Biology subjects

Mackin, S.

Publications and source records attributed to Mackin, S..

5 recordsLinked to original sources

bioRxiv2023

Disrupted excitation-inhibition balance in cognitively normal individuals at risk of Alzheimers disease

BackgroundSex differences impact Alzheimers disease (AD) neuropathology, but cell-to-network level dysfunctions in the prodromal phase are unclear. Alterations in hippocampal excitation-inhibition balance (EIB) have recently been linked to early AD pathology. ObjectiveExamine how AD risk factors (age, APOE-{varepsilon}4, amyloid-{beta}) relate to hippocampal EIB in cognitively normal males and females using connectome-level measures. MethodsIndividuals from the OASIS-3 cohort (age 42-95) were studied (N = 437), with a subset aged 65+ undergoing neuropsychological testing (N = 231). ResultsIn absence of AD risk factors (APOE-{varepsilon}4/A{beta}+), whole-brain EIB decreases with age more significantly in males than females (p = 0.021, {beta} = -0.007). Regression modeling including APOE-{varepsilon}4 allele carriers (A{beta}-) yielded a significant positive AGE-by-APOE interaction in the right hippocampus for females only (p = 0.013, {beta} = 0.014), persisting with inclusion of A{beta}+ individuals (p = 0.012, {beta} = 0.014). Partial correlation analyses of neuropsychological testing showed significant associations with EIB in females: positive correlations between right hippocampal EIB with categorical fluency and whole-brain EIB with the trail-making test (p < 0.05). ConclusionSex differences in EIB emerge during normal aging and progresses differently with AD risk. Results suggest APOE-{varepsilon}4 disrupts hippocampal balance more than amyloid in females. Increased excitation correlates positively with neuropsychological performance in the female group, suggesting a duality in terms of potential beneficial effects prior to cognitive impairment. This underscores the translational relevance of APOE-{varepsilon}4 related hyperexcitation in females, potentially informing therapeutic targets or early interventions to mitigate AD progression in this vulnerable population.

neuroscience↗

bioRxiv2022

Resilience of S309 and AZD7442 monoclonal antibody treatments against infection by SARS-CoV-2 Omicron lineage strains

Omicron variant strains encode large numbers of changes in the spike protein compared to historical SARS-CoV-2 isolates. Although in vitro studies have suggested that several monoclonal antibody therapies lose neutralizing activity against Omicron variants1-4, the effects in vivo remain largely unknown. Here, we report on the protective efficacy against three SARS-CoV-2 Omicron lineage strains (BA.1, BA.1.1, and BA.2) of two monoclonal antibody therapeutics (S309 [Vir Biotechnology] monotherapy and AZD7442 [AstraZeneca] combination), which correspond to ones used to treat or prevent SARS-CoV-2 infections in humans. Despite losses in neutralization potency in cell culture, S309 or AZD7442 treatments reduced BA.1, BA.1.1, and BA.2 lung infection in susceptible mice that express human ACE2 (K18-hACE2). Correlation analyses between in vitro neutralizing activity and reductions in viral burden in K18-hACE2 or human Fc{gamma} R transgenic mice suggest that S309 and AZD7442 have different mechanisms of protection against Omicron variants, with S309 utilizing Fc effector function interactions and AZD7442 acting principally by direct neutralization. Our data in mice demonstrate the resilience of S309 and AZD7442 mAbs against emerging SARS-CoV-2 variant strains and provide insight into the relationship between loss of antibody neutralization potency and retained protection in vivo.

microbiology↗

bioRxiv2022

Boosting with Omicron-matched or historical mRNA vaccines increases neutralizing antibody responses and protection against B.1.1.529 infection in mice

The B.1.1.529 Omicron variant jeopardizes vaccines designed with early pandemic spike antigens. Here, we evaluated in mice the protective activity of the Moderna mRNA-1273 vaccine against B.1.1.529 before or after boosting with preclinical mRNA-1273 or mRNA-1273.529, an Omicron-matched vaccine. Whereas two doses of mRNA-1273 vaccine induced high levels of serum neutralizing antibodies against historical WA1/2020 strains, levels were lower against B.1.1.529 and associated with infection and inflammation in the lung. A primary vaccination series with mRNA-1273.529 potently neutralized B.1.1.529 but showed limited inhibition of historical or other SARS-CoV-2 variants. However, boosting with mRNA-1273 or mRNA-1273.529 vaccines increased serum neutralizing titers and protection against B.1.1.529 infection. Nonetheless, the levels of inhibitory antibodies were higher, and viral burden and cytokines in the lung were slightly lower in mice given the Omicron-matched mRNA booster. Thus, in mice, boosting with mRNA-1273 or mRNA-1273.529 enhances protection against B.1.1.529 infection with limited differences in efficacy measured.

microbiology↗

bioRxiv2021

Protective activity of mRNA vaccines against ancestral and variant SARS-CoV-2 strains

Although mRNA vaccines prevent COVID-19, variants jeopardize their efficacy as immunity wanes. Here, we assessed the immunogenicity and protective activity of historical (mRNA-1273, designed for Wuhan-1 spike) or modified (mRNA-1273.351, designed for B.1.351 spike) preclinical Moderna mRNA vaccines in 129S2 and K18-hACE2 mice. Immunization with high or low dose formulations of mRNA vaccines induced neutralizing antibodies in serum against ancestral SARS-CoV-2 and several variants, although levels were lower particularly against the B.1.617.2 (Delta) virus. Protection against weight loss and lung pathology was observed with all high-dose vaccines against all viruses. Nonetheless, low-dose formulations of the vaccines, which produced lower magnitude antibody and T cell responses, and serve as a possible model for waning immunity, showed breakthrough lung infection and pneumonia with B.1.617.2. Thus, as levels of immunity induced by mRNA vaccines decline, breakthrough infection and disease likely will occur with some SARS-CoV-2 variants, suggesting a need for additional booster regimens.

microbiology↗

bioRxiv2018

Cortisol Predicts Antidepressant Treatment Outcome, Memory Improvement, and Brain Response to Negative Emotions: The Importance of Aging

BackgroundStudies testing the relationship between cortisol levels, depression, and antidepressant treatment response have yielded divergent results suggesting the possibility of moderators of a cortisol effect. Several studies indicate that age may moderate the relationship between cortisol and psychopathology. In patients with Major Depressive Disorder (MDD), we studied the interactive effects of age and cortisol on predicting diagnostic status, improvement in mood and memory function with antidepressant treatment, and brain response to negative emotional stimuli.\n\nMethods66 unmedicated patients with MDD and 75 matched healthy controls had serum assayed at pre-treatment baseline for cortisol. Logistic regression was used to determine an association of age, cortisol and their interaction with MDD diagnosis. Thirty-four of the MDD participants (age range: 19-65 years; median: 36) underwent treatment with a selective serotonin reuptake inhibitor (SSRl) for 8 weeks. Clinician and self-ratings of depression symptoms, as well as tests of verbal and visual delayed recall were obtained at baseline and post treatment. Moderation analyses determined the effect of age on the relationship between baseline cortisol and treatment outcome. A separate sample of 8 MDD participants prospectively underwent fMRI neuroimaging and cortisol collection while viewing negative emotional faces.\n\nResultsAge moderated the effects of cortisol on predicting MDD diagnosis (p<.05), treatment-associated reduction of depression symptoms (p<.001), improvement of delayed recall (p<.001), and baseline brain response to negative emotions (p<.05, whole brain corrected). Modeling the Age X Cortisol interaction suggested that for the participants below the median age of our sample, lower cortisol levels predicted a lower rate of MDD diagnosis, higher antidepressant effects and decreased brain reactivity in emotion regulation regions such as the anterior cingulate gyrus. On the contrary, in those above the median sample age, lower cortisol predicted a higher rate of MDD, less improvement in depression symptoms and memory performance, and more brain reactivity in the anterior cingulate.\n\nConclusionsOur results indicate that age moderates the relationship between peripheral cortisol levels and (1) MDD diagnosis, (2) brain reactivity to emotional stimuli, and (3) antidepressant-associated improvement in depression and memory symptoms. These results indicate that previous disparities in the literature linking peripheral cortisol levels with depression characteristics and treatment response may critically relate, at least in part, to the age of the patients studied.

physiology↗