In silico identification of microRNAs predicted to regulate the drug metabolizing cytochrome P450 genes

OBJECTIVE: Cytochrome P450 (CYP) enzymes exhibit high interindividual variability that is not completely explained by known environmental and genetic factors. To further understand this variability, we hypothesized that microRNAs (miRNAs) may regulate CYP expression. METHODS: MiRNA identification algorithms were used to identify the miRNAs that are predicted to regulate twelve major drug metabolizing CYPs and to identify polymorphisms in CYP mRNA 3'-UTRs that are predicted to interfere with normal mRNA-miRNA interactions. RESULTS: All twelve CYPs were predicted to be targets of miRNAs. Additionally, 38 SNPs in CYP mRNA 3'-UTRs were predicted to interfere with miRNA targeting of mRNAs. These predicted miRNAs and SNPs are candidates for future in vitro studies focused on understanding the molecular regulation of these CYP genes. CONCLUSION: These in silico results provide strong support for a role of miRNA in the regulation and variability of CYP expression

Comment on "Resilience of gated avalanche photodiodes against bright illumination attacks in quantum cryptography"

This is a comment on the publication by Yuan et al. [Appl. Phys. Lett. 98, 231104 (2011); arXiv:1106.2675v1 [quant-ph]].Comment: 2 page

PASSPORT-seq: A Novel High-Throughput Bioassay to Functionally Test Polymorphisms in Micro-RNA Target Sites

Next-generation sequencing (NGS) studies have identified large numbers of genetic variants that are predicted to alter miRNA-mRNA interactions. We developed a novel high-throughput bioassay, PASSPORT-seq, that can functionally test in parallel 100s of these variants in miRNA binding sites (mirSNPs). The results are highly reproducible across both technical and biological replicates. The utility of the bioassay was demonstrated by testing 100 mirSNPs in HEK293, HepG2, and HeLa cells. The results of several of the variants were validated in all three cell lines using traditional individual luciferase assays. Fifty-five mirSNPs were functional in at least one of three cell lines (FDR ≤ 0.05); 11, 36, and 27 of them were functional in HEK293, HepG2, and HeLa cells, respectively. Only four of the variants were functional in all three cell lines, which demonstrates the cell-type specific effects of mirSNPs and the importance of testing the mirSNPs in multiple cell lines. Using PASSPORT-seq, we functionally tested 111 variants in the 3' UTR of 17 pharmacogenes that are predicted to alter miRNA regulation. Thirty-three of the variants tested were functional in at least one cell line

Adherence and Tolerability of Alzheimer's Disease Medications: A Pragmatic Randomized Trial

BACKGROUND/OBJECTIVES: Post-marketing comparative trials describe medication use patterns in diverse, real-world populations. Our objective was to determine if differences in rates of adherence and tolerability exist among new users to acetylcholinesterase inhibitors (AChEI's). DESIGN: Pragmatic randomized, open label comparative trial of AChEI's currently available in the United States. SETTING: Four memory care practices within four healthcare systems in the greater Indianapolis area. PARTICIPANTS: Eligibility criteria included older adults with a diagnosis of possible or probable Alzheimer's disease (AD) who were initiating treatment with an AChEI. Participants were required to have a caregiver to complete assessments, access to a telephone, and be able to understand English. Exclusion criteria consisted of a prior severe adverse event from AChEIs. INTERVENTION: Participants were randomized to one of three AChEIs in a 1:1:1 ratio and followed for 18 weeks. MEASUREMENTS: Caregiver-reported adherence, defined as taking or not taking study medication, and caregiver-reported adverse events, defined as the presence of an adverse event. RESULTS: 196 participants were included with 74.0% female, 30.6% African Americans, and 72.9% who completed at least twelfth grade. Discontinuation rates after 18 weeks were 38.8% for donepezil, 53.0% for galantamine, and 58.7% for rivastigmine (P = .063) in the intent to treat analysis. Adverse events and cost explained 73.1% and 25.4% of discontinuation. No participants discontinued donepezil due to cost. Adverse events were reported by 81.2% of all participants; no between-group differences in total adverse events were statistically significant. CONCLUSIONS: This pragmatic comparative trial showed high rates of adverse events and cost-related non-adherence with AChEIs. Interventions improving adherence and persistence to AChEIs may improve AD management. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01362686 (https://clinicaltrials.gov/ct2/show/NCT01362686)

Secure gated detection scheme for quantum cryptography

Several attacks have been proposed on quantum key distribution systems with gated single-photon detectors. The attacks involve triggering the detectors outside the center of the detector gate, and/or using bright illumination to exploit classical photodiode mode of the detectors. Hence a secure detection scheme requires two features: The detection events must take place in the middle of the gate, and the detector must be single-photon sensitive. Here we present a technique called bit-mapped gating, which is an elegant way to force the detections in the middle of the detector gate by coupling detection time and quantum bit error rate. We also discuss how to guarantee single-photon sensitivity by directly measuring detector parameters. Bit-mapped gating also provides a simple way to measure the detector blinding parameter in security proofs for quantum key distribution systems with detector efficiency mismatch, which up until now has remained a theoretical, unmeasurable quantity. Thus if single-photon sensitivity can be guaranteed within the gates, a detection scheme with bit-mapped gating satisfies the assumptions of the current security proofs.Comment: 7 pages, 3 figure

Analytical Validation of Variants to Aid in Genotype-Guided Therapy for Oncology

The Clinical Laboratory Improvement Amendments (CLIA) of 1988 requires that pharmacogenetic genotyping methods need to be established according to technical standards and laboratory practice guidelines before testing can be offered to patients. Testing methods for variants in ABCB1, CBR3, COMT, CYP3A7, C8ORF34, FCGR2A, FCGR3A, HAS3, NT5C2, NUDT15, SBF2, SEMA3C, SLC16A5, SLC28A3, SOD2, TLR4, and TPMT were validated in a CLIA-accredited laboratory. As no known reference materials were available, DNA samples that were from Coriell Cell Repositories (Camden, NJ) were used for the analytical validation studies. Pharmacogenetic testing methods developed here were shown to be accurate and 100% analytically sensitive and specific. Other CLIA-accredited laboratories interested in offering pharmacogenetic testing for these genetic variants, related to genotype-guided therapy for oncology, could use these publicly available samples as reference materials when developing and validating new genetic tests or refining current assays

A translational bioinformatic approach in identifying and validating an interaction between Vitamin A and CYP19A1

INTRODUCTION: One major challenge in personalized medicine research is to identify the environmental factors that can alter drug response, and to investigate their molecular mechanisms. These environmental factors include co-medications, food, and nutrition or dietary supplements. The increasing use of dietary supplements and their potential interactions with cytochrome P450 (CYP450) enzymes is a highly significant personalized medicine research domain, because most of the drugs on the market are metabolized through CYP450 enzymes. METHODS: Initial bioinformatics analysis revealed a number of regulators of CYP450 enzymes from a human liver bank gene expression quantitative loci data set. Then, a compound-gene network was constructed from the curated literature data. This network consisted of compounds that interact with either CYPs and/or their regulators that influence either their gene expression or activity. We further evaluated this finding in three different cell lines: JEG3, HeLa, and LNCaP cells. RESULTS: From a total of 868 interactions we were able to identify an interesting interaction between retinoic acid (i.e. Vitamin A) and the aromatase gene (i.e. CYP19A1). Our experimental results showed that retinoic acid at physiological concentration significantly influenced CYP19A1 gene expressions. CONCLUSIONS: These results suggest that the presence of retinoic acid may alter the efficacy of agents used to suppress aromatase expression

Effects of detector efficiency mismatch on security of quantum cryptosystems

We suggest a type of attack on quantum cryptosystems that exploits variations in detector efficiency as a function of a control parameter accessible to an eavesdropper. With gated single-photon detectors, this control parameter can be the timing of the incoming pulse. When the eavesdropper sends short pulses using the appropriate timing so that the two gated detectors in Bob's setup have different efficiencies, the security of quantum key distribution can be compromised. Specifically, we show for the Bennett-Brassard 1984 (BB84) protocol that if the efficiency mismatch between 0 and 1 detectors for some value of the control parameter gets large enough (roughly 15:1 or larger), Eve can construct a successful faked-states attack causing a quantum bit error rate lower than 11%. We also derive a general security bound as a function of the detector sensitivity mismatch for the BB84 protocol. Experimental data for two different detectors are presented, and protection measures against this attack are discussed.Comment: v3: identical to the journal version. However, after publication we have discovered that Eq. 11 is incorrect: the available bit rate after privacy amplification is reduced even in the case (QBER)=0 [see Quant. Inf. Comp. 7, 73 (2007)

Common genetic polymorphisms of adenosine A2A receptor do not influence response to regadenoson

Aim: Hemodynamic response to regadenoson varies greatly, and underlying mechanisms for variability are poorly understood. We hypothesized that five common variants of adenosine A2A receptor (ADORA2A) are associated with altered response to regadenoson. Methods: Consecutive subjects (n = 357) undergoing resting regadenoson nuclear stress imaging were enrolled. Genotyping was performed using Taqman-based assays for rs5751862, rs2298383, rs3761422, rs2267076 and rs5751876. Results: There was no significant difference in heart rate or blood pressure between different genotypes following regadenoson administration. There was also no significant difference in myocardial ischemia detected by nuclear perfusion imaging as defined by summed difference score, or in self-reported side effects among the genotypes tested. Conclusion: The common A2A variants studied are not associated with variability in hemodynamic response to regadenoson or variability in detection of ischemia with nuclear perfusion stress imaging

On the electromagnetic properties of active media

Several results concerning active media or metamaterials are proved and discussed. In particular, we consider the permittivity, permeability, wave vector, and refractive index, and discuss stability, refraction, gain, and fundamental limitations resulting from causality