Epistatic effects of IGHG and FCGRIIB genes on the development of Alzheimer's disease in African Americans.

Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified a large number of susceptibility genes, but most of AD heritability remains unexplained, implying the existence of additional genes. Furthermore, the majority of the GWAS have been conducted in people of European descent, and the genes important for AD susceptibility in people of African descent have been underexplored. In this hypothesis-generating prospective cohort study, we genotyped 191 African Americans (AAs) from three longitudinal cohorts on aging for the IgG3 allotype GM6, which is expressed exclusively in people of African descent, and assessed its interaction with IGHG, FCGRIIB, and HLA-DRB1 genes.

Isoflurane-lipid emulsion injection as an anticonvulsant and neuroprotectant treatment for nerve agent exposure.

We have shown that briefly inhaled isoflurane rapidly halts convulsions and protects the central nervous system (CNS) from organophosphate-induced neuronal loss when administered at 5% for 5 min, even as late as 1 h after organophosphate exposure. In the current study we investigated if an injectable form of isoflurane was as effective as inhaled isoflurane. We used a mixture of 10% isoflurane dissolved in an IV-compatible lipid-water emulsion for intravenous administration.

Phase 1 trial evaluating safety and pharmacokinetics of HIV-1 broadly neutralizing mAbs 10E8VLS and VRC07-523LS.

BACKGROUNDBroadly neutralizing monoclonal antibodies (bNAbs) represent a promising strategy for HIV-1 immunoprophylaxis and treatment. 10E8VLS and VRC07-523LS are bNAbs that target the highly conserved membrane-proximal external region (MPER) and the CD4-binding site of the HIV-1 viral envelope glycoprotein, respectively.METHODSIn this phase 1, open-label trial, we evaluated the safety and pharmacokinetics of 5 mg/kg 10E8VLS administered alone, or concurrently with 5 mg/kg VRC07-523LS, via s.

Brief isoflurane administration as an adjunct treatment to control organophosphate-induced convulsions and neuropathology.

Organophosphate-based chemical agents (OP), including nerve agents and certain pesticides such as paraoxon, are potent acetylcholinesterase inhibitors that cause severe convulsions and seizures, leading to permanent central nervous system (CNS) damage if not treated promptly. The current treatment regimen for OP poisoning is intramuscular injection of atropine sulfate with an oxime such as pralidoxime (2-PAM) to mitigate cholinergic over-activation of the somatic musculature and autonomic nervous system. This treatment does not provide protection against CNS cholinergic overactivation and therefore convulsions require additional medication.

GM Allotypes and COVID-19. A Pilot Study Performed on Sicilian Patients.

Several studies suggest that genetic variants that influence the onset, maintenance and resolution of the immune response might be fundamental in predicting the evolution of COVID-19. In the present paper, we analysed the distribution of GM allotypes (the genetic markers of immunoglobulin γ chains) in symptomatic and asymptomatic COVID-19 patients and in healthy controls, all born and residing in Sicily. Indeed, the role played by GM allotypes in immune responses and infection control is well known.

Acss2 Deletion Reveals Functional Versatility via Tissue-Specific Roles in Transcriptional Regulation.

The coordination of cellular biological processes is regulated in part via metabolic enzymes acting to match cellular metabolism to current conditions. The acetate activating enzyme, acyl-coenzyme A synthetase short-chain family member 2 (Acss2), has long been considered to have a predominantly lipogenic function. More recent evidence suggests that this enzyme has regulatory functions in addition to its role in providing acetyl-CoA for lipid synthesis.

Immunoglobulin γ chain allotypes and humoral immunity to HSV1 in Parkinson's disease.

The aim of this investigation was to determine if particular immunoglobulin GM (γ marker) alleles and genotypes were associated with Parkinson's disease (PD) and whether they contributed to the interindividual differences in the level of antibodies to herpes simplex virus type 1 (HSV1), which has been implicated in PD pathology. Using a case-control study design, 94 PD patients and 157 controls were characterized for anti-HSV1 IgG antibodies and genotyped for GM alleles expressed on IgG1 (3,17) and IgG2 (23 +, 23-). The homozygosity for the GM 3 and GM 23 alleles was significantly associated with susceptibility to PD (p = 0.

The pathogenesis of, and pharmacological treatment for, Canavan disease.

Canavan disease (CD) is an inherited leukodystrophy resulting from mutations in the gene encoding aspartoacylase (ASPA). ASPA is highly expressed in oligodendrocytes and catalyzes the cleavage of N-acetylaspartate (NAA) to produce aspartate and acetate. In this review, we examine the pathologies and clinical presentation in CD, the metabolism and transportation of NAA in the brain, and the hypothetical mechanisms whereby ASPA deficiency results in dysmyelination and a failure of normal brain development.

Inhibitory Fcγ Receptor and Paired Immunoglobulin Type 2 Receptor Alpha Genotypes in Alzheimer's Disease.

We investigated whether FCGRIIB (rs1050501 C/T) and PILRA (rs1859788 A/G) genotypes contributed to the development of Alzheimer's disease (AD). We genotyped 209 African American (AA) and 638 European American (EA) participants for the FCGRIIB and PILRA alleles. In the AA cohort, subjects homozygous for the C allele of FCGRIIB were more than 4 times as likely to develop AD as those homozygous for the alternative T allele.

Immunoglobulin GM and KM allotypes are associated with antibody responses to Pseudomonas aeruginosa antigens in chronically infected cystic fibrosis patients.

Background: Chronic infection with Pseudomonas aeruginosa (P. aeruginosa) is a leading cause of death in patients with cystic fibrosis (CF). Immunobiology of P.

Acetate Revisited: A Key Biomolecule at the Nexus of Metabolism, Epigenetics, and Oncogenesis - Part 2: Acetate and ACSS2 in Health and Disease.

Acetate, the shortest chain fatty acid, has been implicated in providing health benefits whether it is derived from the diet or is generated from microbial fermentation of fiber in the gut. These health benefits range widely from improved cardiac function to enhanced red blood cell generation and memory formation. Understanding how acetate could influence so many disparate biological functions is now an area of intensive research.

The ketone ester, 3-hydroxybutyl-3-hydroxybutyrate, attenuates neurobehavioral deficits and improves neuropathology following controlled cortical impact in male rats.

Traumatic brain injury (TBI) is a leading cause of human death and disability with no effective therapy to fully prevent long-term neurological deficits in surviving patients. Ketone ester supplementation is protective in animal models of neurodegeneration, but its efficacy against TBI pathophysiology is unknown. Here, we assessed the neuroprotective effect of the ketone monoester, 3-hydroxybutyl-3-hydroxybutyrate, (KE) in male Sprague Dawley rats (=32).

Acetate Revisited: A Key Biomolecule at the Nexus of Metabolism, Epigenetics and Oncogenesis-Part 1: Acetyl-CoA, Acetogenesis and Acyl-CoA Short-Chain Synthetases.

Acetate is a major end product of bacterial fermentation of fiber in the gut. Acetate, whether derived from the diet or from fermentation in the colon, has been implicated in a range of health benefits. Acetate is also generated in and released from various tissues including the intestine and liver, and is generated within all cells by deacetylation reactions.

Quinolinate as a Marker for Kynurenine Metabolite Formation and the Unresolved Question of NAD Synthesis During Inflammation and Infection.

Quinolinate (Quin) is a classic example of a biochemical double-edged sword, acting as both essential metabolite and potent neurotoxin. Quin is an important metabolite in the kynurenine pathway of tryptophan catabolism leading to the synthesis of nicotinamide adenine dinucleotide (NAD). As a precursor for NAD, Quin can direct a portion of tryptophan catabolism toward replenishing cellular NAD levels in response to inflammation and infection.

Safety and pharmacokinetics of broadly neutralising human monoclonal antibody VRC07-523LS in healthy adults: a phase 1 dose-escalation clinical trial.

Background: Human monoclonal antibodies that potently and broadly neutralise HIV-1 are under development to prevent and treat HIV-1 infection. In this phase 1 clinical trial we aimed to determine the safety, tolerability, and pharmacokinetic profile of the broadly neutralising monoclonal antibody VRC07-523LS, an engineered variant of VRC01 that targets the CD4 binding site of the HIV-1 envelope protein.

Methods: This phase 1, open-label, dose-escalation clinical trial was done at the National Institutes of Health Clinical Center in Bethesda, MD, USA.

Association of immunoglobulin GM allotypes with longevity in long-living individuals from Southern Italy.

Background: The aim of this study was to analyse the role of GM allotypes, i.e. the hereditary antigenic determinants expressed on immunoglobulin polypeptide chains, in the attainment of longevity.

IGHG, IGKC, and FCGR genes and endogenous antibody responses to GARP in patients with breast cancer and matched controls.

Glycoprotein-A repetitions predominant (GARP) is a transmembrane protein that is highly expressed in breast cancer. Its overexpression correlates with worse survival, and antibodies to GARP appear to play a protective role in a mouse model. No large-scale studies of immunity to GARP in humans have yet been undertaken.

Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: A Phase 1 open-label clinical trial in healthy adults.

Background: VRC01 is a human broadly neutralizing monoclonal antibody (bnMAb) against the CD4-binding site of the HIV-1 envelope glycoprotein (Env) that is currently being evaluated in a Phase IIb adult HIV-1 prevention efficacy trial. VRC01LS is a modified version of VRC01, designed for extended serum half-life by increased binding affinity to the neonatal Fc receptor.

Methods And Findings: This Phase I dose-escalation study of VRC01LS in HIV-negative healthy adults was conducted by the Vaccine Research Center (VRC) at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD).

Endogenous antibody responses to mucin 1 in a large multiethnic cohort of patients with breast cancer and healthy controls: Role of immunoglobulin and Fcγ receptor genes.

High levels of naturally occurring IgG antibodies to mucin 1 (MUC1), a membrane-bound glycoprotein that is overexpressed in patients with breast cancer, are associated with good prognosis. This suggests that endogenous anti-MUC1 antibodies have a protective effect and, through antibody-mediated host immunosurveillance mechanisms, might contribute to a cancer-free state. To test this possibility, we characterized a large number of multiethnic patients with breast cancer and matched controls for IgG antibodies to MUC1.

Brief isoflurane administration as a post-exposure treatment for organophosphate poisoning.

Organophosphate chemical threat agents (OP-CTA) exert toxic effects through cholinergic over-activation. However, after the initial cholinergic phase, the pathophysiology shifts to a non-cholinergic phase which leads to prolonged status epilepticus (SE), irreversible neuronal degeneration and long-term damage to the central nervous system. The efficacy of delayed treatments against OP-CTA is generally low due to the fact that most drugs fail to inhibit the later phase of non-cholinergic activation.

Immunoglobulin genotypes and cognitive functions in schizophrenia.

Exposure to neurotropic viruses, such as herpes simplex virus type 1 and human cytomegalovirus, has been reported to be associated with cognitive impairment in schizophrenia. These viruses have evolved highly sophisticated strategies for decreasing the efficacy of the host immune response and interfering with viral clearance. Particular immunoglobulin GM (γ marker) genotypes modulate these viral immunoevasion strategies, influence antibody responsiveness to viral proteins, and are also associated with susceptibility to schizophrenia, providing an excellent rationale for determining their possible involvement in the cognitive functions in this highly heritable neurodevelopmental disorder.

Genetic markers of immunoglobulin G and immunity to cytomegalovirus in patients with breast cancer.

Human cytomegalovirus (CMV), a ubiquitous herpesvirus, has been implicated in the etiology of breast cancer. It is clear that not all people exposed to CMV are equally likely to develop this malignancy, implying the presence of host genetic factors that might modulate the cancer-spurring properties of the virus. CMV has evolved sophisticated strategies for evading host immunosurveillance.

Efficacy of N-Acetylserotonin and Melatonin in the EAE Model of Multiple Sclerosis.

Melatonin and N-acetylserotonin (NAS) are tryptophan metabolites that have potent anti-oxidant, anti-inflammatory and neuroprotective properties in several animal models of neurological injury and disease including multiple sclerosis (MS). The therapeutic effect of NAS has not been reported previously in experimental autoimmune encephalomyelitis (EAE), a commonly used animal model of MS. Using a MOG-peptide induced EAE mouse model we examined the effects of melatonin and NAS on clinical score, inflammatory markers, free radical generation, and sparing of axons, oligodendrocytes and myelin.

Immunoglobulin G genotypes and the risk of schizophrenia.

Genes of the immune system are relevant to the etiology of schizophrenia. However, to our knowledge, no large-scale studies, using molecular methods, have been undertaken to investigate the role of highly polymorphic immunoglobulin GM (γ marker) genes in this disorder. In this investigation, we aimed to determine whether particular GM genotypes were associated with susceptibility to schizophrenia.

The end of the road for the tryptophan depletion concept in pregnancy and infection.

We hypothesize that: (1) L-tryptophan (Trp) is greatly utilized and not depleted in pregnancy; (2) fetal tolerance is achieved in part through immunosuppressive kynurenine (Kyn) metabolites produced by the flux of plasma free (non-albumin-bound) Trp down the Kyn pathway; (3) the role of indoleamine 2,3-dioxygenase (IDO) in infection is not related to limitation of an essential amino acid, but is rather associated with stress responses and the production of Kyn metabolites that regulate the activities of antigen presenting cells and T-cells, as well as increased NAD(+) synthesis in IDO-expressing cells; (4) Trp depletion is not a host defence mechanism, but is a consequence of Trp utilization. We recommend that future studies in normal and abnormal pregnancies and in patients with infections or cancer should include measurements of plasma free Trp, determinants of Trp binding (albumin and non-esterified fatty acids), total Trp, determinants of activities of the Trp-degrading enzymes Trp 2,3-dioxygenase (TDO) (cortisol) and IDO (cytokines) and levels of Kyn metabolites. We also hypothesize that abnormal pregnancies and failure to combat infections or cancer may be associated with excessive Trp metabolism that can lead to pathological immunosuppression by excessive production of Kyn metabolites.