Miracle-dz/UniFAR-FTUs huggingface dataset:
Establishment of a Novel Method for Screening Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance Mutations in Lung Cancer

Background: Drug resistance to targeted therapies occurs in lung cancer, and resistance mechanisms related to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are continuously being discovered. We aimed to establish a novel method for highly parallel multiplexed detection of genetic mutations related to EGFR TKI-resistant lung cancer using Agena iPLEX chemistry and matrix-assisted laser desorption ionization time-of-flight analysis on the MassARRAY mass spectrometry platform. Methods: A review of the literature revealed 60 mutation hotspots in seven target genes (EGFR, KRAS, PIK3CA, BRAF, ERBB2, NRAS, and BIM) that are closely related to EGFR TKI resistance to lung cancer. A total of 183 primers comprised 61 paired forward and reverse amplification primers, and 61 matched extension primers were designed using Assay Design Software. The detection method was established by analyzing nine cell lines, and by comparison with LungCarta™ kit in ten lung cancer specimens. EGFR, KRAS, and BIM genes in all cell lines and clinical samples were subjected to Sanger sequencing for confirming reproducibility. Results: Our data showed that designed panel was a high-throughput and robust tool, allowing genotyping for sixty hotspots in the same run. Moreover, it made efficient use of patient diagnostic samples for a more accurate EGFR TKIs resistance analysis. The proposed method could accurately detect mutations in lung cancer cell lines and clinical specimens, consistent with those obtained by the LungCarta™ kit and Sanger sequencing. We also established a method for detection of large-fragment deletions based on single-base extension technology of MassARRAY platform. Conclusions: We established an effective method for high-throughput detection of genetic mutations related to EGFR TKI resistance based on the MassARRAY platform, which could provide more accurate information for overcoming cancers with de novo or acquired resistance to EGFR-targeted therapies.
Influence of protein kinase RIPK4 expression on the apoptosis and proliferation of chondrocytes in osteoarthritis

The present study aimed to investigate the expression of receptor-interacting protein kinase 4 (RIPK4) and its effect on the apoptosis and proliferation of chondrocytes in osteoarthritis (OA). A total of 28 OA cartilage tissues and 20 normal cartilage tissues were collected to detect the expression of RIPK4 by using reverse transcription-quantitative polymerase chain reaction and western blot analysis. Chondrocytes were isolated from OA cartilage tissues and divided into OA, NC, si-RIPK4, Wnt3a, and si-RIPK4+Wnt3a groups, and those isolated from normal cartilage tissues were considered the Normal group. Chondrocytes proliferation was detected by MTT assay, cell apoptosis was indicated using flow cytometry and Wnt/β-catenin signaling pathway related-proteins were investigated using western blot analysis. RIPK4 mRNA and protein expression levels in OA cartilage tissues and OA chondrocytes were increased compared with normal controls (all P<0.05). Additionally, OA chondrocytes showed reduced cell proliferation, increased cell apoptosis and upregulated expression levels of Wnt/β-catenin signaling pathway related-proteins (all P<0.05). Once transfected with si-RIPK4, the proliferation ability of chondrocytes was enhanced, but apoptosis was notably decreased. Furthermore, the expression levels of Wnt/β-catenin signaling pathway related-proteins were significantly downregulated (all P<0.05). Results indicated that Wnt3a reversed the effect of si-RIPK4 on chondrocyte proliferation and apoptosis (all P<0.05). Thus, silencing RIPK4 promoted the proliferation and inhibited the apoptosis of chondrocytes. In addition, silencing RIPK4 blocked the Wnt/β-catenin signaling pathway, thus contributing to alleviating the OA pathogenesis.
In Search of Consistent Predictors of Children’s Physical Activity

Physical activity is pivotal for children’s health and well-being, yet participation declines across teenage years. Efforts to increase physical activity need to be strengthened to combat this, however, evidence for the design and planning of physical activity promotion in children is lacking. The aim was to identify predictors of physical activity that were relatively consistent across three different measures of physical activity, in pre- and early adolescent South Australians. This is the first study to compare correlates of physical activity across three measures of physical activity in a single sample, in this age group. Children (n = 324) aged 9–13 years and their parents were surveyed on personal, interpersonal and environmental correlates of physical activity. Child physical activity was objectively measured using pedometers (7 days). Self-reported physical activity was determined from organised sport participation and the Physical Activity Questionnaire for Adolescents. Regression models were used to identify consistent predictors of three physical activity measures. Consistent predictors across multiple physical activity measures were: parent support for physical activity, having appropriate clothing for sport, enjoyment of physical activity and perceived availability of sporting clubs. These predictors identify potential avenues for directing intervention efforts to increase physical activity in early adolescents.
A Critical Review of Methods and Results in the Search for Genetic Contributors to Alcohol Sensitivity

Attributes of alcohol sensitivity are present before alcohol use disorders (AUDs) develop, they predict those adverse alcohol outcomes, are familial in nature, and many are heritable. Whether measured by alcohol challenges or retrospective reports of numbers of drinks required for effects, alcohol sensitivity reflects multiple phenotypes, including low levels of alcohol response and alcohol-related stimulation. Identification of genes that contribute to alcohol sensitivity could help identify individuals carrying risks for AUDs through their alcohol responses for whom early intervention might mitigate their vulnerability. Such genes could also improve understanding of biological underpinnings of AUDs, which could lead to new treatment approaches. However, the existing literature points to a wide range of genetic mechanisms that might contribute to alcohol responses, and few such genetic findings have been widely replicated. This critical review describes the potential impact of the diverse methods used to study sensitivity on the diversity of genetic findings that have been reported, places the genetic variants mentioned in the literature into broader categories rather than isolated results, and offers suggestions regarding how to advance the field by interpreting findings in light of the methods used to select research subjects and to measure alcohol sensitivity. To date, the most promising results have been for GABA, glutamate, opioid, dopamine, serotonin, and cholinergic system genes. The more gene variants that can be identified as contributors to sensitivity the better future gene screening platforms or polygenic scores are likely to be.
Early development in synthetic aperture lidar sensing and processing for on-demand high resolution imaging

The quest for real-time high resolution is of prime importance for surveillance applications specially in disaster management and rescue mission. Synthetic aperture radar provides meter-range resolution images in all weather conditions. Often installed on satellites the revisit time can be too long to support real-time operations on the ground. Synthetic aperture lidar can be lightweight and offers centimeter-range resolution. Onboard airplane or unmanned air vehicle this technology would allow for timelier reconnaissance. INO has developed a synthetic aperture radar table prototype and further used a real-time optronic processor to fulfill image generation on-demand. The early positive results using both technologies are presented in this paper.
Coarse-to-Fine Deep Kernel Networks

In this paper, we address the issue of efficient computation in deep kernel networks. We propose a novel framework that reduces dramatically the complexity of evaluating these deep kernels. Our method is based on a coarse-to-fine cascade of networks designed for efficient computation; early stages of the cascade are cheap and reject many patterns efficiently while deep stages are more expensive and accurate. The design principle of these reduced complexity networks is based on a variant of the cross-entropy criterion that reduces the complexity of the networks in the cascade while preserving all the positive responses of the original kernel network. Experiments conducted - on the challenging and time demanding change detection task, on very large satellite images - show that our proposed coarse-to-fine approach is effective and highly efficient.
Clinical Benefits and Cost-Effectiveness of Laboratory Monitoring Strategies to Guide Antiretroviral Treatment Switching in India

Abstract Current Indian guidelines recommend twice-annual CD4 testing to monitor first-line antiretroviral therapy (ART), with a plasma HIV RNA test to confirm failure if CD4 declines, which would prompt a switch to second-line ART. We used a mathematical model to assess the clinical benefits and cost-effectiveness of alternative laboratory monitoring strategies in India. We simulated a cohort of HIV-infected patients initiating first-line ART and compared 11 strategies with combinations of CD4 and HIV RNA testing at varying frequencies. We included adaptive strategies that reduce the frequency of tests after 1 year from 6 to 12 months for virologically suppressed patients. We projected life expectancy, time on failed first-line ART, cumulative 10-year HIV transmissions, lifetime cost (2014 US dollars), and incremental cost-effectiveness ratios (ICERs). We defined strategies as cost-effective if their ICER was <1 × the Indian per capita gross domestic product (GDP, $1,600). We found that the current Indian guidelines resulted in a per person life expectancy (from mean age 37) of 150.2 months and a per person cost of $2,680. Adding annual HIV RNA testing increased survival by ∼8 months; adaptive strategies were less expensive than similar nonadaptive strategies with similar life expectancy. The most effective strategy with an ICER <1 × GDP was the adaptive HIV RNA strategy (ICER $840/year). Cumulative 10-year transmissions decreased from 27.2/1,000 person-years with standard-of-care to 20.9/1,000 person-years with adaptive HIV RNA testing. In India, routine HIV RNA monitoring of patients on first-line ART would increase life expectancy, decrease transmissions, be cost-effective, and should be implemented.
A Web-based Large-scale Timelapse Editor for Creating and Sharing Guided Video Tours and Interactive Slideshows

Scientists, journalists, and photographers have used advanced camera technology to capture extremely high-resolution timelapse and developed information visualization tools for data exploration and analysis. However, it takes a great deal of effort for professionals to form and tell stories after exploring data, since these tools usually provide little aids in creating visual elements. We present a web-based timelapse editor to support the creation of guided video tours and interactive slideshows from a collection of large-scale spatial and temporal images. Professionals can embed these two visual elements into web pages in conjunction with various forms of digital media to tell multimodal and interactive stories.
Software metrics to predict the health of a project?: An assessment in a major IT company

More and more companies would like to mine software data with the goal of assessing the health of their software projects. The hope is that some software metrics could be tracked to predict failure risks or confirm good health. If a factor of success was found, projects failures could be anticipated and early actions could be taken by the organisation to help or to monitor closely the project, allowing one to act in a preventive mode rather than a curative one. We were called by a major IT company to fulfil this goal. We conducted a study to check whether software metrics can be related to project failure. The study was both theoretic with a review of literature on the subject, and practical with mining past projects data and interviews with project managers. We found that metrics used in practice are not reliable to assess project outcome.
Prevalence and cardiometabolic associations of the glucocorticoid receptor gene polymorphisms N363S and BclI in obese and non-obese black and white Mississippians

OBJECTIVEPolymorphisms (SNP) in the glucocorticoid receptor (GR) gene can alter sensitivity to glucocorticoids. Previous studies of the N363S and BclI SNP in the GR gene have shown a metabolic syndrome phenotype in mostly non-African populations. The obesity phenotype of African Americans (AA) seems to be more severe than that of Caucasians.DESIGNWe aimed to assess the prevalence of N363S and BclI in obese and non-obese Caucasian (n=26) and African (n=23) Mississippians (age: 23–63 years) to investigate associations with body composition (body mass index/BMI, waist-to-hip ratio), metabolic parameters (salivary cortisol, fasting glucose and insulin, hemoglobin A1C, fructosamine, HOMA-IR index), and psychological stress perception (blood pressure/BP, perceived stress scale/PSS). RESULTSAll subjects were homozygous for wildtype N363N. BclI polymorphism genotype frequencies among the 23 AA were: homozygous CC (57%), GG (4%), and heterozygous CG (39%), and among the 26 white women: homozygous CC (35%), GG (19%), and heterozygous CG (46%). Linear and logistic regression analyses including a parsimonious model identified BMI as a statistically significant parameter between the two ethnic groups (BMI was 3.13 kg/m2 higher in AA). Within the AA group, BMI, waist-to-hip ratio, log (HOMA-IR), PSS scores, BP, and hyperlipidemia showed no statistically significant relationships for the BclI polymorphism. PSS scores were 15.2 for AA vs. 14.7 for white women (normal mean: 14.7 vs. 12.8). CONCLUSIONBlack Mississippians have a higher BMI than whites, which may be related to the presence of the BclI polymorphism and increased glucocorticoid sensitivity. Although more blacks (52%) than whites (38%) had elevated BP, PSS scores in both groups suggest that a high BMI is not regarded as abnormal or stressful. This might negatively impact behavior change regarding lifestyle modifications with increased physical activity and healthier food choices. Larger studies, particularly in African populations, are needed to better define metabolic and psychological characteristics in relation to the N363S and BclI GR gene polymorphisms.
Quartz Crystal Microbalance Monitoring of Poly(Vinyl Alcohol) Sol during the Freeze–Thaw Process

A quartz crystal microbalance (QCM) working under cryo-conditions was applied to analyzing the gelation and/or phase behavior of poly(vinyl alcohol) (PVA) sol during repeated freeze–thaw processes. The development of a porous structure with the gelation of PVA sol during the freeze–thaw cycle was examined in terms of the thermal behavior of the water in the sol and the viscoelastic behavior of the sol through thermal and QCM analyses. Water was liberated from the hydrophilic PVA during the freeze–thaw process through the aggregation of PVA. The water decreased the freezing temperature and increased the melting temperature because of the development of the porous structure with gelation by the thermal treatment. The state of the water during the gelation was estimated from the phase transition temperature and enthalpy change of the water during the thermal scan by using water-saturated silica gels with a series of pore size distributions. The viscoelasticity of the PVA sol during the freeze–thaw process was measured by cryo-QCM using admittance analysis (QCM-A). The free water and/or porous structure in the PVA sol was found to increase from the viscoelastic point of view by QCM measurements showing a shift in the resonance parameters (fs, R1). A hard gel was confirmed to form by the decrease in fs and the increase in R1 with the thermal scan treatment. The cryo-QCM was found to be an effective probe for clarifying the gelation and phase behavior of PVA sol in detail with high resolution.
Fabrication of Tungsten-Rhenium Cladding materials via Spark Plasma Sintering for Ultra High Temperature Reactor Applications

This research will develop an optimized, cost-effective method for producing high-purity tungsten-rhenium alloyed fuel clad forms that are crucial for the development of a very high-temperature nuclear reactor. The study will provide critical insight into the fundamental behavior (processing-microstructure- property correlations) of W-Re alloys made using this new fabrication process comprising high-energy ball milling (HEBM) and spark plasma sintering (SPS). A broader goal is to re-establish the U.S. lead in the research field of refractory alloys, such as W-Re systems, with potential applications in very high-temperature nuclear reactors. An essential long-term goal for nuclear power is to develop the capability of operating nuclear reactors at temperatures in excess of 1,000K. This capability has applications in space exploration and some special terrestrial uses where high temperatures are needed in certain chemical or reforming processes. Refractory alloys have been identified as being capable of withstanding temperatures in excess of 1,000K and are considered critical for the development of ultra hightemperature reactors. Tungsten alloys are known to possess extraordinary properties, such as excellent high-temperature capability, including the ability to resist leakage of fissile materials when used as a fuel clad. However, there are difficulties with the development of refractory alloys: 1) lack ofmore » basic experimental data on thermodynamics and mechanical and physical properties, and 2) challenges associated with processing these alloys. « less
Primary processes in the bacterial reaction center probed by two-dimensional electronic spectroscopy

Significance The remarkable near-unity quantum efficiency of photosynthetic charge separation has motivated decades of research to uncover the underlying design principles. Much of our current understanding of photosynthetic charge separation is rooted in studies of the bacterial reaction center (BRC). We present two-dimensional electronic spectroscopy of the BRC as it undergoes charge separation, resolving the energy-transfer and charge-separation processes with time and excitation frequency resolution. These measurements reveal the excitonic structure of the BRC, including a previously hidden exciton state. We present a multiexcitation 2D global analysis method that supports two-step sequential charge separation in the BRC without evidence for secondary charge separation pathways. We extract the spectral signatures of the charge-separation intermediates. In the initial steps of photosynthesis, reaction centers convert solar energy to stable charge-separated states with near-unity quantum efficiency. The reaction center from purple bacteria remains an important model system for probing the structure–function relationship and understanding mechanisms of photosynthetic charge separation. Here we perform 2D electronic spectroscopy (2DES) on bacterial reaction centers (BRCs) from two mutants of the purple bacterium Rhodobacter capsulatus, spanning the Qy absorption bands of the BRC. We analyze the 2DES data using a multiexcitation global-fitting approach that employs a common set of basis spectra for all excitation frequencies, incorporating inputs from the linear absorption spectrum and the BRC structure. We extract the exciton energies, resolving the previously hidden upper exciton state of the special pair. We show that the time-dependent 2DES data are well-represented by a two-step sequential reaction scheme in which charge separation proceeds from the excited state of the special pair (P*) to P+HA− via the intermediate P+BA−. When inhomogeneous broadening and Stark shifts of the B* band are taken into account we can adequately describe the 2DES data without the need to introduce a second charge-separation pathway originating from the excited state of the monomeric bacteriochlorophyll BA*.
Oxysterol‐binding protein recruitment and activity at the endoplasmic reticulum‐Golgi interface are independent of Sac1

Oxysterol‐binding protein (OSBP) localizes to endoplasmic reticulum (ER)‐Golgi contact sites where it transports cholesterol and phosphatidylinositol 4‐phosphate (PI‐4P), and activates lipid transport and biosynthetic activities. The PI‐4P phosphatase Sac1 cycles between the ER and Golgi apparatus where it potentially regulates OSBP activity. Here we examined whether the ER‐Golgi distribution of endogenous or ectopically expressed Sac1 influences OSBP activity. OSBP and Sac1 co‐localized at apparent ER‐Golgi contact sites in response to 25‐hydroxycholesterol (25OH), cholesterol depletion and p38 MAPK inhibitors. A Sac1 mutant that is unable to exit the ER did not localize with OSBP, suggesting that sterol perturbations cause Sac1 transport to the Golgi apparatus. Ectopic expression of Sac1 in the ER or Golgi apparatus, or Sac1 silencing, did not affect OSBP localization to ER‐Golgi contact sites, OSBP‐dependent activation of sphingomyelin synthesis, or cholesterol esterification in the ER. p38 MAPK inhibition and retention of Sac1 in the Golgi apparatus also caused OSBP phosphorylation and OSBP‐dependent activation of sphingomyelin synthesis at ER‐Golgi contacts. These results demonstrate that Sac1 expression in either the ER or Golgi apparatus has a minimal impact on the PI‐4P that regulates OSBP activity or recruitment to contact sites.
Vitamin C Deficiency Reduces Muscarinic Receptor Coronary Artery Vasoconstriction and Plasma Tetrahydrobiopterin Concentration in Guinea Pigs

Vitamin C (vitC) deficiency is associated with increased cardiovascular disease risk, but its specific interplay with arteriolar function is unclear. This study investigates the effect of vitC deficiency in guinea pigs on plasma biopterin status and the vasomotor responses in coronary arteries exposed to vasoconstrictor/-dilator agents. Dunkin Hartley female guinea pigs (n = 32) were randomized to high (1500 mg/kg diet) or low (0 to 50 mg/kg diet) vitC for 10–12 weeks. At euthanasia, coronary artery segments were dissected and mounted in a wire-myograph. Vasomotor responses to potassium, carbachol, sodium nitroprusside (SNP), U46619, sarafotoxin 6c (S6c) and endothelin-1 (ET-1) were recorded. Plasma vitC and tetrahydrobiopterin were measured by HPLC. Plasma vitC status reflected the diets with deficient animals displaying reduced tetrahydrobiopterin. Vasoconstrictor responses to carbachol were significantly decreased in vitC deficient coronary arteries independent of their general vasoconstrictor/vasodilator capacity (p < 0.001). Moreover, in vitC deficient animals, carbachol-induced vasodilator responses correlated with coronary artery diameter (p < 0.001). Inhibition of cyclooxygenases with indomethacin increased carbachol-induced vasoconstriction, suggesting an augmented carbachol-induced release of vasodilator prostanoids. Atropine abolished carbachol-induced vasomotion, supporting a specific muscarinic receptor effect. Arterial responses to SNP, potassium, S6c, U46619 and ET-1 were unaffected by vitC status. The study shows that vitC deficiency decreases tetrahydrobiopterin concentrations and muscarinic receptor mediated contraction in coronary arteries. This attenuated vasoconstrictor response may be linked to altered production of vasoactive arachidonic acid metabolites and reduced muscarinic receptor expression/signaling.