RAGE: A journey from the complications of diabetes to disorders of the nervous system – striking a fine balance between injury and repair

This is the published version. Copyright 2005 IOS Press.The Receptor for Advanced Glycation End Products (RAGE) is a multiligand member of the immunoglobulin superfamily. RAGE interacts with AGEs, the products of nonenzymatic glycation/oxidation of proteins and lipids that accumulate in diverse settings, such as diabetes, inflammation, renal failure, pro-oxidant states and natural aging. In addition, RAGE is also a receptor for amyloid-β peptide and β-sheet fibril species. Recent studies underscore the premise that RAGE interacts with pro-inflammatory molecules, including S100/calgranulins and amphoterin, the latter also known as high mobility group box 1 (HMGB1). In chronic neurodegenerative disorders as well as in nerve tissue upon acute injury, evidence points to upregulation of both RAGE and these ligand families. In this review, we will discuss the implications of transient/self-limited upregulation of RAGE and its ligands, vs sustained/chronic upregulation of this axis in neurodegeneration vs repair in both the central and peripheral nervous systems. Experimental evidence supports the premise that RAGE bears both homeostatic and injurious properties in the nervous system, thereby highlighting "yin/yang" features of this receptor and its ligand families

Trust as a mediator in the relationship between childhood sexual abuse and IL-6 level in adulthood

Childhood sexual abuse (CSA) has been shown to predict the coupling of depression and inflammation in adulthood. Trust within intimate relationships, a core element in marital relations, has been shown to predict positive physical and mental health outcomes, but the mediating role of trust in partners in the association between CSA and inflammation in adulthood requires further study. The present study aimed to examine the impact of CSA on inflammatory biomarkers (IL-6 and IL-1β) in adults with depression and the mediating role of trust. A cross-sectional survey data set of adults presenting with mood and sleep disturbance was used in the analysis. CSA demonstrated a significant negative correlation with IL-6 level (r = -0.28, p<0. 01) in adults with clinically significant depression, while trust showed a significant positive correlation with IL-6 level (r = 0.36, p < .01). Sobel test and bootstrapping revealed a significant mediating role for trust between CSA and IL-6 level. CSA and trust in partners were revealed to have significant associations with IL-6 level in adulthood. Counterintuitively, the directions of association were not those expected. Trust played a mediating role between CSA and adulthood levels of IL-6. Plausible explanations for these counterintuitive findings are discussed

Pilot study of PET imaging of 124I-iodoazomycin galactopyranoside (IAZGP), a putative hypoxia imaging agent, in patients with colorectal cancer and head and neck cancer

Background: Hypoxia within solid tumors confers radiation resistance and a poorer prognosis. 124I-iodoazomycin galactopyranoside (124I-IAZGP) has shown promise as a hypoxia radiotracer in animal models. We performed a clinical study to evaluate the safety, biodistribution, and imaging characteristics of 124I-IAZGP in patients with advanced colorectal cancer and head and neck cancer using serial positron emission tomography (PET) imaging. Methods: Ten patients underwent serial whole-torso (head/neck to pelvis) PET imaging together with multiple whole-body counts and blood sampling. These data were used to generate absorbed dose estimates to normal tissues for 124I-IAZGP. Tumors were scored as either positive or negative for 124I-IAZGP uptake. Results: There were no clinical toxicities or adverse effects associated with 124I-IAZGP administration. Clearance from the whole body and blood was rapid, primarily via the urinary tract, with no focal uptake in any parenchymal organ. The tissues receiving the highest absorbed doses were the mucosal walls of the urinary bladder and the intestinal tract, in particular the lower large intestine. All 124I-IAZGP PET scans were interpreted as negative for tumor uptake. Conclusions: It is safe to administer 124I-IAZGP to human subjects. However, there was insufficient tumor uptake to support a clinical role for 124I-IAZGP PET in colorectal cancer and head and neck cancer patients. Trial registration: ClinicalTrials.gov NCT0058827

Optics and Quantum Electronics

Contains reports on eleven research projects.National Science Foundation (Grant EET 87-00474)Joint Services Electronics Program (Contract DAALO03-86-K-O002)Charles Stark Draper Laboratory, Inc. (Grant DL-H-2854018)National Science Foundation (Grant DMR 84-18718)National Science Foundation (Grant EET 87-03404)National Science Foundation (ECS 85-52701)US Air Force - Office of Scientific Research (Contract AFOSR-85-0213)National Institutes of Health (Contract 5-RO1-GM35459)US Navy - Office of Naval Research (Contract N00014-86-K-0117

Optics and Quantum Electronics

Contains table of contents for Section 2 and reports on eighteen research projects.National Science Foundation (Grant EET 87-00474)Joint Services Electronics Program (Contract DAAL03-86-K-0002)Joint Services Electronics Program (Contract DAALO3-89-C-0001)Charles Stark Draper Laboratory (Grant DL-H-285408)Charles Stark Draper Laboratory (Grant DL-H-2854018)National Science Foundation (Grant EET 87-03404)National Science Foundation (Grant ECS 84-06290)U.S. Air Force - Office of Scientific Research (Contract F49620-88-C-0089)AT&T Bell FoundationNational Science Foundation (Grant ECS 85-52701)National Institutes of Health (Grant 5-RO1-GM35459)Massachusetts General Hospital (Office of Naval Research Contract N00014-86-K-0117)Lawrence Livermore National Laboratory (Subcontract B048704

A Revamped Rat Reference Genome Improves the Discovery of Genetic Diversity in Laboratory Rats

The seventh iteration of the reference genome assembly for Rattus norvegicus-mRatBN7.2-corrects numerous misplaced segments and reduces base-level errors by approximately 9-fold and increases contiguity by 290-fold compared with its predecessor. Gene annotations are now more complete, improving the mapping precision of genomic, transcriptomic, and proteomics datasets. We jointly analyzed 163 short-read whole-genome sequencing datasets representing 120 laboratory rat strains and substrains using mRatBN7.2. We defined ∼20.0 million sequence variations, of which 18,700 are predicted to potentially impact the function of 6,677 genes. We also generated a new rat genetic map from 1,893 heterogeneous stock rats and annotated transcription start sites and alternative polyadenylation sites. The mRatBN7.2 assembly, along with the extensive analysis of genomic variations among rat strains, enhances our understanding of the rat genome, providing researchers with an expanded resource for studies involving rats

Autoantibodies against type I IFNs in patients with critical influenza pneumonia

In an international cohort of 279 patients with hypoxemic influenza pneumonia, we identified 13 patients (4.6%) with autoantibodies neutralizing IFN-alpha and/or -omega, which were previously reported to underlie 15% cases of life-threatening COVID-19 pneumonia and one third of severe adverse reactions to live-attenuated yellow fever vaccine. Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-alpha 2 alone (five patients) or with IFN-omega (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-alpha 2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-omega. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients 70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-alpha 2 and IFN-omega (OR = 11.7, P = 1.3 x 10(-5)), especially those <70 yr old (OR = 139.9, P = 3.1 x 10(-10)). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for similar to 5% of cases of life-threatening influenza pneumonia in patients <70 yr old

Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population