Securing Safety in Collaborative Cyber-Physical Systems through Fault Criticality Analysis

Collaborative Cyber-Physical Systems (CCPS) are systems that contain tightly coupled physical and cyber components, massively interconnected subsystems, and collaborate to achieve a common goal. The safety of a single Cyber-Physical System (CPS) can be achieved by following the safety standards such as ISO 26262 and IEC 61508 or by applying hazard analysis techniques. However, due to the complex, highly interconnected, heterogeneous, and collaborative nature of CCPS, a fault in one CPS's components can trigger many other faults in other collaborating CPSs. Therefore, a safety assurance technique based on fault criticality analysis would require to ensure safety in CCPS. This paper presents a Fault Criticality Matrix (FCM) implemented in our tool called CPSTracer, which contains several data such as identified fault, fault criticality, safety guard, etc. The proposed FCM is based on composite hazard analysis and content-based relationships among the hazard analysis artifacts, and ensures that the safety guard controls the identified faults at design time; thus, we can effectively manage and control the fault at the design phase to ensure the safe development of CPSs. To validate our approach, we introduce a case study on the Platooning system (a collaborative CPS). We perform the criticality analysis of the Platooning system using FCM in our developed tool. After the detailed fault criticality analysis, we investigate the results to check the appropriateness and effectiveness with two research questions. Also, by performing simulation for the Platooning, we showed that the rate of collision of the Platooning system without using FCM was quite high as compared to the rate of collisions of the system after analyzing the fault criticality using FCM.Comment: This paper is an extended version of an article submitted to KCSE-202

Phase Transition Behavior of Poly(N-isopropylacrylamide-co-N,Ndimethylaminopropylacrylamide) Hydrogels

The copolymer hydrogel of N-isopropylacrylamide (NIPAAm) and N,N-dimethylaminopropylacrylamide (DMAPAA) was synthesized by free radical copolymerization. The phase transition behavior of p(NIPAAmco-DMAPAA) hydrogels as a function of temperature and SDS concentration was studied. The p(NIPAAmco-DMAPAA) hydrogels exhibited larger swelling capacity than the homo p(NIPAAm) hydrogel. The phase transition temperature of p(NIPAAm-co-DMAPAA) hydrogels increased with an increase of DMAPAA content. In aqueous SDS solution, the swelling capacity of p(NIPAAm-co-DMAPAA) hydrogel decreased with an increase of SDS concentration. The phase transition temperature of p(NIPAAm-co-DMAPAA) hydrogels was found to be almost independent of the SDS concentration

Evaluation in 3 Months Duration of Neointimal Coverage After Zotarolimus-Eluting Stent Implantation by Optical Coherence Tomography The ENDEAVOR OCT Trial

ObjectivesWe performed this study to investigate the vascular response in early period after zotarolimus-eluting stent (ZES) (Endeavor Sprint, Medtronic CardioVascular, Minneapolis, Minnesota) implantation.BackgroundThe ZES has different characteristics, with biocompatible polymer and rapid drug-elution, compared with the first-generation drug-eluting stents (DES).MethodsThe ENDEAVOR OCT (Evaluation in 3 Months Duration of Neointimal Coverage after Zotarolimus-Eluting Stent Implantation by Optical Coherence Tomography) trial is a prospective, single-center study evaluating vascular healing patterns with optical coherence tomography (OCT) at 3 months after stent implantation. A total of 31 ZES in 30 patients underwent serial OCT at immediate post-intervention and 3 months. Neointimal growth and malapposition were analyzed at each stent strut of cross-sectional OCT images with 0.5-mm intervals.ResultsThe incidence of malapposition at post-intervention and 3 months was 6.0% and 0.2%, respectively. However, late acquired malapposition was not detected at 3 months. Of 31 stents, 27 stents (87.1%) were covered completely with neointima, but the remaining 4 stents had 2 (0.8%), 4 (0.9%), 4 (1.2%), and 6 (1.4%) uncovered struts. Overall mean percentage of covered stent struts was 99.9 ± 0.4%. This finding was consistent among groups with acute coronary syndrome and stable angina pectoris (99.9 ± 0.3% vs. 99.9 ± 0.4%, p = 0.92). Intracoronary thrombus was documented in 1 stent (3.2%) among 31 stents.ConclusionsMost of the stent struts were covered with neointima, and late acquired malapposition was not found at 3 months after ZES implantation. Therefore, the current study demonstrated that ZES might have a favorable in vivo vascular response at 3 months after stent implantation. (Evaluation of Zotarolimus Eluting Stent at 3 Months Using Optical Coherence Tomography [ENDEAVOR OCT]; NCT00815139

TRAIL Enhances Apoptosis of Human Hepatocellular Carcinoma Cells Sensitized by Hepatitis C Virus Infection: Therapeutic Implications

Hepatitis C virus (HCV) infection causes chronic liver diseases leading to hepatocellular carcinoma (HCC) and liver failure. We have previously shown that HCV sensitizes hepatocytes to mitochondrial apoptosis via the TRAIL death receptors DR4 and DR5. Although TRAIL and its receptors are selective targets for cancer therapy, their potential against HCC with chronic HCV infection has not been explored yet. Here we show that HCV induces DR4/DR5-dependent activation of caspase-8 leading to elevation of apoptotic signaling in infected cells and also present TRAIL effect in HCV-induced apoptotic signaling. HCV induced proteolytic cleavage of caspase-9 by stimulating DR4 and DR5, resulting in subsequent cleavage of caspase-3. Further, HCV-induced proteolytic cleavage in caspase-8, caspase-9, and caspase-3 was enhanced in the presence of recombinant TRAIL. HCV-induced cleavage in caspase-9 and increase in caspase-3/7 activity was completely suppressed by silencing of either DR4 or DR5. Perturbing DR4/DR5-caspase-8 signaling complex by silencing DR4 and DR5 or by chemical inhibitor specific to caspase-8 led to decrease of HCV-induced cleavage of poly(ADP-ribose) polymerase (PARP), a substrate for caspase-3 during apoptosis, indicating the functional role of caspase-8 in HCV-induced apoptotic signaling network. Furthermore, TRAIL enhanced PARP cleavage in apoptotic response induced by HCV infection, indicating the effect of TRAIL for the induction of selective apoptosis of HCC cells infected with HCV. Given the importance of apoptosis in HCC development, our data suggest that HCV-induced DR4 and DR5 may be considered as an attractive target for TRAIL therapy against HCC with chronic HCV infection

Radiosensitization with combined use of olaparib and PI-103 in triple-negative breast cancer

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Abstract Background Triple-negative breast cancer (TNBC) shows aggressive clinical behavior, but the treatment options are limited due to lack of a specific target. TNBC shares many clinical and pathological similarities with BRCA-deficient breast cancer, for which poly(ADP-ribose) polymerase (PARP) inhibitor is effective, but PARP inhibitor alone failed to show clinical effects in patients with sporadic TNBC. Radiation induces DNA double-strand breaks, and the phosphoinositide 3-kinase (PI3K) signaling pathway has been known to regulate steady-state levels of homologous recombination. A recent preclinical study showed that PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient TNBC to PARP inhibition. Therefore, we assessed the radiosensitizing effect, and the underlying mechanism of combination treatment with PARP inhibitor olaparib and PI3K inhibitor PI-103 in BRCA-proficient TNBC cells. Methods MDA-MB-435S cells were divided into four treatment groups, irradiation (IR) alone, olaparib plus IR, PI-103 plus IR, and olaparib plus PI-103 plus IR. Cells were exposed to the drugs for 2 hours prior to irradiation, and the cell survival curve was obtained using a clonogenic assay. Western blotting and immunofluorescent detection of γH2AX foci were performed. Xenograft and bioluminescence imaging were carried out to assess in vivo radiosensitivity. Results Combined use of olaparib and PI-103 enhanced radiation-induced death of MDA-MB-435S (sensitizer enhancement ratio[SER]0.05,1.7) and MDA-MB-231-BR (SER0.05,2.1) cells and significantly reduced tumor volume in a xenograft models (P < 0.001). Treatment with PI-103 showed persistent γH2AX foci, indicating delayed repair of DNA strand breaks. PI-103 alone increased levels of poly(ADP-ribose) and phosphorylated extracellular signal-regulated kinase, and downregulated BRCA1. Conclusions Combined use of olaparib and PI-103 enhanced radiation-induced cell death in BRCA-proficient MDA-MB-435S and MDA-MB-231-BR cells and xenografts. TNBC patients have high incidences of locoregional relapse and distant metastasis, and radiation therapy targets both locoregional control and treatment of distant recurrences such as brain metastasis or other oligometastasis. Targeting of the PI3K signaling pathway combined with PARP inhibition maybe a feasible approach to enhance effects of radiation in BRCA-proficient TNBC

Inhibitory Effect of KP-A038 on Osteoclastogenesis and Inflammatory Bone Loss Is Associated With Downregulation of Blimp1

Excessive osteoclastic activity results in pathological bone resorptive diseases, such as osteoporosis, periodontitis, and rheumatoid arthritis. As imidazole-containing compounds possess extensive therapeutic potential for the management of diverse diseases, we synthesized a series of imidazole derivatives and investigated their effects on osteoclast differentiation and function. In the present study, we found that a novel imidazole derivative, KP-A038, suppressed receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis and bone-resorbing activity in vitro and attenuated lipopolysaccharide (LPS)-induced bone destruction in vivo. KP-A038 significantly inhibited the induction of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and the expression of its target genes, including tartrate-resistant acid phosphatase (Acp5), cathepsin K (Ctsk), dendritic cell-specific transmembrane protein (Dcstamp), and matrix metallopeptidase 9 (Mmp9). KP-A038 upregulated the expression of negative regulators of osteoclast differentiation, such as interferon regulatory factor-8 (Irf8) and B-cell lymphoma 6 (Bcl6). Consistently, KP-A038 downregulated the expression of B lymphocyte-induced maturation protein-1 (Blimp1 encoded by Prdm1), a repressor for Irf8 and Bcl6. Moreover, administration of KP-A038 reduced LPS-induced bone erosion by suppressing osteoclast formation in vivo. Thus, our findings suggest that KP-A038 may serve as an effective therapeutic agent for the treatment and/or prevention of bone loss in pathological bone diseases, including osteoporosis and periodontitis

Clinical Features and Rate of Infective Endocarditis in Non-Faecalis and Non-faecium Enterococcal Bacteremia

Non-faecalis and non-faecium enterococci are an occasional cause of bacteremia, and some cases of infective endocarditis caused by these pathogens have been reported. However, the rate of infective endocarditis in non-faecalis and non-faecium enterococcal bacteremia is still undetermined. We compared the clinical features and the rate of infective endocarditis of 70 cases of non-faecalis and non-faecium enterococcal bacteremia with those of 65 cases of Enterococcus faecalis bacteremia. Non-faecalis and non-faecium enterococcal bacteremia was more frequently associated with biliary tract infection and polymicrobial bacteremia, and was less frequently associated with infective endocarditis, than was E. faecalis bacteremia (57% vs. 28%, p<0.01; 47% vs. 31%, p=0.05; 1% vs. 14%, p<0.01, respectively)

Monoclonal Antibodies to Human Transglutaminase 4

Transglutaminase 4 (TG4) is a member of the enzyme family that catalyzes the calcium-dependent post-translational modification of proteins via cross-linking, polyamination, or deamidation. TG4 exhibits prostate-specific expression pattern and plays a crucial role in the formation of the copulatory plug in rodents. However, the physiological function(s) of human TG4 remains speculative. Human TG4 has been postulated to participate in the maturation process of sperm by modifying its cell surface, which results in suppression of sperm antigenicity in the female genital tract. To better understand the pathophysiological role of TG4 in prostate tissue, we generated monoclonal antibodies (MAb) against human TG4 in mice by repeated injections with the recombinant human TG4. Western blot analysis demonstrated that the selected MAbs react specifically with TG4, but not with other isoenzymes of the TG family. Immunocytochemical and immunohistochemical analyses showed that specific staining is observed with the cells overexpressing TG4 and with the paraffin-embedded prostate tissue specimens obtained from the benign prostate hyperplasia and prostate cancer patients, respectively. Our results indicate that these MAbs are suitable for detecting TG4 in the cultured cells or prostate tissues for investigating the biological functions of human TG4.Shin DM, 2004, J BIOL CHEM, V279, P15032, DOI 10.1074/jbc.M308734200Jeon JH, 2003, EMBO J, V22, P5273Lorand L, 2003, NAT REV MOL CELL BIO, V4, P140, DOI 10.1038/nrm1014Jeon JH, 2002, BIOCHEM BIOPH RES CO, V294, P818An G, 1999, UROLOGY, V54, P1105Dubbink HJ, 1999, GENE, V240, P261Dubbink HJ, 1999, LAB INVEST, V79, P141Choi K, 1998, EXP MOL MED, V30, P41Esposito C, 1996, J BIOL CHEM, V271, P27416Dubbink HJ, 1996, BIOCHEM J, V315, P901SEITZ J, 1991, BIOCHIM BIOPHYS ACTA, V1078, P139PAONESSA G, 1984, SCIENCE, V226, P852MUKHERJEE DC, 1983, SCIENCE, V219, P989WILLIAMSASHMAN HG, 1977, BIOCHEM BIOPH RES CO, V79, P1192WILLIAMS.HG, 1972, P NATL ACAD SCI USA, V69, P2322