The CCL2 Synthesis Inhibitor Bindarit Targets Cells of the Neurovascular Unit, and Suppresses Experimental Autoimmune Encephalomyelitis

Background Production of the chemokine CCL2 by cells of the neurovascular unit (NVU) drives critical aspects of neuroinflammation. Suppression of CCL2 therefore holds promise in treating neuroinflammatory disease. Accordingly, we sought to determine if the compound bindarit, which inhibits CCL2 synthesis, could repress the three NVU sources of CCL2 most commonly reported in neuroinflammation – astrocytes, microglia and brain microvascular endothelial cells (BMEC) – as well as modify the clinical course of neuroinflammatory disease. Methods The effect of bindarit on CCL2 expression by cultured murine astrocytes, microglia and BMEC was examined by quantitative reverse transcription polymerase chain reaction (qRTPCR). Bindarit action on mouse brain and spinal cord in vivo was similarly investigated by qRT-PCR following LPS injection in mice. And to further gauge the potential remedial effects of bindarit on neuroinflammatory disease, its impact on the clinical course of experimental autoimmune encephalomyelitis (EAE) in mice was also explored. Results Bindarit repressed CCL2 expression by all three cultured cells, and antagonized upregulated expression of CCL2 in both brain and spinal cord in vivo following LPS administration. Bindarit also significantly modified the course and severity of clinical EAE, diminished the incidence and onset of disease, and evidenced signs of disease reversal. Conclusion Bindarit was effective in suppressing CCL2 expression by cultured NVU cells as well as brain and spinal cord tissue in vivo. It further modulated the course of clinical EAE in both preventative and therapeutic ways. Collectively, these result

Active Induction of Experimental Autoimmune Encephalomyelitis by MOG35-55 Peptide Immunization is Associated with Differential Responses in Separate Compartments of the Choroid Plexus

Background There is increasing awareness that, aside from producing cerebrospinal fluid, the choroid plexus (CP) might be a key regulator of immune activity in the central nervous system (CNS) during neuroinflammation. Specifically, the CP has recently been posited to control entry of sentinel T cells into the uninflamed CNS during the early stages of neuroinflammatory diseases, like multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). As the CP is compartmentalized into a stromal core containing fenestrated capillaries devoid of typical blood–brain barrier properties, surrounded by a tight junction-expressing choroidal epithelium, each of these compartments might mount unique responses that instigate the neuroinflammatory process. Methods To discern responses of the respective CP stromal capillary and choroidal epithelial tissues during evolving neuroinflammation, we investigated morphology and in situ expression of 93 immune-related genes during early stages of EAE induced by immunization with myelin oligodendrocyte glycoprotein peptide (MOG35-55). Specifically, 3-D immunofluorescent imaging was employed to gauge morphological changes, and laser capture microdissection was coupled to an Immune Panel TaqMan Low Density Array to detail alterations in gene expression patterns at these separate CP sites on days 9 and 15 post-immunization (p.i.). To resolve CP effects due to autoimmunity against MOG peptide, from those due to complete Freund’s adjuvant (CFA) and pertussis toxin (PTX) included in the immunization, analysis was performed on MOG-CFA/PTX-treated, CFA/PTX-treated, and naïve cohorts. Results The CP became swollen and displayed significant molecular changes in response to MOGCFA/ PTX immunization. Both stromal capillary and choroidal epithelial tissues mounted vigorous, yet different, changes in expression of numerous genes over the time course analyzed - including those encoding adhesion molecules, cytokines, chemokines, statins, interleukins, T cell activation markers, costimulatory molecules, cyclooxygenase, proinflammatory transcription factors and pro-apoptotic markers. Moreover, CFA/PTXtreatment, alone, resulted in extensive, though less robust, alterations in both CP compartments. Conclusions MOG-CFA/PTX immunization significantly affects CP morphology and stimulates distinct expression patterns of immune-related genes in CP stromal capillary and epithelial tissues during evolving EAE. CFA/PTX treatment, alone, causes widespread gene alterations that could prime the CP to unlock the CNS to T cell infiltration during neuroinflammatory disease

Lookout, Volume 8, Number 5, November 1903

In 1896, the students of the Storrs Agricultural College established a student newspaper, The Lookout. Published every month, The Lookout had a small, unpaid staff who laid out the pages by hand using tiny metal slugs with embossed letters from a printer\u27s California job case. By 1914, the paper had changed its name to The Connecticut Campus, reflecting the growth of the institution that had become the Connecticut Agricultural College in 1899 and the student newspaper increased its publication schedule to twice a month. The paper continued to grow along with the campus in Storrs, CT, and in 1953 the The Connecticut Campus, which had moved from being published monthly, to weekly and then to a three days a week publication schedule made its last transition to becoming a daily newspaper. In 1955, the renamed Connecticut Daily Campus becomes a morning paper that is printed on newsprint. In the 1970s, the University of Connecticut Board of Trustees granted the Connecticut Daily Campus its independence from the Associated Student Government. Currently, Daily Campus is the largest daily college newspaper in the state of Connecticut and employs more than 120 students during the academic year. Published Monday through Friday during the academic year, 10,000 copies are delivered to over 80 locations both on- and off-campus

Lookout, Volume 7, Number 8, February 1903

In 1896, the students of the Storrs Agricultural College established a student newspaper, The Lookout. Published every month, The Lookout had a small, unpaid staff who laid out the pages by hand using tiny metal slugs with embossed letters from a printer\u27s California job case. By 1914, the paper had changed its name to The Connecticut Campus, reflecting the growth of the institution that had become the Connecticut Agricultural College in 1899 and the student newspaper increased its publication schedule to twice a month. The paper continued to grow along with the campus in Storrs, CT, and in 1953 the The Connecticut Campus, which had moved from being published monthly, to weekly and then to a three days a week publication schedule made its last transition to becoming a daily newspaper. In 1955, the renamed Connecticut Daily Campus becomes a morning paper that is printed on newsprint. In the 1970s, the University of Connecticut Board of Trustees granted the Connecticut Daily Campus its independence from the Associated Student Government. Currently, Daily Campus is the largest daily college newspaper in the state of Connecticut and employs more than 120 students during the academic year. Published Monday through Friday during the academic year, 10,000 copies are delivered to over 80 locations both on- and off-campus

Conservation and Diversification of Appendage Identity Specification Mechanisms Along the Anteroposterior and Proximodistal Axes in Panarthropoda

In Chapter 1, the roles of genes that specify antennal identity in Drosophila melanogaster were investigated in the flour beetle Tribolium castaneum. Antenna-to-leg transformations occurred in response to RNA interference (RNAi) against homothorax, extradenticle, spineless and Distal-less. However, for homothorax/extradenticle RNAi, the extent of transformation along the proximodistal axis differed between embryogenesis and metamorphosis. In chapter 2, the metamorphic roles of the Hox genes, extradenticle, and homothorax were compared in T. castaneum. homothorax/extradenticle RNAi and Hox RNAi produced similar body wall phenotypes but different appendage phenotypes. These results suggest that Hox genes require extradenticle and homothorax to specify sclerite identities in the thorax and abdomen during metamorphosis. On the other hand, the Hox genes act independently of extradenticle or homothorax to specify appendage identities along the body axis, while extradenticle and homothorax do not require Hox genes to impart proximal identity to appendage podomeres. In Chapter 3, the body plan of the tardigrade Hypsibius dujardini was characterized using anti-β-tubulin immunostaining and phalloidin staining. These methods revealed differences in the nervous system and musculature that make each segment unique. In Chapter 4, the embryonic role of the gene Distal-less was investigated in H. dujardini. It is expressed in the pharyngeal stylets and across the entire proximodistal appendage axis. The uniform expression of Distal-less in developing appendages is consistent with the lesser degree of morphological regionalization exhibited in tardigrade appendages relative to arthropod appendages

On the Integrated Squared Error of the Linear Wavelet Density Estimator

Archival abstract submitte

The Impact of Brief Clinical Interventions on Cardiovascular Reactions to Acute Stress

The Impact of Brief Clinical Interventions on Cardiovascular Reactions to Acute Stress Katherine Elizabeth O’Leary University of Connecticut, 2013 Stress is a major public health concern due to its’ harmful effects on physical and mental health. An important goal for clinical health practitioners is to help patients reduce the psychological and physiological burden of stress. The present study sought to examine the impact brief clinical interventions have on cardiovascular reactions to acute stress. Additionally, we explored how depressive and anxiety symptomatology influence cardiovascular reactivity and recovery, and their moderating effects on treatment response to interventions. To address these aims, subjects were randomized into one of three conditions (Acceptance and Commitment Therapy, Autogenic Training, Attention-only Control group) prior to undergoing an acute psychosocial stress paradigm, the Trier Social Stress Test (TSST). Psychosocial measures were given at baseline, and heart rate and blood pressure measurements were obtained at various time points throughout the protocol. Our results indicated a time by group interaction for heart rate (HR) and diastolic blood pressure (DBP), demonstrating that brief interventions differentially affected heart rate and diastolic blood pressure over time. Within the Autogenic Training group results showed that subjects with higher levels of depressive symptomatology had lower systolic blood pressure reactivity compared to those with lower levels of depressive symptoms. Additionally, within the Autogenic Training group, greater recovery in both systolic and diastolic blood pressure was found in subjects with higher levels of social anxiety. Our results offer important implications for clinical assessment and intervention, particularly within the field of behavioral medicine