The epidemiology of the first wave of H1N1 influenza pandemic in Australia : a population-based study

Objectives: Following the recent H1N1 influenza pandemic we were able to describe seropositivity in a repre-sentative sample of adults prior to the availability of a specific vaccine.Methods: This cross-sectional serological study is set in the Barwon Statistical Division, Australia. Blood samples were collected from September 2009 through to May 2010, from 1184 individuals (569 men, 615 women; median age 61.7 years), randomly selected from electoral rolls. Serum was analysed for specific H1N1 immunity using a haemagglutina-tion inhibition test. A self-report provided information about symptoms, demographics and healthcare. Associations be-tween H1N1 infection, gender, households and occupation were determined using logistic regression, adjusting for age.Results: Of 1184 individuals, 129 (58 men, 71 women) were seropositive. Gender-adjusted age-specific prevalence was: 8.3% 20-29 years, 13.5% 30-39, 10.4% 40-49, 6.5% 50-59, 9.7% 60-69, 10.3% 70-79, 18.8% 80+. Standardised preva-lence was 10.3% (95%CI 9.6-11.0). No associations were detected between seropositivity and gender (OR=0.82, 95%CI 0.57-1.19) or being a healthcare worker (OR=1.43, 95%CI 0.62-3.29). Smokers (OR=1.86, 95%CI 1.09-3.15) and those socioeconomically disadvantaged (OR=2.52, 95%CI 1.24-5.13) were at increased risk. Among 129 seropositive individu-als, 31 reported symptoms that were either mild (n = 13) or moderate (time off work, doctor visit, n = 18). For age &lt;60, 39.6% of seropositive individuals reported symptoms, whereas the proportion was 13.2% for age 60+.Conclusions: Following the pandemic, the proportion of seropositive adults was low, but significant subclinical infection was found. Social disadvantage increased the likelihood of infection. The low symptom rate for older ages may relate to pre-existing immunity.<br /

Topology profile for a glutamate receptor: Three transmembrane domains and a channel-lining reentrant membrane loop

We investigated the transmembrane topology of the GluR3 subunit that was translated in rabbit reticulocytes supplemented with microsomal membranes. A prolactin reporter epitope was fused to GluR3 at six locations, bracketing each of the proposed transmembrane domains. The sidedness of the epitope in the microsomal membrane was then assessed by proteinase K sensitivity. The N terminus and the entire region between M3 and M4 was extracellular, and the C terminus was intracellular by this method. Four native N-linked glycosylation sites in the amino terminus and one introduced site between M3 and M4 were utilized, confirming the extracellular location of these regions. Epitopes inserted upstream and downstream of M2 were protease sensitive and thus intracellular. Our results support a topological model for glutamate receptor subunits that consists of three transmembrane domains, M1, M3, and M4, and another domain, the proposed channel-lining M2, which forms a reentrant membrane segment with both ends facing the cytoplasm

'Stranger in a strange land' – reclaiming the terrain for a disorientating dilemma and the possibility of forgiveness

This is an accepted manuscript of a chapter published in Daley, M., Orr, K. and Petrie, J. (Eds.) Caliban's dance: FE after The Tempest by Trentham Books (UCL IOE Press) in September 2020. The accepted version of the publication may differ from the final published version. For re-use please see the publisher's terms and conditions

Persistent sensitization of dopamine neurotransmission in ventral striatum (nucleus accumbens) produced by prior experience with (+)-amphetamine: a microdialysis study in freely moving rats

In humans the repeated use of amphetamine (AMPH) produces a hypersensitivity to the psychotogenic effects of AMPH that persists for months to years after the cessation of drug use. To explore the neurobiological basis of this phenomenon the long-term effects of dextroamphetamine ((+)-AMPH) on brain monoamines and behavior were studied in an animal model of AMPH psychosis. An escalating dose pretreatment regimen (from 1 to 10 mg/kg over 5 weeks) was used to mimic the pattern of drug use associated with the development of addiction and AMPH psychosis. The effect of pretreatment with AMPH on dopamine (DA) release in the ventral striatum (nucleus accumbens) was determined by measuring the extracellular concentrations of DA and DA metabolites using in vivo microdialysis, both before and after an AMPH challenge. The postmortem tissue concentrations of DA, serotonin and their metabolites were measured to determine if this treatment was neurotoxic. Escalating doses of (+)-AMPH were not neurotoxic, and 25-30 days after the cessation of drug treatment animals showed relatively normal levels of spontaneous motor activity across the day-night cycle. However, AMPH pretreatment produced robust behavioral sensitization. Animals showed a marked hypersensitivity to the motor stimulant effects of an AMPH challenge, even after 15-20 days of withdrawal. Most importantly, this hyperdopaminergic behavioral syndrome was accompanied by significantly elevated DA release in the ventral striatum. In contrast, AMPH pretreatment had no effect on the basal extracellular concentrations of DA. It is suggested that the sensitization produced by chronic AMPH use is due to enduring changes in the releasability of DA, and that this may represent an example of neural plasticity common to other forms of behavioral adaptation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27094/1/0000085.pd

Multiple Gene Variants Linked to Alzheimer\u27s-Type Clinical Dementia via GWAS are Also Associated with Non-Alzheimer\u27s Neuropathologic Entities

The classic pathologic hallmarks of Alzheimer’s disease (AD) are amyloid plaques and neurofibrillary tangles (AD neuropathologic changes, or ADNC). However, brains from individuals clinically diagnosed with “AD-type” (amnestic) dementia usually harbor heterogeneous neuropathologies in addition to, or other than, ADNC. We hypothesized that some AD-type dementia associated genetic single nucleotide variants (SNVs) identified from large genomewide association studies (GWAS) were associated with non-ADNC neuropathologies. To test this hypothesis, we analyzed data from multiple studies with available genotype and neuropathologic phenotype information. Clinical AD/dementia risk alleles of interest were derived from the very large GWAS by Bellenguez et al. (2022) who reported 83 clinical AD/dementia-linked SNVs in addition to the APOE risk alleles. To query the pathologic phenotypes associated with variation of those SNVs, National Alzheimer’s disease Coordinating Center (NACC) neuropathologic data were linked to AD Sequencing Project (ADSP) and AD Genomics Consortium (ADGC) data. Separate data were obtained from the harmonized Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). A total of 4811 European participants had at least ADNC neuropathology data and also genotype data available; data were meta-analyzed across cohorts. As expected, a subset of dementia-associated SNVs were associated with ADNC risk in Europeans—e.g., BIN1, PICALM, CR1, MME, and COX7C. Other gene variants linked to (clinical) AD dementia were associated with non-ADNC pathologies. For example, the associations of GRN and TMEM106B SNVs with limbic-predominant age-related TDP-43 neuropathologic changes (LATE-NC) were replicated. In addition, SNVs in TNIP1 and WNT3 previously reported as ADrelated were instead associated with hippocampal sclerosis pathology. Some genotype/neuropathology association trends were not statistically significant at P \u3c 0.05 after correcting for multiple testing, but were intriguing. For example, variants in SORL1 and TPCN1 showed trends for association with LATE-NC whereas Lewy body pathology trended toward association with USP6NL and BIN1 gene variants. A smaller cohort of non-European subjects (n = 273, approximately one-half of whom were African-Americans) provided the basis for additional exploratory analyses. Overall, these findings were consistent with the hypothesis that some genetic variants linked to AD dementia risk exert their affect by influencing non-ADNC neuropathologies

24-Hour Rhythms of DNA Methylation and Their Relation with Rhythms of RNA Expression in the Human Dorsolateral Prefrontal Cortex

Circadian rhythms modulate the biology of many human tissues, including brain tissues, and are driven by a near 24-hour transcriptional feedback loop. These rhythms are paralleled by 24-hour rhythms of large portions of the transcriptome. The role of dynamic DNA methylation in influencing these rhythms is uncertain. While recent work in Neurospora suggests that dynamic site-specific circadian rhythms of DNA methylation may play a role in modulating the fungal molecular clock, such rhythms and their relationship to RNA expression have not, to our knowledge, been elucidated in mammalian tissues, including human brain tissues. We hypothesized that 24-hour rhythms of DNA methylation exist in the human brain, and play a role in driving 24-hour rhythms of RNA expression. We analyzed DNA methylation levels in post-mortem human dorsolateral prefrontal cortex samples from 738 subjects. We assessed for 24-hour rhythmicity of 420,132 DNA methylation sites throughout the genome by considering methylation levels as a function of clock time of death and parameterizing these data using cosine functions. We determined global statistical significance by permutation. We then related rhythms of DNA methylation with rhythms of RNA expression determined by RNA sequencing. We found evidence of significant 24-hour rhythmicity of DNA methylation. Regions near transcription start sites were enriched for high-amplitude rhythmic DNA methylation sites, which were in turn time locked to 24-hour rhythms of RNA expression of nearby genes, with the nadir of methylation preceding peak transcript expression by 1–3 hours. Weak ante-mortem rest-activity rhythms were associated with lower amplitude DNA methylation rhythms as were older age and the presence of Alzheimer's disease. These findings support the hypothesis that 24-hour rhythms of DNA methylation, particularly near transcription start sites, may play a role in driving 24-hour rhythms of gene expression in the human dorsolateral prefrontal cortex, and may be affected by age and Alzheimer's disease

Deconvolving the contributions of cell-type heterogeneity on cortical gene expression

Complexity of cell-type composition has created much skepticism surrounding the interpretation of bulk tissue transcriptomic studies. Recent studies have shown that deconvolution algorithms can be applied to computationally estimate cell-type proportions from gene expression data of bulk blood samples, but their performance when applied to brain tissue is unclear. Here, we have generated an immunohistochemistry (IHC) dataset for five major cell-types from brain tissue of 70 individuals, who also have bulk cortical gene expression data. With the IHC data as the benchmark, this resource enables quantitative assessment of deconvolution algorithms for brain tissue. We apply existing deconvolution algorithms to brain tissue by using marker sets derived from human brain single cell and cell-sorted RNA-seq data. We show that these algorithms can indeed produce informative estimates of constituent cell-type proportions. In fact, neuronal subpopulations can also be estimated from bulk brain tissue samples. Further, we show that including the cell-type proportion estimates as confounding factors is important for reducing false associations between Alzheimer\u27s disease phenotypes and gene expression. Lastly, we demonstrate that using more accurate marker sets can substantially improve statistical power in detecting cell-type specific expression quantitative trait loci (eQTLs)

The PSEN1, p.E318G Variant Increases the Risk of Alzheimer's Disease in APOE-ε4 Carriers

The primary constituents of plaques (Aβ42/Aβ40) and neurofibrillary tangles (tau and phosphorylated forms of tau [ptau]) are the current leading diagnostic and prognostic cerebrospinal fluid (CSF) biomarkers for AD. In this study, we performed deep sequencing of APP, PSEN1, PSEN2, GRN, APOE and MAPT genes in individuals with extreme CSF Aβ42, tau, or ptau levels. One known pathogenic mutation (PSEN1 p.A426P), four high-risk variants for AD (APOE p.L46P, MAPT p.A152T, PSEN2 p.R62H and p.R71W) and nine novel variants were identified. Surprisingly, a coding variant in PSEN1, p.E318G (rs17125721-G) exhibited a significant association with high CSF tau (p = 9.2×10−4) and ptau (p = 1.8×10−3) levels. The association of the p.E318G variant with Aβ deposition was observed in APOE-ε4 allele carriers. Furthermore, we found that in a large case-control series (n = 5,161) individuals who are APOE-ε4 carriers and carry the p.E318G variant are at a risk of developing AD (OR = 10.7, 95% CI = 4.7–24.6) that is similar to APOE-ε4 homozygous (OR = 9.9, 95% CI = 7.2.9–13.6), and double the risk for APOE-ε4 carriers that do not carry p.E318G (OR = 3.9, 95% CI = 3.4–4.4). The p.E318G variant is present in 5.3% (n = 30) of the families from a large clinical series of LOAD families (n = 565) and exhibited a higher frequency in familial LOAD (MAF = 2.5%) than in sporadic LOAD (MAF = 1.6%) (p = 0.02). Additionally, we found that in the presence of at least one APOE-ε4 allele, p.E318G is associated with more Aβ plaques and faster cognitive decline. We demonstrate that the effect of PSEN1, p.E318G on AD susceptibility is largely dependent on an interaction with APOE-ε4 and mediated by an increased burden of Aβ deposition

Intermediate Phenotypes Identify Divergent Pathways to Alzheimer's Disease

Background: Recent genetic studies have identified a growing number of loci with suggestive evidence of association with susceptibility to Alzheimer's disease (AD). However, little is known of the role of these candidate genes in influencing intermediate phenotypes associated with a diagnosis of AD, including cognitive decline or AD neuropathologic burden. Methods/Principal Findings: Thirty-two single nucleotide polymorphisms (SNPs) previously implicated in AD susceptibility were genotyped in 414 subjects with both annual clinical evaluation and completed brain autopsies from the Religious Orders Study and the Rush Memory and Aging Project. Regression analyses evaluated the relation of SNP genotypes to continuous measures of AD neuropathology and cognitive function proximate to death. A SNP in the zinc finger protein 224 gene (ZNF224, rs3746319) was associated with both global AD neuropathology (p = 0.009) and global cognition (p = 0.002); whereas, a SNP at the phosphoenolpyruvate carboxykinase locus (PCK1, rs8192708) was selectively associated with global cognition (p = 3.57×10−4). The association of ZNF224 with cognitive impairment was mediated by neurofibrillary tangles, whereas PCK1 largely influenced cognition independent of AD pathology, as well as Lewy bodies and infarcts. Conclusions/Significance: The findings support the association of several loci with AD, and suggest how intermediate phenotypes can enhance analysis of susceptibility loci in this complex genetic disorder