Atomicity is an important specification that enables programmers to understand atomic blocks of code in a multi-threaded program as if they are sequential. This significantly simplifies the programmer's job to reason about correctness. Several modern multithreaded programming languages provide no built-in support to ensure atomicity; instead they rely on the fact that programmers would use locks properly in order to guarantee that atomic code blocks are indeed atomic. However, improper use of locks can sometimes fail to ensure atomicity. Therefore, we need tools that can check atomicity properties of lock-based code automatically.We propose a randomized dynamic analysis technique to detect a special, but important, class of atomicity violations that are often found in real-world programs. Specifically, our technique modifies the existing Java thread scheduler behavior to create atomicity violations with high probability. Our approach has several advantages over existing dynamic analysis tools. First, we can create a real atomicity violation and see if an exception can be thrown. Second, we can replay an atomicity violating execution by simply using the same seed for random number generation-we do not need to record the execution. Third, we give no false warnings unlike existing dynamic atomicity checking techniques. We have implemented the technique in a prototype tool for Java and have experimented on a number of large multi-threaded Java programs and libraries. We report a number of previously known and unknown bugs and atomicity violations in these Java programs.
We present a novel dynamic analysis technique that finds real deadlocks in multi-threaded programs. Our technique runs in two stages. In the first stage, we use an imprecise dynamic analysis technique to find potential deadlocks in a multi-threaded program by observing an execution of the program. In the second stage, we control a random thread scheduler to create the potential deadlocks with high probability. Unlike other dynamic analysis techniques, our approach has the advantage that it does not give any false warnings. We have implemented the technique in a prototype tool for Java, and have experimented on a number of large multi-threaded Java programs. We report a number of previously known and unknown real deadlocks that were found in these benchmarks.
In an effort to find topical agents that prevent or retard cutaneous aging, seven functional lipids were screened for their procollagen-upregulating and matrix metalloproteinase (MMP)-1-downregulating activities in human dermal fibroblasts by Western blotting. The preventive effect on ultraviolet (UV)-induced decrease of procollagen was demonstrated in phosphatidylserine (PS), lysophosphatidylserine (LPS), lysophosphatidic acid (LPA), N-acetyl phytosphingosine (NAPS), and tetraacetyl phytosphingosine (TAPS). Furthermore, PS, LPS, and LPA upregulated procollagen expression in unirradiated basal conditions. The inhibitory effect on UV-induced MMP-1 expression was seen in NAPS, TAPS, LPA, PS, lysophosphatidylglycerol, and LPS. PS was chosen as the most suitable candidate anti-aging chemical for the subsequent in vivo studies. We investigated the effects of PS on acute UV response and chronologic skin aging by topically applying it to young skin before UV irradiation and to aged human skin, respectively. Real-time PCR and Western blot revealed that in the young skin, PS treatment prevented UV-induced reduction in procollagen expression and inhibited UVinduced MMP-1 expression. PS also blocked UV-induced IL-6 and COX-2 gene expression in cultured fibroblasts dosedependently. In the aged skin, PS caused increased procollagen transcription and procollagen immunostaining in the upper dermis, and a significant decrease in MMP-1 expression at both mRNA and protein levels.These results indicate that topical PS has anti-skin-aging properties and point to the potential use of PS as a therapeutic agent in the prevention and treatment of cutaneous aging. Skin aging is the sum of intrinsic aging and photoaging caused by repeated exposure to ultraviolet (UV) light. Whereas naturally aged skin is smooth, pale, and finely wrinkled, photoaged skin shows coarse, deep wrinkles and dyspigmentation and telangiectasia (1). In both chronologic aging and photoaging, decreased procollagen expression and increased matrix metalloproteinases (MMPs), a group of matrix-degrading enzymes secreted by epidermal keratinocytes and dermal fibroblasts, are characteristic. The alterations in collagen, the major structural component of the dermis, are thought to be responsible for wrinkle formation (2).MMP expression is increased by various stimuli, including UV light, oxidative stress, and cytokines. UV irradiation induces MMPs, including MMP-1 (collagenase), , and MMP-9 (gelatinase) (3). UVinduced MMP-1 initiates collagen breakdown by cleaving the fibrillar collagen (types I and III) at a single cleavage site. Once collagen is cleaved by MMP-1, it is further degraded by MMP-3 and MMP-9, whose expression levels are also increased by UV irradiation (3).The search for topical agents that prevent or retard cutaneous aging has become the quest of many basic researchers as well as the pharmaceutical and cosmeceutical industries. As part of the endeavor, in this study, seven functional lipids, including two sphingolipids and five phospholipids, were...
Rice bran contains various polyphenolic compounds with anti-oxidative activities, and it has long been known to inhibit melanogenesis, but the inhibition mechanism has not been fully elucidated. Cofermentation of rice bran with Lactobacillus rhamnosus and Saccharomyces cerevisiae significantly reduced the cytotoxicity of the resulting extract to B16F1 melanoma cells. Marked reduction of alpha-melanocyte stimulating hormone (MSH) induced melanin synthesis was also observed upon treatment with fermented rice bran extract but it had no direct inhibitory effect on tyrosinase activity, while the intracellular tyrosinase activity was reduced by the extract. This result was further confirmed by an immunoblot assay measuring the level of tyrosinase protein. In addition, the expression of microphthalmia-associated transcription factor (MITF), a key regulator of melanogenesis, was significantly decreased by the extract. All together, the fermented rice bran extracts showed an inhibitory effect on melanogenesis through downregulation of MITF, along with reduced cytotoxicity.
Sphingosine 1-phosphate (S1P), a product of sphingosine kinases (SphK), mediates diverse biological processes such as cell differentiation, proliferation, motility and apoptosis. In an effort to search and identify specific inhibitors of human SphK, the inhibitory effects of synthetic sphingoid analogs on kinase activity were examined.Among the analogs tested, we found two, SG12 and SG14, that have specific inhibitory effects on hSphK2. N,N-Dimethylsphingosine (DMS), a well known SphK inhibitor, displayed inhibitory effects for both SphK1 and SphK2, as well as protein kinase C. In contrast, SG12 and SG14 exhibited selective inhibitory effects on hSphK2. Furthermore, SG14 did not affect PKC. In isolated platelets, SG14 blocked the conversion of sphingosine into sphingosine 1-phosphate significantly. This is the first report on the identification of a hSphK2-specific inhibitor, which may provide a useful tool for studying the biological functions of hSphK2.2
Antigen-induced degranulation of mast cells plays a pivotal role in allergic and inflammatory responses. Recently, ceramide kinase (CERK) and its phosphorylated product ceramide 1-phosphate (C1P) have emerged as important players in mast cell degranulation. Here, we describe the synthesis of a novel F-12509A olefin isomer, K1, as an effective CERK inhibitor. In vitro kinase assays demonstrated that K1 effectively inhibits CERK without inhibiting sphingosine kinase and diacylglycerol kinase. Treating RBL-2H3 cells with K1 reduced cellular C1P levels to 40% yet had no effect on cell growth. Furthermore, treatment with K1 significantly suppressed both calcium ionophore-and IgE/antigen-induced degranulation, indicating that K1 interferes with signals that happen downstream of Ca 2+ mobilization. Finally, we show that K1 affects neither IgE/antigen-induced global tyrosine phosphorylation nor subsequent Ca 2+ elevation, suggesting a specificity for CERK-mediated signals. Our novel CERK inhibitor provides a useful tool for studying the biological functions of CERK and C1P. Moreover, to our knowledge, this is the first report demonstrating that inhibition of CERK suppresses IgE/antigen-induced mast cell degranulation. This finding suggests that CERK inhibitors might be a potential therapeutic tool in the treatment of allergic diseases.
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