Inhibition of glucocorticoid-induced apoptosis by targeting splice variants of \u3ci\u3eBIM\u3c/i\u3e mRNA with small interfering RNA and short hairpin RNA.

Glucocorticoids (GCs) induce apoptosis in lymphocytes and are effective agents for the treatment of leukemia. The activated glucocorticoid receptor (GR) initiates a transcriptional program leading to caspase activation and cell death, but the critical signaling intermediates in GC-induced apoptosis remain largely undefined. We have observed that GC induction of the three major protein products of the Bcl-2 relative Bim (BimEL, BimS and BimL) correlates with GC sensitivity in a panel of human pre-B acute lymphoblastic leukemia (ALL) cell lines. To test the hypothesis that Bim facilitates GC-induced apoptosis, we reduced BIM mRNA levels and Bim protein levels by RNA interference (RNAi) in highly GC-sensitive pre-B ALL cells. Reducing Bim proteins by either electroporation of synthetic siRNA duplexes or lentiviral-mediated stable expression of shRNA inhibited activation of caspase-3 and increased cell viability following GC exposure. We also observed that the extent of GC resistance correlated with siRNA silencing potency. siRNA duplexes that reduced only BimEL or BimEL and BimL (but not BimS) exhibited less GC resistance than a potent siRNA that silenced all three major isoforms, implying that induction of all three Bim proteins contributes to cell death. Finally, the modulation of GC-induced apoptosis caused by Bim silencing was independent of Bcl-2 expression levels, negating the hypothesis that the ratio of Bim to Bcl-2 regulates apoptosis. These results offer evidence that induction of Bim by GC is a required event for the complete apoptotic response in pre-B ALL cells

The Effectiveness of Cache Coherence Implemented on the Web

The popularity of the World Wide Web (Web) has generated so much network traffic that it has increased concerns as to how the Internet will scale to meet future demand. The increased population of users and the large size of files being transmitted have resulted in concerns for different types of Internet users. Server administrators want a manageable load on their servers. Network administrators need to eliminate unnecessary traffic, thereby allowing more bandwidth for useful information. End users desire faster document retrieval. Proxy caches decrease the number of messages that enter the network by satisfying requests before they reach the server. However, the use of proxies introduces a concern with how to maintain consistency among cached document versions. Existing consistency protocols used in the Web are proving to be insufficient to meet the growing needs of the World Wide Web population. For example, too many messages are due to caches guessing when their copy is inconsistent. One option is to apply the cache coherence strategies already in use for many other distributed systems, such as parallel computers. However, these methods are not satisfactory for the World Wide Web due to its larger size and range of users. This paper provides insight into the characteristics of document popularity and how often these popular documents change. The frequency of proxy accesses to documents is also studied to test the feasibility of providing coherence at the server. The main goal is to determine whether server invalidation is the most effective protocol to use on the Web today. We make recommendations based on how frequently documents change and are accessed

Geometric Performance Analysis of Mutual Exclusion: The Model

This paper is motivated by the need to better understand parallel program run-time behavior. The paper first formally describes a general model of program execution based on Djkstra's progress graphs. The paper then defines a special case of the model representing two cyclic processes sharing mutually exclusive, reusable resources. Processes synchronize through semaphore operations that are not embedded in conditionally executed code segments. Model parameters are the times at which each semaphore operation completes and the independently derived, constant execution time required by each process between points of completion of semaphore operations

Terminating Parallel Simulations

This paper presents two different general solutions to the simulation termination problem for various simulation protocols and parallel architectures. Implementation of both solutions with conservative-synchronous, optimistic, and conservative-asynchronous simulation protocols as well as synchronous shared-memory, distributed, and asynchronous shared memory architectures is discussed

Geometric Performance Analysis of Semaphore Programs

A key problem in designing parallel programs that achieve a desired performance goal is the ability to analyze exactly program performance, given a specification of the process syncronization structure and the execution timings of all code segments. The problem solved in this paper is to derive, for all possible process starting times, the set of all possible limit cycle execution sequences in which a process blocks. This paper makes two contributions. First, it employs a novel analysis method that derives timed execution sequences from a geometric model of program execution, called timed progress graphs. Second, it solves the timed progress graph not by a computational geometric algorithm, as employed by most solutions in the literature to untimed progress graphs, but by an analytic solution

Software Engineering Tools for Scientific Models

Software tools were constructed to address issues the NASA Fortran development community faces, and they were tested on real models currently in use at NASA. These proof-of-concept tools address the High-End Computing Program and the Modeling, Analysis, and Prediction Program. Two examples are the NASA Goddard Earth Observing System Model, Version 5 (GEOS-5) atmospheric model in Cell Fortran on the Cell Broadband Engine, and the Goddard Institute for Space Studies (GISS) coupled atmosphere- ocean model called ModelE, written in fixed format Fortran