Intra-Accumbens Injection of a Dopamine Aptamer Abates MK-801-Induced Cognitive Dysfunction in a Model of Schizophrenia

Systemic administration of the noncompetitive NMDA-receptor antagonist, MK-801, has been proposed to model cognitive deficits similar to those seen in patients with schizophrenia. The present work investigated the ability of a dopamine-binding DNA aptamer to regulate these MK-801-induced cognitive deficits when injected into the nucleus accumbens. Rats were trained to bar press for chocolate pellet rewards then randomly assigned to receive an intra-accumbens injection of a DNA aptamer (200 nM; n = 7), tris buffer (n = 6) or a randomized DNA oligonucleotide (n = 7). Animals were then treated systemically with MK-801 (0.1 mg/kg) and tested for their ability to extinguish their bar pressing response. Two control groups were also included that did not receive MK-801. Data revealed that injection of Tris buffer or the random oligonucleotide sequence into the nucleus accumbens prior to treatment with MK-801 did not reduce the MK-801-induced extinction deficit. Animals continued to press at a high rate over the entire course of the extinction session. Injection of the dopamine aptamer reversed this MK-801-induced elevation in lever pressing to levels as seen in rats not treated with MK-801. Tests for activity showed that the aptamer did not impair locomotor activity. Results demonstrate the in vivo utility of DNA aptamers as tools to investigate neurobiological processes in preclinical animal models of mental health disease

Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk

Acridones Are Highly Potent Inhibitors of Tachyzoites.

Acridone derivatives, which have been shown to have and activity against spp, inhibit proliferation at picomolar concentrations. Using enzymatic assays, we show that acridones inhibit both cytochrome and dihydroorotate dehydrogenase and identify acridones that bind preferentially to the Q site of cytochrome . We identify acridones that have efficacy in a murine model of systemic toxoplasmosis. Acridones have potent activity against and represent a promising new class of preclinical compounds

In Vivo Use of a Multi-DNA Aptamer-Based Payload/Targeting System to Study Dopamine Dysregulation in the Central Nervous System

The delivery of therapeutics across the blood-brain barrier remains a considerable challenge in investigating central nervous system related processes. In this work, a liposome vehicle was surface-modified with an aptamer that binds to the transferrin receptor and was loaded with two different dopamine-binding aptamer payloads. This system was effectively used to promote the delivery of the aptamer cargo from the peripheral injection site into the brain. Th

Transitional care programs for older adults moving from hospital to home in Canada: A systematic review of text and opinion.

BackgroundInvesting in transitional care programs is critical for ensuring continuity of health and coordinated care for older adults transitioning across health settings. However, literature delineating the scope of transitional care programs across Canada is limited. The aim of this systematic review of text and opinion is to characterize Canadian transitional care programs for older adults transitioning from hospital to home.MethodsFollowing JBI guidelines for systematic review of text and opinion, we conducted a search of Canadian grey literature sources published online between 2016 to 2023. A 3-phase search was undertaken for: 1) Canadian databases and organizational websites; 2) advanced Google search of national sources and news media reports; and 3) advanced Google search of provincial/territorial sources. Two reviewers independently screened sources for eligibility against inclusion criteria. Data were extracted by one reviewer and verified by a second. Textual data were extracted from multiple sources to characterize each transitional care program.ResultsGrey literature search produced a total of 17,092 text and opinion sources, identifying 119 transitional care programs in Canada. Model of care was a key characteristic defining the design and delivery of transitional care programs within community (n = 42), hospital (n = 45), and facility-based (n = 32) settings. Programs were characterized by goal, population and eligibility, setting and length of program, intervention and services, and healthcare team members. Patient, caregiver, and health system outcomes were reported for 18 programs. The province of Ontario has the most transitional care programs (n = 84) and reported outcomes, followed by British Columbia (n = 10).ConclusionsCharacterizing transitional care programs is important for informing health services planning and scaling up of transitional care program models across Canada. Recognizing transitional care programs as a core health service is critical to meet the health care needs of older adults at the right time and place.Trial registrationPROSPERO ID 298821

Personalized Oncogenomics: Clinical Experience with Malignant Peritoneal Mesothelioma Using Whole Genome Sequencing

<div><p>Peritoneal mesothelioma is a rare and sometimes lethal malignancy that presents a clinical challenge for both diagnosis and management. Recent studies have led to a better understanding of the molecular biology of peritoneal mesothelioma. Translation of the emerging data into better treatments and outcome is needed. From two patients with peritoneal mesothelioma, we derived whole genome sequences, RNA expression profiles, and targeted deep sequencing data. Molecular data were made available for translation into a clinical treatment plan. Treatment responses and outcomes were later examined in the context of molecular findings. Molecular studies presented here provide the first reported whole genome sequences of peritoneal mesothelioma. Mutations in known mesothelioma-related genes <i>NF2</i>, <i>CDKN2A</i>, <i>LATS2</i>, amongst others, were identified. Activation of <i>MET</i>-related signaling pathways was demonstrated in both cases. A hypermutated phenotype was observed in one case (434 vs. 18 single nucleotide variants) and was associated with a favourable outcome despite sarcomatoid histology and multifocal disease. This study represents the first report of whole genome analyses of peritoneal mesothelioma, a key step in the understanding and treatment of this disease.</p></div

Patient 1 and 2 large-scale genomic alterations.

<p>Circos Plots for patients 1 (A) and 2 (B). Copy number gains shown in red, copy number losses shown in green (height of bars is proportional to the number of copies gained or lost). Purple lines indicate interchromosomal translocations. Orange lines indicate intrachromosomal translocation.</p