44 research outputs found
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Men's Cross Country team, 1973
No full textFront Row: R. Danurand, J. Osowski, D. Long, N. Wright, B. Belliveau, R. LaFreniere, R. Mandevill, A. Hallquist, P. Graffey, D. Legnard; Second Row- S. Sweeney, C. Keenan, R. Newhouse, D. Fowler, A. Briggs, A. Vogt, J. Wnek, M. Schesser, C. Owne, A. Richard; Back Row: M. Severino, Asst. Coach A. Hoffman, K. Lutgens, M. Koronkowicz, A. Clark, Mgr. J. Fitzpatrick, Coach F. Sanell
Multimodal pain therapy for treatment of chronic pain syndrome. Consensus paper of the ad hoc commission on multimodal interdisciplinary pain management of the German Pain Society on treatment contents
No full textMultimodal pain management is a comprehensive treatment of complex chronic pain syndromes. In addition to medical therapy various other specialized therapeutic interventions based on the biopsychosocial model of pain origin and chronic pain development, are added. During the last few years treatment centers for chronic pain have been established throughout Germany. Multimodal pain management has been included in the official catalogue of the recognized medical procedures for day clinic units as well as for inpatient pain management. In daily practice there is, however, still a lack of clarity and of consistency about the components that multimodal pain management should contain. This is the reason for the ad hoc commission on multimodal interdisciplinary pain management of the German Pain Society to propose the following position paper that has been worked out in a multilevel and interdisciplinary consensus process. The paper describes the mandatory treatment measures in the four core disciplines of multimodal pain management, pain medicine, psychotherapy, exercise therapy including physiotherapy and assistant medical professions including nurses
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Pathogenicity Modeling of the Chlamydia trachomatis T3SS Effector CT694 Reveals Novel Host Targets
No full textChlamydia trachomatis is the most prevalent bacterial sexually transmitted disease as well as the leading cause of preventable blindness worldwide. Virulence of C. trachomatis depends on the secretion and translocation of effector proteins into host cells through a type III secretion system. One such effector is CT694, a protein that is specific to C. trachomatis and C. muridarum. Previous studies demonstrated that CT694 localizes to the plasma membrane of HeLa cells, where the C-terminus of CT694 interacts with the giant human protein Ahnak. Expression of CT694 also disrupts actin stress fibers; however, this is at least partially independent of interaction with the cytoskeletal protein-associated Ahnak, suggesting that a separate domain is responsible for this phenotype. Evidence is presented herein that endogenous CT694 localizes to host cell membranes and that this localization is dependent on a discrete domain, termed the membrane localization domain (MLD). Further, localization and localization-dependent activity of ectopically-expressed CT694 is also manifested in two unrelated species of yeast, suggesting that the host cell target of CT694 is highly conserved. Truncation analyses in fission yeast Schizosaccharomyces pombe further revealed the presence of a toxicity domain located between amino acids 151 and 222, which was confirmed by epifluorescent imaging of HeLa cells expressing CT694 deletion mutants. A synthetic genetic analysis in S. pombe was undertaken to identify pathways targeted by CT694 expression. As a result, the Elongator complex and Cdc42 were identified as novel host cell targets of CT694.</p
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The Role of PDGF AND Rac1-induced Oxidative Signaling in the Viral Oncogenesis of Kaposi's Sarcoma
No full textKaposi's sarcoma (KS), caused by the oncogenic Kaposi's sarcoma herpesvirus (KSHV), is an angiogenic tumor characterized by intense angiogenesis, inflammation and proliferation of KSHV-infected spindle cells. We describe the characterization of a mouse model of KS by transfection of a KSHV bacterial artificial chromosome (KSHVBac36) into mouse bone marrow endothelial-lineage cells which generated a cell (mECK36) that forms KS-like tumors in mice. Our results define mECK36 as a biologically sensitive animal model of KSHV-dependent KS with the following characteristics: (1) the pathological phenotype is a consequence of KSHV gene expression in normal progenitor cells subjected to in vivo growth conditions, (2) the histopathologic phenotype of the tumors resembles KS lesions, and (3) the model is suitable for analysis of vGPCR-driven tumorigenesis in the context of the whole KSHV genome. The mechanism by which vGPCR promotes tumorigenesis is not fully understood. The characterization of a Rac1 transgenic mouse model that produces KS-like lesions that highly resemble human KS has helped us to identify the potential role of Rac1, which is activated by vGPCR, in the pathogenesis of KS. The results from the RacCA transgenic mouse suggest that viral and host genes triggering Rac1 and ROS production may play an important role in KS tumorigenesis. We set out to determine how vGPCR physiologically activates Rac1 in KSHV-infected cells in the KS model mECK36. We found that KSHV oncogenesis in mECK36 is promoted by vGPCR activation of a paracrine oncogenic mechanism through PDGF-BB, which requires a Rac1- and ROS-mediated loop, leading to STAT3 transcriptional activation of c-Myc, VEGF and KSHV latent viral gene expression. We also found that the latency-associated nuclear antigen (LANA) upregulates the PDGFR in vivo, priming latently-infected cells to the PDGF signaling pathway. This oncogenic mechanism can be targeted with the antioxidant N-acetylcysteine (NAC) and FDA-approved PDGF receptor inhibitors to control KSHV-induced tumorigenesis. Our results highlight a ROS-dependent axis whereby Rac1 activating oncogenes and inflammatory signaling drive paracrine stimulation of neoplastic growth and angiogenesis in neighboring cells, defining this axis and its components as attractive anti-tumor targets in KS pathogenesis.</p
Ribosome Degradation in Escherichia coli
No full textUpon termination of translation, the fate of ribosomes is determined largely by the rate at which cells are growing. During periods of exponential growth, ribosomes are rapidly recycled, translation is re-initiated, and the ribosomes are extremely stable. However, when nutrient sources become limiting, and ribosomes are not actively translating, they may become substrates for degradation. While this phenomenon is well known, details of how the process is initiated and what are the signals for degradation have, until now, remained elusive. Here, I present in vitro and in vivo data showing that free ribosome subunits are the targets of degradative enzymes, whereas 70S particles that remain associated are protected from such degradation. Conditions that increase the formation of subunits both in vitro and in vivo lead to enhanced degradation. Thus, the simple presence of free 50S and 30S subunits is sufficient to serve as the mechanism that initiates ribosome degradation. In order to identify RNases involved in ribosome degradation, both in vitro and in vivo assays were developed. Together, they have provided evidence for a multi-step degradation process involving both endo- and exoribonucleases. Examination of extracts from strains deficient in known RNases revealed that the endoribonucleases, RNase E and RNase G, may be involved in the initial cleavages. The resulting fragments, some of which are small enough oligoribonucleotides that they remain part of the acid-soluble fraction are degraded to mononucleotides primarily by the 3'-5' exoribonucleases, RNase R and polynucleotide phosphorylase.</p
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Murine Neonates Infected with Yersinia enterocolitica Develop Rapid and Robust Pro-Inflammatory Responses in the Intestinal Lymphoid Tissues
No full textIt is becoming increasingly apparent that neonates are not immune-compromised, but rather immune-variant. We have described a neonatal model of Yersinia enterocolitica infection in which protective inflammation occurs at the level of the mesenteric lymph nodes (MLN). The expression of pro-inflammatory, but not anti-inflammatory, cytokine genes was markedly induced in the neonatal MLN early after infection. Strikingly, the expression levels in neonates greatly exceeded those seen in infected adults. Elevated pro-inflammatory gene expression was quickly followed by enhanced innate phagocyte recruitment to the MLN of neonates, compared to adults. Neither CD4+ nor B cells were required for inflammation in the neonatal MLN; however, CD4+ and CD8+ cells did increase as well as innate cells as early as 24 hours post-infection. Although MyD88 was shown to be critical in eliciting inflammation in neonates, neither TLR4 nor TLR9 were required. Because Y. enterocolitica contains ligands for multiple TLRs, it is possible that compensation by other TLRs is sufficient to elicit inflammation in the absence of TLR4 or TLR9. Bacterial components were also critical in eliciting high level inflammation in the neonatal MLN. The virulence plasmid of Y. enterocolitica was required for selected pro-inflammatory gene expression and neutrophil recruitment to the neonatal MLN. TNF-alpha protein expression and neutrophil recruitment was markedly enhanced in the neonatal MLN after infection with the delta-yopP strain, while only a modest increase occurred in adults. These models suggest that the level of intestinal inflammation in neonates is critical in determining whether protection or pathology occurs following infection with microbial pathogens.</p
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Ribosome Degradation in Escherichia coli
No full textUpon termination of translation, the fate of ribosomes is determined largely by the rate at which cells are growing. During periods of exponential growth, ribosomes are rapidly recycled, translation is re-initiated, and the ribosomes are extremely stable. However, when nutrient sources become limiting, and ribosomes are not actively translating, they may become substrates for degradation. While this phenomenon is well known, details of how the process is initiated and what are the signals for degradation have, until now, remained elusive. Here, I present in vitro and in vivo data showing that free ribosome subunits are the targets of degradative enzymes, whereas 70S particles that remain associated are protected from such degradation. Conditions that increase the formation of subunits both in vitro and in vivo lead to enhanced degradation. Thus, the simple presence of free 50S and 30S subunits is sufficient to serve as the mechanism that initiates ribosome degradation. In order to identify RNases involved in ribosome degradation, both in vitro and in vivo assays were developed. Together, they have provided evidence for a multi-step degradation process involving both endo- and exoribonucleases. Examination of extracts from strains deficient in known RNases revealed that the endoribonucleases, RNase E and RNase G, may be involved in the initial cleavages. The resulting fragments, some of which are small enough oligoribonucleotides that they remain part of the acid-soluble fraction are degraded to mononucleotides primarily by the 3'-5' exoribonucleases, RNase R and polynucleotide phosphorylase.</p
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Physiological Role and Substrates of Rnase D and RNase BN in Escherichia Coli
No full textThere are many ribonucleases in Escherichia coli and, presumably, each one has an important role in RNA metabolism. After an individual RNA has been fully transcribed, the fate of that RNA is determined by its sequence, structure, and the availability of RNases which may be determined by conditions inside and outside of the cell. During periods of exponential growth, the majority of RNA degradation is carried out by RNase II, RNase R and polynucleotide phosphorylase, and the short RNA fragments generated by the degradation process are reduced to individual nucleotides by oligoribonuclease. Maturation of RNAs is performed primarily by RNase III, RNase P, RNase E, RNase G, RNase T and RNase PH. These processes of degradation and maturation represent most of RNA metabolism in cells, and can be accounted for by the aforementioned RNases. However, there are two additional RNases that have no known primary role in RNA metabolism – RNase D and RNase BN. Here, I present in vivo and in vitro data showing that RNase D and, to a lesser extent, RNase BN are responsible for fine tuning regulatory elements in cells by removing at least one RNA that is deleterious for growth and survival when present in excess. This is the mRNA for CsrA, an RNA binding protein that acts in concert with the sigma factor RpoS when cells are growing slowly or not at all. I will also show that cells lacking RNase D take more time to exit lag phase than do cells in which RNase D is present and that this defect is not due to aberrant maturation of ribosomal RNAs. In order to identify RNAs that are substrates for RNase D and RNase BN in vivo, Northern analyses of many stable and messenger RNAs, electrophoresis of radiolabeled RNA and tRNA nucleotidyltransferase assays were carried out, among others. These ruled out tRNA and rRNA as the primary substrates for RNase D and RNase BN during stationary phase and recovery from prolonged starvation. They also revealed that the mRNA for CsrA is upregulated 3- to 4- fold in cells lacking RNase D during early stationary phase and that RNase D and RNase BN are expressed most abundantly during rapid growth. Assays of growth, cell morphology and ability to synthesize critical cellular components like flagella and extracellular matrix were utilized concurrently with the previously noted molecular techniques. These showed that cells lacking RNase D have a reduced ability to synthesize extracellular matrix, show reduced motility, took longer to recover from prolonged starvation, and synthesize more of the messenger molecule cyclic-di-GMP than wild type cells. Cells lacking RNase D and RNase BN were at a competitive disadvantage when grown in low pH conditions. Together, these studies have revealed that these two RNases do indeed have a role in E. coli allowing cells to more efficiently enter and exit rapid growth by fine-tuning the availability of at least one specific RNA that has a deleterious effect when overexpressed. The studies presented here indicate that the roles of of RNase R and RNase BN are subtle and while many substrates have been ruled out, undoubtedly additional substrates remain to be discovered.</p
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Functional Analysis of Human and Mouse Splenic B cells
No full textT-cell independent (TI) antibodies may be critical in closing the gap between early innate and late adaptive immune responses against bacterial pathogens. In the mouse, innate marginal zone (MZ) B cells rapidly produce these antibodies. In humans, the characterization of a MZ B cell equivalent to that of mice is controversial because of phenotypic differences between the two species. Studies suggest that TLR activation upregulate BAFF receptors, TACI and BR3 in mouse splenic B. Upregulation of BAFF receptors is important because the ligands for these receptors, BAFF and APRIL, are critical in the regulation of humoral immune responses and immunoglobulin (Ig) isotype class switching in the context of TI antigens. By comparison of human splenic MZ B cells (MZ) with their well characterized mouse counterparts we investigated a role for innate TLRs and BAFF receptors (BR3 and TACI) in TI antibody responses. I show in this dissertation that among splenic B cells, the bulk of TI antibodies are produced by MZ B cells relative to follicular I and II B cells (FOBI and FOBII) both in human and mouse. Although MZ B cells were most responsive to TLR stimulation in both species, they differed qualitatively in the regulation of BAFF receptors. Human MZ B cells increased TACI, but not BR3. Once the TACI was increased, human MZ B cells produced more IgM and switched to IgA and to a lesser extent to IgG1 in the presence of BAFF or APRIL. Bruton’s tyrosine kinase (Btk) was found to be required to mediate TLR signaling that enhanced expression of antibody regulators, TACI and an atypical IκB, NF-κBid. Together these results suggest that like mouse, human splenic MZ B cells are the major responders to TLR ligand containing TI antigens and require Btk signaling for these TLR driven TI antibody responses.</p
