JAVA INSTRUMENTATION OPTIMIZATION TECHNIQUES

Techniques are described herein for reducing overhead, risk, and code maintenance for Java® instrumentation required to monitor customer-facing applications. These techniques avoid transforms and retransforms, thereby eliminating risk and overhead as there are no transformers registered with the Java Virtual Machine (JVM). This may use the same call mechanism as a typical transform, and therefore requires no code changes in instrumentation. The dummy transform may always obtain a real class (not a null) that has not been initialized. Thus, a user may add a static block or other one-time-only objects. These techniques are also portable, because the only hook is in the core JVM classloader, and compact, because very little code is required for the agent itself

APP-CENTRIC DISTRIBUTED MESSAGING BUS FOR PERFORMANCE MONITORING

A novel messaging system simplifies integration of dissimilar devices and instrumentation to enable a distributed application performance intelligence

Precise Frequency Control of the Voltage Controlled Oscillator Using Finite Digital Word Lengths

For an oscillator that is periodically swept in frequency between some upper and lower bound, the output amplitude may easily be made constant and therefore known with a high degree of certainty. The instantaneous frequency exists only at a point in time and therefore possesses a zero probability of existing at any point. This thesis deals with the development of a method for interchanging the probability density functions of amplitude and frequency so that the latter becomes known with certainty while the former is known only to the extent that it is within a certain range. The method developed makes practical the use of the fast tuned voltage controlled oscillator as the local oscillator in a frequency scanning superheterodyne receiver. Exact frequency is expressed by a digital word of finite bit length that, in actuality, expresses the value of a quantized amplitude variable whose quantized value represents a precise frequency. Because of the interrelationship of amplitude, frequency, and time through the Fourier Transform, functions of these variables are also interrelated suggesting the possibility that the original certainty of amplitude information may be traded with the original uncertainty of frequency information. The success of the method presented makes use of the precise knowledge of the frequencies of the sidebands generated by the angle modulation process rather than make direct use of the instantaneous frequency. After mathematical development, a design example addresses the actual frequency range in the microwave region where the scanning superheterodyne receiver finds military application. To demonstrate the concept of precise frequency control with words of finite length, a practical frequency model is designed and constructed by scaling megahertz to hertz. Extensive use is made of monolithic waveform generators, balanced mixers, and operational amplifiers used as active filters and time domain summers. All assemblies within the model have practical microwave counterparts. Time and frequency domain waveforms are observed at virtually every major point of the model corresponding to the functional block interfaces and are compared with the mathematical predictions. The ultimate goal of precise frequency selection as a function of an imprecise independent variable is also obtained with the aid of a spectrum analyzer and dual trace oscilloscope. The causes of less than optimum signal level separation of adjacent discrete frequencies are analyzed in a qualitative manner. Reasons for the ineffectiveness of a quantitative critique are also presented. Experimental results, however, are demonstrated proof of the feasibility of the concept of exchanging probability density functions of related variables and that refinement is the only ingredient missing to render the fast scan VCO a useful local oscillator

The design and construction of an in-pile irradiation sample and associated instrumentation for the simulation of very high flux neutron irradiation effects on semi-conductor material.

http://www.archive.org/details/designconstructi00hul

PREVENTING DATA LEAKS FROM APPLICATION SCREEN-SHARING

According to a recent and comprehensive analysis of information security breaches, 23% of attacks are attributable to internal instances. Presented herein are techniques for protecting businesses against the sharing of confidential information within applications with unauthorized meeting participants. In particular, techniques presented herein restrict screen sharing of confidential information by preventing confidential content from being displayed on an unauthorized user’s endpoint device during a collaboration session

Cytogenetic and Array-CGH Characterization of a Complex de novo Rearrangement Involving Duplication and Deletion of 9p and Clinical Findings in a 4-Month-Old Female

Approximately 15 patients with partial trisomy 9p involving de novo duplications have been previously described. Here, we present clinical, cytogenetic, FISH and aCGH findings in a patient with a de novo complex rearrangement in the short arm of chromosome 9 involving an inverted duplication at 9p24→p21.3 and a deletion at 9pter→p24.2. FISH probes generated from BACs selected from the UCSC genome browser were utilized to verify this rearrangement. It is likely that some previously described duplications of 9p may also be products of complex chromosomal aberrations. This report in which FISH and aCGH were used to more comprehensively characterize the genomic rearrangement in a patient with clinical manifestations of 9p duplication syndrome underscores the importance of further characterizing cytogenetically detected rearrangements

Human Folliculin Delays Cell Cycle Progression through Late S and G2/M-Phases: Effect of Phosphorylation and Tumor Associated Mutations

The Birt-Hogg-Dube disease occurs as a result of germline mutations in the human Folliculin gene (FLCN), and is characterized by clinical features including fibrofolliculomas, lung cysts and multifocal renal neoplasia. Clinical and genetic evidence suggest that FLCN acts as a tumor suppressor gene. The human cell line UOK257, derived from the renal cell carcinoma of a patient with a germline mutation in the FLCN gene, harbors a truncated version of the FLCN protein. Reconstitution of the wild type FLCN protein into UOK257 cells delays cell cycle progression, due to a slower progression through the late S and G2/M-phases. Similarly, Flcn–/– mouse embryonic fibroblasts progress more rapidly through the cell cycle than wild type controls (Flcnflox/flox). The reintroduction of tumor-associated FLCN mutants (FLCN ΔF157, FLCN 1–469 or FLCN K508R) fails to delay cell cycle progression in UOK257 cells. Additionally, FLCN phosphorylation (on Serines 62 and 73) fluctuates throughout the cell cycle and peaks during the G2/M phase in cells treated with nocodazole. In keeping with this observation, the reintroduction of a FLCN phosphomimetic mutant into the UOK257 cell line results in faster progression through the cell cycle compared to those expressing the wild type FLCN protein. These findings suggest that the tumor suppression function of FLCN may be linked to its impact on the cell cycle and that FLCN phosphorylation is important for this activity. Additionally, these observations describe a novel in vitro assay for testing the functional significance of FLCN mutations and/or genetic polymorphisms

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

BRCA1 and BRCA2 pathogenic sequence variants in women of African origin or ancestry.

BRCA1 and BRCA2 (BRCA1/2) pathogenic sequence variants (PSVs) confer elevated risks of multiple cancers. However, most BRCA1/2 PSVs reports focus on European ancestry individuals. Knowledge of the PSV distribution in African descent individuals is poorly understood. We undertook a systematic review of the published literature and publicly available databases reporting BRCA1/2 PSVs also accessed the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) database to identify African or African descent individuals. Using these data, we inferred which of the BRCA PSVs were likely to be of African continental origin. Of the 43,817 BRCA1/2 PSV carriers in the CIMBA database, 469 (1%) were of African descent. Additional African descent individuals were identified in public databases (n = 291) and the literature (n = 601). We identified 164 unique BRCA1 and 173 unique BRCA2 PSVs in individuals of African ancestry. Of these, 83 BRCA1 and 91 BRCA2 PSVs are of likely or possible African origin. We observed numerous differences in the distribution of PSV type and function in African origin versus non-African origin PSVs. Research in populations of African ancestry with BRCA1/2 PSVs is needed to provide the information needed for clinical management and decision-making in African descent individuals worldwide