age 51 ± 11 y, consumed 2 apples/d [Renetta Canada, rich in proanthocyanidins (PAs)] or a sugar- and energy-matched apple control beverage (CB) for 8 wk each, separated by a 4-wk washout period. Fasted blood was collected before and after each treatment. Serum lipids, glucose, insulin, bile acids, and endothelial and inflammation biomarkers were measured, in addition to microvascular reactivity, using laser Doppler imaging with iontophoresis, and arterial stiffness, using pulse wave analysis. RESULTS Whole apple (WA) consumption decreased serum total (WA: 5.89 mmol/L; CB: 6.11 mmol/L; P = 0.006) and LDL cholesterol (WA: 3.72 mmol/L; CB: 3.86 mmol/L; P = 0.031), triacylglycerol (WA: 1.17 mmol/L; CB: 1.30 mmol/L; P = 0.021), and intercellular cell adhesion molecule-1 (WA: 153.9 ng/mL; CB: 159.4 ng/mL; P = 0.028), and increased serum uric acid (WA: 341.4 μmol/L; CB: 330 μmol/L; P = 0.020) compared with the CB. The response to endothelium-dependent microvascular vasodilation was greater after the apples [WA: 853 perfusion units (PU), CB: 760 PU; P = 0.037] than after the CB. Apples had no effect on blood pressure or other CVD markers. Conclusions These data support beneficial hypocholesterolemic and vascular effects of the daily consumption of PA-rich apples by mildly hypercholesterolemic individuals. This trial was registered at clinicaltrials.gov as NCT01988389.
CTLA4 blockade promotes vessel normalization in breast tumors via the accumulation of eosinophils

Immune checkpoint blockade (ICB) has shown long‐term survival benefits, but only in a small fraction of cancer patients. Recent studies suggest that improved vessel perfusion by ICB positively correlates with its therapeutic outcomes. However, the underlying mechanism of such a process remains unclear. Here, we show that anti‐cytotoxic T‐lymphocyte‐associated protein 4 (CTLA4) treatment‐induced tumor vessel normalization was accompanied by an increased infiltration of eosinophils into breast tumors. Eosinophil accumulation was positively correlated with the responsiveness of a breast tumor to anti‐CTLA4 therapy. Depletion of eosinophils subsequently negated vessel normalization, reduced antitumor immunity and attenuated tumor growth inhibition by anti‐CTLA4 therapy. Moreover, intratumoral accumulation of eosinophils relied on T lymphocytes and interferon γ production. Together, these results suggest that eosinophils partially mediate the antitumor effects of CTLA4 blockade through vascular remodeling. Our findings uncover an unidentified role of eosinophils in anti‐CTLA4 therapy, providing a potential new target to improve ICB therapy and to predict its efficacy.
Acoustic Characteristics of Rhotic Vowel Productions of Young Children

Aims: This study examined the acoustic characteristics of perceptually acceptable rhotic vowels produced by young children with and without speech sound disorders (SSDs). Productions were analyzed in relation to the overall rhotic proficiency level of each child, as determined by rhotic vowel and consonant accuracy. The effect of the surrounding phonetic contexts on acoustic realization of rhotic vowels was also examined. Methods: Participants included 18 children aged 2–6 years with and without SSD, grouped by overall rhotic sound proficiency (high rhotic proficiency: ≥70% correct rhotic consonants and vowels; intermediate rhotic proficiency: ≤30% correct rhotic consonants, but ≥70% correct rhotic vowels; low rhotic proficiency: ≤30% correct rhotic consonants and vowels). Target sounds included stressed and unstressed rhotic monophthongs ([ɝ] and [ɚ], respectively) and 4 rhotic diphthongs that differ by pre-rhotic vowel type (/ɪ͡ɚ/, /ɛ͡ɚ/, /ɔ͡ɚ/, /ɑ͡ɚ/). F3 and F3-F2 measures were compared across groups and contexts. Results: No significant differences in F3 and F3-F2 by rhotic sound proficiency group were found in rhotic vowels produced by children with above 70% rhotic vowel accuracy, regardless of their proficiency with rhotic consonants. Acoustic patterns differed by phonetic contexts, but the effect varied by rhotic sound proficiency group. Conclusion: Results showed that once children learn to produce rhotic vowels, they show a comparable degree of rhoticity as those produced by children with high rhotic vowel and consonant accuracy. Results also suggest that rhotic sounds develop earlier in certain phonetic contexts than in others (e.g., [ɝ] before [ɚ]; /ɪ͡ɚ/ and /ɑ͡ɚ/ before /ɔ͡ɚ/).
Improving drug response prediction by integrating multiple data sources: matrix factorization, kernel and network-based approaches

Abstract Predicting the response of cancer cell lines to specific drugs is one of the central problems in personalized medicine, where the cell lines show diverse characteristics. Researchers have developed a variety of computational methods to discover associations between drugs and cell lines, and improved drug sensitivity analyses by integrating heterogeneous biological data. However, choosing informative data sources and methods that can incorporate multiple sources efficiently is the challenging part of successful analysis in personalized medicine. The reason is that finding decisive factors of cancer and developing methods that can overcome the problems of integrating data, such as differences in data structures and data complexities, are difficult. In this review, we summarize recent advances in data integration-based machine learning for drug response prediction, by categorizing methods as matrix factorization-based, kernel-based and network-based methods. We also present a short description of relevant databases used as a benchmark in drug response prediction analyses, followed by providing a brief discussion of challenges faced in integrating and interpreting data from multiple sources. Finally, we address the advantages of combining multiple heterogeneous data sources on drug sensitivity analysis by showing an experimental comparison. Contact: betul.guvenc@aalto.fi
Advancing the state of the art in automatic extraction of adverse drug events from narratives

€ Ozlem Uzuner, Amber Stubbs, and Leslie Lenert Department of Information Sciences and Technology, George Mason University, Fairfax, Virginia, USA, Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA, Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA, Division of Mathematics, Computing, and Statistics, Simmons University, Boston, Massachusetts, USA, and Department of Medicine, Medical College of South Carolina, Charleston, South Carolina, USA
Ecogenomics of the SAR11 clade

Summary Members of the SAR11 clade, despite their high abundance, are often poorly represented by metagenome‐assembled genomes. This fact has hampered our knowledge about their ecology and genetic diversity. Here we examined 175 SAR11 genomes, including 47 new single‐amplified genomes. The presence of the first genomes associated with subclade IV suggests that, in the same way as subclade V, they might be outside the proposed Pelagibacterales order. An expanded phylogenomic classification together with patterns of metagenomic recruitment at a global scale have allowed us to define new ecogenomic units of classification (genomospecies), appearing at different, and sometimes restricted, metagenomic data sets. We detected greater microdiversity across the water column at a single location than in samples collected from similar depth across the global ocean, suggesting little influence of biogeography. In addition, pangenome analysis revealed that the flexible genome was essential to shape genomospecies distribution. In one genomospecies preferentially found within the Mediterranean, a set of genes involved in phosphonate utilization was detected. While another, with a more cosmopolitan distribution, was unique in having an aerobic purine degradation pathway. Together, these results provide a glimpse of the enormous genomic diversity within this clade at a finer resolution than the currently defined clades.
Multiple microRNAs control ecdysone signaling in the midgut of Spodoptera litura

Metamorphosis is one of the most important physiological processes in insects. It is regulated by a serial of ecdysone cascade genes. Recently, lots of microRNAs (miRNAs) were investigated in insects; however, their function in metamorphosis is largely unknown. In the present study, the dynamics of a small RNA population was investigated by RNA sequencing from the midgut of a lepidopteran pest Spodoptera litura during larval–pupal metamorphosis. A total of 101 miRNAs were identified, and 75 miRNAs were differentially expressed during the metamorphic process. The relationship between these differentially expressed miRNAs and 12 ecdysone cascade genes was analyzed by four classical software programs, and a multiple‐to‐multiple regulatory network was found to exist between these miRNAs and their targets. Among them, miR‐14‐3p and its two targets (EcR and E75) were chosen for further validation. MiR‐14‐3p had higher expression level in the 6th instar larvae as compared with either the prepupae or pupae, which was opposite to that of both EcR and E75, two ecdysone cascade genes. Luciferase reporter assay confirmed that both EcR and E75 were regulated by miR‐14‐3p. Interestingly, the 3′ untranslated regions are nearly identical to each other among different transcript variants of the ecdysone cascade genes, including EcR, USP, E75, E74, E78, E93, Hr3, Hr4, Hr39, Krh1 and Ftzf1. Thus, different transcript variants of one ecdysone cascade gene could be regulated by the same miRNA. The above data suggest that the ecdysone signaling pathway is under the tight control of miRNA. These findings expand our understanding of the mechanism of insect metamorphosis and may also provide a novel possibility for the control of pest insects in the future.
Influence of miR-199a on rats with non-small cell lung cancer via regulating the HIF-1α/VEGF signaling pathway.

OBJECTIVE Micro-ribonucleic acids (miRNAs) are involved in the occurrence of various cancers, and the hypoxia-inducible factor 1-α (HIF-1α) is the main regulator of cell proliferation induced by hypoxia. The relationships of miR-199a and HIF-1α expressions with non-small cell lung cancer (NSCLC) remain unclear, so they were explored in this work. MATERIALS AND METHODS On the basis of establishing the rat model of NSCLC, the messenger RNA (mRNA) expressions of miR-199a, HIF-1α and the vascular endothelial growth factor (VEGF) were analyzed in NSCLC rats, and the correlations of miR-199a with the mRNAs of HIF-1α and VEGF and cancer staging were investigated. To further study the role of miR-199a in NSCLC cell proliferation via the HIF-1α/VEGF signaling pathway, NSCLC cells were treated with the signaling pathway inhibitor and transfected with miR-199a mimics, respectively. Also, the roles of the inhibitor PX-478 and miR-199a mimics in the expressions of miR-199a, HIF-1α, and VEGF proteins, as well as their influences on cell proliferation ability were detected. RESULTS In NSCLC rats, the expression of miR-199a was substantially decreased (p<0.01), but the expressions of HIF-1α and VEGF were notably raised (p<0.01). MiR-199a was negatively correlated with the expression of VEGF. As cancer developed, the expression of miR-199a was gradually lowered, but the expressions of HIF-1α and VEGF were gradually increased. Both HIF-1α/VEGF signaling pathway inhibitor PX-478 and miR-199a mimics significantly reduced the expressions of HIF-1α and VEGF proteins (p<0.01) and suppressed the cell proliferation activity. CONCLUSIONS MiR-199a prevents the proliferation of NSCLC cells via the targeted down-regulation of the HIF-1α/VEGF signaling pathway.
Increased expression of CART, nNOS, VIP, PACAP, SP and GAL in enteric neurons of the porcine stomach prepyloric region following hydrochloric acid infusion.

INTRODUCTION Stomach hyperacidity leads to damage of the mucus/bicarbonate barrier, ulcerations and the development of stomach cancer. Key regulators of the mucosal barrier/luminal acid balance are neurotransmitters secreted by intramural neurons. The aim of the current study was to determine the expression of gastric neuropeptides and nNOS in the porcine stomach following hydrochloric acid instillation. We report on increased expression of enteric neurotransmitters involved in adaptive reaction to an experimentally-induced hyperacidity state. MATERIAL AND METHODS The investigation was conducted on eight 12-18 kg pigs. The influence of intragastric infusion of hydrochloric acid on the expression of cocaine- and amphetamine-regulated transcript peptide (CART), neuronal nitric oxide synthase (nNOS), vasoactive intestinal polypeptide (VIP), pituitary adenylate cyclase-activating peptide (PACAP), substance P (SP) and galanin (GAL) in the submucous and myenteric gastric neurons of the pig has been studied with double immunofluorescence. RESULTS A mimicked hyperacidity state significantly increased the proportion of enteric neurons immunoreactive to CART, nNOS, VIP, PACAP, SP and GAL in the submucous gastric neurons. In the myenteric plexus, a significant increase of the number of VIP-, CART- and GAL-immunoreactive (IR) neurons was found. Similarly, the percentage of myenteric nNOS-IR and PACAP-IR neurons tended to increase, while the fraction of SP-IR cells did not change. CONCLUSIONS Stomach hyperacidity modifies the expression of the studied neurotransmitters in a specific way depending on the location of the neurons in particular plexuses of the stomach. Increased numbers of neurons expressing CART, nNOS, VIP, PACAP, SP and GAL clearly indicate their regulatory engagement in the restoration of the physiological gastric balance following hyperacidity.
Food democracy, health disparities and the New York City trans fat policy

Abstract Objective: To investigate food democracy and health disparities in the New York City (NYC) trans fat policy process. Design: Texts from semi-structured interviews, public testimony and comments on the policy were analysed using categorization and thematic coding. A priori content analysis for themes of food democracy was followed by open, axial and selective coding for sub-themes on health disparities. Data and method triangulation and respondent validation were used to establish data dependability, trustworthiness and representativeness. Setting: NYC. Participants: Interviews from a purposive, snowballed sample of thirty-three participants included restaurateurs, scientists, health and consumer advocates, consumers and policy makers. Additionally, 261 pages of transcript from public testimony of fifty-three participants and a purposive sample of public comments on the policy from a pool of 2157 were analysed. Results: Principles of food democracy involving inclusive citizenship, access to information, collaborative participation and focus on collective good were well represented in the data. Additionally, sub-themes linked to health disparities included: government responsibility for fairer access to healthier foods; recognition that people made choices based on circumstances; concern for vulnerable groups; and outrage with a food industry viewed as unconcerned for public health. Conclusions: Principles of food democracy present in the successful process of adoption of the 2006 NYC trans fat policy addressed nutrition-related health. Food democracy is a contemporary food system and policy approach with potential for public health benefits in reducing nutrition-related health disparities.
Preventive effect of ursolic acid derivative on particulate matter 2.5‐induced chronic obstructive pulmonary disease involves suppression of lung inflammation

Respiratory diseases like chronic obstructive pulmonary disease (COPD) are associated with the presence of particulate matter 2.5 (PM2.5) in the air. In the present study, the effect of synthesized ursolic acid derivatives on mice model of PM2.5‐induced COPD was investigated in vivo. The mice model of COPD was established by the administration of 25 μL of PM2.5 suspension through intranasal route daily for 1 week. The levels of oxidative stress markers and inflammatory cytokines like tumor necrosis factors‐α and interleukin‐6 in the mice bronchoalveolar fluids increased markedly on administration with PM2.5. However, treatment with ursolic acid derivative caused a significant suppression in PM2.5‐induced increase in oxidative stress markers and inflammatory cytokines in dose‐dependent manner. Hematoxylin and eosin staining showed excessive inflammatory cell infiltration in pulmonary tissues in mice with COPD. The inflammatory cell infiltration was inhibited on treatment of the mice with ursolic acid derivative. The ursolic acid derivative treatment increased level of superoxide dismutase in mice with COPD. The lung injury induced by PM2.5 in mice was also prevented on treatment with ursolic acid derivative. Thus, ursolic acid derivative inhibits pulmonary tissues damage in mice through suppression of inflammatory cytokine and oxidative enzymes. Therefore, ursolic acid derivative can be of therapeutic importance for treatment of PM2.5‐induced COPD.
Development and functional characterization of a lncRNA‐HIT conditional loss of function allele

Analysis of the human and murine transcriptomes has identified long noncoding RNAs (lncRNAs) as major functional components in both species. Transcriptional profiling of the murine limb led to our discovery of lncRNA‐HIT, which our previous in vitro analyses suggested a potential role for this lncRNA in the development of limb, craniofacial, and genitourinary tissues (Carlson et al., 2015). To test this hypothesis, we developed a conditional lncRNA‐HIT loss of function allele which uses Cre recombinase to activate an shRNA specific for lncRNA‐HIT. Activation of the lncRNA‐HIT shRNA allele resulted in a robust knock‐down of lncRNA‐HIT as well as co‐activation of a mCherry reporter, confirming the efficacy of the shRNA allele to reduce endogenous lncRNA levels in a tissue‐ and cell‐type specific manner. Developmental analyses of embryos expressing the activated shRNA and mCherry co‐reporter revealed multiple malformations corresponding to the sites of shRNA activation, affecting craniofacial, limb, and genitourinary tissue development. These results confirm the efficacy of lncRNA‐HIT shRNA allele to knock‐down endogenous transcripts in tissue‐ and cell type specific manner and indicate a requirement for lncRNA‐HIT in the development of these tissues.
Plant profit maximisation improves predictions of European forest responses to drought.

Knowledge of how water stress impacts the carbon and water cycles is a key uncertainty in terrestrial biosphere models. We tested a new profit maximisation model, where photosynthetic uptake of CO2 is optimally traded against plant hydraulic function, as an alternative to the empirical functions commonly used in models to regulate gas exchange during periods of water stress. We conducted a multi-site evaluation of this model at the ecosystem scale, before and during major droughts in Europe. Additionally, we asked whether the maximum hydraulic conductance in the soil-plant continuum (kmax ) - a key model parameter which is not commonly measured - could be predicted from long-term site climate. Compared to a control model with an empirical soil moisture function, the profit maximisation model improved the simulation of evapotranspiration during the growing season, reducing the Normalised Mean Square Error by c. 63%, across mesic and xeric sites. We also showed that kmax could be estimated from long-term climate, with improvements in the simulation of evapotranspiration at eight out of the 10 forest sites during drought. Although the generalisation of this approach is contingent upon determining kmax , it presents a mechanistic trait-based alternative to regulate canopy gas exchange in global models.
Impact of Sleep Disorder as a Risk Factor for Dementia in Men and Women

Sleep is an essential physiological process, especially for proper brain function through the formation of new pathways and processing information and cognition. Therefore, when sleep is insufficient, this can result in pathophysiologic conditions. Sleep deficiency is a risk factor for various conditions, including dementia, diabetes, and obesity. Recent studies have shown that there are differences in the prevalence of sleep disorders between genders. Insomnia, the most common type of sleep disorder, has been reported to have a higher incidence in females than in males. However, sex/gender differences in other sleep disorder subtypes are not thoroughly understood. Currently, increasing evidence suggests that gender issues should be considered important when prescribing medicine. Therefore, an investigation of the gender-dependent differences in sleep disorders is required. In this review, we first describe sex/gender differences not only in the prevalence of sleep disorders by category but in the efficacy of sleep medications. In addition, we summarize sex/gender differences in the impact of sleep disorders on incident dementia. This may help understand gender-dependent pathogenesis of sleep disorders and develop therapeutic strategies in men and women.
Synthesis, aphicidal activity and conformation of novel insect kinin analogues as potential eco-friendly insecticides.

BACKGROUND The discovery of ecofriendly insecticides through new strategy for aphid control is important because of the substantial resistance and unexpected eco-toxicity to honeybees caused by traditional insecticide. The insect kinins, a class of multifunctional insect neuropeptides, are considered for potential application in pest control. In our previous work, we have developed several series of insect kinin analogues and found a promising lead II-1 with good aphicidal activity. For the further discovery of eco-friendly aphicides, the further optimization on II-1 is carried out herein. RESULTS 15 novel Yaa3 modified analogues based on the lead II-1 were synthesized. The aphicidal tests indicated that IV-3, IV-5, and IV-10 exhibited significant activity against the soybean aphid Aphis glycines with LC50 values of 0.0029, 0.0072 and 0.0086 mmol/L, respectively, higher than that of lead II-1 and the commercial Pymetrozine. The molecular modeling results showed that analogues II-1, IV-3, IV-5, IV-7 and IV-10 formed a β-turn-like conformation, while the conformation of analogues IV-1, IV-2 and IV-9 seemed to be linear. Some structural elements favorable for the activity were proposed based on the analysis of analogues conformation-activity relationship. CONCLUSION Insect kinins analogues derived from lead II-1 by modifying the hydrolysis site Yaa3 with natural, sterically hindered α- and β-amino acids showed great potency in the discovery of eco-friendly insecticides. Inspiringly, the most active analogue IV-3 can be a candidate for further development. The β-turn-like conformation and the orientation of the aromatic rings of the side chain of Phe2 and Trp4 may be critical factors beneficial to activity. This article is protected by copyright. All rights reserved.