Search

Type 1 diabetes is a T-cell-mediated autoimmune disease, resulting in destruction of the insulin-producing beta cells in the pancreas. Disease progression is thought to involve the action of T-cells, particularly those producing Th1-type cytokines. Given the complexity in understanding the precise etiology of autoimmune diseases, the diversity of autoantigens, and the variability that exists between individual patients, it might be very difficult to eliminate autoaggressive T-cell responses without resorting to generalized means of immunosuppression. However, recent evidence shows that autoimmune processes are composed not only of autoaggressive T-cell responses but also of autoreactive regulatory components. Enhancing regulatory T-cell responses, therefore, has become an area of intense focus as a means of treating autoimmune diseases like type 1 diabetes. This review will concentrate on two different types of regulatory T-cells, the naturally occurring (‘professional’) CD4+CD25+ T-cells and antigen-induced (‘adaptive’) CD4+ Th2-like regulatory T-cells. Copyright © 2004 John Wiley & Sons, Ltd.

A notion of resource-bounded Baire category is developed for the class PC[0,1] of all polynomial-time computable real-valued functions on the unit interval. The meager subsets of PC[0,1] are characterized in terms of resource-bounded Banach-Mazur games. This characterization is used to prove that, in the sense of Baire category, almost every function in PC[0,1] is nowhere differentiable. This is a complexity-theoretic extension of the analogous classical result that Banach proved for the class C[0, 1] in 1931. (© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

The precise cause for most human autoimmune diseases remains poorlydefined. Autoimmunity may be one of the consequences of the developmentof a complex mammalian immune system required to ensure the organism’shomeostasis in a dynamic environment. The manifestation of clinicalautoimmunity is the result of an intricate interplay between genetic andenvironmental factors that is, for the most part, incompletely understood.In particular, infectious agents have been invoked in triggering autoim-mune diseases under conditions of genetic susceptibility (comprehensivelyreviewed in reference [1]), but they can also stop autoimmune processes[2]. Some aspects of this dichotomy are highlighted in this article and theexperimental models presented might help to guide clinicians in ongoing andfuture epidemiologic and immunologic investigations in humans.Enhancement of autoimmunity by viral infectionsMany viral infections have been shown to be associated with commonhuman autoimmune diseases, such as multiple sclerosis and type 1 diabetes(T1D) [1,3,4]. To account for this positive link between infections anddevelopment of autoaggression, two not mutually exclusive aspects ofpathogenesis have to be considered. First, infection of a particular targetorgan can lead to an inflammatory milieu that creates an environmentconducive to the development of autoimmunity, possibly by directly(chemokines/cytokines) or indirectly (release of autoantigens) activating

The T-box transcription factor T-bet is known to control lineage commitment and interferon-γ production by T helper 1 (Th1) CD4 lymphocytes. We report here that T-bet is essential for development of CD8 lymphocyte-dependent autoimmune diabetes (type 1 diabetes [T1D]) in the rat insulin promoter–lymphocytic choriomeningitis virus (LCMV) transgenic model for virally induced T1D. In the absence of T-bet, autoaggressive (anti-LCMV) CD8 lymphocytes were reduced in number and produced less IFN-γ, but increased IL-2 compared with controls. Further analysis showed that T-bet intrinsically controls the generation, but not apoptosis, maintenance, or secondary expansion of antiviral effector/memory CD8 lymphocytes. This observation points toward a therapeutic opportunity for the treatment of T1D and other autoimmune disorders.

Susceptible strains of mice that are naturally or experimentally infected with murine intestinal helicobacter species develop hepatic inflammatory lesions that have previously been described as chronic active hepatitis. The inflammatory infiltrates in some models of chronic autoimmunity or inflammation resemble tertiary lymphoid organs hypothesized to arise by a process termed lymphoid organ neogenesis. To determine whether hepatic inflammation caused by infection with helicobacter could give rise to tertiary lymphoid organs, we used fluorescence-activated cell sorting, immunohistochemistry, and in situ hybridization techniques to identify specific components characteristic of lymphoid organs in liver tissue sections and liver cell suspensions from helicobacter-infected mice. Small venules (high endothelial venules [HEVs]) in inflammatory lesions inHelicobacterspecies-infected livers were positive for peripheral node addressin. Mucosal addressin cell adhesion molecule also stained HEVs and cells with a staining pattern consistent with scattered stromal cells. The chemokines SLC (CCL 21) and BLC (CXCL13) were present, as were B220-positive B cells and T cells. The latter included a naïve (CD45lo-CD62Lhi) population. These findings suggest that helicobacter-induced chronic active hepatitis arises through the process of lymphoid organ neogenesis.

The inapproximability of non-NP-hard optimization problems is investigated. Techniques are given to show that the problems LOG DOMINATING SET and LOG HYPERGRAPH VERTEX COVER cannot be approximated to a constant ratio in polynomial time unless the corresponding NP-hard versions are also approximable in deterministic subexponential time. A direct connection is established between non-NP-hard problems and a PCP characterization of NP. Reductions from the PCP characterization show that LOG CLIQUE is not approximable in polynomial time and MAX SPARSE SAT does not have a FPTAS under the assumption that NP⊈DTIME(2O(nlogn)). A number of nontrivial approximation-preserving reductions are also presented, making it possible to extend inapproximability results to more natural non-NP-hard problems such as TOURNAMENT DOMINATING SET and RICH HYPERGRAPH VERTEX COVER.

During experimental autoimmune encephalomyelitis (EAE), autoreactive Th1 T cells invade the CNS. Before performing their effector functions in the target organ, T cells must recognize Ag presented by CNS APCs. Here, we investigate the nature and activity of the cells that present Ag within the CNS during myelin oligodendrocyte glycoprotein-induced EAE, with the goal of understanding their role in regulating inflammation. Both infiltrating macrophages (Mac-1+CD45high) and resident microglia (Mac-1+CD45int) expressed MHC-II, B7-1, and B7-2. Macrophages and microglia presented exogenous and endogenous CNS Ags to T cell lines and CNS T cells, resulting in IFN-γ production. In contrast, Mac-1− cells were inefficient APCs during EAE. Late in disease, after mice had partially recovered from clinical signs of disease, there was a reduction in Ag-presenting capability that correlated with decreased MHC-II and B7-1 expression. Interestingly, although CNS APCs induced T cell cytokine production, they did not induce proliferation of either T cell lines or CNS T cells. This was attributable to production by CNS cells (mainly by macrophages) of NO. T cell proliferation was restored with an NO inhibitor, or if the APCs were obtained from inducible NO synthase-deficient mice. Thus, CNS APCs, though essential for the initiation of disease, also play a down-regulatory role. The mechanisms by which CNS APCs limit the expansion of autoreactive T cells in the target organ include their production of NO, which inhibits T cell proliferation, and their decline in Ag presentation late in disease.

L'auteur passe en revue les sites Web constituant des sources d'information substantielles et bien structurees sur la question de la diversite et des minorites ethniques et culturelles au sein de l'enseignement superieur aux Etats-Unis.

In the literature, prefix Kolmogorov complexity is defined either in terms of self-delimiting Turing machines or in terms of partial recursive prefix functions. These notions of prefix Kolmogorov complexity are equivalent because, as Chaitin showed, every partial recursive prefix function can be simulated by a self-delimiting Turing machine. However, the simulation given by Chaitin's construction is not efficient, and so questions regarding the time-bounded equivalence of these notions remained unresolved. Here we closely examine these questions. As our main result, we show that every partial recursive prefix function can be simulated with polynomial efficiency by a self-delimiting Turing machine if and only if P = NP. Thus, it is unlikely that Chaitin's construction can be used to show the polynomial-time equivalence of these notions of prefix Kolmogorov complexity. Here we further examine the relationships between these notions of time-bounded prefix Kolmogorov complexity.

Experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 (H-2b) mice is characterized by early (day 12) acute paralysis, followed by a sustained chronic clinical course that gradually stabilizes. Extensive inflammation and demyelination coincide with clinical signs of disease. To identify the mechanisms of these processes, individual proinflammatory and anti-inflammatory cytokines and chemokines were studied. Sensitive single-cell assays were utilized to determine the cellular origin and kinetics of cytokine production in the CNS. Immunization with MOG35–55 peptide resulted in priming of both Th1 (lymphotoxin, IFN-γ, and TNF-α) and Th2 (IL-4) cells in the spleen. However, only Th1 cells were apparent in the CNS. CD4 T cells that produced IFN-γ or TNF-α were present in the CNS by day 7 after immunization with MOG35–55, peaked at day 20, and then waned. TNF-α was also produced in the CNS by Mac-1+ cells. On days 7 and 10 after immunization, the TNF-α-producing Mac1+ cells were predominantly microglia. By day 14, a switch occurred in that the Mac1+ TNF-α-producing cells had the phenotype of infiltrating macrophages. RANTES, IFN-inducible protein 10 (IP-10), and monocyte chemotactic protein 1 chemokine mRNA were detected in the CNS by day 8 after immunization. The early presence of monocyte chemotactic protein 1 (MCP-1) in the CNS provides a mechanism for the recruitment of macrophages. These data implicate TNF-α production by a continuum of T cells, microglia, and macrophages at various times during the course of disease. The importance of Th1 cytokines is highlighted, with little evidence for a role of Th2 cytokines.

Activation-induced cell death resulting in peripheral deletion of CD8+ T cells is associated with the accumulation of large numbers of apoptotic T cells in the liver. The hypothesis that this accumulation results from the intrahepatic trapping of T cells from the circulating pool predicts that the liver should retain T cells, which subsequently undergo apoptosis. Here we test this prediction. Perfusion of the liver with lymphocyte mixtures showed retention of activated, but neither resting nor apoptosing, T cells. This trapping was selective for CD8+ cells and was mediated primarily by ICAM-1 constitutively expressed on sinusoidal endothelial cells and Kupffer cells. T cells trapped in the liver became apoptotic. The normal liver is therefore a “sink” for activated T cells.

Two algebraic structures with the same universe are called term-equivalent if they have the same clone of term operations. We show that the problem of determining whether two finite algebras of finite similarity type are term-equivalent is complete for deterministic exponential time.

Myelin oligodendrocyte glycoprotein (MOG) induced experimental allergic encephalomyelitis (EAE) is an animal model for the central nervous system disease multiple sclerosis (MS). The roles of individual components of the immune system have not been completely defined in the mouse model, and to determine the role of B cells and Abs in the induction of EAE and demyelination, B cell-deficient μMT (H-2b) mice were immunized with MOG peptide 35–55. The μMT mice were susceptible to MOG-induced EAE and developed a chronic sustained disease, with inflammatory lesions and primary demyelination in the spinal cord, brain, and optic nerves, similar to that seen in wild-type C57BL/6 mice. The inflammatory cells in the central nervous system of μMT mice included both activated and memory T cells and macrophages. The data suggest that B cells and Abs are not necessary for primary demyelination in MOG-induced EAE in mice.

Database searching presents special difficulties for humanists because many subjects may be covered, many synonyms may be used to describe a single concept, and terms may vary in precision. Databases may be searched by using controlled vocabularies, free-text (natural language) terms, or a combination of both. A significant cause of recall failure in a free-text search is the inability of the searcher to think of all the terms an author may have used. The current study was undertaken to determine the potential value to humanists of a thesaurus integrating free-text terms from the humanities and social sciences. In the first part of the study, a sample of common-noun subject headings from the "Humanities Index" was analyzed to determine how many have at least quasi-synonymous terms. The subject headings were compared to terms in "The Contemporary Thesaurus of Social Science Terms and Synonyms: A Guide for Natural Language Computer Searching" to determine the overlap of terminology between the humanities an...

The spectrin membrane skeleton is a ubiquitous cytoskeletal structure with several cellular roles, including the maintenance of cell integrity, determination of cell shape and as a contributor to cell polarity. We have isolated mutations in the gene encoding βHeavy-spectrin in Drosophila, and have named this essential locus karst. karst mutant individuals have a pleiotropic phenotype characterized by extensive larval lethality and, in adult escapers, rough eyes, bent wings, tracheal defects and infertility. Within karst mutant eyes, a significant number of ommatidia specifically lack photoreceptor R7 alongside more complex morphological defects. Immunolocalization of βHeavy-spectrin in wild-type eye-antennal and wing imaginal discs reveals that βHeavy-spectrin is present in a restricted subdomain of the membrane skeleton that colocalizes with DE-cadherin. We propose a model where normal levels of Sevenless signaling are dependent on tight cell-cell adhesion facilitated by the βHeavy-spectrin membrane skeleton. Immunolocalization of βHeavy-spectrin in the adult and larval midgut indicates that it is a terminal web protein, but we see no gross morphological defects in the adult apical brush border in karst mutant flies. Rhodamine phalloidin staining of karst mutant ovaries similarly reveals no conspicuous defect in the actin cytoskeleton or cellular morphology in egg chambers. This is in contrast to mutations in α-spectrin, the molecular partner of βHeavy-spectrin, which affect cellular structure in both the larval gut and adult ovaries. Our results emphasize the fundamental contribution of the spectrin membrane skeleton to normal development and reveals a critical interplay between the integrity of a cell’s membrane skeleton, the structure of cell-cell contacts and cell signaling.

The Appalachian Cohort for Engineering (ACE) at Ohio University is an NSF S-STEM funded scholarship program for students in Engineering and Computer Science that combines intensive early intervention approaches (i.e., learning communities, peer-led team learning, midterm progress reports, and purposeful selection of academic advisors) with peer advising and cohort building activities. The intent of this program is to help academically capable but financially insecure students from the economically disadvantaged Appalachian counties of Ohio and surrounding states to complete important early milestones in their academic careers. The ultimate goal of this project is to build evidence-based approaches for encouraging retention and early academic milestone completion for a broad range of undergraduate students in the STEM disciplines. The research component of this project seeks to determine which services are most effective at encouraging and supporting these students to reach early academic milestones to promote long-term retention and degree completion. This component involves substantial data collection that includes observational field notes and one-on-one contact records, along with the required NSF data elements. Much of the data collection is provided by trained peer advisors; capturing the following dimensions of academic wellness: personal/transitional, social, academic, financial, health and stress-coping, study sessions and tutoring, goal setting, follow up data, and academic reviews by course. In addition, field notes are collected that describe the setting, attendees, acts, and reflections on specific events that happen throughout the year. This project is in its first year of implementation. In this work-in-progress paper, we report on the design of the project, early successes and challenges, the data collection strategy, and the preliminary results of this project. In this first year, early observational results indicated that this body of students needed both social and academic support; with both being equal emphasis. Furthermore, this body of students indicated that one-on-one support and goal setting were important components of their early success.

This paper investigates the distribution and nonuniform complexity of problems that are complete or weakly complete for ESPACE under nonuniform many-one reductions that are computed by polynomial-size circuits (P/Poly-many-one reductions). Every weakly P/Poly-many-one-complete problem is shown to have a dense, exponential, nonuniform complexity core. An exponential lower bound on the space-bounded Kolmogorov complexities of weakly P/Poly-Turing-complete problems is established. More importantly, the P/Poly-many-one-complete problems are shown to be unusually simple elements of ESPACE, in the sense that they obey nontrivial upper bounds on nonuniform complexity (size of nonuniform complexity cores and space-bounded Kolmogorov complexity) that are violated by almost every element of ESPACE. More generally, a Small Span Theorem for P/Poly-many-one reducibility in ESPACE is proven and used to show that every P/Poly-many-one degree -including the complete degree — has measure 0 in ESPACE. (In contrast, almost every element of ESPACE is weakly P-many-one complete.) All upper and lower bounds are shown to be tight.

Certain natural decision problems are known to be intractable because they are complete for E, the class of all problems decidable in exponential time. Lutz recently conjectured that many other seemingly intractable problems are not complete for E, but are intractable nonetheless because they areweakly complete for E (i.e., they are in E and hard for more than a measure 0 subset of E). The main result of this paper shows that Lutz's intuition is at least partially correct: many more problems are weakly complete for E than are complete for E.

This paper reviews and investigates Bennett's notions of strong and weak computational depth (also called logical depth) for infinite binary sequences. Roughly, an infinite binary sequence x is defined to be weakly useful if every element of nonnegligible set of decidable sequences is reducible to x in recursively bounded time. It is shown that every weakly useful sequence is strongly deep. This result (which generalizes Bennett's observation that the halting problem is strongly deep) implies that every high Turing degree contains strongly deep sequences. It is also shown that, in the sense of Baire category, almost every infinite binary sequence is weakly deep, but not strongly deep.

Tobacco smoke exhaled from smokers is a key component of secondhand smoke, contributing to lung alveolar wall destruction seen in chronic lung diseases. Although mainstream and sidestream tobacco smoke are cyto-toxic to lung cells, it is unclear whether exhaled smoke induces lung cell injury or even death. We sought to establish an in vitro model to examine the effects of exhaled smoke on lung cells. Phosphate-buffered saline-conditioned cigarette smoke (CCS) derived from a blow-by system was used to mimic exhaled tobacco smoke exposure. Exposure of medium to CCS leads to dose-dependent increases in nicotine/cotinine levels. Scanning spectrophotometric analysis of the CCS-exposed medium reveals an absorption peak at 290 nm wavelength. The OD values at 290 nm are correlated with nicotine levels in the exposed medium, indicating that a simple measurement of OD at 290 nm can be used to monitor CCS exposure. Tobacco smoke contacts the microvascular endothelium located at lung alveoli, before it enters the blood stream. Hence, human lung microvascular endothelial cells (hMVEC) were exposed to CCS and assessed for cell injury and death. Exposure of hMVEC to CCS equivalent to burning 12-16 cigarettes leads to increased LDH release from the cells into the medium. This suggests that CCS can induce lung cell injury. CCS at a low level increases cell growth, whereas the high level of CCS decreases cell viability. In addition, CCS exposure induces cell detachment and morphological changes. Our results demonstrate that exposure of buffer-conditioned mainstream cigarette smoke leads to increased nicotine/cotinine levels and cell injury/death, which may contribute to the pathophysiology of passive smoking-associated lung diseases.

The incubation of isolated hepatocytes with the inhibitor of protein mono ADP-ribosylation, m-iodobenzylguanidine (MIBG), resulted in an increase in the size of the mitochondrial Ca2+ pool, without alteration of the non-mitochondrial Ca2+ store(s). This increase was abolished when the cytosolic free Ca2+ concentration ([Ca2+]i) was buffered by prior loading of the cells with fluo 3. Elevating [Ca2+]i by releasing the endoplasmic reticular Ca2+ store with 2,5-di-(tert-butyl)-1,4-hydroquinone resulted in a synergistic increase in the magnitude of the mitochondrial Ca2+ pool. A role for protein ADP-ribosylation in the intracellular regulation of mitochondrial Ca2+ homeostasis is suggested.

Cyclosporin A (CsA) is a potent inhibitor of the prooxidant-induced release of Ca2+ from isolated mitochondria. In this investigation, pretreatment of hepatocytes with CsA before exposure to the prooxidants tert-butyl hydroperoxide (tBH), cumene hydroperoxide or 3,5-dimethyl-N-acetyl-p-benzoquinone imine (3,5-Me2-NAPQI) prevented the loss of cell viability. HPLC analysis of adenine and pyridine nucleotide concentrations in hepatocytes treated with 3,5-Me2-NAPQI showed a rapid depletion of ATP prior to the loss of cell viability versus the maintenance of near control levels of ATP in hepatocytes treated with CsA before 3,5-Me2-NAPQI. In 3,5-Me2-NAPQI-exposed hepatocytes there was also a rapid loss of cellular NAD+ which could be accounted for initially by a transient increase in NADP+. Measurement of the intracellular Ca2+ pools showed an early depletion of the mitochondrial Ca2+ pool in hepatocytes exposed to 3,5-Me2-NAPQI, tBH or cumene hydroperoxide; this loss was prevented by CsA. In conclusion, these results show that CsA protected hepatocytes from prooxidant injury by preventing mitochondrial Ca2+ cycling and subsequent mitochondrial dysfunction. This suggests that in prooxidant injury, excessive Ca2+ cycling is an early and important event leading to mitochondrial damage and subsequently to cell death.

The glutathione, cysteine and acid-soluble thiol status of Atlantic croaker (Micropogonias undulatus) tissues and the accumulation and subcellular distribution of lead were investigated after oral ingestion of lead chloride (equivalent to 1.2 mg Pb/100 g body weight/day) for up to 6 weeks. The glutathione contents of the liver and intestine increased to 1.4 × and 4.4 × control levels, respectively, after ingestion of lead for one week and did not increase further during chronic treatment. Significant increases in the glutathione contents of brain and kidney tissues were only observed after six weeks lead administration. These elevations in glutathione content accounted for most of the increases in acid-soluble thiol concentrations ob served in croaker tissues after lead treatment. The intestine accumulated the most lead (up to 50 μg/g), followed by the kidney (20 μg/g), liver (2 μg/g) and brain (< 1.0 μg), There was no apparent relationship between the accumulation of lead and glutathione content in these tissues above the threshold level of 1μg Pb/g tissue. Subcellular fractionation of hepatic tissue after injection with210Pb showed that nearly half of the lead was present in the cytosolic fraction which eluted on a Sephadex G-75 column in a peak with a molecular weight above 64,000, no210Pb was associated with glutathione or any other low molecular weight thiols. Incorporation of14C-glycine into hepatic glutathione, a measure of glutathione synthesis, was increased 1.8-fold in lead-exposed fish, whereas glutathione turnover was unaltered. These results suggest that the increase in glutathione content observed in lead-exposed fish is due to an increase in glutathione synthesis rather than a decrease in utilization of the tripeptide or to its sequestration by lead.

Hypoxia-increased endothelin-1 (ET-1) expression contributes to vasoconstriction and vessel wall thickening, often seen in the progression of pulmonary hypertension. We sought to investigate whether hypoxic modulation of preproET-1 transcription is associated with protein tyrosine kinase and phosphatidylinositol-3-kinase (PI3K). ET-1 is predominantly produced in and secreted from the vascular endothelium. Cultured human pulmonary artery endothelial cells (PAEC) in basic medium EBM-2 were exposed to hypoxia (1% oxygen, 5% CO(2), 37 degrees C) or normoxia (room air containing 5% CO(2)) for 0-48 hr. RNA was extracted from the treated cells and subjected to quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Hypoxia increases the relative levels of steady-state preproET-1 mRNA. The results of actinomycin D chase studies suggest that hypoxia-increased levels of preproET-1 mRNA are unlikely to be caused by increased RNA stability. A modified nuclear run-on method coupled with the sensitive qRT-PCR technique was used to assess preproET-1 gene transcription. The synthesis rate of preproET-1 mRNA in the cells exposed to hypoxia is higher than that in normoxic cells. The inhibitors of protein tyrosine kinases and PI3K, genistein and PI3Kgamma inhibitor II, were used to elucidate the role of protein tyrosine kinase and PI3K in hypoxic modulation of preproET-1 expression. Pre-incubation of human PAEC with genistein or PI3Kgamma inhibitor II abolishes hypoxia-increased levels of preproET-1 mRNA. Our observations support the notion that hypoxia increases the level of preproET-1 mRNA through upregulation of RNA synthesis, which is associated with protein tyrosine kinase- and PI3K-mediated signal transduction pathways. This implies that therapeutic interventions targeting protein tyrosine kinases and/or PI3K might be used to treat hypoxic pulmonary hypertension.

This work-in-progress paper describes a web- based system that is being developed at Ohio University for developing and administering active learning assignments. The paper describes the design of the system, and its intended use in outcomes-based assessment of student learning in Computer Science. The system allows students to access active learning exercises via the web and provides students with immediate feedback on their work. Faculty use the system to design active learning assignments that tie student performance to achievement of specific course outcomes. This work-in-progress paper describes initial experiences with this system in an advanced course where both the software package JFLAP (An Interactive Formal Languages and Automata Package) and C++ programming are used.

During an autoimmune process, the autoaggressive response spreads from the initiating autoantigen to other antigens expressed in the target organ. Based on evidence from experimental models for multiple sclerosis, such “antigenic spreading” can play an important role in the exacerbation of clinical disease. We evaluated whether pathogenesis of spontaneous diabetes in NOD mice could be accelerated in a similar way when a novel autoantigen was expressed in pancreatic β-cells. Unexpectedly, we found that the expression of the lymphocytic choriomeningitis virus nucleoprotein only led to marginal enhancement of diabetes, although such NOD-nucleoprotein mice were not tolerant to nucleoprotein. Although the frequency of nucleoprotein-specific CD8 T-cells in the pancreatic draining lymph node was comparable with the frequency of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific T-cells, more IGRP-specific CD8 T-cells were found both systemically and in the islets where there was a fourfold increase. Interestingly, and in contrast to nucleoprotein-specific CD8 T-cells, IGRP-specific T-cells showed increased CXCR3 expression. Thus, autoreactivity toward de novo–expressed β-cell autoantigens will not accelerate autoimmunity unless large numbers of antigen-experienced autoreactive T-cells expressing the appropriate chemokine receptors are present.

This paper describes recent improvements to and experiences with Web-based grading software that has been developed by the author at Ohio University. The software, named WBGP for the web-based grading project, provides facilities to build, test, and annotate student source code with comments concerning programming style and documentation. The software produces a collection of Web-pages for each student project that describes the results of testing, the grading decisions, and the resulting score. The software is able to build student portfolios consisting of all students projects for a given course. In addition, the software is able to generate reports on the type and frequency of grading comments and the correctness of student projects. The paper describes continued experiences in web-based grading of computer science projects at Ohio University. In particular, we describe the various challenges of grading interactive student projects. Finally, this paper describes the results of a student survey concerning the web-based grading software. Students were surveyed concerning the ease of use and understanding of the generated Web-pages, their attitudes towards students portfolios, and their attitudes towards web-based grading. In general, the students responses were positive

Dynamic real-time systems require adaptive resource management to accommodate varying processing needs. This paper addresses the problem of resource management on a single resource for soft real-time systems (no hard deadline requirements) consisting of tasks that have discrete quality of service (QoS) settings that correspond to varying resource requirements and varying utility. Our approach employs a feedback architecture wherein task QoS settings are adjusted on-line in order to maintain a desired amount of resource slack. These adjustments are calculated based on incremental changes in resource slack using computationally efficient algorithms that provide nearly optimal utility with computable performance bounds. The feedback architecture provides robustness in the presence of additional resource load and imperfect task resource requirement specifications.

This paper extends the previous work on the maximal allowable workload (MAW) problem [D. Juedes et al., (2004)] by investigating a resource allocation problem for distributed real-time systems that contain replicable applications. The systems may use multiple resources of a single type and be affected by multiple environmental factors. The approach searches for a feasible allocation that maximizes a user defined metric of stability. Several algorithms were developed and experiments were conducted to demonstrate the relative strength of these algorithms. The results showed that simulated annealing provides results that are the closest to the optimal for maximizing environmental parameter settings. In addition modified greedy first fit is shown to be the best performing algorithm for finding feasible allocations.

Integration of middleware scheduling and resource management services enables open distributed real-time embedded (DRE) applications to meet end-to-end quality of service (QoS) requirements in highly variable operating environments. This paper describes our research on integrating CORBA scheduling and resource management services, and presents experiments we conducted to validate and quantify the benefits of this integration. Our experimental results show that integrating distributed scheduling and resource management in middleware for open DRE systems can offer significant improvements in predictability. Specifically, integrating our stand-alone resource management service with a previously unmanaged experimental baseline application reduced the ratio of missed deadlines from 26% to 10%, and the same application performed even better under the control of integrated scheduling and resource management services, with a missed deadline ratio of only 1%.

This paper describes a project to build a Web-based grading system and reports on experiences in using a Web-based grading system in a sophomore-level course on data structures. The Web-based grading system consists of electronic submission and retrieval programs, automated testing and Web-based evaluation software, Web-based code annotation software, and Web-based report generation software. The software was designed with electronic grading and delivery as the primary objective and with course-based assessment as a secondary objective. In addition, the software provides the means to capture electronic examples of student work for assessment and accreditation purposes and the means to create electronic portfolios for individual students. The results of our experience with the Web-based grading software in a sophomore-level course on data structures are also described. The software system provided a means to examine detailed information on the overall performance of students on programming projects. In particular, the software recorded information concerning the performance of student projects on test cases and recorded the frequency and type of design and documentation errors. This information was used to evaluate the overall performance of students and to identify common errors that merited additional course time and review.

Summary form only given. We describe the quality-based adaptive resource management architecture, QARMA, a framework for resource management within CORBA. QARMA consists of three major components: the system repository service, the resource management service, and the enactor service. QARMA serves as a basis for integration of existing CORBA services and management mechanisms into a single, coherent framework for resource management. QARMA supports the management of a wide variety of applications developed using various development paradigms, easily integrates with other management and infrastructure components that already exist as CORBA services, and is easily extended to allow the use of new resource management mechanisms as they become available.

Summary form only given. We examine several heuristic algorithms for the maximum allowable workload (MAW) problem for real-time systems with tasks having variable workloads. Briefly, the problem concerns the allocation of tasks to m processors, where each task t is characterized by a function t.r(w) that gives the running time of the task in terms of its workload (or input size) w. The objective of the maximum allowable workload problem is to find an allocation of tasks to processors so that the allocation is feasible (no task misses its deadline) when each task is given a workload of w or smaller and w is maximized. This optimization problem uses a robustness measure that is closely related to the MAIL (maximum allowable increase in load) metric recently proposed by Gertphol et al. The main contribution of this paper is the comparison of several heuristic algorithms for the MAW-RMS problem. Hillclimbing, random search, simulated annealing, and first-fit heuristics are presented and evaluated via simulation. As we show here, the first-fit greedy heuristic produces solutions of a reasonable quality compared to the other algorithms. In addition, we demonstrate the applicability of our model in air defense systems.

Summary form only given. We propose architecture and a general optimization framework for dynamic, distributed real-time systems. Interesting features of this model include the consideration of adaptive applications and utility functions. We extend by formalizing the corresponding multicriterial optimization problem. As the most difficult part of this problem, we identified the evaluation and comparison of the quality of single allocations and sets of allocations, respectively. To this end, we propose and examine metrics for measuring the goodness of solutions within our general resource management framework. These metrics lay the basis for further work on developing both online and offline algorithms to tackle the general optimization problem and provide an efficient adaptive resource manager for dynamic, distributed real-time systems.

The paper presents a model that is useful for developing resource allocation algorithms for distributed real-time systems that operate in dynamic environments. Interesting aspects of the model include dynamic environments, utility and service levels, which provide a means for graceful degradation in resource-constrained situations and support optimization of the allocation of resources. The paper also provides an allocation algorithm that illustrates how to use the model for producing feasible, optimal resource allocations.

This paper revisits design and analysis techniques for fixed parameter algorithms for Planar Dominating Set and other problems on planar structures. As our main result, we use new geometric arguments concerning treewidth-based algorithms to show that determining whether a planar graph G has a dominating set of size k can be solved in \(O(2^{16.4715 \sqrt{k}}+ n^3)\) steps. This result improves on the best known treewidth-based algorithm by Kanj and Perkovic that runs in time \(O(2^{27\sqrt{k}}n)\). Our main result nearly matches the new branchwidth-based algorithm for Planar Dominating Set by Fomin and Thilikos that runs in time \(O(2^{15.13 \sqrt{k}}k +n^3)\). Algorithms for other problems on planar structures are explored. In particular, we show that Planar Red/Blue Dominating Set can be solved in time \(O(2^{24.551 \sqrt{k}}n)\). This leads to the main results, namely, that faster parameterized algorithms can be obtained for a variety of problems that can be described by planar boolean formulae. This gives the best-known parameterized algorithms for Planar Vertex Cover, Planar Edge Dominating Set, and Face Cover.

This paper examines a parameterized problem that we refer to as n–kGraph Coloring, i.e., the problem of determining whether a graph G with n vertices can be colored using n–k colors. As the main result of this paper, we show that there exists a O(kn2 +k2 + 23.8161k)=O(n2) algorithm for n–kGraph Coloring for each fixed k. The core technique behind this new parameterized algorithm is kernalization via maximum (and certain maximal) matchings. The core technical content of this paper is a near linear-time kernelization algorithm for n–kClique Covering. The near linear-time kernelization algorithm that we present for n–kClique Covering produces a linear size (3k–3) kernel in O(k(n+m)) steps on graphs with n vertices and m edges. The algorithm takes an instance 〈G,k 〉 of Clique Covering that asks whether a graph G can be covered using |V|–k cliques and reduces it to the problem of determining whether a graph G′=(V′,E′) of size ≤ 3k–3 can be covered using |V′| – k′ cliques. We also present a similar near linear-time algorithm that produces a 3k kernel for Vertex Cover. This second kernelization algorithm is the crown reduction rule.

It is well established that antigen-presenting cells (APCs) such as dendritic cells (DCs) possess potent immune-stimulatory function. They are considered to be the key driving element for most immune, autoimmune, and host-defense responses. However, recent evidence suggests that as much as APCs can turn things on, they also have the capability to turn things off. To summarize the evidence for such regulatory function of APCs is the purpose of this review article. We are just beginning to understand whether regulatory APC function can be mapped to a separate lineage of APCs or whether it is more commonly acquired under certain maturation conditions. Furthermore, it becomes apparent that it is important to consider differences between human and mouse DCs as well as splenic-, lymph node-, or blood-derived APCs. We believe that, in the upcoming years, better understanding of positive and negative roles of APCs in immune regulation will benefit both sides of APC therapy: their use in enhancing immunity, for example, in vaccine design and cancer, as well as their application for the treatment of autoimmunity.

Type 1 immunity relies on the differentiation of two major subsets of T lymphocytes, the CD4+T helper (Th) cell and the CD8+cytotoxic T cell, that direct inflammatory and cytotoxic responses essential for the destruction of intracellular and extracellular pathogens. In contrast to CD4 cells, little is known about transcription factors that control the transition from the CD8 naïve to effector cell stage. Here, we report that the transcription factor T-bet, known to regulate Th cell differentiation, also controls the generation of the CD8+cytotoxic effector cell. Antigen-driven generation of effector CD8+cells was impaired in OT-I T cell receptor transgenic mice lacking T-bet, resulting in diminished cytotoxicity and a marked shift in cytokine secretion profiles. Furthermore, mice lacking T-bet responded poorly to infection with lymphocytic choriomeningitis virus. T-bet is a key player in the generation of type 1 immunity, in both Th and T cytotoxic cells.

Most computer science departments provide their students with a mathematical foundation which enables them to master theoretic concepts. However, students often express the concern that they are applying their theoretic background to "toy" problems only. They wonder what "real" problems look like and whether or not their background will be sufficient for them when they are faced with an industrial situation. At the same time companies who are hoping to hire well prepared computer programmers, systems analysts, and other technical staff express their concern that recent graduates entering the workforce are not adequately prepared for dealing with large problems in a real world setting. The approach presented here addresses the problem of bridging the gap between theory and practice by actively seeking out industrial partners who provide academics with real problems that can be addressed by teams of students in the academic setting.

A new computer science course is being developed in a collaboration with faculty at three universities and industrial partners, the purpose of which is to bridge the gap between theory and practice and to promote a partnership between industry and academia. Industrial partners provide requirements statements for real problems from their own workload. Students use their knowledge to design solutions by applying research ideas. The course differs significantly from standard industrial project courses in that the case-studies are used both for instructional as well as project purposes and are carefully chosen and designed a priori. The course has the following broad objectives: to expose students to a variety of prototypical real-world projects; to apply, in a noncompartmentalized manner, a combination of formal and theoretical concepts, techniques and results in real situations; to illustrate recent theoretical research results in the context of a chain of applications leading to the solution of a real-world problem; and to involve students in design and implementation of one or two subsystems while being conscious of the subsystem role in the overall system being developed.

Measure-theoretic aspects of the /spl les//sub m//sup P/-reducibility structure of exponential time complexity classes E=DTIME(2/sup linear/) and E/sub 2/=DTIME(2/sup polynomial/) are investigated. Particular attention is given to the complexity (measured by the size of complexity cores) and distribution (abundance in the sense of measure) of languages that are /spl les//sub m//sup P/-hard for E and other complexity classes. Tight upper and lower bounds on the size of complexity cores of hard languages are derived. The upper bounds say that the /spl les//sub m//sup P/-hard languages for E are unusually simple in, the sense that they have smaller complexity cores than most languages in E. It follows that the /spl les//sub m//sup P/-complete languages for E form a measure 0 subset of E (and similarly in E/sub 2/). This latter fact is seen to be a special case of a more general theorem, namely, that every /spl les//sub m//sup P/-degree (e.g. the degree of all /spl les//sub m//sup P/-complete languages for NP) has measure 0 in E and in E/sub 2/. >

Given a collection of biologically related protein or DNA sequences, the basic multiple sequence alignment problem is to determine the most biologically plausible alignment of these sequences. Under the assumption that the collection of sequences arose from some common ancestor, an alignment can be used to infer the evolutionary history among the sequences, i.e., the most likely pattern of insertions, deletions and mutations that transformed one sequence into another. The general multiple sequence alignment problem is known to be NP-hard, and hence the problem of finding the best possible multiple sequence alignment is intractable. However, this does not preclude the possibility of developing algorithms that produce near optimal multiple sequence alignments in polynomial time. We examine techniques to combine efficient algorithms for near optimal global and local multiple sequence alignment with evolutionary computation techniques to search for better near optimal sequence alignments. We describe our evolutionary computation approach to multiple sequence alignment and present preliminary simulation results on a set of 17 clusters of orthologous groups of proteins (COGs). We compare the fitness of the alignments given by the proposed techniques with the fitness of CLUSTAL W alignments given in the COG database.

Platelet/endothelial cell adhesion molecule-1 (PECAM-1, CD31), a 130-kDa glycoprotein member of the Ig superfamily of transmembrane proteins, is expressed on endothelial cells, platelets, and subsets of leukocytes. It functions as a cell adhesion molecule as well as a scaffolding molecule capable of modulating cellular signaling pathways. In this study, using PECAM-1–deficient (KO) mice, as well as cells derived from these mice, we demonstrate that the absence of PECAM-1 expression is associated with an early onset of clinical symptoms during experimental autoimmune encephalomyelitis (EAE), a mouse model for the human autoimmune disease multiple sclerosis. During EAE, mononuclear cell extravasation and infiltration of the CNS occur at earlier time points in PECAM-KO mice than in wild-type mice. In vitro, T lymphocyte transendothelial migration across PECAM-KO endothelial cells is enhanced, regardless of expression of PECAM-1 on transmigrating T cells. Additionally, cultured PECAM-KO endothelial cells exhibit prolonged permeability changes in response to histamine treatment compared with PECAM-1–reconstituted endothelial cells. Lastly, we demonstrate an exaggerated and prolonged CNS vascular permeability during the development of EAE and a delay in restoration of dermal vascular integrity following histamine challenge in PECAM-KO mice.