長期再参照のためのキャッシュライン追い出し不可属性の提案

プロセッサアーキテクチャにおいて，メモリサブシステム，キャッシュシステムの性能は依然として主要な課題の一つである．近年では半導体微細化に伴いキャッシュメモリ，特にラストレベルキャッシュ (Last Level Cache, LLC) の大容量化が進み，これを上手く利用するためにプリフェッチに協調するスマートなキャッシュ置き換えアルゴリズムが提案されている．しかしながら，これらの賢いキャッシュアルゴリズムをもってしても救えていないキャッシュミスが存在する．本研究の調査で，それは一度アクセスされたあるアドレスに対応するラインがキャッシュに載った後，実行命令数が1M命令以上経過した後に再度アクセスされた場合に生じるキャッシュミスであることが明らかになった．本研究ではこれを長期再参照ミスと命名した．これらの調査から，特にLLCでのキャッシュミスのボリュームゾーンは長期再参照ミスであることがわかった．この調査を踏まえて，本研究では，ある基準によって定めたキャッシュラインを長期間追い出さないことを特長としたキャッシュアルゴリズムの基本戦略を提案する．実行履歴に基づき置き換えを起こすアルゴリズムによって救えないキャッシュミスであるならば，いっそヒストリに頼った直近の再参照に期待するのはやめて，置き換えを起こさない手法として試行した．我々はこれにStubborn戦略と名付けた．“Stubborn”は“頑固”を意味する． Stubborn戦略は，キャッシュ中に追い出しを起こさない領域をつくることで実現させている．本提案手法を，LRUをベースに実装し，シミュレーションによる評価を行った．このようなシンプルな戦略にも関わらず，結果として最大で23.9%のIPC向上，幾何平均でも2MB構成，Prefetch awareなLRUベースでのランダム採択を行うStubbornキャッシュで最大の2.40%向上が得られた．電気通信大学201

TNF-α and IL-17A induce the expression of lympho-epithelial Kazal-type inhibitor in epidermal keratinocytes

BACKGROUND: Serine proteases have important roles in skin barrier function and desquamation, and the aberrant expression or the dysfunction of serine proteases is associated with the pathogenesis of skin diseases. Serine protease activities are tightly regulated by serine proteases such as kallikrein-related peptidases (KLKs) and serine protease inhibitors such as lympho-epithelial Kazal-type related inhibitor (LEKTI). For a better understating of diseases' pathogenesis, the regulation mechanism of serine proteases and the inhibitors' expression in epidermal keratinocytes must be clarified. OBJECTIVES: To investigate the effects of the cytokines on the expression of LEKTI in epidermal keratinocytes. METHODS: Normal human epidermal keratinocytes (NHEKs) were stimulated with panels of inflammatory cytokines. The expression of serine protease inhibitors was analyzed using quantitative real-time PCR and ELISA. LEKTI expression in normal human skin and lesions from psoriasis or atopic dermatitis (AD) were analyzed by immunohistochemically and tape-stripping. Trypsin- and chymotrypsin-like serine protease activities in culture supernatants were measured by using specific substrates. RESULTS: TNF-α and IL-17A significantly induced the expression of LEKTI in NHEKs. The immunohistochemical and tape-stripping analysis revealed that psoriatic skin lesions had higher LEKTI expression compared to normal skin and AD lesions. Trypsin- and chymotrypsin-like protease activities in the culture media were upregulated 3-5 days later but attenuated 6-7 days later period by these cytokines. CONCLUSIONS: In epidermal keratinocytes, the Th1&Th17 cytokines TNF-α and IL-17A induce the expression of serine protease inhibitor LEKTI, and it might occur to suppress the increase in the serine protease activities under inflammation

Proton Decay Signatures of Orbifold GUTs

In grand unified theories based on orbifold constructions in higher dimensions, Higgsino-mediated proton decay is absent. However, proton decay mediated by $X$ and $Y$ gauge bosons is typically enhanced to levels detectable by current and future experiments. We analyse the phenomenology of proton decay induced by the minimal coupling of $X,Y$ gauge bosons. In particular, we show that the novel realization of matter in orbifold GUTs can lead to unusual final state flavour structure, for example, the dominance of the $p\to K^0\mu^+$ mode. Furthermore, we discuss proton decay induced by higher-derivative brane operators, finding potentially observable rates for natural values of the operator coefficients.Comment: Latex, 10 pages, referencing error correcte

Multifaceted Analyses of Epidermal Serine Protease Activity in Patients with Atopic Dermatitis

The serine proteases kallikrein-related peptidase (KLK) 5 and KLK7 cleave cell adhesion molecules in the epidermis. Aberrant epidermal serine protease activity is thought to play an important role in the pathogenesis of atopic dermatitis (AD). We collected the stratum corneum (SC) from healthy individuals (n = 46) and AD patients (n = 63) by tape stripping and then measuring the trypsin- and chymotrypsin-like serine protease activity. We also analyzed the p.D386N and p.E420K of SPINK5 variants and loss-of-function mutations of FLG in the AD patients. The serine protease activity in the SC was increased not only in AD lesions but also in non-lesions of AD patients. We found, generally, that there was a positive correlation between the serine protease activity in the SC and the total serum immunoglobulin E (IgE) levels, serum thymus and activation-regulated chemokine (TARC) levels, and peripheral blood eosinophil counts. Moreover, the p.D386N or p.E420K in SPINK5 and FLG mutations were not significantly associated with the SC's serine protease activity. Epidermal serine protease activity was increased even in non-lesions of AD patients. Such activity was found to correlate with a number of biomarkers of AD. Further investigations of serine proteases might provide new treatments and prophylaxis for AD

Large Quark Rotations, Neutrino mixing and Proton Decay

Right-handed (RH) rotations do not play a role in the Standard Model, and only the differences of the LH mixing angles are involved in {\bf V}_{\scr \textrm{CKM}}. This leads to the huge freedom in the fermionic mass matrices. However, that is no more true in extensions of the Standard Model. For example in GUTs large RH rotations of the quarks can be related to the observed large neutrino mixing or in particular, all mixing angles are relevant for the proton decay. We present a simple realistic non-SUSY SO(10) GUT with large RH and LH mixing and study the corresponding nucleon decay rates.Comment: Latex2e file with 3 PS figures, minor corrections,the final version to be published in Nucl. Phys.

Not Even Decoupling Can Save Minimal Supersymmetric SU(5)

We make explicit the statement that Minimal Supersymmetric SU(5) has been excluded by the Super-Kamiokande search for the process $p \to K^{+} \overline{\nu}$. This exclusion is made by first placing limits on the colored Higgs triplet mass, by forcing the gauge couplings to unify. We also show that taking the superpartners of the first two generations to be very heavy in order to avoid flavor changing neutral currents, the so-called ``decoupling'' idea, is insufficient to resurrect the Minimal SUSY SU(5). We comment on various mechanisms to further suppress proton decay in SUSY SU(5). Finally, we address the contributions to proton decay from gauge boson exchange in the Minimal SUSY SU(5) and flipped SU(5) models.Comment: 8 pages, 4 figure

Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases

Aims The genetic cause of cardiac conduction system disease (CCSD) has not been fully elucidated. Whole-exome sequencing (WES) can detect various genetic variants; however, the identification of pathogenic variants remains a challenge. We aimed to identify pathogenic or likely pathogenic variants in CCSD patients by using WES and 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines as well as evaluating the usefulness of functional studies for determining them. Methods and Results We performed WES of 23 probands diagnosed with early-onset (<65 years) CCSD and analyzed 117 genes linked to arrhythmogenic diseases or cardiomyopathies. We focused on rare variants (minor allele frequency < 0.1%) that were absent from population databases. Five probands had protein truncating variants in EMD and LMNA which were classified as “pathogenic” by 2015 ACMG standards and guidelines. To evaluate the functional changes brought about by these variants, we generated a knock-out zebrafish with CRISPR-mediated insertions or deletions of the EMD or LMNA homologs in zebrafish. The mean heart rate and conduction velocities in the CRISPR/Cas9-injected embryos and F2 generation embryos with homozygous deletions were significantly decreased. Twenty-one variants of uncertain significance were identified in 11 probands. Cellular electrophysiological study and in vivo zebrafish cardiac assay showed that 2 variants in KCNH2 and SCN5A, 4 variants in SCN10A, and 1 variant in MYH6 damaged each gene, which resulted in the change of the clinical significance of them from “Uncertain significance” to “Likely pathogenic” in 6 probands. Conclusions Of 23 CCSD probands, we successfully identified pathogenic or likely pathogenic variants in 11 probands (48%). Functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants in patients with CCSD. SCN10A may be one of the major genes responsible for CCSD. Translational Perspective Whole-exome sequencing (WES) may be helpful in determining the causes of cardiac conduction system disease (CCSD), however, the identification of pathogenic variants remains a challenge. We performed WES of 23 probands diagnosed with early-onset CCSD, and identified 12 pathogenic or likely pathogenic variants in 11 of these probands (48%) according to the 2015 ACMG standards and guidelines. In this context, functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants, and SCN10A may be one of the major development factors in CCSD

Analysis of All 34 Exons of the SPINK5 Gene in Japanese Atopic Dermatitis Patients

Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is a large multidomain serine protease inhibitor that is expressed in epidermal keratinocytes. Nonsense mutations of the SPINK5 gene, which codes for LEKTI, cause Netherton syndrome, which is characterized by hair abnormality, ichthyosis, and atopy. A single nucleotide polymorphism (SNP) of SPINK5, p.K420E, is reported to be associated with the pathogenesis of atopic dermatitis (AD). We studied all 34 exons of the SPINK5 gene in Japanese 57 AD patients and 50 normal healthy controls. We detected nine nonsynonymous variants, including p.K420E; these variants had already been registered in the SNP database. Among them, p.R654H (n=1) was found as a heterozygous mutation in the AD patients, but not in the control. No new mutation was detected. We next compared the data of the AD patients with data from the Human Genetic Variation Database provided by Kyoto University; a significant difference was found in the frequency of the p.S368N genotype distribution. PolyPhen-2 and SIFT, two algorithms for predicting the functional effects of amino acid substitutions, showed significant scores for p.R654H. Therefore, R654H might be a risk factor for epidermal barrier dysfunction in some Japanese AD patients

Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease.

RATIONALE: Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition. OBJECTIVE: To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. METHODS AND RESULTS: We sequenced the exons of the CETP gene in 58 469 participants from 12 case-control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case-control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18-27; P<1.0×10-4), lower low-density lipoprotein cholesterol (-12.2 mg/dL; 95% confidence interval, -23 to -0.98; P=0.033), and lower triglycerides (-6.3%; 95% confidence interval, -12 to -0.22; P=0.043). CETP PTV carrier status was associated with reduced risk for CHD (summary odds ratio, 0.70; 95% confidence interval, 0.54-0.90; P=5.1×10-3). CONCLUSIONS: Compared with noncarriers, carriers of PTV at CETP displayed higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, lower triglycerides, and lower risk for CHD