Therapy of experimental allergic encephalomyelitis under circumstances relevant to human multiple sclerosis - Part II [abstract]

Abstract only availableFaculty Mentor: Habib Zaghouani, Molecular Microbiology and ImmunologyExperimental allergic encephalomyelitis (EAE) is an inflammatory disease of the central nervous system (CNS) that resembles human multiple sclerosis (MS). EAE and MS develop when proteins of the myelin sheath that covers axons are released and encounter cells of the immune system such as T lymphocytes. Activation of these lymphocytes will trigger inflammation that destroys the myelin leading to clinical signs that manifest mostly in the form of motion impairment and muscle paralysis. Inactivation of myelin specific lymphocytes is currently viewed as a means to halt immune attack against the brain and reverse the course of disease. Previous research in our lab has shown that peptide delivery on immunoglobulin (Ig) is effective against EAE. This method of treatment presents a clinical challenge for use in humans, however, because it involves intraperitoneal injection of the chimeric Ig (Ig-MOG). We have determined that the oral route, which is more practical, yields comparable results against the disease. This model is also useful for investigation of mechanisms of oral tolerance.Life Sciences Undergraduate Research Opportunity Progra

Ergonomic assessment of musculoskeletal risk factors at four mine sites: underground coal, surface copper, surface phosphate, and underground limestone

"This study examined musculoskeletal injury risk at four mining sites: underground coal, underground limestone, surface copper, and surface phosphate. Each site offered opportunities to investigate musculoskeletal disorder (MSD) injury risks and how those risks might be identified and categorized. The National Institute for Occupational Safety and Health (NIOSH) worked with these sites to (1) identify work activities that showed evidence of MSD injury risk, (2) examine physical risk factors that can lead to MSDs for a handful of work tasks at each site, and (3) develop a set of ideas for problem-solving to help reduce risk factors for examined work tasks. For each site, NIOSH implemented a plan that was refined over the time period of this study. The plan consisted of four steps. The first step was to use mine injury records, a musculoskeletal discomfort questionnaire, front-line supervisor interviews, and a list of management concerns to identify work groups and work activities that have significant evidence of MSD risk factors. The second step was to select work tasks for evaluation. The third step was to interview those who do the work and make observations to characterize the MSD risk factors and musculoskeletal symptoms that exist for target tasks. The final step was to conduct brainstorming sessions with workers who perform the work or have a stake in the production task. The brainstorming sessions served to identify general strategies (ideas) for reducing MSD risk factor exposures. A final report of findings was presented to mine management and workforce representatives at each site. The risk factors and ideas for improvement identified for each site were specific to the target tasks examined. These target tasks were diverse, but there were some key similarities. For instance, jobs were found at each site that required a significant amount of manual work involving the upper extremities and low back. Handling heavy and awkward objects, forceful arm and shoulder exertions, and working in awkward postures were common for a variety of jobs across the four sites." - NIOSHTIC-2by William J. Wiehagen and Fred C. Turin."August 2004."Also available via World Wide Web.Includes bibliographical references (p. 12)

Forkhead Transcription Factors Foxp1 and Foxp4 Regulate T Cell Development and Function

Transcription factors regulate T cell fates at every stage of development and differentiation. Members of the FoxP family of Forkhead transcription factors are essential for normal T lineage development; Foxp3 is required for regulatory T cell generation and function, and Foxp1 is necessary for the development of naïve T cells. FoxP family member Foxp4 is highly homologous to Foxp1 and has been shown to dimerize with other FoxP proteins. In this thesis, we report the first studies of Foxp4 in T lymphocytes. Using a CD4Cre-mediated conditional knockout approach we evaluated the roles for Foxp4 regulation in the T lineage. T cell development and homeostasis are normal in the absence of Foxp4. Despite effective control of infection with Toxoplasma gondii or acute Lymphocytic choriomeningitis virus in vivo, cytokine production during antigen-specific rechallenge is reduced in the absence of Foxp4. We conclude that Foxp4 is dispensable for T cell development, but necessary for normal memory T cell recall responses to antigen in acutely or chronically infected mice. Next we determined whether FoxP family members compensate for one another in Foxp1- or Foxp4-knockout models. We utilized a similar CD4Cre approach to delete both Foxp1 and Foxp4 in T cells. Foxp1/4-deficient T cells exhibit abnormal thymic development and T cell receptor signaling. Loss of Foxp1/4 results in significantly reduced T cell numbers, and altered T cell effector function, reminiscent of Foxp1-deficient T cells. Lastly, we examined the functions of Foxp1/4 in Foxp3+ regulatory T cells (Tregs). Tregs are critical for prevention of autoimmunity and controlling immune responses during infection. While conditional deletion of either Foxp1 or Foxp4 in T cells has little effect on Tregs, combined deletion results in abnormal Treg generation. Foxp1/4-deficient Tregs exhibited significant defects in both development and homeostasis. Under competitive conditions, double-deficient Tregs are at a significant developmental disadvantage relative to wild-type competitors. Furthermore, Foxp1/4-deficient Tregs exhibit impaired cytokine-induced STAT5 phosphorylation and reduced expression of Foxp3, suggesting Foxp1/4 is required for normal Treg generation. Together, these findings demonstrate that the FoxP family regulates multiple facets of T cell development and function, and actively contributes to the maintenance of immunological tolerance

Learning and consistency

In designing learning algorithms it seems quite reasonable to construct them in such a way that all data the algorithm already has obtained are correctly and completely reflected in the hypothesis the algorithm outputs on these data. However, this approach may totally fail. It may lead to the unsolvability of the learning problem, or it may exclude any efficient solution of it. Therefore we study several types of consistent learning in recursion-theoretic inductive inference. We show that these types are not of universal power. We give “lower bounds ” on this power. We characterize these types by some versions of decidability of consistency with respect to suitable “non-standard ” spaces of hypotheses. Then we investigate the problem of learning consistently in polynomial time. In particular, we present a natural learning problem and prove that it can be solved in polynomial time if and only if the algorithm is allowed to work inconsistently. 1

Learning Recursive Functions Refutably

Learning of recursive functions refutably means that for every recursive function, the learning machine has either to learn this function or to refute it, i.e., to signal that it is not able to learn it. Three modi of making precise the notion of refuting are considered. We show that the corresponding types of learning refutably are of strictly increasing power, where already the most stringent of them turns out to be of remarkable topological and algorithmical richness. All these types are closed under union, though in different strengths. Also, these types are shown to be different with respect to their intrinsic complexity; two of them do not contain function classes that are “most difficult” to learn, while the third one does. Moreover, we present characterizations for these types of learning refutably. Some of these characterizations make clear where the refuting ability of the corresponding learning machines comes from and how it can be realized, in general. For learning with anomalies refutably, we show that several results from standard learning without refutation stand refutably. Then we derive hierarchies for refutable learning. Finally, we show that stricter refutability constraints cannot be traded for more liberal learning criteria

On Learning of Functions Refutably

Learning of recursive functions refutably informally means that for every recursive function, the learning machine has either to learn this function or to refute it, that is to signal that it is not able to learn it. Three modi of making precise the notion of refuting are considered. We show that the corresponding types of learning refutably are of strictly increasing power, where already the most stringent of them turns out to be of remarkable topological and algorithmical richness. Furthermore, all these types are closed under union, though in different strengths. Also, these types are shown to be different with respect to their intrinsic complexity; two of them do not contain function classes that are “most difficult” to learn, while the third one does. Moreover, we present several characterizations for these types of learning refutably. Some of these characterizations make clear where the refuting ability of the corresponding learning machines comes from and how it can be realized, in general.For learning with anomalies refutably, we show that several results from standard learning without refutation stand refutably. From this we derive some hierarchies for refutable learning. Finally, we prove that in general one cannot trade stricter refutability constraints for more liberal learning criteria

A Map of Update Constraints in Inductive Inference

We investigate how different learning restrictions reduce learning power and how the different restrictions relate to one another. We give a complete map for nine different restrictions both for the cases of complete information learning and set-driven learning. This completes the picture for these well-studied \emph{delayable} learning restrictions. A further insight is gained by different characterizations of \emph{conservative} learning in terms of variants of \emph{cautious} learning. Our analyses greatly benefit from general theorems we give, for example showing that learners with exclusively delayable restrictions can always be assumed total.Comment: fixed a mistake in Theorem 21, result is the sam

Prevalence and ergonomic risk factors of work-related musculoskeletal injuries amongst underground mine workers in Zambia

Work-related musculoskeletal injuries (WMSIs) are common in both developed and third world countries. Most researchers agree that exposure to ergonomic risk factors is a major contributor to these injuries. Objective: The aim of this study was to determine the prevalence of and ergonomic risk factors associated with WMSIs amongst underground mine workers in Kitwe, Zambia. Methods: A cross-sectional quantitative study was conducted using a sample size of 500 workers. A stratified random sampling method according to mining work activity type was used to obtain the sample. Data was collected by means of a structured questionnaire, and the Statistical Package for Social Sciences (SPSS) was used to analyze data using descriptive and inferential statistical methods. Results were significant at 5%. Results: A response rate of 40.4% (202) was obtained. The 12-month prevalence of WMSIs was 42.6%. The mean age of the workers was 40.31 years (SD +/− 8.57 years). Electricians and mechanics reported the highest injury frequencies. The back was the most affected body part. Ergonomic risk factors consistently reported by workers included poor postures and heavy lifting. There were significant (p=0.020) associations between working with the back bent and sustaining a back injury. Significant (p=0.049) associations were also found between injuries of the wrists/hands and grasping an unsupported object(s). Conclusions: This study revealed significant associations between WMSIs and ergonomic risk factors like working with the back bent and grasping object.Web of Scienc

Therapy of experimental allergic encephalomyelitis under circumstances relevant to human multiple sclerosis

Abstract only availableExperimental allergic encephalomyelitis (EAE) is an inflammatory disease of the central nervous system (CNS) that resembles human multiple sclerosis (MS). EAE and MS develop when proteins of the myelin sheath that covers axons are released and encounter cells of the immune system such as T lymphocytes. Activation of these lymphocytes will trigger inflammation that destroys the myelin leading to clinical signs that manifest mostly in the form of motion impairment and muscle paralysis. Inactivation of myelin specific lymphocytes is currently viewed as a means to halt immune attack against the brain and reverse the course of disease. In this study we devised an antigen specific approach against EAE and tested its efficacy in an advanced genetic setting, which would better represent the human genetic polymorphism. Therefore, we have created an F1(SJL/J x Bl/6) mouse for analysis of the reversal of compatible as well as “in trans” EAE where the disease is induced by a peptide restricted to one parent and the treatment uses a fusion protein carrying a peptide restricted to the other parent. The results indicate that the effectiveness of the treatment depends on the method of disease induction and the genetic makeup of the mouse.Life Sciences Undergraduate Research Opportunity Progra