Time-varying effect of oil market shocks on the stock market

AbstractA mixture innovation time-varying parameter VAR model is used to examine the impact of structural oil price shocks on U.S. stock market return. Time variation is evident in both the coefficients and the variance–covariance matrix. The standard deviations of the demand side structural shocks reached forty year peaks during the global financial crisis and have remained high since. In the real stock return equation the coefficient of global real economic activity has declined since the late 1990s and that of oil-market specific demand oil shock has been lower since the early 1990s than before. The structural oil shocks account for 25.7% of the long-run variation in real stock returns overall, with substantial change in levels and sources of contribution over time. The contribution of shocks to global real economic activity to real stock return variation rose sharply to 22% in 2009 (and remains 17% over 2009–2012). The contribution of oil-market specific demand price shocks rose unevenly from 5% in the mid-1970s to about 15% in 2007, with a subsequent decline. The contribution of oil supply shocks has trended downward from 17% to 5% over 1973–2012

Implications of the formation of small polarons in Li2O2 for Li-air batteries

Lithium-air batteries (LABs) are an intriguing next-generation technology due to their high theoretical energy density of similar to 11 kWh/kg. However, LABs are hindered by both poor rate capability and significant polarization in cell voltage, primarily due to the formation of Li2O2 in the air cathode. Here, by employing hybrid density functional theory, we show that the formation of small polarons in Li2O2 limits electron transport. Consequently, the low electron mobility mu = 10(-10)-10(-9) cm(2)/Vs contributes to both the poor rate capability and the polarization that limit the LAB power and energy densities. The self-trapping of electrons in the small polarons arises from the molecular nature of the conduction band states of Li2O2 and the strong spin polarization of the O 2p state. Our understanding of the polaronic electron transport in Li2O2 suggests that designing alternative carrier conduction paths for the cathode reaction could significantly improve the performance of LABs at high current densities.open20

Arabidopsis ABCG14 is essential for the root-to-shoot translocation of cytokinin.

Cytokinins are phytohormones that induce cytokinesis and are essential for diverse developmental and physiological processes in plants. Cytokinins of the trans-zeatin type are mainly synthesized in root vasculature and transported to the shoot, where they regulate shoot growth. However, the mechanism of long-distance transport of cytokinin was hitherto unknown. Here, we report that the Arabidopsis ATP-binding cassette (ABC) transporter subfamily G14 (AtABCG14) is mainly expressed in roots and plays a major role in delivering cytokinins to the shoot. Loss of AtABCG14 expression resulted in severe shoot growth retardation, which was rescued by exogenous trans-zeatin application. Cytokinin content was decreased in the shoots of atabcg14 plants and increased in the roots, with consistent changes in the expression of cytokinin-responsive genes. Grafting of atabcg14 scions onto wild-type rootstocks restored shoot growth, whereas wild-type scions grafted onto atabcg14 rootstocks exhibited shoot growth retardation similar to that of atabcg14. Cytokinin concentrations in the xylem are reduced by similar to 90% in the atabcg14 mutant. These results indicate that AtABCG14 is crucial for the translocation of cytokinin to the shoot. Our results provide molecular evidence for the long-distance transport of cytokinin and show that this transport is necessary for normal shoot development.open118380Ysciescopu

Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study

BACKGROUND: The multicohort, phase II, nonrandomized KEYNOTE-059 study evaluated pembrolizumab ± chemotherapy in advanced gastric/gastroesophageal junction cancer. Results from cohorts 2 and 3, evaluating first-line therapy, are presented. METHODS: Patients ≥ 18 years old had previously untreated recurrent or metastatic gastric/gastroesophageal junction adenocarcinoma. Cohort 3 (monotherapy) had programmed death receptor 1 combined positive score ≥ 1. Cohort 2 (combination therapy) received pembrolizumab 200 mg on day 1, cisplatin 80 mg/m2 on day 1 (up to 6 cycles), and 5-fluorouracil 800 mg/m2 on days 1-5 of each 3-week cycle (or capecitabine 1000 mg/m2 twice daily in Japan). Primary end points were safety (combination therapy) and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by central review, and safety (monotherapy). RESULTS: In the combination therapy and monotherapy cohorts, 25 and 31 patients were enrolled; median follow-up was 13.8 months (range 1.8-24.1) and 17.5 months (range 1.7-20.7), respectively. In the combination therapy cohort, grade 3/4 treatment-related adverse events occurred in 19 patients (76.0%); none were fatal. In the monotherapy cohort, grade 3-5 treatment-related adverse events occurred in seven patients (22.6%); one death was attributed to a treatment-related adverse event (pneumonitis). The objective response rate was 60.0% [95% confidence interval (CI), 38.7-78.9] (combination therapy) and 25.8% (95% CI 11.9-44.6) (monotherapy). CONCLUSIONS: Pembrolizumab demonstrated antitumor activity and was well tolerated as monotherapy and in combination with chemotherapy in patients with previously untreated advanced gastric/gastroesophageal junction adenocarcinoma

Safety, pharmacokinetics, and antitumor activity of the anti-CEACAM5-DM4 antibody–drug conjugate tusamitamab ravtansine (SAR408701) in patients with advanced solid tumors: first-in-human dose-escalation study

Antibody–drug conjugate; Dose-escalation study; Tusamitamab ravtansineConjugado anticuerpo-fármaco; Estudio de escalada de dosis; Tusamitamab ravtansinaConjugat anticossos-fàrmac; Estudi d'escalada de dosi; Tusamitamab ravtansinaTusamitamab ravtansine (SAR408701) is an antibody–drug conjugate composed of a humanized monoclonal antibody that binds carcinoembryonic antigen-related cell adhesion molecule-5 (CEACAM5) and a cytotoxic maytansinoid that selectively targets CEACAM5-expressing tumor cells. In this phase I dose-escalation study, we evaluated the safety, pharmacokinetics, and preliminary antitumor activity of tusamitamab ravtansine in patients with solid tumors. Patients and methods Eligible patients were aged ≥18 years, had locally advanced/metastatic solid tumors that expressed or were likely to express CEACAM5, and had an Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were treated with ascending doses of tusamitamab ravtansine intravenously every 2 weeks (Q2W). The first three dose levels (5, 10, and 20 mg/m2) were evaluated using an accelerated escalation protocol, after which an adaptive Bayesian procedure was used. The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during the first two cycles, graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. Results Thirty-one patients received tusamitamab ravtansine (range 5-150 mg/m2). The DLT population comprised 28 patients; DLTs (reversible grade 3 microcystic keratopathy) occurred in three of eight patients treated with tusamitamab ravtansine 120 mg/m2 and in two of three patients treated with 150 mg/m2. The maximum tolerated dose was identified as 100 mg/m2. Twenty-two patients (71%) experienced ≥1 treatment-related treatment-emergent adverse event (TEAE), seven patients (22.6%) experienced ≥1 treatment-related grade ≥3 TEAE, and three patients (9.7%) discontinued treatment due to TEAEs. The most common TEAEs were asthenia, decreased appetite, keratopathy, and nausea. Three patients had confirmed partial responses. The mean plasma exposure of tusamitamab ravtansine increased in a dose-proportional manner from 10 to 150 mg/m2. Conclusions Tusamitamab ravtansine had a favorable safety profile with reversible, dose-related keratopathy as the DLT. Based on the overall safety profile, pharmacokinetic data, and Bayesian model recommendations, the maximum tolerated dose of tusamitamab ravtansine was defined as 100 mg/m2 Q2W.This work was supported by Sanofi, France (no grant number)

Principal components ancestry adjustment for Genetic Analysis Workshop 17 data

Statistical tests on rare variant data may well have type I error rates that differ from their nominal levels. Here, we use the Genetic Analysis Workshop 17 data to estimate type I error rates and powers of three models for identifying rare variants associated with a phenotype: (1) by using the number of minor alleles, age, and smoking status as predictor variables; (2) by using the number of minor alleles, age, smoking status, and the identity of the population of the subject as predictor variables; and (3) by using the number of minor alleles, age, smoking status, and ancestry adjustment using 10 principal component scores. We studied both quantitative phenotype and a dichotomized phenotype. The model with principal component adjustment has type I error rates that are closer to the nominal level of significance of 0.05 for single-nucleotide polymorphisms (SNPs) in noncausal genes for the selected phenotype than the model directly adjusting for population. The principal component adjustment model type I error rates are also closer to the nominal level of 0.05 for noncausal SNPs located in causal genes for the phenotype. The power for causal SNPs with the principal component adjustment model is comparable to the power of the other methods. The power using the underlying quantitative phenotype is greater than the power using the dichotomized phenotype

Generation of Multiple Bioactive Macrolides by Hybrid Modular Polyketide Synthases in Streptomyces venezuelae

AbstractThe plasmid-based replacement of the multifunctional protein subunits of the pikromycin PKS in S. venezuelae by the corresponding subunits from heterologous modular PKSs resulted in recombinant strains that produce both 12- and 14-membered ring macrolactones with predicted structural alterations. In all cases, novel macrolactones were produced and further modified by the DesVII glycosyltransferase and PikC hydroxylase, leading to biologically active macrolide structures. These results demonstrate that hybrid PKSs in S. venezuelae can produce a multiplicity of new macrolactones that are modified further by the highly flexible DesVII glycosyltransferase and PikC hydroxylase tailoring enzymes. This work demonstrates the unique capacity of the S. venezuelae pikromycin pathway to expand the toolbox of combinatorial biosynthesis and to accelerate the creation of novel biologically active natural products

Traumatic Experiences and Mental Health of North Korean Refugees in South Korea

OBJECTIVE: This study was conducted at Hanawon-a government sponsored educational facility for the settlement of North Korean refugees during their initial phase in South Korea-in 2004 to explore their mental health status and traumatic experiences in North Korea and during their escape period. METHODS: A survey was conducted in November 2004 with 62 North Korean refugees at Hanawon, and the Trauma Checklist was used to measure their traumatic experiences. To measure their psychological-mental health status, the Personality Assessment Inventory was administered. RESULTS: In comparison with the traumatic experiences of the North Korean refugees found in the study conducted in 2001 at Hanawon using the same methods, the current study showed a relatively lower frequency of traumatic experiences among the participants. The Personality Assessment Inventory results revealed that the study participants scored higher than average South Koreans in all clinical scales. Particularly, their mania (62.51) and schizophrenia (61.75) scores were above 60, a clinically meaningful score. In the gender comparison, the males exhibited meaningfully higher levels of alcohol problem, non-support, and warmth scale scores. CONCLUSION: Compared to the 2001 study, the overall traumatic experiences among North Korean refugees participated in this study. But continous support is necessary for their successful adaptation to South Korean Society have declined. The North Korean refugees at Hanawon experienced difficulties maintaining their mental health and the men in particular requested more intensive care and support for this purpose.ope

Exploiting Inter- and Intra-Memory Asymmetries for Data Mapping in Hybrid Tiered-Memories

Modern computing systems are embracing hybrid memory comprising of DRAM and non-volatile memory (NVM) to combine the best properties of both memory technologies, achieving low latency, high reliability, and high density. A prominent characteristic of DRAM-NVM hybrid memory is that it has NVM access latency much higher than DRAM access latency. We call this inter-memory asymmetry. We observe that parasitic components on a long bitline are a major source of high latency in both DRAM and NVM, and a significant factor contributing to high-voltage operations in NVM, which impact their reliability. We propose an architectural change, where each long bitline in DRAM and NVM is split into two segments by an isolation transistor. One segment can be accessed with lower latency and operating voltage than the other. By introducing tiers, we enable non-uniform accesses within each memory type (which we call intra-memory asymmetry), leading to performance and reliability trade-offs in DRAM-NVM hybrid memory. We extend existing NVM-DRAM OS in three ways. First, we exploit both inter- and intra-memory asymmetries to allocate and migrate memory pages between the tiers in DRAM and NVM. Second, we improve the OS's page allocation decisions by predicting the access intensity of a newly-referenced memory page in a program and placing it to a matching tier during its initial allocation. This minimizes page migrations during program execution, lowering the performance overhead. Third, we propose a solution to migrate pages between the tiers of the same memory without transferring data over the memory channel, minimizing channel occupancy and improving performance. Our overall approach, which we call MNEME, to enable and exploit asymmetries in DRAM-NVM hybrid tiered memory improves both performance and reliability for both single-core and multi-programmed workloads.Comment: 15 pages, 29 figures, accepted at ACM SIGPLAN International Symposium on Memory Managemen

Transduction of artificial transcriptional regulatory proteins into human cells

Protein transduction (PT) is a method for delivering proteins into mammalian cells. PT is accomplished by linking a small peptide tag—called a PT domain (PTD)—to a protein of interest, which generates a functional fusion protein that can penetrate efficiently into mammalian cells. In order to study the functions of a transcription factor (TF) of interest, expression plasmids that encode the TF often are transfected into mammalian cells. However, the efficiency of DNA transfection is highly variable among different cell types and is usually very low in primary cells, stem cells and tumor cells. Zinc-finger transcription factors (ZF-TFs) can be tailor-made to target almost any gene in the human genome. However, the extremely low efficiency of DNA transfection into cancer cells, both in vivo and in vitro, limits the utility of ZF-TFs. Here, we report on an artificial ZF-TF that has been fused to a well-characterized PTD from the human immunodeficiency virus-1 (HIV-1) transcriptional activator protein, Tat. This ZF-TF targeted the endogenous promoter of the human VEGF-A gene. The PTD-attached ZF-TF was delivered efficiently into human cells in vitro. In addition, the VEGF-A-specific transcriptional repressor retarded the growth rate of tumor cells in a mouse xenograft experiment