Genetic Variation of the IL-28B Promoter Affecting Gene Expression

The current standard of care for the treatment of chronic hepatitis C is pegylated interferon-α (PEG-IFNα) and ribavirin (RBV). The treatment achieves a sustained viral clearance in only approximately 50% of patients. Recent whole genome association studies revealed that single nucleotide polymorphisms (SNPs) around IL-28B have been associated with response to the standard therapy and could predict treatment responses at approximately 80%. However, it is not clear which SNP is most informative because the genomic region containing significant SNPs shows strong linkage disequilibrium. We focused on SNPs in close proximity to the IL-28B gene to evaluate the function of each and identify the SNP affecting the IL-28B expression level most. The structures of IL-28A/B from 5′ to 3′-UTR were determined by complete cDNA cloning. Both IL-28A and 28B genes consisted of 6 exons, differing from the CCDS data of NCBI. Two intron SNPs and a nonsynonymous SNP did not affect IL-28B gene function and expression levels but a SNP located in the proximal promoter region influenced gene expression. A (TA) dinucleotide repeat, rs72258881, located in the promoter region was discovered by our functional studies of the proximal SNPs upstream of IL-28B; the transcriptional activity of the promoter increased gradually in a (TA)n length-dependent manner following IFN-α and lipopolysaccharide stimulation. Healthy Japanese donors exhibited a broad range of (TA) dinucleotide repeat numbers from 10 to 18 and the most prevalent genotype was 12/12 (75%), differing from the database (13/13). However, genetic variation of IL-28A corresponding to that of IL-28B was not detected in these Japanese donors. These findings suggest that the dinucleotide repeat could be associated with the transcriptional activity of IL-28B as well as being a marker to improve the prediction of the response to interferon-based hepatitis C virus treatment

RCABench: Open Benchmarking Platform for Root Cause Analysis

Fuzzing has contributed to automatically identifying bugs and vulnerabilities in the software testing field. Although it can efficiently generate crashing inputs, these inputs are usually analyzed manually. Several root cause analysis (RCA) techniques have been proposed to automatically analyze the root causes of crashes to mitigate this cost. However, outstanding challenges for realizing more elaborate RCA techniques remain unknown owing to the lack of extensive evaluation methods over existing techniques. With this problem in mind, we developed an end-to-end benchmarking platform, RCABench, that can evaluate RCA techniques for various targeted programs in a detailed and comprehensive manner. Our experiments with RCABench indicated that the evaluations in previous studies were not enough to fully support their claims. Moreover, this platform can be leveraged to evaluate emerging RCA techniques by comparing them with existing techniques.Comment: Accepted by NDSS 2023 Workshop on Binary Analysis Research (BAR); Best Paper Awar

Negative regulation of hepatitis B virus replication by forkhead box protein A in human hepatoma cells

AbstractHepatitis B virus (HBV) replication is controlled by liver-enriched transcriptional factors, including forkhead box protein A (FOXA) members. Here, we found that FOXA members are directly and indirectly involved in HBV replication in human hepatic cells. HBV replication was elevated in HuH-7 treated with individual FOXA members-specific siRNA. Reciprocally, the downregulation of HBV replication was observed in FOXA-induced HuH-7. However, the mechanism of downregulation is different among FOXA members at the level of HBV RNA transcription, such as precore/pg RNA and 2.1kb RNA. In addition, FOXA1 and FOXA2 suppressed nuclear hormone receptors, such as HNF4α, that are related to HBV replication

Security Analysis of Cryptosystems Using Short Generators over Ideal Lattices

In this paper, we analyze the security of cryptosystems using short generators over ideal lattices such as candidate multilinear maps by Garg, Gentry and Halevi and fully homomorphic encryption by Smart and Vercauteren. Our approach is based on a recent work by Cramer, Ducas, Peikert and Regev on analysis of recovering a short generator of an ideal in the $q$-th cyclotomic field for a prime power $q$. In their analysis, implicit lower bounds of the special values of Dirichlet $L$-functions at 1 are essentially used for estimating some sizes of the dual basis in the log-unit lattice of the $q$-th cyclotomic field. Our main contribution is to improve Cramer et al.\u27s analysis by giving explicit lower and upper bounds of the special values of Dirichlet $L$-functions at 1 for any non-trivial even Dirichlet characters modulo $q$. Moreover, we give various experimental evidence that recovering short generators of principle ideals in $2k$-th cyclotomic fields for $k \geq 10$ is succeeded with high probability. As a consequence, our analysis suggests that the security of the above cryptosystems based on the difficulty of recovering a short generator is reduced to solving the principal ideal problem under the number theoretical conjecture so-called Weber\u27s class number problem

Suppression of HBV replication by the expression of nickase-and nuclease dead-Cas9

Kurihara, T., Fukuhara, T., Ono, C. et al. Suppression of HBV replication by the expression of nickase- and nuclease dead-Cas9. Sci Rep 7, 6122 (2017). https://doi.org/10.1038/s41598-017-05905-

Anti-reflection coating with mullite and Duroid for large-diameter cryogenic sapphire and alumina optics

We developed a broadband two-layer anti-reflection (AR) coating for use on a sapphire half-wave plate (HWP) and an alumina infrared (IR) filter for the cosmic microwave background (CMB) polarimetry. Measuring the faint CMB B-mode signals requires maximizing the number of photons reaching the detectors and minimizing spurious polarization due to reflection with an off-axis incident angle. Sapphire and alumina have high refractive indices of 3.1 and are highly reflective without an AR coating. This paper presents the design, fabrication, quality control, and measured performance of an AR coating using thermally-sprayed mullite and Duroid 5880LZ. This technology enables large optical elements with diameters of 600 mm. We also present a newly developed thermography-based nondestructive quality control technique, which is key to assuring good adhesion and preventing delamination when thermal cycling. We demonstrate the average reflectance of about 2.6% (0.9%) for two observing bands centered at 90/150 (220/280) GHz. At room temperature, the average transmittance of a 105 mm square test sample at 220/280 GHz is 83%, and it will increase to 90% at 100 K, attributed to reduced absorption losses. Therefore, our developed layering technique has proved effective for 220/280 GHz applications, particularly in addressing dielectric loss concerns. This AR coating technology has been deployed in the cryogenic HWP and IR filters of the Simons Array and the Simons observatory experiments and applies to future experiments such as CMB-S4

Blue-emitting acridine-tagged silver(i)-bis-N-heterocyclic carbene

Herein, the photophysical properties of an acridine derivative of a bis-N-heterocyclic carbene silver complex were investigated. The HOMO and LUMO energy differences between 9-[(N-methyl imidazol-2-ylidene)]acridine and 4,5-bis[(N-methyl-imidazol-2-ylidene)methyl]acridine were theoretically compared. Based on the calculation, the 4,5-bis N-heterocyclic carbene-tethered acridine type of ligand was found to be a potential source for tuning the fluorescent nature of the resultant metal derivatives. Thus, a 4,5-bis N-heterocyclic carbene (NHC)-tethered acridine silver(I) salt was synthesized, and its photophysical properties were investigated. The 4,5-bis[(N-isopropylimidazol-2-ylidene)methyl]acridine silver(I) hexafluorophosphate complex was obtained from the reaction between [4,5-bis{(N-isopropylimidazolium)methyl}acridine] hexafluorophosphate and Ag2O in very good yield; this molecule was characterized by elemental analysis and FTIR, multinuclear (1H and 13C) NMR, UV-Vis, and fluorescence spectroscopic techniques. The molecular structure has been confirmed by single-crystal X-ray diffraction analysis, which has revealed that the complex is a homoleptic mononuclear silver(I) cationic solid. The charge of the Ag(I)–NHC cation is balanced by the hexafluorophosphate anion. The cationic moieties are closely packed in the chair and inverted chair forms where silver(I) possesses a quasi-linear geometry. Moreover, the silver complex provided blue emission from all the three excitations with good fluorescence quantum yield. The fluorescence lifetime of the silver(I) complex has been determined using the time-correlated single photon counting technique. Interestingly, the fluorescence decay pattern and the fluorescence lifetimes of the silver complex are largely different from those of the parent ligand acridine imidazolium salt. Moreover, the theoretical predictions have been found to be in good agreement with the experimental results

The Simons Observatory: Development and Optical Evaluation of Achromatic Half-Wave Plates

The Simons Observatory (SO) experiment is a cosmic microwave background (CMB) experiment located in the Atacama Desert, Chile. The SO' s small aperture telescopes (SATs) consist of three telescopes designed for precise CMB polarimetry at large angular scales. Each SAT uses a cryogenic rotating half-wave plate (HWP) as a polarization modulator to mitigate atmospheric 1/f noise and other systematics. To realize efficient polarization modulation over the observation bands, we fabricated an achromatic HWP (AHWP) consisting of three sapphire plates with anti-reflection coatings. The AHWP is designed to have broadband modulation efficiency and transmittance. This paper reports on the design and the preliminary characterization of the AHWPs for SATs

Role of PERK in mitochondrial function

Mitochondria play a central role in the function of brown adipocytes (BAs). Although mitochondrial biogenesis, which is indispensable for thermogenesis, is regulated by coordination between nuclear DNA transcription and mitochondrial DNA transcription, the molecular mechanisms of mitochondrial development during BA differentiation are largely unknown. Here, we show the importance of the ER-resident sensor PKR-like ER kinase (PERK) in the mitochondrial thermogenesis of brown adipose tissue. During BA differentiation, PERK is physiologically phosphorylated independently of the ER stress. This PERK phosphorylation induces transcriptional activation by GA-binding protein transcription factor α subunit (GABPα), which is required for mitochondrial inner membrane protein biogenesis, and this novel role of PERK is involved in maintaining the body temperatures of mice during cold exposure. Our findings demonstrate that mitochondrial development regulated by the PERK–GABPα axis is indispensable for thermogenesis in brown adipose tissue