Miracle-dz/UniFAR-FTUs huggingface dataset:
Kinin and Purine Signaling Contributes to Neuroblastoma Metastasis

Bone marrow metastasis occurs in approximately 350,000 patients that annually die in the U.S. alone. In view of the importance of tumor cell migration into the bone marrow, we have here investigated effects of various concentrations of stromal cell-derived factor-1 (SDF-1), bradykinin- and ATP on bone marrow metastasis. We show for first time that bradykinin augmented chemotactic responsiveness of neuroblastoma cells to SDF-1 and ATP concentrations, encountered under physiological conditions. Bradykinin upregulated VEGF expression, increased metalloproteinase activity and induced adhesion of neuroblastoma cells. Bradykinin augmented SDF-1-induced intracellular Ca2+ mobilization as well as resensitization and expression of ATP-sensing P2X7 receptors. Bradykinin treatment resulted in higher gene expression levels of the truncated P2X7B receptor compared to those of the P2X7A full-length isoform. Bradykinin as pro-metastatic factor induced tumor proliferation that was significantly decreased by P2X7 receptor antagonists; however, the peptide did not enhance cell death nor P2X7A receptor-related pore activity, promoting neuroblastoma growth. Furthermore, immunodeficient nude/nude mice transplanted with bradykinin-pretreated neuroblastoma cells revealed significantly higher metastasis rates compared to animals injected with untreated cells. In contrast, animals receiving Brilliant Blue G, a P2X7 receptor antagonist, did not show any specific dissemination of neuroblastoma cells to the bone marrow and liver, and metastasis rates were drastically reduced. Our data suggests correlated actions of kinins and purines in neuroblastoma dissemination, providing novel avenues for clinic research in preventing metastasis.
A Science of Monetary Policy

This paper exposits the monetary policy design problem within the limits of an empirical framework for the Indian economy. Four main issues are examined. The paper first looks at a few of the theories that have been advanced to explain the stylised facts of economic fluctuations and then examines the main features of business cycles in the Indian economy over the past 50 years. In the process, it presents forecasts of aggregate economic activity for 2002-03 and 2003-04 besides obtaining quantitative estimates of the impact of the business cycle on the fiscal deficit. Second, it empirically measures the threshold rate of inflation within the framework of growth-inflation trade-offs and derives the optimal rate of monetary expansion needed to smooth out fluctuations and stabilise the inflation rate at its threshold level. Third, it specifies a theoretical model (linking growth, inflation, interest rates and money supply) capable of deriving an optimal fiscal deficit which maximises the real growth rate; and applies it within the Indian context to measure the desired amount of fiscal consolidation. Finally, it provides estimates of a comprehensive macroeconomic conditions index which can very effectively be incorporated into a simple Taylor-type interest rate rule (reaction function) for monetary policy.
Subliminal encoding and flexible retrieval of objects in scenes

Our episodic memory stores what happened when and where in life. Episodic memory requires the rapid formation and flexible retrieval of where things are located in space. Consciousness of the encoding scene is considered crucial for episodic memory formation. Here, we question the necessity of consciousness and hypothesize that humans can form unconscious episodic memories. Participants were presented with subliminal scenes, that is, scenes invisible to the conscious mind. The scenes displayed objects at certain locations for participants to form unconscious object‐in‐space memories. Later, the same scenes were presented supraliminally, that is, visibly, for retrieval testing. Scenes were presented absent the objects and rotated by 90°–270° in perspective to assess the representational flexibility of unconsciously formed memories. During the test phase, participants performed a forced‐choice task that required them to place an object in one of two highlighted scene locations and their eye movements were recorded. Evaluation of the eye tracking data revealed that participants remembered object locations unconsciously, irrespective of changes in viewing perspective. This effect of gaze was related to correct placements of objects in scenes, and an intuitive decision style was necessary for unconscious memories to influence intentional behavior to a significant degree. We conclude that conscious perception is not mandatory for spatial episodic memory formation.
Earth’s magnetic field is probably not reversing

Significance Earth’s magnetic field is generated in Earth’s convecting liquid iron outer core and protects Earth’s surface from harmful solar radiation. The field has varied on different timescales throughout geological history, and these variations reflect changes deep within the Earth. Two of the field’s most extreme variations are reversals and excursions. During such events, the strength of the field decreases and the magnetic poles rapidly flip polarity, with reversals characterized by the pole retaining an opposite polarity, while excursions are marked by a return to the original polarity. Field strength over the past centuries has also been decreasing strongly; however, through analyzing previous excursions, we infer that Earth’s magnetic field is not in an early stage of a reversal or excursion. The geomagnetic field has been decaying at a rate of ∼5% per century from at least 1840, with indirect observations suggesting a decay since 1600 or even earlier. This has led to the assertion that the geomagnetic field may be undergoing a reversal or an excursion. We have derived a model of the geomagnetic field spanning 30–50 ka, constructed to study the behavior of the two most recent excursions: the Laschamp and Mono Lake, centered at 41 and 34 ka, respectively. Here, we show that neither excursion demonstrates field evolution similar to current changes in the geomagnetic field. At earlier times, centered at 49 and 46 ka, the field is comparable to today’s field, with an intensity structure similar to today’s South Atlantic Anomaly (SAA); however, neither of these SAA-like fields develop into an excursion or reversal. This suggests that the current weakened field will also recover without an extreme event such as an excursion or reversal. The SAA-like field structure at 46 ka appears to be coeval with published increases in geomagnetically modulated beryllium and chlorine nuclide production, despite the global dipole field not weakening significantly in our model during this time. This agreement suggests a greater complexity in the relationship between cosmogenic nuclide production and the geomagnetic field than is commonly assumed.
Very Early-onset Inflammatory Bowel Disease: Gaining Insight Through Focused Discovery

Abstract:The pathogenesis of pediatric inflammatory bowel disease (IBD) is only partially understood. Strong evidence implicates a strong genetic component including high monozygotic twin concordance and familial disease phenotype concordance rates. Genome-wide association studies have identified associations between >160 genetic loci and the risk for developing IBD. The roles of implicated genes are largely immune-mediated, although other functions include cellular migration, oxidative stress, and carbohydrate metabolism. Additionally, growing literature describes monogenic causes of IBD that frequently present as infantile or very early-onset IBD. The interplay between IBD risk single nucleotide polymorphisms and rare genetic variants has yet to be determined. Studying patients with very early-onset IBD may elicit genetic factors that could be applied to broader populations of IBD. This review describes what is known about the genetic causes of very early-onset IBD and genetic strategies that may unravel more of the genetic causes of IBD.
Angiopoietin-like protein 3 (ANGPTL3) deficiency and familial combined hypolipidemia

Three members of the angiopoietin-like (ANGPTL) protein family-ANGPTL3, ANGPTL4 and ANGPTL8- are important regulators of plasma lipoproteins. They inhibit the enzyme lipoprotein lipase, which plays a key role in the intravascular lipolysis of triglycerides present in some lipoprotein classes. This review focuses on the role of ANGPTL3 as emerged from the study of genetic variants of Angptl3 gene in mice and humans. Both loss of function genetic variants and inactivation of Angptl3 gene in mice are associated with a marked reduction of plasma levels of triglyceride and cholesterol and an increased activity of lipoprotein lipase and endothelial lipase. In humans with ANGPTL3 deficiency, caused by homozygous loss of function (LOF) variants of Angptl3 gene, the levels of all plasma lipoproteins are greatly reduced. This plasma lipid disorder referred to as familial combined hypolipidemia (FHBL2) does not appear to be associated with distinct pathological manifestations. Heterozygous carriers of LOF variants have reduced plasma levels of total cholesterol and triglycerides and are at lower risk of developing atherosclerotic cardiovascular disease, as compared to non-carriers. These observations have paved the way to the development of strategies to reduce the plasma level of atherogenic lipoproteins in man by the inactivation of ANGPTL3, using either a specific monoclonal antibody or anti-sense oligonucleotides.
Does Trade Dependence Matter? A Quantitative Analysis of the Effect of Trade Dependence on the Outcome of Economic Sanctions

Iana Shevtsova for the degree of Master of Public Policy Presented on June 4, 2015 Title: Does trade dependence matter? A quantitative analysis of the effect of trade dependence on the outcome of economic sanctions Economic sanctions are widely used in the international arena in order to reconcile political conflicts and retain peace between countries. Most states prefer to use economic sanctions rather than military interventions as a more efficient tool to maintain political stability and protect their own interests. Nevertheless, sanctions are not always effective in achieving the policy goal and often result in failure and welfare losses for both parties. This analysis focuses on testing the implications of power-dependence theory on economic sanctions by examining the role of trade dependence between the sender and the target in sanctions outcome. Based on power-dependence theory, the existence of trade dependence would imply that each state has some degree of control and influence over the other state. Thus, the more countries are mutually trade dependent, the more control and power they should have over each other. This empirical study utilizes the Hufbauer, Schott, Elliot, and Oegg (2007) dataset that contains information on sanctions cases from 1914 to 2000. Through logistic analysis of sanctions effectiveness this paper presents the evidence that trade dependence between the sender and the target has a significant positive effect on the achievement of sanctions policy goal. It confirms the idea that the higher the trade dependence between countries, the more likely that sanctions will be successful.
Is the Abnormal Post-IPO Underperformance Really Abnormal? The Evidence from CEE Emerging Markets

ABSTRACT Using sorting procedures and cross-sectional tests, we investigate the long-run post-IPO performance and its sources in the Central and Eastern European (CEE) markets. We examine over 1100 stocks from 11 CEE countries for the period 2002–2014. We find that “old stocks” perform significantly better than “young stocks”, but only when the market beta is the sole risk factor considered. After accounting for the size and value effects, the IPO firms perform neither better nor worse than non-issuing companies. The sources of the initial low B/M ratios of debuting companies may lie in time-varying financial quality. The market newcomers are financially healthier than their older counterparts. However, over 2–5 years the fundamentals deteriorate and the financial standing regresses to the mean.
Views of Primary Care Physicians Regarding the Promotion of Healthy Lifestyles and Weight Management Among Their Patients

Vol. 24, No. 6 June 2017 JCOM 259 AbstrAct • Objective: To assess primary care physicians’ practices, knowledge, and beliefs regarding their efforts to promote healthy lifestyles and weight management among their patients. • Methods: Study participants consisted of 25 primary care physicians from a regional primary care practice-based research network that includes 37 university-affiliated patient-centered medical homes and 2 nearby unaffiliated primary care sites. Participating physicians completed an online modified version of the Physician Survey of Practices on Diet, Physical Activity, and Weight Control–Adult Questionnaire. • Results: The majority (88%) of participating physicians strongly believed it was their responsibility to promote a healthy diet, physical activity, and healthy weight loss and weight maintenance among patients. The 3 most commonly endorsed barriers were (a) not enough time, (b) minimal patient interest in improving his/her weight, and (c) lack of adequate weight-loss referral resources. The top 3 physicianperceived practice improvements that would be helpful with these practices were (a) better tools to communicate diet, physical activity, or weight problems to patients or family; (b) better mechanisms to connect patients to weight-loss referral resources; and (c) better counseling tools to guide patients regarding lifestyle modifications. 76% of the participating physicians correctly identified the BMI cutoff ranges for adult obesity, but only 32% did so for childhood obesity. • Conclusion: It is important to provide primary care physicians with knowledge, effective tools, and resources to promote healthy lifestyles and weight loss and weight management among their patients.
Combined Recirculatory-compartmental Population Pharmacokinetic Modeling of Arterial and Venous Plasma S(+) and R(–) Ketamine Concentrations

What We Already Know about This TopicRecirculatory pharmacokinetic models describe intravascular mixing by incorporating cardiac output and its distribution to characterize the oscillations of arterial and venous drug concentrations in the minutes after rapid IV drug administrationArterial drug concentrations during a drug infusion are higher than venous concentrations but are lower than postinfusion venous concentrations What This Article Tells Us That Is NewA ketamine dataset with simultaneously collected arterial and venous blood samples was used to develop an intravascular mixing model that reconciled the divergent arterial and venous concentration versus time relationships during and after drug infusionHigher arterial concentrations during drug infusion result from the contribution of both partially mixed drug from the upstream infusion and mixed recirculating drugThe partially mixed concentration is proportional to the ratio of the drug infusion rate and cardiac outputHigher postinfusion venous concentrations are due to contributions of drug eluting from tissue Background: The pharmacokinetics of infused drugs have been modeled without regard for recirculatory or mixing kinetics. We used a unique ketamine dataset with simultaneous arterial and venous blood sampling, during and after separate S(+) and R(–) ketamine infusions, to develop a simplified recirculatory model of arterial and venous plasma drug concentrations. Methods: S(+) or R(–) ketamine was infused over 30 min on two occasions to 10 healthy male volunteers. Frequent, simultaneous arterial and forearm venous blood samples were obtained for up to 11 h. A multicompartmental pharmacokinetic model with front-end arterial mixing and venous blood components was developed using nonlinear mixed effects analyses. Results: A three-compartment base pharmacokinetic model with additional arterial mixing and arm venous compartments and with shared S(+)/R(–) distribution kinetics proved superior to standard compartmental modeling approaches. Total pharmacokinetic flow was estimated to be 7.59 ± 0.36 l/min (mean ± standard error of the estimate), and S(+) and R(–) elimination clearances were 1.23 ± 0.04 and 1.06 ± 0.03 l/min, respectively. The arm-tissue link rate constant was 0.18 ± 0.01 min–1, and the fraction of arm blood flow estimated to exchange with arm tissue was 0.04 ± 0.01. Conclusions: Arterial drug concentrations measured during drug infusion have two kinetically distinct components: partially or lung-mixed drug and fully mixed-recirculated drug. Front-end kinetics suggest the partially mixed concentration is proportional to the ratio of infusion rate and total pharmacokinetic flow. This simplified modeling approach could lead to more generalizable models for target-controlled infusions and improved methods for analyzing pharmacokinetic-pharmacodynamic data.
Institutions and State Spending: An Overview

U.S. fiscal policy at the federal, state, and local level is on an unsustainable path. Although reformers look for ways to reduce spending on particular budget items, tomorrow’s legislatures may easily reverse these cuts. In contrast, a change in the rules that govern the political process — the “institutions” that shape a budget — can have a lasting effect on spending for years to come. Codified in statutes and in constitutions,these institutions include the rules of budgeting, electioneering, and legislating. They influence the decisions of legislators, governors, presidents, bureaucrats, voters, and even lobbyists. Institutional reform can be a more effective and sustainable path to fiscal probity than a one-time budget cut. In this article, we summarize the empirical investigations of more than a dozen state-level institutions. The lesson for both state and federal policymakers is that a number of institutional reforms are more likely to put spending on a more sustainable path.
Risk of Intradialytic Hypotension in Hemodialysis Patients with Different Residual Urine Volume

Background: Relationship between intradialytic hypotension (IDH) and residual urine volume (RUV) in hemodialysis (HD) patients remained unclear. In the present study, we aimed to evaluate the risk of intradialytic hypotension in hemodialysis patients with different residual urine volume. Method: This work was a prospective observational study of incident and prevalent HD patients. From January 1, 2013 to February 28, 2014, patients were recruited from a single HD center of the Second Affiliated Hospital of Nanchang University. Eligible patients were categorized into three groups: group A (RUV > 400 ml/24 hours), group B (RUV of 100-400 ml/24 hours) and group C (RUV < 100 ml/24 hours). A Logistic regression model was used to examine patient characteristics associated with predictive odds of RUV with 100-400 ml/24 hours and < 100 ml/24 hours. Hazard ratio (HR) of IDH was calculated by the Cox proportional hazards model for three groups. Results: Totally, 150 HD patients were enrolled in this study, with mean follow-up of 9.9 ± 5.1 months. Older age, longer HD vintage and lower levels of hemoglobin were independently associated with RUV with 100-400 ml/24 hours, whereas thrice-weekly HD, longer HD vintage, diabetes and lower levels of phosphate were independently associated with RUV 400 ml/24 hours, even when extensive demographics, comorbidities and lab adjustments were made. Similarly, in a maximally adjusted model, risk of IDH in patients with RUV of 100-400 ml/24 hours was 2.36 times than that in those with RUV > 400 ml/24 hours (95% CI 1.75-7.47, p=0.043). Conclusion: HD patients with lower RUV may have an increased risk of presenting IDH, which suggested that preserving RUV may be conducive to preventing of IDH occurrence.
Temozolomide Enhances Triple-Negative Breast Cancer Virotherapy In Vitro

Triple-negative breast cancer (TNBC) is one of the most aggressive types of cancer, and treatment is limited to chemotherapy and radiation. Oncolytic virotherapy may be a promising approach to treat TNBC. However, oncolytic adenovirus (OAd)-based mono-therapeutic clinical trials have resulted in modest outcomes. The OAd potency could be increased by chemotherapy-induced autophagy, an intracellular degradation system that delivers cytoplasmic constituents to the lysosome. In this study, the ability of alkylating agent temozolomide (TMZ)-induced autophagy to increase OAd replication and oncolysis in TNBC cells was evaluated. Human TNBC MDA-MB-231 and HCC1937 cells and mouse 4T1 cells were infected with an OAd expressing the red fluorescent protein mCherry on the virus capsid (OAdmCherry) alone or in combination with TMZ. TNBC cells treated with OAdmCherry/TMZ displayed greater mCherry and adenovirus (Ad) early region 1A (E1A) expression and enhanced cancer-cell killing compared to OAdmCherry or TMZ alone. The combined therapy-mediated cell death was associated with virus replication and accumulation of the autophagy marker light chain 3 (LC3)-II. Overall, this study provides experimental evidence of TMZ’s ability to increase oncolytic virotherapy in both human and murine TNBC cells.
Double/Debiased Machine Learning for Treatment and Structural Parameters

We revisit the classic semiparametric problem of inference on a low dimensional parameter θ_0 in the presence of high-dimensional nuisance parameters η_0. We depart from the classical setting by allowing for η_0 to be so high-dimensional that the traditional assumptions, such as Donsker properties, that limit complexity of the parameter space for this object break down. To estimate η_0, we consider the use of statistical or machine learning (ML) methods which are particularly well-suited to estimation in modern, very high-dimensional cases. ML methods perform well by employing regularization to reduce variance and trading off regularization bias with overfitting in practice. However, both regularization bias and overfitting in estimating η_0 cause a heavy bias in estimators of θ_0 that are obtained by naively plugging ML estimators of η_0 into estimating equations for θ_0. This bias results in the naive estimator failing to be N^(-1/2) consistent, where N is the sample size. We show that the impact of regularization bias and overfitting on estimation of the parameter of interest θ_0 can be removed by using two simple, yet critical, ingredients: (1) using Neyman-orthogonal moments/scores that have reduced sensitivity with respect to nuisance parameters to estimate θ_0, and (2) making use of cross-fitting which provides an efficient form of data-splitting. We call the resulting set of methods double or debiased ML (DML). We verify that DML delivers point estimators that concentrate in a N^(-1/2)-neighborhood of the true parameter values and are approximately unbiased and normally distributed, which allows construction of valid confidence statements. The generic statistical theory of DML is elementary and simultaneously relies on only weak theoretical requirements which will admit the use of a broad array of modern ML methods for estimating the nuisance parameters such as random forests, lasso, ridge, deep neural nets, boosted trees, and various hybrids and ensembles of these methods. We illustrate the general theory by applying it to provide theoretical properties of DML applied to learn the main regression parameter in a partially linear regression model, DML applied to learn the coefficient on an endogenous variable in a partially linear instrumental variables model, DML applied to learn the average treatment effect and the average treatment effect on the treated under unconfoundedness, and DML applied to learn the local average treatment effect in an instrumental variables setting. In addition to these theoretical applications, we also illustrate the use of DML in three empirical examples.