Miracle-dz/UniFAR-FTUs huggingface dataset:
Science Objectives for Flagship-Class Mission Concepts for the Search for Evidence of Life at Enceladus

Cassini revealed that Saturn's Moon Enceladus hosts a subsurface ocean that meets the accepted criteria for habitability with bio-essential elements and compounds, liquid water, and energy sources available in the environment. Whether these conditions are sufficiently abundant and collocated to support life remains unknown and cannot be determined from Cassini data. However, thanks to the plume of oceanic material emanating from Enceladus’ south pole, a new mission to Enceladus could search for evidence of life without having to descend through kilometers of ice. In this article, we outline the science motivations for such a successor to Cassini, choosing the primary science goal to be determining whether Enceladus is inhabited and assuming a resource level equivalent to NASA's Flagship-class missions. We selected a set of potential biosignature measurements that are complementary and orthogonal to build a robust case for any life detection result. This result would be further informed by quantifications of the habitability of the environment through geochemical and geophysical investigations into the ocean and ice shell crust. This study demonstrates that Enceladus’ plume offers an unparalleled opportunity for in situ exploration of an Ocean World and that the planetary science and astrobiology community is well equipped to take full advantage of it in the coming decades.
Positive Interventional Effect of Engineered Butyrate-Producing Bacteria on Metabolic Disorders and Intestinal Flora Disruption in Obese Mice

Obesity is a chronic metabolic disease with an imbalance between energy intake and energy expenditure, and obesity-related metabolic diseases have become increasingly common. There is an urgent need to develop effective interventions for the prevention and treatment of obesity. ABSTRACT The substantially increased prevalence of obesity and obesity-related diseases has generated considerable concern. Currently, synthetic biological strategies have played an essential role in preventing and treating chronic diseases such as obesity. A growing number of symbiotic bacteria used as vectors for genetic engineering have been applied to create living therapeutics. In this study, using Bacillus subtilis as a cellular chassis, we constructed the engineered butyrate-producing strain BsS-RS06551 with a butyrate yield of 1.5 g/liter. A mouse model of obesity induced by a high-fat diet (HFD) was established to study the long-term intervention effects of this butyrate-producing bacteria on obesity. Combined with phenotypic assay results, we found that BsS-RS06551 could effectively retard body weight gain induced by a high-fat diet and visceral fat accumulation of mice, whereas it could improve glucose tolerance and insulin tolerance, reducing liver damage. We explored the BsS-RS06551 mechanism of action on host function and changes in intestinal flora by integrating multiple omics profiling, including untargeted metabolomics and metagenomics. The results showed that 24 major differential metabolites were involved in the metabolic regulation of BsS-RS06551 to prevent obesity in mice, including bile acid metabolism, branch chain amino acids, aromatic amino acids, and other metabolic pathways. Continuous ingestion of BsS-RS06551 could regulate gut microbiota composition and structure and enhance intestinal flora metabolic function abundance, which was closely related to host interactions. Our results demonstrated that engineered butyrate-producing bacteria had potential as an effective strategy to prevent obesity. IMPORTANCE Obesity is a chronic metabolic disease with an imbalance between energy intake and energy expenditure, and obesity-related metabolic diseases have become increasingly common. There is an urgent need to develop effective interventions for the prevention and treatment of obesity. This study showed that long-term consumption of BsS-RS06551 had a significant inhibitory effect on obesity induced by a high-fat diet and was more potent in inhibiting obesity than prebiotic inulin. In addition, this study showed a beneficial effect on host glucose, lipid metabolism, and gut microbe composition. Considering its colonization potential, this engineered bacteria provided a new strategy for the effective and convenient treatment of obesity in the long term.
Competing in the Ramadan fasted state: for spirituality, health and performance

All professional athletes require effective nutrition, hydration and sleep strategies to optimise physical and mental health during training and competition. This is an annual challenge for Muslim athletes during the holy month of Ramadan, when they abstain from ingestion of food and liquids during daylight hours in an act of spiritual devotion. During Ramadan, the length of each day’s fast depends on geographical location (latitude) and season: in the north of the UK, for example, daylight lasts less than 6 hours in winter but almost 19 hours in midsummer. Athletes who fast usually report reduced total sleep time to accommodate prefast/postfast meals (suhoor and iftar), social activities and nighttime prayers. 2 Medical teams can promote inclusivity by implementing safety criteria to optimise performance and support athletes who train and compete during Ramadan.
Protective effect of phillyrin against cerebral ischemia/reperfusion injury in rats and oxidative stress-induced cell apoptosis and autophagy in neurons

ABSTRACT This study explored the role and potential molecular mechanism of phillyrin in cerebral ischemia/reperfusion (I/R) injury. The rat middle cerebral artery occlusion (MCAO)/R model was constructed, and cerebral infarction volume, brain water content, and neurological score were measured. Neuron morphological structures in brain tissues and primary neuron apoptosis were detected using hematoxylin and eosin (H&E) staining and Hoechst 33258 staining, respectively. In MCAO/R rats, phillyrin markedly reduced cerebral infarction volume, neurological score, and brain water content and inhibited neuron apoptosis. In vitro experiments showed that phillyrin remarkably increased viability and decreased lactate dehydrogenase (LDH) release of H2O2-injured neurons. Moreover, phillyrin remarkably downregulated the proportion of apoptosis-related protein B-associated X (Bax)/B-cell lymphoma protein 2 (Bcl-2) and reduced procaspase-3, phospho-Akt (p-Akt-1), and phosphorylation-mammalian target of rapamycin (p-mTOR) levels in H2O2-injured neurons. Furthermore, phosphatidylinositol-3 kinase (PI3K) inhibitor ZSTK474 weakened the effects of phillyrin on p-mTOR, p-Akt-1, characteristic proteins of autophagy 3-II (LC3-II) and beclin-1 levels, and H2O2-induced neuronal apoptosis and autophagy. Taken together, phillyrin alleviates I/R injury by inhibiting neuronal cell apoptosis and autophagy pathway, which may provide a new treatment strategy for cerebral I/R injury. Graphical Abstract
A Social-Ecological Approach to Understanding Activity Engagement Patterns Among Older Chinese Immigrants

Few studies have focused on activity engagement among older immigrants. We aim to map the patterns of activity engagement and examine the associations with social-ecological factors in a sample of older Chinese immigrants. Participants were from the Population Study of Chinese Elderly in Chicago (PINE). Four patterns of activity engagement were identified through latent class analysis: restricted, diverse, informal social, and community-based social. Intrapersonal, interpersonal, cultural, and environmental factors distinguished latent classes of activity engagement. In particular, acculturation and family-oriented immigration differentiated the restricted from the diverse class membership. Positive attributes of social environment such as social network size, positive social support, and neighborhood cohesion were associated with the likelihood of categorization in the diverse, informal social, and community-based social groups relative to the restricted group. Findings point to the importance of positive attributes of social environment in enhancing engagement with life among older Chinese immigrants.
Evaluating thyroid function in pregnant women

Abstract Thyroid hormones are primarily responsible for regulating the basal metabolic rate but also make important contributions to reproductive function and fetal development. Both hyper- and hypothyroidism in pregnancy have been associated with increased risks of complications that include preeclampsia and low birth weight, among others. Furthermore, thyroid hormone deficiency in the developing fetus results in neurodevelopmental delay. As the fetus is exclusively reliant on maternal thyroid hormone for most of the first trimester and requires continued maternal supply until birth, identifying maternal thyroid dysfunction is critically important. However, evaluating thyroid function in pregnancy is challenging because of the many physiological changes that affect concentrations of thyroid-related analytes. Increasing plasma human chorionic gonadotropin (hCG) concentrations in the second half of the first trimester elicit a corresponding transient decrease in thyroid-stimulating hormone (TSH), and continually increasing estradiol concentrations throughout pregnancy cause substantial increases in thyroxine-binding globulin (TBG) and total thyroxine (T4) relative to the nonpregnant state. Lastly, free T4 concentrations gradually decrease with increasing gestational age. For these reasons, it is essential to interpret thyroid function test results in the context of trimester-specific reference intervals to avoid misclassification of thyroid status. This review summarizes the effects of thyroid dysfunction prior to conception and during pregnancy and describes considerations for the laboratory assessment of thyroid function in pregnant women.
Clinical use of intracoronary imaging modalities in Poland. Expert opinion of the Association of Cardiovascular Interventions of the Polish Cardiac Society.

The paper presents the most common, current indications for the use of intravascular invasive imaging diagnostic techniques, i.e. intravascular ultrasound and optical coherence tomography in Polish invasive cardiology centers. The application of the above-mentioned techniques in the diagnosis of stenosis of the left main coronary artery, optimization of stent implantation procedures, treatment of calcified lesions and other clinically important issues are discussed.
The Lever of Riches: Technological Creativity and Economic Progress

Why are some nations more technically creative than others and why do some highly innovative societies eventually stagnate? In this provocative study of the value and meaning of technological advance, Joel Mokyr considers how past physical and social conditions have influenced the development and reception of new ideas, and shows how these trends can guide future industrial strategies at a time when more countries than ever before are competing for the rewards of technical ingenuity. Available in OSO: http://www.oxfordscholarship. com/oso/public/content/economicsfinance/9780195074772/toc.html
STRATEGY FOR CONTROL TYPE SOFT SWICHING CONVERTERS

Paper clears up the definition of control type soft switching and presents five characteristics for control type soft switching. The theory of five characteristics is verified in the existing control type soft switching topologies. And a series of new control type soft switching topologies, such as Buck, Boost, Buck-boost, Cuk, Zeta, Sepic, Flyback, and Forward are constructed by using the theory of five characteristics. A 200kHz prototype of 48V input, 19V output, whose conversion efficiency is 96.1% is built to further verify the theory of five characters for control type soft switching.
Corticofugal regulation of predictive coding

Sensory systems must account for both contextual factors and prior experience to adaptively engage with the dynamic external environment. In the central auditory system, neurons modulate their responses to sounds based on statistical context. These response modulations can be understood through a hierarchical predictive coding lens: responses to repeated stimuli are progressively decreased, in a process known as repetition suppression, whereas unexpected stimuli produce a prediction error signal. Prediction error incrementally increases along the auditory hierarchy from the inferior colliculus (IC) to the auditory cortex (AC), suggesting that these regions may engage in hierarchical predictive coding. A potential substrate for top-down predictive cues is the massive set of descending projections from the auditory cortex to subcortical structures, although the role of this system in predictive processing has never been directly assessed. We tested the effect of optogenetic inactivation of the auditory cortico-collicular feedback in awake mice on responses of IC neurons to stimuli designed to test prediction error and repetition suppression. Inactivation of the cortico-collicular pathway led to a decrease in prediction error in IC. Repetition suppression was unaffected by cortico-collicular inactivation, suggesting that this metric may reflect fatigue of bottom-up sensory inputs rather than predictive processing. We also discovered populations of IC neurons that exhibit repetition enhancement, a sequential increase in firing with stimulus repetition. Cortico-collicular inactivation led to a decrease in repetition enhancement in the central nucleus of IC, suggesting that it is a top-down phenomenon. Negative prediction error, a stronger response to a tone in a predictable rather than unpredictable sequence, was suppressed in shell IC units during cortico-collicular inactivation. These changes in predictive coding metrics arose from bidirectional modulations in the response to the standard and deviant contexts, such that neurons in IC responded more similarly to each context in the absence of cortical input. We also investigated how these metrics compare between the anesthetized and awake states by recording from the same neurons under both conditions. We found that metrics of predictive coding and deviance detection differ depending on the anesthetic state of the animal, with negative prediction error emerging in the central IC and repetition enhancement and prediction error being more prevalent in the absence of anesthesia. Overall, our results demonstrate that the auditory cortex provides cues about the statistical context of sound to subcortical brain regions via direct feedback, regulating processing of both prediction and repetition.
Effect of Cyclosporin A and Impact of Dose Staggering on OATP1B1/1B3 Endogenous Substrates and Drug Probes for Assessing Clinical Drug Interactions

This study was designed to assess the quantitative performance of endogenous biomarkers for organic anion transporting polypeptide (OATP) 1B1/1B3‐mediated drug‐drug interactions (DDIs). Ten healthy volunteers orally received OATP1B1/1B3 probe cocktail (0.2 mg pitavastatin, 1 mg rosuvastatin, and 2 mg valsartan) and an oral dose of cyclosporin A (CysA, 20 mg and 75 mg) separated by a 1‐hour interval (20 mg (−1 hour), and 75 mg (−1 hour)). CysA 75 mg was also given with a 3‐hour interval (75 mg (−3 hours)) to examine the persistence of OATP1B1/1B3 inhibition. The area under the plasma concentration‐time curve ratios (AUCRs) were 1.63, 3.46, and 2.38 (pitavastatin), 1.39, 2.16, and 1.81 (rosuvastatin), and 1.42, 1.77, and 1.85 (valsartan), at 20 mg, 75 mg (−1 hour) and 75 mg (−3 hours) of CysA, respectively. CysA effect on OATP1B1/1B3 was unlikely to persist at the dose examined. Among 26 putative OATP1B1/1B3 biomarkers evaluated, AUCR and maximum concentration ratio (CmaxR) of CP‐I showed the highest Pearson’s correlation coefficient with CysA AUC (0.94 and 0.93, respectively). Correlation between AUCR of pitavastatin, and CmaxR or AUCR of CP‐I were consistent between this study and our previous study using rifampicin as an OATP1B1/1B3 inhibitor. Nonlinear regression analysis of AUCR−1 of pitavastatin and CP‐I against CysA Cmax yielded Ki,OATP1B1/1B3,app (109 ± 35 and 176 ± 42 nM, respectively), similar to the Ki,OATP1B1/1B3 estimated by our physiologically‐based pharmacokinetic model analysis described previously (107 nM). The endogenous OATP1B1/1B3 biomarkers, particularly CmaxR and AUCR of CP‐I, corroborates OATP1B1/1B3 inhibition and yields valuable information that improve accurate DDI predictions in drug development, and enhance our understanding of interindividual variability in the magnitude of DDIs.
Pharmacokinetic drug interactions of asciminib with the sensitive cytochrome P450 probe substrates midazolam, warfarin, and repaglinide in healthy participants

Asciminib, a first‐in‐class BCR‐ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP), is a new treatment option for patients with chronic myeloid leukemia who no longer benefit from currently approved tyrosine kinase inhibitors. In vitro, asciminib reversibly inhibits cytochrome P450 (CYP) 3A4/5, CYP2C9, and CYP2C8. This phase I, open‐label, two‐stage study in healthy participants evaluated the effect of asciminib (40 mg b.i.d. at steady‐state) as a potential perpetrator on single‐dose pharmacokinetics of a two‐drug cocktail containing midazolam (CYP3A substrate) and warfarin (CYP2C9 substrate) in stage 1 (n = 22), and of repaglinide (CYP2C8 substrate) in stage 2 (n = 25). For midazolam plus asciminib versus midazolam, geometric mean (Gmean) ratios (90% confidence interval) for midazolam area under the curve from zero to infinity (AUCinf) and maximum plasma concentration (Cmax) were 1.28 (1.15, 1.43) and 1.11 (0.96, 1.28), respectively. For warfarin plus asciminib versus warfarin, Gmean ratios for S‐warfarin AUCinf and Cmax were 1.41 (1.37, 1.45) and 1.08 (1.04, 1.13), respectively. Results for R‐warfarin were in line with those for S‐warfarin. For repaglinide plus asciminib versus repaglinide, Gmean ratios for AUCinf and Cmax were 1.08 (1.02, 1.14) and 1.14 (1.01, 1.28), respectively. The treatments were generally well tolerated, and the asciminib safety profile was consistent with previous studies of asciminib in the absence of probe substrates. Overall, the results indicate that asciminib (40 mg b.i.d.) is a weak inhibitor of CYP3A and CYP2C9 and has no meaningful effect on CYP2C8.
Current commercial dPCR platforms: technology and market review

Abstract Digital polymerase chain reaction (dPCR) technology has provided a new technique for molecular diagnostics, with superior advantages, such as higher sensitivity, precision, and specificity over quantitative real-time PCRs (qPCR). Eight companies have offered commercial dPCR instruments: Fluidigm Corporation, Bio-Rad, RainDance Technologies, Life Technologies, Qiagen, JN MedSys Clarity, Optolane, and Stilla Technologies Naica. This paper discusses the working principle of each offered dPCR device and compares the associated: technical aspects, usability, costs, and current applications of each dPCR device. Lastly, up-and-coming dPCR technologies are also presented, as anticipation of how the dPCR device landscape may likely morph in the next few years.
Performance and Power Prediction for Concurrent Execution on GPUs

The unprecedented growth of edge computing and 5G has led to an increased offloading of mobile applications to cloud servers or edge cloudlets.1 The most prominent workloads comprise computer vision applications. Conventional wisdom suggests that computer vision workloads perform significantly well on SIMD/SIMT architectures such as GPUs owing to the dominance of linear algebra kernels in their composition. In this work, we debunk this popular belief by performing a lot of experiments with the concurrent execution of these workloads, which is the most popular pattern in which these workloads are executed on cloud servers. We show that the performance of these applications on GPUs does not scale well with an increase in the number of concurrent applications primarily because of contention at the shared resources and lack of efficient virtualization techniques for GPUs. Hence, there is a need to accurately predict the performance and power of such ensemble workloads on a GPU. Sadly, most of the prior work in the area of performance/power prediction is for only a single application. To the best of our knowledge, we propose the first machine learning-based predictor to predict the performance and power of an ensemble of applications on a GPU. In this article, we show that by using the execution statistics of stand-alone workloads and the fairness of execution when these workloads are executed with three representative microbenchmarks, we can get a reasonably accurate prediction. This is the first such work in the direction of performance and power prediction for concurrent applications that does not rely on the features extracted from concurrent executions or GPU profiling data. Our predictors achieve an accuracy of 91% and 96% in estimating the performance and power of executing two applications concurrently, respectively. We also demonstrate a method to extend our models to four or five concurrently running applications on modern GPUs.
Acceptability of Manufacturer-Proposed Utility Values for NICE Cancer Medicine Appraisals: Analysis of Manufacturers’ Information Sources

Abstract Objectives The National Institute for Health and Care Excellence’s (NICE) method guide for technology appraisals (TAs) encourages medicine manufacturers to use the EuroQol 5 Dimensions (EQ-5D) in relevant clinical trials to obtain utility values; however, the EQ-5D may have low sensitivity when compared to disease-specific measures. This study investigated whether the NICE TA committee’s acceptance of manufacturer-proposed utility values is dependent on the manufacturers’ sources of the utility values. Methods Using publicly available data for 2011–2020, we identified 136 single TAs of cancer medicines, the health-related quality-of-life-measures used in relevant clinical trials, manufacturers’ sources of utility values, and the NICE TA committee’s acceptance of these values. Fisher’s exact tests were performed to compare the acceptability of different value sources and reasons for non-acceptance. Results The number of appraisals for which the EQ-5D in the relevant clinical trials was the source of the manufacturer-proposed utility values increased continuously over time. The TA committee’s acceptance of values was not dependent on the information source. In cases where a submission for which the information source was the EQ-5D was rejected, the reason was generally related to inappropriate values for the UK population or inappropriate data adjustment, not data reliability. Conclusions Our results demonstrated that according with the NICE’s method guide regarding utility values does not guarantee acceptance by the TA committee. Manufacturers must consider in advance possible differences between their clinical trials and clinical practice in the UK and refine plans for EQ-5D measurement in order to obtain convincing evidence.
The genetics of glaucoma: Disease associations, personalised risk assessment and therapeutic opportunities‐A review

Glaucoma refers to a heterogenous group of disorders characterised by progressive loss of retinal ganglion cells and associated visual field loss. Both early‐onset and adult‐onset forms of the disease have a strong genetic component. Here, we summarise the known genetic associations for various forms of glaucoma and the possible functional roles for these genes in disease pathogenesis. We also discuss efforts to translate genetic knowledge into clinical practice, including gene‐based tests for disease diagnosis and risk‐stratification as well as gene‐based therapies.