Pyridazinediones and amino acid receptors: theoretical studies, design, synthesis, and evaluation of novel analogues

http://www.pharmacol.usyd.edu.au/thesis This thesis is primarily concerned with a class of chemical compounds known as pyridazinediones, being 6-membered aromatic rings containing two adjacent nitrogen atoms (pyridazine), doubly substituted with oxygen. In particular, the work focuses on pyridazine-3,6-diones, derivatives of maleic hydrazide (1). Understanding of the chemistry of these compounds is extended, using theoretical and synthetic techniques. This thesis is also concerned with two very important classes of receptors which bind amino acids in the brain: firstly, the inhibitory GABA receptor, which binds g-aminobutyric acid (GABA) (2) in vivo, and for which muscimol (3) is an agonist of the GABAA subclass; secondly, Excitatory Amino Acid (EAA) receptors, which bind glutamate (4) in vivo, and in particular the AMPA subclass, for which (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) (5) is an agonist. The connection between pyridazinediones and amino acid receptors is the design, synthesis, and evaluation of structures based on pyridazinediones as potential GABA and EAA receptor ligands. Techniques of theoretical chemistry, molecular modelling, synthetic chemistry, and in vitro pharmacology are used to explore pyridazine-3,6-dione derivatives as ligands

No Treatment versus 24 or 60 Weeks of Antiretroviral Treatment during Primary HIV Infection: The Randomized Primo-SHM Trial

Background: The objective of this study was to assess the benefit of temporary combination antiretroviral therapy (cART) during primary HIV infection (PHI). Methods and Findings: Adult patients with laboratory evidence of PHI were recruited in 13 HIV treatment centers in the Netherlands and randomly assigned to receive no treatment or 24 or 60 wk of cART (allocation in a 1:1:1 ratio); if therapy was clinically indicated, participants were randomized over the two treatment arms (allocation in a 1:1 ratio). Primary end points were (1) viral set point, defined as the plasma viral load 36 wk after randomization in the no treatment arm and 36 wk after tr Conclusions: In this trial, temporary cART during PHI was found to transiently lower the viral set point and defer the restart of cART during chronic HIV infection

Influence of Chemical Structure on the Stability and Conductance of Porphyrin Single-Molecule Junctions

Quantum Matter and Optic

Track E Implementation Science, Health Systems and Economics

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138412/1/jia218443.pd

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria

A Namurian brachiopod fauna from Meré (Province of Oviedo, Spain)

An interesting brachiopod fauna from Namurian (Marsdenian?) deposits — provisionally named the Meré beds herein — is described. The fauna contains seven new species: Drahanorhynchus cantabricus, Anopliopsis? parva, Caenanoplia martinezi, Tornquistia scutiformis, Aseptella asturica, Kitakamithyris merensis, and Plicotorynifer lamellosus; and one new genus: Aseptella with the type species A. asturica. The material of a new productellid and a new ambocoeliid was too poor to give them formal names. The special character of this fauna — only a much older fauna from the Chappel Limestone of Texas (U.S.A.) being closely comparable — indicates special environmental conditions: presumably a soft, muddy bottom. The brachiopod fauna indicates a Namurian, probably Namurian B-C, age. This is in good agreement with the late Namurian Β (Marsdenian) age found for the goniatites and with the stratigraphical position of the beds

'ADHD, wat kan de juf (m/v) er mee?' Een onderzoek naar de effectiviteit van een leerkrachttraining

In dit onderzoek werd de effectiviteit onderzocht van een gedragstherapeutische training voor leerkrachten van kinderen met adhd. Achtentwintig leerkracht-leerling koppels in een experimentele behandelconditie en 25 in een wachtlijst-controleconditie werden in een quasi-experimenteel onderzoek met elkaar vergeleken. De leerkrachten werden getraind in het direct beïnvloeden van gedrag door middel van het ontwerpen en uitvoeren van individuele beloningsprogramma’s (contingentiemanagement) om de werkhouding en het gedrag van de leerling op school te verbeteren. Samenwerking met ouders en een positieve professionele houding van de leerkracht waren twee andere kernthema’s in de training. Metingen werden voor en na de training verricht door middel van gedragsvragenlijsten. Leerlingen in de behandelconditie vertoonden bij de nameting een significante verbetering in werkhouding. Leerkrachten in de behandelconditie rapporteerden een significant sterker gevoel van competentie dan leerkrachten in de controleconditie. De betekenis van deze resultaten voor leerkrachttrainingen bij kinderen met adhd worden bediscussieerd

Inflammatory plasma biomarkers in subjects with preclinical Alzheimer's disease

Background: This study investigated plasma biomarkers for neuroinflammation associated with Alzheimer's disease (AD) in subjects with preclinical AD compared to healthy elderly. How these biomarkers behave in patients with AD, compared to healthy elderly is well known, but determining these in subjects with preclinical AD is not and will add information related to the onset of AD. When found to be different in preclinical AD, these inflammatory biomarkers may be used to select preclinical AD subjects who are most likely to develop AD, to participate in clinical trials with new disease-modifying drugs.Methods: Healthy elderly (n= 50; age 71.9; MMSE >24) and subjects with preclinical AD (n=50; age 73.4; MMSE >24) defined by CSF A beta 1-42 levels < 1000 pg/mL were included. Four neuroinflammatory biomarkers were determined in plasma, GFAP, YKL-40, MCP-1, and eotaxin-1. Differences in biomarker outcomes were compared using ANCOVA. Subject characteristics age, gender, and APOE epsilon 4 status were reported per group and were covariates in the ANCOVA. Least square means were calculated for all 4 inflammatory biomarkers using both the A beta+/A beta- cutoff and Ptau/A beta 1-42 ratio.Results: The mean (standard deviation, SD) age of the subjects (n=100) was 72.6 (4.6) years old with 62 male and 38 female subjects. Mean (SD) overall MMSE score was 28.7 (0.49) and 32 subjects were APOE epsilon 4 carriers. The number of subjects in the different APOE epsilon 4 status categories differed significantly between the A beta+ and A beta- groups. Plasma GFAP concentration was significantly higher in the A beta+ group compared to the A beta- group with significant covariates age and sex, variables that also correlated significantly with GFAP.Conclusion: GFAP was significantly higher in subjects with preclinical AD compared to healthy elderly which agrees with previous studies. When defining preclinical AD based on the Ptau181/A beta 1-42 ratio, YKL-40 was also significantly different between groups. This could indicate that GFAP and YKL-40 are more sensitive markers of the inflammatory process in response to the A beta misfolding and aggregation that is ongoing as indicated by the lowered A beta 1-42 levels in the CSF. Characterizing subjects with preclinical AD using neuroinflammatory biomarkers is important for subject selection in new disease-modifying clinical trials