؉/؊ mice, but not Nrf2 ؊/؊ , confirming the Nrf2-specific action of the inducer in vivo. Increased Nrf2 activity alone was sufficient to protect animals from 3-NP toxicity because intrastriatal adenovirus-mediated Nrf2 overexpression significantly reduced lesion size compared with green fluorescent protein overexpressing controls. In cultured astrocytes, 3-NP was found to increase Nrf2 activity leading to antioxidant response element-dependent gene expression providing a potential mechanism for the increased sensitivity of Nrf2

Abnormalities of amount and function of presynaptic terminals may have an important role in the mechanism of illness in schizophrenia. The SNARE proteins (SNAP-25, syntaxin, and VAMP) are enriched in presynaptic terminals, where they interact to form a functional complex to facilitate vesicle fusion. SNARE protein amounts are altered in the cortical regions in schizophrenia, but studies of proteinprotein interactions are limited. We extended these investigations to the striatal regions (such as the nucleus accumbens, ventromedial caudate (VMC), and dorsal caudate) relevant to disease symptoms. In addition to measuring SNARE protein levels, we studied SNARE protein-protein interactions using a novel ELISA method. The possible effect of antipsychotic treatment was investigated in parallel in the striatum of rodents that were administered haloperidol and clozapine. In schizophrenia samples, compared with controls, SNAP-25 was 32% lower (P ¼ 0.015) and syntaxin was 26% lower (P ¼ 0.006) in the VMC. In contrast, in the same region, SNARE protein-protein interactions were higher in schizophrenia (P ¼ 0.008). Confocal microscopy of schizophrenia and control VMC showed qualitatively similar SNARE protein immunostaining. Haloperidol treatment of rats increased levels of SNAP-25 (mean 24%, P ¼ 0.003), syntaxin (mean 18%, P ¼ 0.010), and VAMP (mean 16%, P ¼ 0.001), whereas clozapine increased only the VAMP level (mean 13%, P ¼ 0.004). Neither drug altered SNARE protein-protein interactions. These results indicate abnormalities of amount and interactions of proteins directly related to presynaptic function in the VMC in schizophrenia. SNARE proteins and their interactions may be a novel target for the development of therapeutics.

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Motherhood differentially affects learning and memory performance and this effect depends on reproductive experience. In turn, evidence suggests that the effects of oestradiol on learning and memory are mediated through binding to oestrogen receptors in the hippocampus and that this is related to hippocampal neurogenesis. The present study investigated the effect of pregnancy and reproductive experience on ERalpha expression throughout the hippocampus, as well as cell proliferation, new cell survival and cell death (as measured by pyknotic cells) in the granule cell layer of the hippocampus. Three groups of female Sprague-Dawley rats were used: virgin, primigravid and multigravid. All rats were injected with 5-bromo-2-deoxyuridine (BrdU; 200 mg/kg) on the afternoon of impregnation and at matched time-points in virgins. Rats were perfused either during early pregnancy (gestation day 1) or late pregnancy (gestation day 21) after BrdU injection. The results obtained show that, during late pregnancy, females, whether first or second pregnancy, have fewer ERalpha-positive cells in the CA3 region of the dorsal hippocampus than virgin females. In addition during early pregnancy, females have significantly fewer pyknotic cells in the granule cell layer than virgin females. There were no other differences between groups in the number of ERalpha-positive, BrdU-positive or pyknotic cells. Future studies will aim to investigate the mechanisms and consequences of the alteration in ERalpha expression in the hippocampus during late pregnancy, as well as the possible changes in ERbeta expression at this time.

Pre-existing cross-reactivity to SARS-CoV-2 may occur in absence of prior viral exposure. However, this has been difficult to quantify at the population level due to a lack of reliably defined seroreactivity thresholds. Using an orthogonal antibody testing approach, we estimated that 0.6% of non-triaged adults from the greater Vancouver area, Canada between May 17 th and June 19 th 2020 showed clear evidence of a prior SARS-CoV-2 infection, after adjusting for false-positive and false-negative test results. Using a highly sensitive multiplex assay and positive/negative thresholds established in infants in whom maternal antibodies have waned, we determine that more than 90% of uninfected adults showed antibody reactivity against the spike, receptor-binding domain (RBD), N-terminal domains (NTD) or the nucleocapsid (N) protein from SARS-CoV-2. This sero-reactivity was evenly distributed across age and sex, correlated with circulating coronaviruses reactivity, and was partially outcompeted by soluble circulating coronaviruses' spike. Using a custom SARS-CoV-2 peptide mapping array, we found that this antibody reactivity broadly mapped to spike, and to conserved non-structural viral proteins. We conclude that most adults display pre-existing antibody cross-reactivity against SARS-CoV-2, which further supports investigation of how this may impact the clinical severity of COVID-19 or SARS-CoV-2 vaccine responses.

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Highlights Immune response kinetics and disease severity affect SARS-CoV-2 antibody results. SARS-CoV-2 serology offers limited clinical utility for individuals. SARS-CoV-2 serology may be useful for seroprevalence studies. Claims regarding protective immunity or infectivity cannot be made using serology. Assay clinical sensitivity and specificity should approach 100% Harmonized reporting of SARS-CoV-2 serology minimizes result misinterpretation.

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