DNA–histone complexes as ligands amplify cell penetration and nuclear targeting of anti‐DNA antibodies via energy‐independent mechanisms

We have generated three monoclonal cell‐penetrating antibodies (CPAbs) from a non‐immunized lupus‐prone (NZB × NZW)F₁ mouse that exhibited high anti‐DNA serum titres. These CPAbs are polyreactive because they bind to DNA and other cellular components, and localize mainly in the nucleus of HeLa cells, albeit with a distinct nuclear labelling profile. Herein, we have examined whether DNA–histone complexes (DHC) binding to CPAbs, before cell entry, could modify the cell penetration of CPAbs or their nuclear staining properties. By applying confocal microscopy and image analysis, we found that extracellular binding of purified CPAbs to DHC significantly enhanced their subsequent cell‐entry, both in terms of percentages of positively labelled cells and fluorescence intensity (internalized CPAb amount), whereas there was a variable effect on their nuclear staining profile. Internalization of CPAbs, either alone or bound to DHC, remained unaltered after the addition of endocytosis‐specific inhibitors at 37° or assay performance at 4°, suggesting the involvement of energy‐independent mechanisms in the internalization process. These findings assign to CPAbs a more complex pathogenetic role in systemic lupus erythematosus where both CPAbs and nuclear components are abundant.     

Connective tissue remodeling: cross-talk between endothelins and matrix metalloproteinases

Connective tissue remodeling is achieved by a complex process involving several cell types, a plethora of growth factors, cytokines, chemokines and turnover of extracellular matrix (ECM). The main enzymes that degrade ECM molecules are matrix metalloproteinases (MMPs) and their activities are regulated by endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Recent studies have indicated that endothelins and their receptor expression affects tissue remodeling and repair. Endothelins are rapidly produced by endothelial cells in response to tissue injury and they have potent vasoconstrictive properties. They also promote tissue remodeling through activation of resident connective tissue cells and controlling the production of MMPs and TIMPs by the activated cells. In this review we present the cross-talk between the endothelins and the MMP-TIMP system and their implications in controlling the normal and abnormal tissue remodeling.     

Electrode dysfunctions in patients with deep brain stimulation: a clinical retrospective study

Background  

Electrode fractures are known hardware problems in patients with deep brain stimulation (DBS) and require surgical revision. Short circuits, loose connections or disconnections of only single contacts of the common quadripolar stimulation electrodes are more subtle dysfunctions and can result in decreased efficacy of DBS. Measuring the impedances of electrodes helps detect such technical dysfunctions. This study evaluates the frequency and clinical implications of abnormal impedance measurements.     

Extracellular matrix synthesis in vascular disease:hypertension,and atherosclerosis

Extracellular matrix(ECM) within the vascular network provides both a structural and regulatory role.The ECM is a dynamic composite of multiple proteins that form structures connecting cells within the network.Blood vessels are distended by blood pressure and,therefore,require ECM components with elasticity yet with enough tensile strength to resist rupture.The ECM is involved in conducting mechanical signals to cells.Most importantly,ECM regulates cellular function through chemical signaling by controlling activation and bioavailability of the growth factors.Cells respond to ECM by remodeling their microenvironment which becomes dysregulated in vascular diseases such hypertension,restenosis and atherosclerosis.This review examines the cellular and ECM components of vessels,with specific emphasis on the regulation of collagen type I and implications in vascular disease.     

A Sex-Stratified Analysis of Monocyte Phenotypes Associated with HIV Infection in Uganda

Women with HIV may experience higher rates of non-AIDS comorbidities compared to men with HIV, but the underlying mechanisms are not well understood. We investigated sex-related differences in the effects of HIV on monocyte phenotypes within the Ugandan Study of HIV effects on the Myocardium and Atherosclerosis (mUTIMA). Of 133 participants who provided blood for flow cytometry assays, 86 (65%) were women and 91 (68%) were persons living with HIV (PLWH) on antiretroviral therapy. The median age was 57 (interquartile range, 52–63) years. PLWH exhibited a lower proportion of circulating CD14⁺CD16^- classical monocytes (66.3% vs. 75.1%; p < 0.001), and higher proportion of CD14⁺CD16⁺ inflammatory monocytes (17% vs. 11.7%; p = 0.005) compared to HIV-uninfected participants. PLWH had an increased expression of the chemokine receptor CX3CR1 in total monocytes (CX3CR1⁺ monocytes, 24.5% vs. 4.7%; p < 0.001) and monocyte subsets. These findings were generally similar when analyzed by sex, with no significant interactions between sex and HIV status in adjusted models. Our data show that the inflammatory monocyte subset is expanded and monocyte CX3CR1 chemokine receptor expression is enhanced among PLWH, regardless of sex. Whether these parameters differentially affect risk for non-AIDS comorbidities and clinical outcomes in women with HIV requires additional investigation.