Biology subjects

McDonald, W.

Publications and source records attributed to McDonald, W..

3 recordsLinked to original sources

bioRxiv2025

Liver transplant rejection features memory cell priming, spatially differentiated networks and novel drug targets.

Acute T-cell-mediated transplant rejection, the earliest contributor to immunological graft failure responds variably to T-cell suppression. Early rejection can co-exist with donor-specific antibodies which also shorten graft survival, without affecting graft histology visibly. Here, during early liver transplant rejection, blood leukocytes manifest primed T-cells with heat shock protein (HSP) signaling and transcriptional programs for memory cell expansion. Corresponding biopsies demonstrate upregulated immune synapse and proteasomal genes in T-cell-infiltrated portal and central regions of the liver lobule. With donor-specific antibodies, the intervening intralobular region demonstrates a germinal-center-like allograft response with upregulated CD40, chemokine, T-follicular and complement signaling, which intensifies along the direction of sinusoidal blood flow from portal to central regions. Proteasomal and HSP90 inhibitors suppress donor-specific alloresponses of T- and B-cells in blood samples from patients with early rejection. The molecular injury spectrum of early rejection is complex, spatially differentiated and reveals novel early immunosuppressive strategies to extend graft survival.

immunology↗

bioRxiv2020

Alterations in Acylcarnitines, Amines, and Lipids Inform about Mechanism of Action of Citalopram/Escitalopram in Major Depression

Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), yet their mechanisms of action are not fully understood and their therapeutic benefit varies among individuals. We used a targeted metabolomics approach utilizing a panel of 180 metabolites to gain insights into mechanisms of action and response to citalopram/escitalopram. Plasma samples from 136 participants with MDD enrolled into the Mayo Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) were profiled at baseline and after 8 weeks of treatment. After treatment, we saw increased levels of short-chain acylcarnitines and decreased levels of medium- and long-chain acylcarnitines, suggesting an SSRI effect on {beta}-oxidation and mitochondrial function. Amines - including arginine, proline, and methionine-sulfoxide - were upregulated while serotonin and sarcosine were downregulated, suggesting an SSRI effect on urea cycle, one-carbon metabolism and serotonin uptake. Eighteen lipids within the phosphatidylcholine (PC aa and ae) classes were upregulated. Changes in several lipid and amine levels correlated with changes in 17-item Hamilton Rating Scale for Depression scores (HRSD17). Differences in metabolic profiles at baseline and post-treatment were noted between participants who remitted (HRSD17[≤]7) and those who gained no meaningful benefits (<30% reduction in HRSD17). Remitters exhibited a) higher baseline levels of C3, C5, alpha-aminoadipic acid, sarcosine and serotonin; and b) higher week-8 levels of PC aa C34:1, PC aa C34:2, PC aa C36:2 and PC aa C36:4. These findings suggest that mitochondrial energetics - including acylcarnitine metabolism, transport and its link to {beta}-oxidation - and lipid membrane remodeling may play roles in SSRI treatment response.

neuroscience↗

bioRxiv2019

Acylcarnitine Metabolomic Profiles Inform Clinically-Defined Major Depressive Phenotypes

BackgroundAcylcarnitines have important functions in mitochondrial energetics and {beta}-oxidation, and have been implicated to play a significant role in metabolic functions of the brain. This retrospective study examined whether plasma acylcarnitine profiles can help biochemically distinguish the three phenotypic subtypes of major depressive disorder (MDD)--(core depression (CD+), anxious depression (ANX+), and neurovegetative symptoms of melancholia (NVSM+))--following treatment with a selective serotonin reuptake inhibitor (SSRI).\n\nMethodsDepressed outpatients (n=240) from the Mayo Clinic Pharmacogenomics Research Network were treated with citalopram or escitalopram for eight weeks. Plasma samples collected at baseline and eight weeks post-treatment were profiled for multiple-, short-, medium- and long-chain acylcarnitine levels using AbsoluteIDQ(R)p180-Kit and LC-MS. Linear mixed effects models were used to examine whether acylcarnitine levels discriminate the clinical phenotypes at baseline or eight weeks post-treatment, and whether temporal changes in acylcarnitine profiles differ between groups.\n\nResultsAt baseline, significantly lower concentrations of short- and long-chain acylcarnitines were found in CD+ and NVSM+ compared to ANX+, and the short-chain acylcarnitines remained lower after eight weeks. At eight weeks, the medium- and long-chain acylcarnitines were significantly lower in NVSM+ compared to ANX+. Regarding changes baseline to week eight, short-chain acylcarnitine levels significantly increased in CD+ and ANX+, and medium- and long-chain acylcarnitines significantly decreased in NVSM+ and CD+.\n\nConclusionsIn depressed patients treated with SSRIs, {beta}-oxidation and mitochondrial energetics as evaluated by levels and changes in acylcarnitines may provide the biochemical basis of the clinical heterogeneity of MDD, especially when combined with clinical characteristics.

biochemistry↗