Progress in intra-articular therapy.

Diarthrodial joints are well suited to intra-articular injection, and the local delivery of therapeutics in this fashion brings several potential advantages to the treatment of a wide range of arthropathies. Possible benefits over systemic delivery include increased bioavailability, reduced systemic exposure, fewer adverse events, and lower total drug costs. Nevertheless, intra-articular therapy is challenging because of the rapid egress of injected materials from the joint space; this elimination is true of both small molecules, which exit via synovial capillaries, and of macromolecules, which are cleared by the lymphatic system. In general, soluble materials have an intra-articular dwell time measured only in hours. Corticosteroids and hyaluronate preparations constitute the mainstay of FDA-approved intra-articular therapeutics. Recombinant proteins, autologous blood products and analgesics have also found clinical use via intra-articular delivery. Several alternative approaches, such as local delivery of cell and gene therapy, as well as the use of microparticles, liposomes, and modified drugs, are in various stages of preclinical development.

Wee1-regulated apoptosis mediated by the crk adaptor protein in Xenopus egg extracts.

Many of the biochemical reactions of apoptotic cell death, including mitochondrial cytochrome c release and caspase activation, can be reconstituted in cell-free extracts derived from Xenopus eggs. In addition, because caspase activation does not occur until the egg extract has been incubated for several hours on the bench, upstream signaling processes occurring before full apoptosis are rendered accessible to biochemical manipulation. We reported previously that the adaptor protein Crk is required for apoptotic signaling in egg extracts (Evans, E.K., W. Lu, S.L. Strum, B.J. Mayer, and S. Kornbluth. 1997. EMBO (Eur. Mol. Biol. Organ.) J. 16:230-241). Moreover, we demonstrated that removal of Crk Src homology (SH)2 or SH3 interactors from the extracts prevented apoptosis. We now report the finding that the relevant Crk SH2-interacting protein, important for apoptotic signaling in the extract, is the well-known cell cycle regulator, Wee1. We have demonstrated a specific interaction between tyrosine-phosphorylated Wee1 and the Crk SH2 domain and have shown that recombinant Wee1 can restore apoptosis to an extract depleted of SH2 interactors. Moreover, exogenous Wee1 accelerated apoptosis in egg extracts, and this acceleration was largely dependent on the presence of endogenous Crk protein. As other Cdk inhibitors, such as roscovitine and Myt1, did not act like Wee1 to accelerate apoptosis, we propose that Wee1-Crk complexes signal in a novel apoptotic pathway, which may be unrelated to Wee1's role as a cell cycle regulator.

Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques.

HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4+ T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast, antibodies that do not neutralize primary HIV-1 strains in the TZM-bl infection assay are readily induced by current vaccine candidates and have also been implicated as secondary correlates of decreased HIV-1 risk in the RV144 vaccine efficacy trial. Here, we have studied the capacity of anti-Env monoclonal antibodies (mAbs) against either the immunodominant region of gp41 (7B2 IgG1), the first constant region of gp120 (A32 IgG1), or the third variable loop (V3) of gp120 (CH22 IgG1) to modulate in vivo rectal mucosal transmission of a high-dose simian-human immunodeficiency virus (SHIV-BaL) in rhesus macaques. 7B2 IgG1 or A32 IgG1, each containing mutations to enhance Fc function, was administered passively to rhesus macaques but afforded no protection against productive clinical infection while the positive control antibody CH22 IgG1 prevented infection in 4 of 6 animals. Enumeration of transmitted/founder (T/F) viruses revealed that passive infusion of each of the three antibodies significantly reduced the number of T/F genomes. Thus, some antibodies that bind HIV-1 Env but fail to neutralize virus in traditional neutralization assays may limit the number of T/F viruses involved in transmission without leading to enhancement of viral infection. For one of these mAbs, gp41 mAb 7B2, we provide the first co-crystal structure in complex with a common cyclical loop motif demonstrated to be critical for infection by other retroviruses.

Justificando el resultado de la suma de dos números pares. Dificultades y errores

En este trabajo utilizamos los razonamientos que llevan a cabo doce alumnos de Secundaria durante la resolución de una tarea matemática para detectar los errores en que incurren y las dificultades que encuentran en su ejecución. Se les propone la tarea en un contexto de entrevista semiestructurada en la que se guía a los alumnos por el camino a seguir. Entre los datos que se obtienen, se encuentran los errores aparecidos en el desarrollo de la tarea. El análisis de dichos errores se ha hecho siguiendo las clasificaciones de Evans (González, 1998) y Radatz (1979), y se conecta dichos errores con dificultades específicas siguiendo la clasificación de Socas (1997). Se concluye este trabajo con algunas reflexiones que conside-ramos interesantes para profesionales de la enseñanza de las matemáticas.

The Exodus evacuation model applied to building evacuation scenarios

The purpose of this paper is to demonstrate the potential of the EXODUS evacuation model in building environments. The latest PC/workstation version of EXODUS is described and is also applied to a large hypothetical supermarket/restaurant complex measuring 50 m x 40 m. A range of scenarios is presented where population characteristics (such as size, individual travel speeds, and individual response times), and enclosure configuration characteristics (such as number of exits, size of exits, and opening times of exits) are varied. The results demonstrate a wide range of occupant behavior including overtaking, queuing, redirection, and conflict avoidance. Evacuation performance is measured by a number of model predicted parameters including individual exit flow rates, overall evacuation flow rates, total evacuation time, average evacuation time per occupant, average travel distance, and average wait time. The simulations highlight the profound impact that variations in individual travel speeds and occupant response times have in determining the overall evacuation performance. 1. Jin, T., and Yamada T., "Experimental Study of Human Behavior in Smoke Filled Corridors," Proceedings of The Second International Symposium on Fire Safety Science, 1988, pp. 511-519. 2. Galea, E.R., and Galparsoro, J.M.P., "EXODUS: An Evacuation Model for Mass Transport Vehicles," UK CAA Paper 93006 ISBN 086039 543X, CAA London, 1993. 3. Galea, E.R., and Galparsoro, J.M.P., "A Computer Based Simulation Model for the Prediction of Evacuation from Mass Transport Vehicles," Fire Safety Journal, Vol. 22, 1994, pp. 341-366. 4. Galea, E.R., Owen, M., and Lawrence, P., "Computer Modeling of Human Be havior in Aircraft Fire Accidents," to appear in the Proceedings of Combus tion Toxicology Symposium, CAMI, Oklahoma City, OK, 1995. 5. Kisko, T.M. and Francis, R.L., "EVACNET+: A Computer Program to Determine Optimal Building Evacuation Plans," Fire Safety Journal, Vol. 9, 1985, pp. 211-220. 6. Levin, B., "EXITT, A Simulation Model of Occupant Decisions and Actions in Residential Fires," Proceedings of The Second International Symposium on Fire Safety Science, 1988, pp. 561-570. 7. Fahy, R.F., "EXIT89: An Evacuation Model for High-Rise Buildings," Pro ceedings of The Third International Sym posium on Fire Safety Science, 1991, pp. 815-823. 8. Thompson, P.A., and Marchant, E.W., "A Computer Model for the Evacuation of Large Building Populations," Fire Safety Journal, Vol. 24, 1995, pp. 131-148. 9. Still, K., "New Computer System Can Predict Human Behavior Response to Building Fires," FIRE 84, 1993, pp. 40-41. 10. Ketchell, N., Cole, S.S., Webber, D.M., et.al., "The Egress Code for Human Move ment and Behavior in Emergency Evacu ations," Engineering for Crowd Safety (Smith, R.A., and Dickie, J.F., Eds.), Elsevier, 1993, pp. 361-370. 11. Takahashi, K., Tanaka, T. and Kose, S., "An Evacuation Model for Use in Fire Safety Design of Buildings," Proceedings of The Second International Symposium on Fire Safety Science, 1988, pp. 551- 560. 12. G2 Reference Manual, Version 3.0, Gensym Corporation, Cambridge, MA. 13. XVT Reference Manual, Version 3.0 XVT Software Inc., Boulder, CO. 14. Galea, E.R., "On the Field Modeling Approach to the Simulation of Enclosure Fires, Journal of Fire Protection Engineering, Vol. 1, No. 1, 1989, pp. 11-22. 15. Purser, D.A., "Toxicity Assessment of Combustion Products," SFPE Handbook of Fire Protection Engineering, National Fire Protection Association, Quincy, MA, pp. 1-200 - 1-245, 1988. 16. Hankin, B.D., and Wright, R.A., "Pas senger Flows in Subways," Operational Research Quarterly, Vol. 9, 1958, pp. 81-88. 17. HMSO, The Building Regulations 1991 - Approved Document B, section B 1 (1992 edition), HMSO publications, London, pp. 9-40. 18. Polus A., Schofer, J.L., and Ushpiz, A., "Pedestrian Flow and Level of Service," Journal of Transportation Engineering, Vol. 109, 1983, pp. 46-47. 19. Muir, H., Marrison, C., and Evans, A., "Aircraft Evacuations: the Effect of Passenger Motivation and Cabin Con figuration Adjacent to the Exit," CAA Paper 89019, ISBN 0 86039 406 9, 1989. 20. Muir, H., Private communication to appear as a CAA report, 1996.

Automatic code generation of overlapped communications in a parallelisation tool

This paper addresses the exploitation of overlapping communication with calculation within parallel FORTRAN 77 codes for computational fluid dynamics (CFD) and computational structured dynamics (CSD). The obvious objective is to overlap interprocessor communication with calculation on each processor in a distributed memory parallel system and so improve the efficiency of the parallel implementation. A general strategy for converting synchronous to overlapped communication is presented together with tools to enable its automatic implementation in FORTRAN 77 codes. This strategy is then implemented within the parallelisation toolkit, CAPTools, to facilitate the automatic generation of parallel code with overlapped communications. The success of these tools are demonstrated on two codes from the NAS-PAR and PERFECT benchmark suites. In each case, the tools produce parallel code with overlapped communications which is as good as that which could be generated manually. The parallel performance of the codes also improve in line with expectation.

Automatic and effective multi-dimensional parallelisation of structured mesh based codes

The most common parallelisation strategy for many Computational Mechanics (CM) (typified by Computational Fluid Dynamics (CFD) applications) which use structured meshes, involves a 1D partition based upon slabs of cells. However, many CFD codes employ pipeline operations in their solution procedure. For parallelised versions of such codes to scale well they must employ two (or more) dimensional partitions. This paper describes an algorithmic approach to the multi-dimensional mesh partitioning in code parallelisation, its implementation in a toolkit for almost automatically transforming scalar codes to parallel form, and its testing on a range of ‘real-world’ FORTRAN codes. The concept of multi-dimensional partitioning is straightforward, but non-trivial to represent as a sufficiently generic algorithm so that it can be embedded in a code transformation tool. The results of the tests on fine real-world codes demonstrate clear improvements in parallel performance and scalability (over a 1D partition). This is matched by a huge reduction in the time required to develop the parallel versions when hand coded – from weeks/months down to hours/days.

The AASK Database V3.0: a database of human experience during aircraft evacuation incidents

This paper describes recent developments with the Aircraft Accident Statistics and Knowledge (AASK) database. The AASK database is a repository of survivor accounts from aviation accidents developed by the Fire Safety Engineering Group of the University of Greenwich with support from the UK CAA. Its main purpose is to store observational and anecdotal data from the actual interviews of the occupants involved in aircraft accidents. Access to the latest version of the database (AASK V3.0) is available over the Internet. AASK consists of information derived from both passenger and cabin crew interviews, information concerning fatalities and basic accident details. Also provided with AASK is the Seat Plan Viewer that graphically displays the starting locations of all the passengers - both survivors and fatalities - as well as the exits used by the survivors. Data entered into the AASK database is extracted from the transcripts supplied by the National Transportation Safety Board in the US and the Air Accident Investigation Branch in the UK. The quality and quantity of the data was very variable ranging from short summary reports of the accidents to boxes of individual accounts from passengers, crew and investigators. Data imported into AASK V3.0 includes information from 55 accidents and individual accounts from 1295 passengers and 110 crew.

The collection of pre-evacuation times from evacuation trials involving a Hospital Outpatient area and a University Library facility

This paper presents data relating to occupant pre-evacuation times from a university and a hospital outpatient facility. Although the two structures are entirely different they do employ relatively similar procedures: members of staff sweeping areas of the structure to encourage individuals to evacuate. However, the manner in which the dependent population reacts to these procedures is quite different. In the hospital case the patients only evacuated once a member of the nursing staff had instructed them to do so while in the university evacuation the students were less dependent upon the actions of the staff with over 50% of them evacuating with no prior prompting. Although this data may be useful in a variety of areas, it was collected primarily for use within evacuation models.

The semi-automatic parallelisation of scientific application codes using a computer aided parallelisation toolkit

The shared-memory programming model can be an effective way to achieve parallelism on shared memory parallel computers. Historically however, the lack of a programming standard using directives and the limited scalability have affected its take-up. Recent advances in hardware and software technologies have resulted in improvements to both the performance of parallel programs with compiler directives and the issue of portability with the introduction of OpenMP. In this study, the Computer Aided Parallelisation Toolkit has been extended to automatically generate OpenMP-based parallel programs with nominal user assistance. We categorize the different loop types and show how efficient directives can be placed using the toolkit's in-depth interprocedural analysis. Examples are taken from the NAS parallel benchmarks and a number of real-world application codes. This demonstrates the great potential of using the toolkit to quickly parallelise serial programs as well as the good performance achievable on up to 300 processors for hybrid message passing-directive parallelisations.