The interaction of anti-DNA antibodies with DNA antigen: Evidence for hysteresis for high avidity binding.

Antibodies to DNA (anti-DNA) are the serological hallmark of systemic lupus erythematosus. Previous studies have indicated that the phosphodiester backbone is the main antigenic target, with electrostatic interactions important for high avidity. To define further these interactions, the effects of ionic strength on anti-DNA binding of SLE plasmas were assessed in association and dissociation assays by ELISA.

Brain glycogen serves as a critical glucosamine cache required for protein glycosylation.

Glycosylation defects are a hallmark of many nervous system diseases. However, the molecular and metabolic basis for this pathology is not fully understood. In this study, we found that N-linked protein glycosylation in the brain is metabolically channeled to glucosamine metabolism through glycogenolysis.

Local elected officials' receptivity to refugee resettlement in the United States.

Local leaders possess significant and growing authority over refugee resettlement, yet we know little about their attitudes toward refugees. In this article, we use a conjoint experiment to evaluate how the attributes of hypothetical refugee groups influence local policymaker receptivity toward refugee resettlement. We sample from a national panel of current local elected officials, who represent a broad range of urban and rural communities across the United States.

Antibody-Mediated Enzyme Therapeutics and Applications in Glycogen Storage Diseases.

The use of antibodies as targeting molecules or cell-penetrating tools has emerged at the forefront of pharmaceutical research. Antibody-directed therapies in the form of antibody-drug conjugates, immune modulators, and antibody-directed enzyme prodrugs have been most extensively utilized as hematological, rheumatological, and oncological therapies, but recent developments are identifying additional applications of antibody-mediated delivery systems. A novel application of this technology is for the treatment of glycogen storage disorders (GSDs) via an antibody-enzyme fusion (AEF) platform to penetrate cells and deliver an enzyme to the cytoplasm, nucleus, and/or other organelles.

Central Nervous System Delivery and Biodistribution Analysis of an Antibody-Enzyme Fusion for the Treatment of Lafora Disease.

Lafora disease (LD) is a fatal juvenile epilepsy characterized by the accumulation of aberrant glucan aggregates called Lafora bodies (LBs). Delivery of protein-based therapeutics to the central nervous system (CNS) for the clearance of LBs remains a unique challenge in the field. Recently, a humanized antigen-binding fragment (hFab) derived from a murine systemic lupus erythematosus DNA autoantibody (3E10) has been shown to mediate cell penetration and proposed as a broadly applicable carrier to mediate cellular targeting and uptake.

A Central Region of NF-κB Essential Modulator Is Required for IKKβ-Induced Conformational Change and for Signal Propagation.

NF-κB essential modulator (NEMO) regulates NF-κB signaling by acting as a scaffold for the kinase IKKβ to direct its activity toward the NF-κB inhibitor, IκBα. Here, we show that a highly conserved central region of NEMO termed the intervening domain (IVD, amino acids 112-195) plays a key role in NEMO function. We determined a structural model of full-length NEMO by small-angle X-ray scattering and show that full-length, wild-type NEMO becomes more compact upon binding of a peptide comprising the NEMO binding domain of IKKβ (amino acids 701-745).

The obesity paradox in ICU patients.

Excessive weight is connected with an increased risk of certain life-threatening diseases. However, some evidence shows that among patients with chronic diseases such as heart failure (HF) chronic kidney disease (CKD) and COPD, increased weight is paradoxically associated with a decreased risk of mortality. This counterintuitive phenomenon is referred to as the obesity paradox.

SOD1 Lysine 123 Acetylation in the Adult Central Nervous System.

Superoxide dismutase 1 (SOD1) knockout () mice exhibit an accelerated aging phenotype. In humans, mutations are linked to familial amyotrophic lateral sclerosis (ALS), and post-translational modification (PTM) of wild-type SOD1 has been associated with sporadic ALS. Reversible acetylation regulates many enzymes and proteomic studies have identified SOD1 acetylation at lysine 123 (K123).

Mutation of nonessential cysteines shows that the NF-κB essential modulator forms a constitutive noncovalent dimer that binds IκB kinase-β with high affinity.

NEMO (NF-κB essential modulator) associates with catalytic subunits IKKα and IKKβ to form the IκB kinase (IKK) complex and is a key regulator of NF-κB pathway signaling. Biochemical and structural characterization of NEMO has been challenging, however, leading to conflicting data about basic biochemical properties such as the oligomeric state of active NEMO and its binding affinity for IKKβ. We show that up to seven of NEMO's 11 cysteine residues can be mutated to generate recombinant full-length NEMO that is highly soluble and active.

Molecular diagnosis of Campylobacter jejuni infection in cases of focal active colitis.

Campylobacter jejuni (CJ) is the most commonly isolated stool pathogen in the United States. Biopsy findings are typically those of focal active colitis (FAC), a nonspecific pattern usually indicating infection or adverse drug effect that is characterized by focal cryptitis and preservation of crypt architecture. We developed a molecular test for CJ that can be performed on routinely processed gastrointestinal biopsy specimens, and assessed what percentage of patients with biopsy findings of FAC have molecular evidence of CJ infection.