Exocrine Proteins Including Trypsin(ogen) as a Key Biomarker in Type 1 Diabetes

   Objective Proteomic profiling can identify useful biomarkers. Monozygotic(MZ) twins, discordant for a condition represent an ideal test population. We aimed to investigate and validate proteomic profiling in twins with type 1 diabetes and in other well characterised cohorts. Research Design and Methods A broad, multiplex analysis of 4068 proteins in sera from MZ twins concordant (n=43) and discordant for type 1 diabetes (n=27) identified major differences which were subsequently validated by a trypsin(ogen) assay in MZ pairs concordant (n=39) and discordant (n=42) for type 1 diabetes, individuals at-risk (n=195) and with type 1 diabetes (n=990), as well as with non-insulin requiring adult-onset diabetes diagnosed as either autoimmune (n=96) or type 2 (n=291). Results Proteomic analysis identified major differences between exocrine enzyme levels in discordant MZ twin pairs despite strong correlation between twins, whether concordant or discordant for type 1 diabetes (p Conclusions Type 1 diabetes is associated with altered exocrine function, even before onset. Twin data suggest roles for genetic and non-genetically determined factors. Exocrine/endocrine interactions are important under-investigated factors in type 1 diabetes.</p

Substances and your senses: The sensory patterns of young people within an alcohol and drug treatment service

Background: Substance use disorders (SUD) and trauma histories in adults have been linked with sensory processing patterns that are significantly different from the general population. Nevertheless, no studies have investigated sensory patterns, or the variables with which they are related, in youth with SUD. This study aimed to compare sensory patterns of this sample with normative data and consider associations between sensory patterns and: substance use, trauma, quality-of-life, mental and physical health. Methods: A cross-sectional quantitative research design was employed with a sample of 87 young people (mean age = 20.8 years) with SUD voluntarily attending a specialist youth outpatient alcohol and other drug (AOD) service. For participants, the Adolescent Adult Sensory Profile was added to measures routinely collected at the service. Results: Participants’ sensory processing patterns for low registration, sensory sensitivity, and sensation avoiding were significantly higher than the normative population, while sensation seeking was both lower and higher. Ninety-one percent reported atypical scores on one or more sensory patterns. High rates of probable Post-Traumatic-Stress-Disorder (PTSD), psychological distress, and low quality-of-life were also reported, which were meaningfully related with sensory patterns. Conclusion: Young people reported complex combinations of sensory processing patterns, with comorbid probable PTSD, psychological distress, and low quality-of-life. Findings reflect studies with adult AOD, trauma, and other clinical conditions, and highlight the potential value of screening for sensory patterns and applying transdiagnostic approaches which simultaneously address substance use, mental health, trauma and sensory needs to optimize outcomes for young people with SUD

Top 20 SNPs for alcohol consumption (ranked by p value) for both mothers and offspring.

<p>Top 20 SNPs for alcohol consumption (ranked by p value) for both mothers and offspring.</p

Summary information of weekly alcohol consumption across all time points.

<p>Summary information of weekly alcohol consumption across all time points.</p

Data_Sheet_1_In vitro characterization of [125I]HY-3-24, a selective ligand for the dopamine D3 receptor.docx

IntroductionDopamine D3 receptor (D3R) ligands have been studied for the possible treatment of neurological and neuropsychiatric disorders. However, selective D3R radioligands for in vitro binding studies have been challenging to identify due to the high structural similarity between the D2R and D3R. In a prior study, we reported a new conformationally-flexible benzamide scaffold having a high affinity for D3R and excellent selectivity vs. D2R. In the current study, we characterized the in vitro binding properties of a new radioiodinated ligand, [125I]HY-3-24.MethodsIn vitro binding studies were conducted in cell lines expressing D3 receptors, rat striatal homogenates, and rat and non-human primate (NHP) brain tissues to measure regional brain distribution of this radioligand.ResultsHY-3-24 showed high potency at D3R (Ki = 0.67 ± 0.11 nM, IC50 = 1.5 ± 0.58 nM) compared to other D2-like dopamine receptor subtypes (D2R Ki = 86.7 ± 11.9 nM and D4R Ki > 1,000). The Kd (0.34 ± 0.22 nM) and Bmax (38.91 ± 2.39 fmol/mg) values of [125I]HY-3-24 were determined. In vitro binding studies in rat striatal homogenates using selective D2R and D3R antagonists confirmed the D3R selectivity of [125I]HY-3-24. Autoradiography results demonstrated that [125I]HY-3-24 specifically binds to D3Rs in the nucleus accumbens, islands of Calleja, and caudate putamen in rat and NHP brain sections.ConclusionThese results suggest that [125I]HY-3-24 appears to be a novel radioligand that exhibits high affinity binding at D3R, with low binding to other D2-like dopamine receptors. It is anticipated that [125I]HY-3-24 can be used as the specific D3R radioligand.</p

Analogues of Arylamide Phenylpiperazine Ligands To Investigate the Factors Influencing D3 Dopamine Receptor Bitropic Binding and Receptor Subtype Selectivity

We have previously reported on the ability of arylamide phenylpiperazines to bind selectively to the D3 versus the D2 dopamine receptor subtype. For these studies, we used LS-3-134 as the prototypic arylamide phenylpiperazine ligand because it binds with high affinity at D3 dopamine receptor (0.17 nM) and exhibits >150-fold D3 vs D2 receptor binding selectivity. Our goal was to investigate how the composition and size of the nonaromatic ring structure at the piperazine position of substituted phenylpiperazine analogues might influence binding affinity at the human D2 and D3 dopamine receptors. Two factors were identified as being important for determining the binding affinity of bitropic arylamide phenylpiperazines at the dopamine D3 receptor subtype. One factor was the strength of the salt bridge between the highly conserved residue Asp^3.32 with the protonated nitrogen of the nonaromatic ring at the piperazine position. The second factor was the configuration of the unbound ligand in an aqueous solution. These two factors were found to be related to the logarithm of the affinities using a simple correlation model, which could be useful when designing high affinity subtype selective bitropic ligands. While this model is based upon the interaction of arylamide phenylpiperazines with the D2 and D3 D2-like dopamine receptor subtypes, it provides insights into the complexity of the factors that define a bitropic mode of the binding at GPCRs

Highly Selective Dopamine D₃ Receptor Antagonists with Arylated Diazaspiro Alkane Cores

A series of potent and selective D₃ receptor (D₃R) analogues with diazaspiro alkane cores were synthesized. Radioligand binding of compounds <b>11</b>, <b>14</b>, <b>15a</b>, and <b>15c</b> revealed favorable D₃R affinity (<i>K</i>_i = 12–25.6 nM) and were highly selective for D₃R vs D₃R (ranging from 264- to 905-fold). Variation of these novel ligand architectures can be achieved using our previously reported 10–20 min benchtop C–N cross-coupling methodology, affording a broad range of arylated diazaspiro precursors

Highly Selective Dopamine D₃ Receptor Antagonists with Arylated Diazaspiro Alkane Cores

A series of potent and selective D₃ receptor (D₃R) analogues with diazaspiro alkane cores were synthesized. Radioligand binding of compounds <b>11</b>, <b>14</b>, <b>15a</b>, and <b>15c</b> revealed favorable D₃R affinity (<i>K</i>_i = 12–25.6 nM) and were highly selective for D₃R vs D₃R (ranging from 264- to 905-fold). Variation of these novel ligand architectures can be achieved using our previously reported 10–20 min benchtop C–N cross-coupling methodology, affording a broad range of arylated diazaspiro precursors

Metal Complexes as Antifungals? From a Crowd-Sourced Compound Library to the First <i>In Vivo</i> Experiments

There are currently fewer than 10 antifungal drugs in clinical development, but new fungal strains that are resistant to most current antifungals are spreading rapidly across the world. To prevent a second resistance crisis, new classes of antifungal drugs are urgently needed. Metal complexes have proven to be promising candidates for novel antibiotics, but so far, few compounds have been explored for their potential application as antifungal agents. In this work, we report the evaluation of 1039 metal-containing compounds that were screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD). We show that 20.9% of all metal compounds tested have antimicrobial activity against two representative Candida and Cryptococcus strains compared with only 1.1% of the >300,000 purely organic molecules tested through CO-ADD. We identified 90 metal compounds (8.7%) that show antifungal activity while not displaying any cytotoxicity against mammalian cell lines or hemolytic properties at similar concentrations. The structures of 21 metal complexes that display high antifungal activity (MIC ≤1.25 μM) are discussed and evaluated further against a broad panel of yeasts. Most of these have not been previously tested for antifungal activity. Eleven of these metal complexes were tested for toxicity in the Galleria mellonella moth larva model, revealing that only one compound showed signs of toxicity at the highest injected concentration. Lastly, we demonstrated that the organo-Pt(II) cyclooctadiene complex Pt1 significantly reduces fungal load in an in vivoG. mellonella infection model. These findings showcase that the structural and chemical diversity of metal-based compounds can be an invaluable tool in the development of new drugs against infectious diseases