Previous studies showed that sensory feedback from the body wall is important and sometimes critical for generating normal, robust swimming activity in leeches. In this paper, we evaluate the role of sensory feedback in intersegmental coordination using both behavioral and physiological measurements. We severed the ventral nerve cord of leeches in midbody and then made video and in situ extracellular recordings from swimming animals. Our electrophysiological recordings unequivocally demonstrate that active intersegmental coordination occurs in leeches with severed nerve cords, refuting earlier conclusions that sensory feedback cannot coordinate swimming activity. Intersegmental coordination can in fact be achieved by sensory feedback alone, without the intersegmental interactions conveyed by the nerve cord.

Estrogen receptor alpha (ER␣) degradation is regulated by ubiquitination, but the signaling pathways that modulate ER␣ turnover are unknown. We found that extracellular signal-regulated kinase 7 (ERK7) preferentially enhances the destruction of ER␣ but not the related androgen receptor. Loss of ERK7 was correlated with breast cancer progression, and all ER␣-positive breast tumors had decreased ERK7 expression compared to that found in normal breast tissue. In human breast cells, a dominant-negative ERK7 mutant decreased the rate of endogenous ER␣ degradation >4-fold in the presence of hormone and potentiated estrogen responsiveness. ERK7 targets the ER␣ ligand-binding domain for destruction by enhancing its ubiquitination. Thus, ERK7 is a novel regulator of estrogen responsiveness through its control of ER␣ turnover.Estrogen receptor alpha (ER␣) belongs to the superfamily of ligand-activated transcription factors (7). This superfamily shares a common modular structure, which consists of an Nterminal region, a DNA-binding domain, and a ligand-binding domain. ER␣ regulates the expression of genes involved in growth and development and plays an important role in breast and endometrial cancers. The cellular response to estrogens in vivo is ER␣ limited (33), and a key mechanism in regulating ER␣ concentration is receptor degradation (2). Loss of ER␣ is associated with aggressive breast tumors and poor clinical outcome, and it is essential, therefore, to understand the molecular basis for the control of ER␣ turnover.In response to estradiol, the rate of ER␣ degradation through ubiquitination and the 26S proteasome pathway is increased by an unknown mechanism (2,20,22,35). The 26S proteasome pathway is the major pathway of regulated proteolysis in eukaryotes and is responsible for the destruction of ubiquitinated substrates (32). Ubiquitin is a 76-amino-acid protein that can be covalently attached to a lysine residue on the substrate through the action of an enzyme cascade involving E1, E2, and E3 enzymes. E1 activates ubiquitin and transfers it to E2 enzymes, which transfer ubiquitin to the substrate by themselves or in cooperation with E3 enzymes. E2 and E3 enzymes both contribute to target specificity.Parallel studies on other members of the nuclear receptor superfamily have suggested a role for mitogen-activated protein kinase (MAPK) (also referred to as extracellular signalregulated kinase 1/2 [ERK1/2]) in regulating receptor turnover. For example, MAPK(ERK1/2) phosphorylation of Ser-294 in the human progesterone receptor increases the progesterone receptor degradation rate (18). MAPK(ERK1/2) is also known to phosphorylate ER␣, and we therefore investigated whether MAPK(ERK1/2) enhances ER␣ turnover (4, 14). MAPK(ERK1/2) belongs to a kinase subgroup, the activity of which is regulated by phosphorylation and/or dephosphorylation of threonine and tyrosine residues present in a Thr-Glu-Tyr (TEY) motif within the activation loop. Other members of this subgroup include ERK5 and ERK7. MAP-K(ERK1/2) and ERK5 are both act...

Objective. To examine the predictive role of HLA genetic markers in scleroderma renal crisis (SRC), beyond the known clinical correlates, in a large population of patients with systemic sclerosis (SSc).Methods. SSc patients from the Scleroderma Family Registry and DNA Repository, the Genetics versus Environment in Scleroderma Outcomes Study, and the rheumatology division registry at the University of Texas Health Science Center at Houston were included in the study. Relevant clinical data were obtained by chart review, and autoantibodies were detected utilizing commercially available kits. HLA class II genotyping was performed on extracted and purified genomic DNA.Results. Overall, 1,519 SSc patients were included in the study, of whom 90 (6%) had developed SRC.

In the HAART era, HIV-infected individuals can be affected by various rheumatic syndromes including arthritis, spondyloarthritis, DILS, vasculitides, connective tissue disease, myopathies, and musculoskeletal diseases. With the use of HAART, the prevalence of spondyloarthritis and Diffuse Infiltrative Lymphocytosis Syndrome has decreased, whereas the musculoskeletal complications of HIV and HAART, such as osteopenia, osteonecrosis, and infection continue to be a concern. With immune restoration, various inflammatory and autoimmune diseases, such as SLE, rheumatoid arthritis, and polymyositis may occur de novo or exacerbate. Most antirheumatic therapies used in HIV-negative individuals appear to be safe and effective in the setting of HIV infection as long as prudent guidelines are followed.