Performance Evaluation of Components Using a Granularity-based Interface Between Real-Time Calculus and Timed Automata

To analyze complex and heterogeneous real-time embedded systems, recent works have proposed interface techniques between real-time calculus (RTC) and timed automata (TA), in order to take advantage of the strengths of each technique for analyzing various components. But the time to analyze a state-based component modeled by TA may be prohibitively high, due to the state space explosion problem. In this paper, we propose a framework of granularity-based interfacing to speed up the analysis of a TA modeled component. First, we abstract fine models to work with event streams at coarse granularity. We perform analysis of the component at multiple coarse granularities and then based on RTC theory, we derive lower and upper bounds on arrival patterns of the fine output streams using the causality closure algorithm. Our framework can help to achieve tradeoffs between precision and analysis time.Comment: QAPL 201

WISP3 and RhoC guanosine triphosphatase cooperate in the development of inflammatory breast cancer

BACKGROUND: Inflammatory breast cancer (IBC) is the most lethal form of locally advanced breast cancer. We found concordant and consistent alterations of two genes in 90% of IBC tumors when compared with stage-matched non-IBC tumors: overexpression of RhoC guanosine triphosphatase and loss of WNT-1 induced secreted protein 3 (WISP3). Further work revealed that RhoC is a transforming oncogene for human mammary epithelial (HME) cells. Despite the aggressiveness of the RhoC-driven phenotype, it does not quantitatively reach that of the true IBC tumors. We have demonstrated that WISP3 has tumor growth and angiogenesis inhibitory functions in IBC. We proposed that RhoC and WISP3 cooperate in the development of IBC. METHODS: Using an antisense approach, we blocked WISP3 expression in HME cells. Cellular proliferation and growth were determined using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay and anchorage-independent growth in a soft agar assay. Vascular endothelial growth factor (VEGF) was measured in conditioned medium by enzyme-linked immunosorbent assay. RESULTS: Antisense inhibition of WISP3 in HME cells increased RhoC mRNA levels and resulted in an increase in cellular proliferation, anchorage-independent growth and VEGF levels in the conditioned medium. Conversely, restoration of WISP3 expression in the highly malignant IBC cell line SUM149 was able to decrease the expression of RhoC protein. CONCLUSION: WISP3 modulates RhoC expression in HME cells and in the IBC cell line SUM149. This provides further evidence that these two genes act in concert to give rise to the highly aggressive IBC phenotype. We propose a model of this interaction as a starting point for further investigations

Moderators of Parent Training for Disruptive Behaviors in Young Children with Autism Spectrum Disorder

We conducted a 6 month, randomized trial of parent training (PT) versus a parent education program (PEP) in 180 young children (158 boys, 22 girls), ages 3-7 years, with autism spectrum disorder (ASD). PT was superior to PEP in decreasing disruptive and noncompliant behaviors. In the current study, we assess moderators of treatment response in this trial. Thirteen clinical and demographic variables were evaluated as potential moderators of three outcome variables: the Aberrant Behavior Checklist-Irritability subscale (ABC-I), Home Situations Questionnaire (HSQ), and Clinical Global Impressions-Improvement Scale (CGI-I). We used an intent-to-treat model and random effects regression. Neither IQ nor ASD severity moderated outcome on the selected outcome measures. Severity of Attention Deficit Hyperactivity Disorder (ADHD) and anxiety moderated outcomes on the ABC-I and HSQ. For instance, there was a 6.6 point difference on the ABC-I between high and low ADHD groups (p = .05) and a 5.3 point difference between high and low Anxiety groups (p = .04). Oppositional defiant disorder symptoms and household income moderated outcomes on the HSQ. None of the baseline variables moderated outcome on the CGI-I. That IQ and ASD symptom severity did not moderate outcome suggests that PT is likely to benefit a wide range of children with ASD and disruptive behavior

Localized Epigenetic Changes Induced by DH Recombination Restricts Recombinase to DJH Junctions

Immunoglobulin heavy chain (Igh) genes are assembled by sequential rearrangements of diversity (DH) and variable (VH) gene segments. Three critical constraints govern VH recombination. These include timing (VH recombination follows DH recombination), precision (VHs recombine only to DJH junctions) and allele specificity (VH recombination is restricted to DJH recombined alleles). We provide a model for these universal features of VH recombination. Analyses of DJH recombined alleles revealed that DJH junctions were selectively epigenetically marked, became nuclease sensitive and bound RAG proteins, thereby permitting DH-associated recombination signal sequences to initiate the second step of Igh gene assembly. We propose that VH recombination is precise because these changes did not extend to germline DH gene segments located 5′ of the DJH junction

Pyroxene structures, cathodoluminescence and the thermal history of the enstatite chondrites

In order to explore the thermal history of enstatite chondrites, we examined the cathodoluminescence (CL) and thermoluminescence (TL) properties of 15 EH chondrites and 21 EL chondrites, including all available petrographic types, both textural types 3-6 and mineralogical types alpha-delta. The CL properties of EL3(alpha) and EH3(alpha) chondrites are similar. Enstatite grains high in Mn and other transition metals display red CL, while enstatite with low concentrations of these elements show blue CL. A few enstatite grains with greater than 5 wt% FeO display no CL. In contrast, the luminescent properties of the metamorphosed EH chondrites are very different from those of metamorphosed EL chondrites. While the enstatites in metamorphosed EH chondrites display predominantly blue CL, the enstatites in metamorphosed EL chondrites display a distinctive magenta CL with blue and red peaks of approximately equal intensity in their spectra. The TL sensitivities of the enstatite chondrites correlate with the intensity of the blue CL and, unlike other meteorite classes, are not simply related to metamorphism. The different luminescent properties of metamorphosed EH and EL chondrites cannot readily be attributed to compositional differences. But x-ray diffraction data suggests that the enstatite in EH5(gamma),(delta) chondrites is predominantly disordered orthopyroxene, while enstatite in EL6(beta) chondrites is predominantly ordered orthopyroxene. The difference in thermal history of metamorphosed EL and EH chondrites is so marked that the use of single 'petrographic' types is misleading, and separate textural and mineralogical types are preferable. Our data confirm earlier suggestions that metamorphosed EH chondrites underwent relatively rapid cooling, and the metamorphosed EL chondrites cooled more slowly and experienced prolonged heating in the orthopyroxene field

Inhibition of CCN6 (WISP3) expression promotes neoplastic progression and enhances the effects of insulin-like growth factor-1 on breast epithelial cells

Abstract Introduction CCN6/WISP3 belongs to the CCN (Cyr61, CTGF, Nov) family of genes that contains a conserved insulin-like growth factor (IGF) binding protein motif. CCN6 is a secreted protein lost in 80% of the aggressive inflammatory breast cancers, and can decrease mammary tumor growth in vitro and in vivo. We hypothesized that inhibition of CCN6 might result in the loss of a growth regulatory function that protects mammary epithelial cells from the tumorigenic effects of growth factors, particularly IGF-1. Method We treated human mammary epithelial (HME) cells with a CCN6 hairpin short interfering RNA. Results CCN6-deficient cells showed increased motility and invasiveness, and developed features of epithelial-mesenchymal transition (EMT). Inhibition of CCN6 expression promoted anchorage-independent growth of HME cells and rendered them more responsive to the growth effects of IGF-1, which was coupled with the increased phosphorylation of IGF-1 receptor and insulin receptor substrate-1 (IRS-1). Conclusion Specific stable inhibition of CCN6 expression in HME cells induces EMT, promotes anchorage-independent growth, motility and invasiveness, and sensitizes mammary epithelial cells to the growth effects of IGF-1.https://deepblue.lib.umich.edu/bitstream/2027.42/137663/1/13058_2005_Article_1330.pd

Potential Cost-effectiveness of Early Identification of Hospital-acquired Infection in Critically Ill Patients

Limitations in methods for the rapid diagnosis of hospital-acquired infections often delay initiation of effective antimicrobial therapy. New diagnostic approaches offer potential clinical and cost-related improvements in the management of these infections. We developed a decision modeling framework to assess the potential cost-effectiveness of a rapid biomarker assay to identify hospital-acquired infection in high-risk patients earlier than standard diagnostic testing. The framework includes parameters representing rates of infection, rates of delayed appropriate therapy, and impact of delayed therapy on mortality, along with assumptions about diagnostic test characteristics and their impact on delayed therapy and length of stay. Parameter estimates were based on contemporary, published studies and supplemented with data from a four-site, observational, clinical study. Extensive sensitivity analyses were performed. The base-case analysis assumed 17.6% of ventilated patients and 11.2% of nonventilated patients develop hospital-acquired infection and that 28.7% of patients with hospital-acquired infection experience delays in appropriate antibiotic therapy with standard care. We assumed this percentage decreased by 50% (to 14.4%) among patients with true-positive results and increased by 50% (to 43.1%) among patients with false-negative results using a hypothetical biomarker assay. Cost of testing was set at $110/d. In the base-case analysis, among ventilated patients, daily diagnostic testing starting on admission reduced inpatient mortality from 12.3 to 11.9$1,640 per patient, resulting in an incremental cost-effectiveness ratio of $21,389 per life-year saved. Among nonventilated patients, inpatient mortality decreased from 7.3 to 7.1$1,381 with diagnostic testing. The resulting incremental cost-effectiveness ratio was $42,325 per life-year saved. Threshold analyses revealed the probabilities of developing hospital-acquired infection in ventilated and nonventilated patients could be as low as 8.4 and 9.8$50,000 per life-year saved. Development and use of serial diagnostic testing that reduces the proportion of patients with delays in appropriate antibiotic therapy for hospital-acquired infections could reduce inpatient mortality. The model presented here offers a cost-effectiveness framework for future test development

Rare deleterious germline variants and risk of lung cancer

Recent studies suggest that rare variants exhibit stronger effect sizes and might play a crucial role in the etiology of lung cancers (LC). Whole exome plus targeted sequencing of germline DNA was performed on 1045 LC cases and 885 controls in the discovery set. To unveil the inherited causal variants, we focused on rare and predicted deleterious variants and small indels enriched in cases or controls. Promising candidates were further validated in a series of 26,803 LCs and 555,107 controls. During discovery, we identified 25 rare deleterious variants associated with LC susceptibility, including 13 reported in ClinVar. Of the five validated candidates, we discovered two pathogenic variants in known LC susceptibility loci, ATM p.V2716A (Odds Ratio [OR] 19.55, 95%CI 5.04–75.6) and MPZL2 p.I24M frameshift deletion (OR 3.88, 95%CI 1.71–8.8); and three in novel LC susceptibility genes, POMC c.*28delT at 3′ UTR (OR 4.33, 95%CI 2.03–9.24), STAU2 p.N364M frameshift deletion (OR 4.48, 95%CI 1.73–11.55), and MLNR p.Q334V frameshift deletion (OR 2.69, 95%CI 1.33–5.43). The potential cancer-promoting role of selected candidate genes and variants was further supported by endogenous DNA damage assays. Our analyses led to the identification of new rare deleterious variants with LC susceptibility. However, in-depth mechanistic studies are still needed to evaluate the pathogenic effects of these specific alleles

A Recurrent Mutation in PARK2 Is Associated with Familial Lung Cancer

PARK2, a gene associated with Parkinson disease, is a tumor suppressor in human malignancies. Here, we show that c.823C>T (p.Arg275Trp), a germline mutation in PARK2, is present in a family with eight cases of lung cancer. The resulting amino acid change, p.Arg275Trp, is located in the highly conserved RING finger 1 domain of PARK2, which encodes an E3 ubiquitin ligase. Upon further analysis, the c.823C>T mutation was detected in three additional families affected by lung cancer. The effect size for PARK2 c.823C>T (odds ratio = 5.24) in white individuals was larger than those reported for variants from lung cancer genome-wide association studies. These data implicate this PARK2 germline mutation as a genetic susceptibility factor for lung cancer. Our results provide a rationale for further investigations of this specific mutation and gene for evaluation of the possibility of developing targeted therapies against lung cancer in individuals with PARK2 variants by compensating for the loss-of-function effect caused by the associated variation

Promoters, enhancers, and transcription target RAG1 binding during V(D)J recombination

RAG1 binding to TCR gene elements is dictated by transcriptional control elements and by transcription itself; these findings provide direct confirmation of the long-held accessibility model