Brewer Wilkinson (zoocover6)

Epi treatment was able to significantly block HG induced increases in TGF-β1, fibronectin, urea, proline, and total collagen protein levels. GPER levels were reduced by HG and restored in CFs treated with Epi an effect associated with the activation (i.e., phosphorylation) of c-Src. Epi treatment also reverted SMAD levels. Altogether, results demonstrate that CFs cultured in HG acquire a profibrotic phenotype, which is blocked by Epi an effect, likely mediated at least, in part, by GPER effects on the SMAD/TGF-β1 pathway.A diagnosis of lymphedema comes with a lifetime requirement for careful self-care and treatment to control skin deterioration and the consequences of excessive fluid and protein buildup leading to abnormal limb volume and an increased risk of infection. The burden of care and psychosocial aspects of physical disfiguration and loss of function are associated with compromised quality of life (QoL). The current standard therapeutic intervention is complex decongestive therapy with manual lymph drainage and frequent wearing of compression garments. With insurance limitations on therapy visits and the time and travel required, additional home treatment options are needed. Pneumatic compression pumps that mimic the manual massage pressure and pattern are sometimes prescribed, but these are bulky, difficult to apply, and require immobility during treatment. An open-label pilot study in 40 subjects was performed to evaluate the QoL and limb volume maintenance efficacy of a novel wearable compression system (Dayspring™) that is low profile, easy to use, and allows for mobility during treatment. After 28 days of use, subjects had a statistically significant 18% (p less then 0.001) improvement in overall QoL as measured by the Lymphedema Quality-of-Life Questionnaire compared with baseline. Individual QoL domains, and limb volume improved with therapy. Adherence was 98% over the course of the study. Results of the clinical evaluation suggest the Dayspring wearable compression device is safe and effective and improves QoL and limb volume. The novel, low-profile device is easy to use and allows for mobility during treatment, addressing a potential barrier to adherence with pneumatic compression devices.GraS is a membrane sensor in S. aureus that induces mprF and dltABCD expression to alter the surface positive charge upon exposure to cationic human defense peptides (HDPs). The sensing domain of GraS likely resides in the 9-residue extracellular loop (EL). In this study, we assessed a hospital-acquired (HA)-MRSA strain (COL) for the specific role of two distinct EL mutations F38G (bulk) and D/35/37/41K (charged inversion). Activation of mprF by polymyxin B (PMB) was reduced in the D35/37/41K mutant vs the D35/37/41G mutant, correlating with reduced surface positive charge; in contrast, these effects were less prominent in the F38G mutant, although still lower than the parent. These data indicated that both electrostatic charge and steric bulk of the EL of GraS influence induction of genes impacting HDP resistance. Using mprF expression as a readout, we confirmed GraS signaling was pH-dependent, increasing as pH was lowered (pH 7.5 ≫ 5.5). UBCS039 molecular weight In contrast to PMB activation, reduction of mprF was comparable at pH 5.5 between the P38G and D35/37/41K point mutants, indicating a likely mechanistic divergence between GraS activation by acidic pH vs. cationic peptides. Survival assays in human blood and purified PMNs revealed lower survival of the D35/37/41K mutant vs. the F38G mutant, with both lower than the parent. Virulence studies in the rabbit endocarditis model mirrored whole blood and PMN killing assay data above. Collectively, these data confirmed the importance of specific residues within the EL of GraS in conferring essential bacterial responses for MRSA survival in infections.In Gram-positive pathogen Staphylococcus aureus, pore-forming toxins (PFTs) such as leukocidins and hemolysins play pr