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"McCulloch, Scott"
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Dietary inulin alters the gut microbiome, enhances systemic metabolism and reduces neuroinflammation in an APOE4 mouse model
The apolipoprotein ε4 allele (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD). APOE4 carriers develop systemic metabolic dysfunction decades before showing AD symptoms. Accumulating evidence shows that the metabolic dysfunction accelerates AD development, including exacerbated amyloid-beta (Aβ) retention, neuroinflammation and cognitive decline. Therefore, preserving metabolic function early on may be critical to reducing the risk for AD. Here, we show that inulin increases beneficial microbiota and decreases harmful microbiota in the feces of young, asymptomatic APOE4 transgenic (E4FAD) mice and enhances metabolism in the cecum, periphery and brain, as demonstrated by increases in the levels of SCFAs, tryptophan-derived metabolites, bile acids, glycolytic metabolites and scyllo-inositol. We show that inulin also reduces inflammatory gene expression in the hippocampus. This knowledge can be utilized to design early precision nutrition intervention strategies that use a prebiotic diet to enhance systemic metabolism and may be useful for reducing AD risk in asymptomatic APOE4 carriers.
Journal Article
The fidelity of DNA synthesis by eukaryotic replicative and translesion synthesis polymerases
In their seminal publication describing the structure of the DNA double helix , Watson and Crick wrote what may be one of the greatest understatements in the scientific literature, namely that ＂It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.＂ Half a century later, we more fully appreciate what a huge challenge it is to replicate six billion nucleotides with the accuracy needed to stably maintain the human genome over many generations. This challenge is perhaps greater than was realized 50 years ago, because subsequent studies have revealed that the genome can be destabilized not only by environmental stresses that generate a large number and variety of potentially cytotoxic and mutagenic lesions in DNA but also by various sequence motifs of normal DNA that present challenges to replication. Towards a better understanding of the many determinants of genome stability, this chapter reviews the fidelity with which undamaged and damaged DNA is copied, with a focus on the eukaryotic B- and Y-family DNA polymerases, and considers how this fidelity is achieved.
Journal Article
Characterising methamphetamine use to inform health and social policies in Manitoba, Canada: a protocol for a retrospective cohort study using linked administrative data
IntroductionRising use of methamphetamine is causing significant public health concern in Canada. The biological and behavioural effects of methamphetamine range from wakefulness, vigour and euphoria to adverse physical health outcomes like myocardial infarction, haemorrhagic stroke, arrhythmia and seizure. It can also cause severe psychological complications such as psychosis. National survey data point to increasing rates of methamphetamine use, as well as increasing ease of access and serious methamphetamine-related harms. There is an urgent need for evidence to address knowledge gaps, provide direction to harm reduction and treatment efforts and inform health and social policies for people using methamphetamine. This protocol describes a study that aims to address this need for evidence.MethodsThe study will use linked, whole population, de-identified administrative data from the Manitoba Population Research Data Repository. The cohort will include individuals in the city of Winnipeg, Manitoba, who came into contact with the health system for reasons related to methamphetamine use from 2013 to 2021 and a comparison group matched on age, sex and geography. We will describe the cohort’s sociodemographic characteristics, calculate incidence and prevalence of mental disorders associated with methamphetamine use and examine rates of health and social service use. We will evaluate the use of olanzapine pharmacotherapy in reducing adverse emergency department outcomes. In partnership with Indigenous co-investigators, outcomes will be stratified by First Nations and Métis identity.Ethics and disseminationThe study was approved by the University of Manitoba Health Research Ethics Board, and access datasets have been granted by all data providers. We also received approval from the First Nations Health and Social Secretariat of Manitoba’s Health Information Research Governance Committee and the Manitoba Métis Federation. Dissemination will be guided by an ‘Evidence 2 Action’ group of public rightsholders, service providers and knowledge users who will ensure that the analyses address the critical issues.
Journal Article
Untargeted metabolomics analysis on kidney tissues from mice reveals potential hypoxia biomarkers
Chronic hypoxia may have a huge impact on the cardiovascular and renal systems. Advancements in microscopy, metabolomics, and bioinformatics provide opportunities to identify new biomarkers. In this study, we aimed at elucidating the metabolic alterations in kidney tissues induced by chronic hypoxia using untargeted metabolomic analyses. Reverse phase ultrahigh performance liquid chromatography-mass spectroscopy/mass spectroscopy (RP–UPLC–MS/MS) and hydrophilic interaction liquid chromatography (HILIC)–UPLC–MS/MS methods with positive and negative ion mode electrospray ionization were used for metabolic profiling. The metabolomic profiling revealed an increase in metabolites related to carnitine synthesis and purine metabolism. Additionally, there was a notable increase in bilirubin. Heme, N-acetyl-
l
-aspartic acid, thyroxine, and 3-beta-Hydroxy-5-cholestenoate were found to be significantly downregulated. 3-beta-Hydroxy-5-cholestenoate was downregulated more significantly in male than female kidneys. Trichome Staining also showed remarkable kidney fibrosis in mice subjected to chronic hypoxia. Our study offers potential intracellular metabolite signatures for hypoxic kidneys.
Journal Article
Biochemical Analysis of DNA Polymerase η Fidelity in the Presence of Replication Protein A
DNA polymerase η (pol η) synthesizes across from damaged DNA templates in order to prevent deleterious consequences like replication fork collapse and double-strand breaks. This process, termed translesion synthesis (TLS), is an overall positive for the cell, as cells deficient in pol η display higher mutation rates. This outcome occurs despite the fact that the in vitro fidelity of bypass by pol η alone is moderate to low, depending on the lesion being copied. One possible means of increasing the fidelity of pol η is interaction with replication accessory proteins present at the replication fork. We have previously utilized a bacteriophage based screening system to measure the fidelity of bypass using purified proteins. Here we report on the fidelity effects of a single stranded binding protein, replication protein A (RPA), when copying the oxidative lesion 7,8-dihydro-8-oxo-guanine(8-oxoG) and the UV-induced cis-syn thymine-thymine cyclobutane pyrimidine dimer (T-T CPD). We observed no change in fidelity dependent on RPA when copying these damaged templates. This result is consistent in multiple position contexts. We previously identified single amino acid substitution mutants of pol η that have specific effects on fidelity when copying both damaged and undamaged templates. In order to confirm our results, we examined the Q38A and Y52E mutants in the same full-length construct. We again observed no difference when RPA was added to the bypass reaction, with the mutant forms of pol η displaying similar fidelity regardless of RPA status. We do, however, observe some slight effects when copying undamaged DNA, similar to those we have described previously. Our results indicate that RPA by itself does not affect pol η dependent lesion bypass fidelity when copying either 8-oxoG or T-T CPD lesions.
Journal Article
Evaluating the strengths and challenges of PAX dream makers approach to mental health promotion: perspectives of youth and community members in indigenous communities in Manitoba, Canada
PAX Good Behaviour Game (PAX-GBG) is an evidence-based approach to co-create a nurturing environment where all children can thrive. This school-based approach was identified as a promising intervention for suicide prevention by First Nations communities in Manitoba, Canada. To enhance this mental health promotion approach, PAX Dream Makers was developed. It is a youth-led addition to PAX-GBG for middle and high school students. This study's aim was to examine, from the communities' perspectives, the influence of PAX Dream Makers on youth as well as its strengths, challenges and suggestions for future improvements. A case study method was conducted using interviews and focus groups with 30 youth and 17 adult mentors and elders. Participants reported that PAX Dream Makers provided support and encouragement to the youth, increased their resilience and provided an opportunity to be positive role models. It strengthened PAX-GBG implementation in schools. Challenges included: adult mentors availability, frequent teacher turn-over and community mental distress. Suggestions expressed were: being mindful of cultural and community contexts, increasing community leadership's understanding of PAX-GBG and better recruitment of mentors and youth. PAX Dream Makers approach was well-received by communities and holds great promise for promoting the well-being of First Nations youth.
Journal Article
Preferential cis–syn thymine dimer bypass by DNA polymerase η occurs with biased fidelity
Human DNA polymerase η (Pol η) modulates susceptibility to skin cancer by promoting DNA synthesis past sunlight-induced cyclobutane pyrimidine dimers that escape nucleotide excision repair (NER)
1
,
2
. Here we have determined the efficiency and fidelity of dimer bypass. We show that Pol η copies thymine dimers and the flanking bases with higher processivity than it copies undamaged DNA, and then switches to less processive synthesis. This ability of Pol η to sense the dimer location as synthesis proceeds may facilitate polymerase switching before and after lesion bypass. Pol η bypasses a dimer with low fidelity and with higher error rates at the 3′ thymine than at the 5′ thymine. A similar bias is seen with
Sulfolobus solfataricus
DNA polymerase 4, which forms a Watson–Crick base pair at the 3′ thymine of a dimer but a Hoogsteen base pair at the 5′ thymine (ref.
3
). Ultraviolet-induced mutagenesis is also higher at the 3′ base of dipyrimidine sequences
4
,
5
,
6
. Thus, in normal people and particularly in individuals with NER-defective xeroderma pigmentosum who accumulate dimers, errors made by Pol η during dimer bypass could contribute to mutagenesis and skin cancer.
Journal Article
Evaluating a Paramedic-Led Fall-Referral Program in Nova Scotia: a Mixed-Methods Study
Falls in older adults are a worldwide health issue, and lead to high morbidity, mortality, and health-care costs. Paramedics play a unique and important role in post-fall management. The objectives of this study were to measure the frequency with which paramedics made referrals to fall-prevention programs, understand the factors influencing these decisions, and compare outcomes between those who received a referral with those who did not.
This mixed-methods study evaluated a paramedic fall-referral program in Nova Scotia for older adults with non-transport dispositions after a 911 response. Patient demographics and outcomes were analyzd using a matched cohort approach, while paramedic beliefs regarding the program were explored using
.
From 2014 to 2019, a total of 289 referrals were made, and a matched cohort analysis (1:2) found no significant difference in the mean number of fall-related 911 calls in the following 12 months between those who were referred (m=0.31, SD=0.94) and those who were not (m=0.30, SD=1.28). Paramedics acknowledged the importance of fall prevention, but felt a lack of education, loop closure-feedback to the referring paramedic, and patient reluctance to consider the program, were all significant barriers to referral.
This study assessed Nova Scotia's paramedic fall-prevention referral program, revealing low referral frequency despite high numbers of fall-related 911 calls, and no significant reduction in relapse 911 calls. Barriers to referral included patient reluctance, poor systematization, and lack of education and feedback.
The study highlights opportunities for improving referral systems, as paramedics play a bigger role in the prevention of age-related health issues such as falls.
Journal Article
Overlap between child protection services and the youth justice system: protocol for a retrospective population-based cohort study using linked administrative data in Manitoba, Canada
IntroductionChildren who have a history of involvement in child protection services (CPS) are over-represented in the youth and adult criminal justice systems. There are significant health and socioeconomic implications for individuals involved in either or both CPS and the justice system. Understanding the ‘overlap’ between these two systems would provide insight into the health and social needs of this population. This protocol describes a research programme on the relationship between the child welfare and the youth justice systems, looking specifically at the population involved in both CPS and the youth justice system. We will examine the characteristics associated with involvement in these systems, justice system trajectories of individuals with a history of CPS involvement and early adult outcomes of children involved in both systems.Methods and analysisAdministrative data sets will be linked at the individual level for three cohorts born 1991, 1994 and 1998 in Manitoba, Canada. Involvement in CPS will be categorised as ‘placed in out-of-home care’, ‘received in-home services, but was not placed in care’ or ‘no involvement’. Involvement in the youth justice system will be examined through contacts with police between ages 12 and 17 that either led to charges or did not proceed. Individual, maternal and neighbourhood characteristics will be examined to identify individuals at greatest risk of involvement in one or both systems.Ethics and disseminationThe study was approved by the University of Manitoba Health Research Ethics Board and permission to access data sets has been granted by all data providers. We also received approval for the study from the First Nations Health and Social Secretariat of Manitoba’s Health Information Research Governance Committee and the Manitoba Metis Federation. Strategies to disseminate study results will include engagement of stakeholders and policymakers through meetings and workshops, scientific publications and presentations, and social media.
Journal Article