Miracle-dz/UniFAR-FTUs huggingface dataset:
The emerging role of xanthine oxidase inhibition for suppression of breast cancer cell migration and metastasis associated with hypercholesterolemia

Hypercholesterolemia is reported to increase reactive oxygen species (ROS) and to promote breast cancer progression. ROS play an important role in tumor biology, and xanthine oxidase (XO) is an enzyme that generates ROS. The effects of febuxostat (FBX), an XO inhibitor, on breast cancer cell migration under LDL stimulation in vitro and metastasis of breast cancer associated with hypercholesterolemia in vivo were studied. In vitro, FBX significantly inhibited LDL‐induced ROS production and cell migration. Treatment of small interfering RNA against XO was consistent with the findings of FBX treatment. In vivo, a significant increase of tumor growth and pulmonary metastasis was observed in a xenograft mouse model with 4T1 cells on a high cholesterol diet (HCD), both of which were markedly inhibited by FBX or allopurinol treatment. Moreover, ERK represented the main target‐signaling pathway that was affected by FBX treatment in a xenograft mouse model on an HCD evaluated by NanoString nCounter analysis. Consistently, MEK/ERK inhibitors directly decreased the LDL‐induced cell migration in vitro. In conclusion, FBX mitigates breast cancer cell migration and pulmonary metastasis in the hyperlipidemic condition, associated with decreased ROS generation and MAPK phosphorylation. The inhibition of ERK pathways is likely to underlie the XO inhibitor‐mediated suppression of breast cancer cell migration. —Oh, S. ‐H. , Choi, S. ‐Y. , Choi, H. ‐J., Ryu, H. ‐M. , Kim, Y. ‐J., Jung, H. ‐Y. , Cho, J.‐H. , Kim, C. ‐D. , Park, S. ‐H. , Kwon, T. ‐H. , Kim, Y. ‐L. The emerging role of xanthine oxidase inhibition for suppression of breast cancer cell migration and metastasis associated with hypercholesterolemia. FASEB J. 33, 7301–7314 (2019). www.fasebj. org
Alterations in Skin Blood Flow at the Fingertip Are Related to Mortality in Patients With Circulatory Shock.

OBJECTIVES Skin blood flow is rapidly altered during circulatory shock and may remain altered despite apparent systemic hemodynamic stabilization. We evaluated whether changes in skin blood flow during circulatory shock were related to survival. DESIGN Prospective study. SETTING Thirty-five-bed medical-surgical university hospital department of intensive care. SUBJECTS Twenty healthy volunteers and 70 patients with circulatory shock (< 12 hr duration), defined as the need for vasopressors to maintain mean arterial pressure greater than or equal to 65 mm Hg and signs of altered tissue perfusion. INTERVENTIONS We assessed skin blood flow using skin laser Doppler on the fingertip for 3 minutes at basal temperature (SBFBT) and at 37°C (SBF37) (thermal challenge test) once in volunteers and at the time of inclusion and after 6, 24, 48, 72, and 96 hours in patients with shock. Capillary refill time and peripheral perfusion index were measured at the same time points on the contralateral hand. MEASUREMENTS AND MAIN RESULTS The thermal challenge response (ΔSBF/ΔT) was calculated using the following formula: (SBF37-SBFBT)/(37-basal temperature). Area under the receiver operating characteristic curves were calculated to evaluate variables predictive of ICU mortality. At inclusion, skin blood flow and ΔSBF/ΔT were lower in patients than in volunteers. Baseline skin blood flow (31 [17-113] vs 16 [9-32] arbitrary perfusion units; p = 0.01) and ΔSBF/ΔT (4.3 [1.7-10.9] vs 0.9 [0.4-2.9] arbitrary perfusion unit/s) were greater in survivors than in nonsurvivors. Capillary refill time was shorter in survivors than in nonsurvivors; peripheral perfusion index was similar in the two groups. ΔSBF/ΔT (area under the receiver operating characteristic curve 0.94 [0.88-0.99]) and SBFBT (area under the receiver operating characteristic curve 0.83 [0.73-0.93]) had the best predictive value for ICU mortality with cutoff values less than or equal to 1.25 arbitrary perfusion unit/°C (sensitivity 88%, specificity 89%) and less than or equal to 21 arbitrary perfusion unit (sensitivity 84%, specificity 81%), respectively. CONCLUSIONS Alterations in fingertip skin blood flow can be evaluated using a laser Doppler thermal challenge technique in patients with circulatory shock and are directly related to outcome. These novel monitoring techniques could potentially be used to guide resuscitation.
VITA—an everyday virtual reality setup for prosthetics and upper-limb rehabilitation

Objective. Currently, there are some 95 000 people in Europe suffering from upper-limb impairment. Rehabilitation should be undertaken right after the impairment occurs and should be regularly performed thereafter. Moreover, the rehabilitation process should be tailored specifically to both patient and impairment. Approach. To address this, we have developed a low-cost solution that integrates an off-the-shelf virtual reality (VR) setup with our in-house developed arm/hand intent detection system. The resulting system, called VITA, enables an upper-limb disabled person to interact in a virtual world as if her impaired limb were still functional. VITA provides two specific features that we deem essential: proportionality of force control and interactivity between the user and the intent detection core. The usage of relatively cheap commercial components enables VITA to be used in rehabilitation centers, hospitals, or even at home. The applications of VITA range from rehabilitation of patients with musculodegenerative conditions (e.g. ALS), to treating phantom-limb pain of people with limb-loss and prosthetic training. Main results. We present a multifunctional system for upper-limb rehabilitation in VR. We tested the system using a VR implementation of a standard hand assessment tool, the Box and Block test and performed a user study on this standard test with both intact subjects and a prosthetic user. Furthermore, we present additional applications, showing the versatility of the system. Significance. The VITA system shows the applicability of a combination of our experience in intent detection with state-of-the art VR system for rehabilitation purposes. With VITA, we have an easily adaptable experimental tool available, which allows us to quickly and realistically simulate all kind of real-world problems and rehabilitation exercises for upper-limb impaired patients. Additionally, other scenarios such as prostheses simulations and control modes can be quickly implemented and tested.
Mutations of Kluyveromyces lactis dolichol kinase enhances secretion of recombinant proteins

Although there are similarities in the core steps of the secretion pathway from yeast to higher eukaryotes, significant functional differences exist even among diverse yeast species. Here, we used next-generation sequencing to identify two mutations in the Kluyveromyces lactis KlSEC59 gene, encoding dolichol kinase (DK), which are responsible for an enhanced secretion phenotype in a previously isolated mutant, MD2/1-9. Compared with the temperature-sensitive Saccharomyces cerevisiae sec59-1 mutant, which exhibits reduced N-glycosylation and decreased secretory efficacy, the identified K. lactis DK mutations had fewer effects on glycosylation, as well as on survival at high temperature and cell wall integrity. Moreover, despite some glycosylation defects, double DK mutations (G405S and I419S) in the K. lactis mutant strain demonstrated three times the level of recombinant α-amylase secretion as the wild-type strain. Overexpression of potential suppressors KlMNN10, KlSEL1, KlERG20, KlSRT1, KlRER2, KlCAX4, KlLPP1 and KlDPP1 in the DK-mutant strain restored carboxypeptidase Y glycosylation to different extents and, with the exception of KISRT1, reduced α-amylase secretion to levels observed in wild-type cells. Our results suggest that enhanced secretion related to reduced activity of mutant DK in K. lactis results from mild glycosylation changes that affect activity of other proteins in the secretory pathway.
Integrating Local Knowledge into a National Programme: Evidence from a Community-Based Diabetes Prevention Education Programme

Type 2 diabetes prevention is a major priority for healthcare services and public health. This study aimed to evaluate how a local authority in England piloted a diabetes prevention programme. The South Gloucestershire Diabetes Prevention (Pilot) Programme (SGDPP) comprised a group health education course over six weeks with subsequent support provision up to six months post-enrolment. Of the 300 patients invited onto the programme, 32% enrolled and 29% completed the full six-month programme. There was an attendance rate of 84% throughout group sessions and at a six-month follow-up. There were significant improvements across most measures at six months, including a 4 kg mean weight loss and a 3.45 mmol/mol mean HbA1c reduction. Clear goals, high quality organization and personal qualities of educators were identified as central for the programme’s success. The unit costs were similar to pilots of other healthy lifestyle programmes. The evaluation found evidence of reduced type 2 diabetes risk markers, positive impacts for dietary and physical activity, and potential cost-effectiveness for this format of group-based diabetes prevention intervention. Feedback from multiple stakeholders provided insight on how to successfully embed and scale-up delivery of diabetes prevention work. This evidence enables the integration of learning in local service delivery and provides a basis to support development of the national diabetes prevention programme.
Animal Models of Hypertension: A Scientific Statement From the American Heart Association

Hypertension is the most common chronic disease in the world, yet the precise cause of elevated blood pressure often cannot be determined. Animal models have been useful for unraveling the pathogenesis of hypertension and for testing novel therapeutic strategies. The utility of animal models for improving the understanding of the pathogenesis, prevention, and treatment of hypertension and its comorbidities depends on their validity for representing human forms of hypertension, including responses to therapy, and on the quality of studies in those models (such as reproducibility and experimental design). Important unmet needs in this field include the development of models that mimic the discrete hypertensive syndromes that now populate the clinic, resolution of ongoing controversies in the pathogenesis of hypertension, and the development of new avenues for preventing and treating hypertension and its complications. Animal models may indeed be useful for addressing these unmet needs.
Centrosome Loss Triggers a Transcriptional Program To Counter Apoptosis-Induced Oxidative Stress

Centrosomes are important mediators of mitotic spindle assembly, and loss of centrosomes can lead to mitotic errors and cell death; however, it is also clear that cells can compensate for centrosome loss through multiple mechanisms. Centrosomes play a critical role in mitotic spindle assembly through their role in microtubule nucleation and bipolar spindle assembly. Loss of centrosomes can impair the ability of some cells to properly conduct mitotic division, leading to chromosomal instability, cell stress, and aneuploidy. Multiple aspects of the cellular response to mitotic error associated with centrosome loss appear to involve activation of JNK signaling. To further characterize the transcriptional effects of centrosome loss, we compared gene expression profiles of wild-type and acentrosomal cells from Drosophila wing imaginal discs. We found elevation of expression of JNK target genes, which we verified at the protein level. Consistent with this, the upregulated gene set showed significant enrichment for the AP-1 consensus DNA-binding sequence. We also found significant elevation in expression of genes regulating redox balance. Based on those findings, we examined oxidative stress after centrosome loss, revealing that acentrosomal wing cells have significant increases in reactive oxygen species (ROS). We then performed a candidate genetic screen and found that one of the genes upregulated in acentrosomal cells, glucose-6-phosphate dehydrogenase, plays an important role in buffering acentrosomal cells against increased ROS and helps protect those cells from cell death. Our data and other recent studies have revealed a complex network of signaling pathways, transcriptional programs, and cellular processes that epithelial cells use to respond to stressors, like mitotic errors, to help limit cell damage and maintain normal tissue development.
Development of an intelligent decision support system for ischemic stroke risk assessment in a population-based electronic health record database

Background Intelligent decision support systems (IDSS) have been applied to tasks of disease management. Deep neural networks (DNNs) are artificial intelligent techniques to achieve high modeling power. The application of DNNs to large-scale data for estimating stroke risk needs to be assessed and validated. This study aims to apply a DNN for deriving a stroke predictive model using a big electronic health record database. Methods and results The Taiwan National Health Insurance Research Database was used to conduct a retrospective population-based study. The database was divided into one development dataset for model training (~70% of total patients for training and ~10% for parameter tuning) and two testing datasets (each ~10%). A total of 11,192,916 claim records from 840,487 patients were used. The primary outcome was defined as any ischemic stroke in inpatient records within 3 years after study enrollment. The DNN was evaluated using the area under the receiver operating characteristic curve (AUC or c-statistic). The development dataset included 672,214 patients (a total of 8,952,000 records) of whom 2,060 patients had stroke events. The mean age of the population was 35.5±20.2 years, with 48.5% men. The model achieved AUC values of 0.920 (95% confidence interval [CI], 0.908–0.932) in testing dataset 1 and 0.925 (95% CI, 0.914–0.937) in testing dataset 2. Under a high sensitivity operating point, the sensitivity and specificity were 92.5% and 79.8% for testing dataset 1; 91.8% and 79.9% for testing dataset 2. Under a high specificity operating point, the sensitivity and specificity were 80.3% and 87.5% for testing dataset 1; 83.7% and 87.5% for testing dataset 2. The DNN model maintained high predictability 5 years after being developed. The model achieved similar performance to other clinical risk assessment scores. Conclusions Using a DNN algorithm on this large electronic health record database is capable of obtaining a high performing model for assessment of ischemic stroke risk. Further research is needed to determine whether such a DNN-based IDSS could lead to an improvement in clinical practice.
Synthesis of Carbon Quantum Dot Nanoparticles Derived from Byproducts in Bio-Refinery Process for Cell Imaging and In Vivo Bioimaging

The carbon quantum dot (CQD), a fluorescent carbon nanoparticle, has attracted considerable interest due to its photoluminescent property and promising applications in cell imaging and bioimaging. In this work, biocompatible, photostable, and sustainably sourced CQDs were synthesized from byproducts derived from a biorefinery process using one-pot hydrothermal treatment. The main components of byproducts were the degradation products (autohydrolyzate) of biomass pretreated by autohydrolysis. The as-synthesized CQDs had a size distribution from 2.0–6.0 nm and had high percentage of sp2 and sp3 carbon groups. The CQDs showed blue-green fluorescence with a quantum yield of ~13%, and the fluorescence behaviors were found to be stable with strong resistance to photobleaching and temperature change. In addition, it is found that the as-synthesized CQDs could be used for imaging of cells and tumors, which show potential applications in bioimaging and related fields such as phototherapy and imaging.
Chronic Nicotine Exposure Alters the Neurophysiology of Habenulo-Interpeduncular Circuitry

Antagonism of nicotinic acetylcholine receptors (nAChRs) in the medial habenula (MHb) or interpeduncular nucleus (IPN) triggers withdrawal-like behaviors in mice chronically exposed to nicotine, implying that nicotine dependence involves the sensitization of nicotinic signaling. Identification of receptor and/or neurophysiological mechanisms underlying this sensitization is important, as it could promote novel therapeutic strategies to reduce tobacco use. Using an approach involving photoactivatable nicotine, we previously demonstrated that chronic nicotine (cNIC) potently enhances nAChR function in dendrites of MHb neurons. However, whether cNIC modulates downstream components of the habenulo-interpeduncular (Hb-IP) circuit is unknown. In this study, cNIC-mediated changes to Hb-IP nAChR function were examined in mouse (male and female) brain slices using molecular, electrophysiological, and optical techniques. cNIC enhanced action potential firing and modified spike waveform characteristics in MHb neurons. Nicotine uncaging revealed nAChR functional enhancement by cNIC on proximal axonal membranes. Similarly, nAChR-driven glutamate release from MHb axons was enhanced by cNIC. In IPN, the target structure of MHb axons, neuronal morphology, and nAChR expression is complex, with stronger nAChR function in the rostral subnucleus [rostral IPN (IPR)]. As in MHb, cNIC induced strong upregulation of nAChR function in IPN neurons. This, coupled with cNIC-enhanced nicotine-stimulated glutamate release, was associated with stronger depolarization responses to brief (1 ms) nicotine uncaging adjacent to IPR neurons. Together, these results indicate that chronic exposure to nicotine dramatically alters nicotinic cholinergic signaling and cell excitability in Hb-IP circuits, a key pathway involved in nicotine dependence. SIGNIFICANCE STATEMENT This study uncovers several neuropharmacological alterations following chronic exposure to nicotine in a key brain circuit involved in nicotine dependence. These results suggest that smokers or regular users of electronic nicotine delivery systems (i.e., “e-cigarettes”) likely undergo sensitization of cholinergic circuitry in the Hb-IP system. Reducing the activity of Hb-IP nAChRs, either volitionally during smoking cessation or inadvertently via receptor desensitization during nicotine intake, may be a key trigger of withdrawal in nicotine dependence. Escalation of nicotine intake in smokers, or tolerance, may involve stimulation of these sensitized cholinergic pathways. Smoking cessation therapeutics are only marginally effective, and by identifying cellular/receptor mechanisms of nicotine dependence, our results take a step toward improved therapeutic approaches for this disorder.
Antipredator response diminishes during periods of resource deficit for a large herbivore.

The starvation-predation hypothesis predicts that, during resource shortages, prey forego antipredator behavior and forage as much as possible to avoid starvation, even when risk of predation is high. We tested this hypothesis using GPS locations collected simultaneously from moose (Alces alces) and wolves (Canis lupus) in the Greater Yellowstone Ecosystem of North America. We assessed shifts in the speed, displacement, and habitat selection of moose 24 h following encounter with wolves (0-1,500 m distance). We examined whether the strength of antipredator behaviors would weaken as winter progressed and the nutritional condition of moose declined. Moose responded to wolf encounters by increasing their rate of movement in early winter, but only within 500 m distance. Importantly, these responses attenuated as winter progressed. Moose did not avoid their preferred foraging habitat (riparian areas) following encounters with wolves at any distance, and instead they more strongly selected riparian areas, especially in early winter. Our findings support theoretical predictions that resource deficits should dampen prey antipredator behavior, and suggest that nutritional condition of prey may buffer against run-away risk effects in food webs involving large mammalian predators and prey.
Autonomic regulation of preterm infants is enhanced by Family Nurture Intervention.

Preterm infants have maturational delays in several neurobehavioral systems. This study assesses the impact of the Family Nurture Intervention (FNI) in the neonatal intensive care unit (NICU) on the maturation of autonomic regulation of preterm infants. Preterm infants born at 26-34 weeks postmenstrual age (PMA) were assigned to groups receiving either standard care (SC) or SC plus FNI, using a randomized controlled trial design. At two collection time points, approximately 35 weeks and 41 weeks PMA, electrocardiograms (ECG) were monitored for approximately 1 hour during sleep. Heart rate and respiratory sinus arrhythmia (RSA) were quantified from the ECG. Across the two time points, the FNI group exhibited greater increases in RSA (Cohen's d = 0.35) and slope between RSA and heart rate, as a measure of vagal efficiency (Cohen's d = 0.62). These results document that FNI resulted in enhanced autonomic regulation consistent with greater maturation of cardiac function. These and previous findings strongly suggest that facilitating early nurturing interactions and emotional connection between preterm infants and their mothers is a practicable and effective means of optimizing postnatal development in preterm infants. Interpretation of these autonomic function results also enriches our understanding of the potential long-term beneficial outcomes of FNI by drawing upon polyvagal theory, which explains how autonomic state provides a neurophysiological platform for optimal co-regulation between infant and caregiver, and by drawing upon calming cycle theory, which provides a model for understanding how repeated mother/infant calming interactions positively condition autonomic state and reinforce approach, prosocial behaviors.
Production of trans-free interesterified fat using indigenously immobilized lipase

Abstract Enzymatic interesterification was carried out between high-oleic canola oil and fully hydrogenated soybean oil using indigenously immobilized Thermomyces lanuginosus lipas substrate concentration, moisture content of enzyme, and enzyme load. Interesterification resulted in a decrease in the concentration of tri-unsaturated and trisaturated TAG and an increase of mono- and di-saturated TAG as observed by reversed-phase HPLC. The alteration in TAG composition and the presence of new TAG species after interesterification was correlated with extended plasticity characterized by lower slip melting point with a significant change in functionality and consistency of the interesterified product. Thermal and structural properties of the blends before and after interesterification were assessed by differential scanning calorimetry (DSC), X-ray diffraction and polarized light microscopy. Trans-fat analysis indicated the absence of any trans fatty acid in the final interesterified product. The resultant interesterified products with varying slip melting points can be used in the formulation of healthier fat and oil products and address a critical industrial demand for trans free formulations for base-stocks of spreads, margarines, and confectionary fats.