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Article ; Online: Blood-Based mtDNA Quantification Indicates Population-Specific Differences Associated with Alzheimer's Disease-Related Risk.

Gorham, Isabelle K / Reid, Danielle Marie / Sun, Jie / Zhou, Zhengyang / Barber, Robert C / Phillips, Nicole R

2024 Volume 97, Issue 3, Page(s) 1407–1419

Abstract: Background: Age is known to be the biggest risk factor for Alzheimer's disease (AD), and Mexican Americans (MAs), who are one of the fastest-aging populations in the United States, are at a uniquely elevated risk. Mitochondrial stress and dysfunction ... ...

Abstract	Background: Age is known to be the biggest risk factor for Alzheimer's disease (AD), and Mexican Americans (MAs), who are one of the fastest-aging populations in the United States, are at a uniquely elevated risk. Mitochondrial stress and dysfunction are key players in the progression of AD and are also known to be impacted by lifestyle and environmental exposures/stressors. Objective: This study aimed to identify population-specific differences in indicators of mitochondrial stress and dysfunction associated with AD risk that are detectable in the blood. Methods: Examining blood from both non-Hispanic white (NHW) and MA participants (N = 527, MA n = 284, NHW n = 243), mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) copy numbers were assessed through quantitative PCR. Data was stratified by population and sample type, and multiple linear regression analyses were performed to identify factors that may influence this phenotype of mitochondrial dysfunction. Results: In the MA cohort, there was a significant relationship between cellular mtDNA:nDNA ratio and body mass index, CDR sum of boxes score, the APOEɛ2/ɛ3 genotype, and education. Further, there was a significant relationship between cell-free mtDNA copy number and both education and CDR sum score. In the NHW cohort, there was a significant relationship between cellular mtDNA:nDNA ratio and both age and CDR sum score. Age was associated with cell-free mtDNA in the NHW cohort. Conclusions: This evidence supports the existence of population-based differences in the factors that are predictive of this blood-based phenotype of mitochondrial dysfunction, which may be indicative of cognitive decline and AD risk.
MeSH term(s)	Humans ; DNA, Mitochondrial/genetics ; Alzheimer Disease/genetics ; Mitochondria/genetics ; Aging ; Mitochondrial Diseases
Chemical Substances	DNA, Mitochondrial
Language	English
Publishing date	2024-01-04
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-230880
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Article ; Online: Mitochondrial SOS: how mtDNA may act as a stress signal in Alzheimer's disease.

Gorham, Isabelle K / Barber, Robert C / Jones, Harlan P / Phillips, Nicole R

Alzheimer's research & therapy

2023 Volume 15, Issue 1, Page(s) 171

Abstract: Background: Alterations in mitochondrial DNA (mtDNA) levels have been observed in Alzheimer's disease and are an area of research that shows promise as a useful biomarker. It is well known that not only are the mitochondria a key player in producing ... ...

Abstract	Background: Alterations in mitochondrial DNA (mtDNA) levels have been observed in Alzheimer's disease and are an area of research that shows promise as a useful biomarker. It is well known that not only are the mitochondria a key player in producing energy for the cell, but they also are known to interact in other important intracellular processes as well as extracellular signaling and communication. BODY: This mini review explores how cells use mtDNA as a stress signal, particularly in Alzheimer's disease. We investigate the measurement of these mtDNA alterations, the mechanisms of mtDNA release, and the immunological effects from the release of these stress signals. Conclusion: Literature indicates a correlation between the release of mtDNA in Alzheimer's disease and increased immune responses, showing promise as a potential biomarker. However, several questions remain unanswered and there is great potential for future studies in this area.
MeSH term(s)	Humans ; DNA, Mitochondrial/genetics ; DNA, Mitochondrial/metabolism ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Mitochondria/metabolism ; Signal Transduction ; Biomarkers/metabolism ; Oxidative Stress
Chemical Substances	DNA, Mitochondrial ; Biomarkers
Language	English
Publishing date	2023-10-11
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-023-01322-6
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Article ; Online: Software to Visualize Proteins and Perform Structural Alignments.

Barber, Robert D

Current protocols

2021 Volume 1, Issue 11, Page(s) e292

Abstract: ... a prominent role in determination of distinct enzyme activities. In contrast, cytochrome c proteins are under ...

Abstract	Availability of protein structural data is accelerating at an astounding rate, facilitating in silico biochemical and biophysical analyses that require visualization methods. In particular, increased accessibility of representatives within respective protein families is empowering investigators to perform structural model comparisons that provide both functional and evolutionary insights at much more refined levels than previously possible. Numerous software platforms, including several free and open source versions, are available for users to interrogate protein structural models. In this article, three structural alignment protocols are described using freely available software to investigate aspects of protein structure evolution at quaternary, tertiary, and domain levels, respectively. Mapping distinct subunit interfaces and active site positioning within the PfpI/DJ-1 protein superfamily reveals quaternary structure that can have a prominent role in determination of distinct enzyme activities. In contrast, cytochrome c proteins are under strong evolutionary constraints due to their critical role in energy generation, and as a result, structural conservation is observed. However, substitutions within these conserved folds occur in distinct species, presumably to influence interactions with protein complexes involved in electron transport. Lastly, evolution of distinct allosteric mechanisms within winged helix-turn-helix transcriptional regulators, as well as protein dynamics, are revealed through visualization of metal- and redox-responsive DNA-binding proteins. The software platforms used in these protocols are Swiss-PDBViewer and PyMOL. Swiss-PDBViewer is an easy to implement, end-user software that is excellent for entry into protein visualization methods. PyMOL is also easy to implement, but offers greater depth for advanced investigations and visualizations, as well as the ability to capture protein structure conformational changes. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Exploring quaternary structure evolution with Swiss-PDBViewer Alternate Protocol: Exploring tertiary structure evolution with Swiss-PDBViewer Basic Protocol 2: Visualizing allostery using PyMOL.
MeSH term(s)	Computer Simulation ; Humans ; Proteins ; Software
Chemical Substances	Proteins
Language	English
Publishing date	2021-05-04
Publishing country	United States
Document type	Journal Article
ISSN	2691-1299
ISSN (online)	2691-1299
DOI	10.1002/cpz1.292
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Article ; Online: Multiomics Investigation of Hypertension and White Matter Hyperintensity as a Source of Vascular Dementia or a Comorbidity to Alzheimer's Disease.

Pathak, Gita A / Barber, Robert C / Phillips, Nicole R

Current Alzheimer research

2021 Volume 18, Issue 2, Page(s) 171–177

Abstract: Background: Age-related comorbidity is common and significantly increases the burden for the healthcare of the elderly. Alzheimer's disease (AD) and hypertension are the two most prevalent age-related conditions and are highly comorbid. While ... ...

Abstract	Background: Age-related comorbidity is common and significantly increases the burden for the healthcare of the elderly. Alzheimer's disease (AD) and hypertension are the two most prevalent age-related conditions and are highly comorbid. While hypertension is a risk factor for vascular dementia (VD), hypertension with AD (ADHyp+) is often characterized as probable vascular dementia. In the absence of imaging and other diagnostic tests, differentiating the two pathological states is difficult. Objective: Our goals are to (1) identify differences in CSF-based vascular dementia profiles, if any, between individuals who have AD only (ADHyp-), and individuals with ADHyp+ using CSF levels of amyloid β, tau and p-tau, and (2) compare genome-wide DNA profiles of ADHyp- and ADHyp+ with an unaffected control population. Method: Genotype and clinical data were used to compare healthy controls to AD Hyp- vs. AD Hyp+. We compared the CSF biomarkers followed by evaluating genome wide profiles in three groups, and mapped SNPs to genes based on position and lowest p-value. The significant genes were examined for co-expression and known disease networks. Results: We found no differences between Aβ, tau and p-tau levels between ADHyp- and ADHyp+. We found TOMM40 to be associated with ADHyp- as expected but not with ADHyp+. Interestingly, SLC9A3R2 polymorphism was associated with ADHyp+, and significant gene expression changes were observed for neighboring genes. Conclusion: Through this exploratory study using a novel cohort stratification design, we highlight the genetic differences in clinically similar phenotypes, indicating the utility of genetic profiling in aiding differential diagnosis of ADHyp+ and VD.
MeSH term(s)	Aged ; Alzheimer Disease/cerebrospinal fluid ; Alzheimer Disease/diagnosis ; Alzheimer Disease/pathology ; Amyloid/cerebrospinal fluid ; Comorbidity ; Dementia, Vascular/cerebrospinal fluid ; Dementia, Vascular/diagnosis ; Female ; Genome-Wide Association Study ; Humans ; Hypertension/complications ; Male ; Membrane Transport Proteins/genetics ; Middle Aged ; Phosphoproteins/genetics ; Sodium-Hydrogen Exchangers/genetics ; White Matter/pathology ; tau Proteins/cerebrospinal fluid
Chemical Substances	Amyloid ; Membrane Transport Proteins ; Phosphoproteins ; Sodium-Hydrogen Exchangers ; TOMM40 protein, human ; sodium-hydrogen exchanger regulatory factor ; tau Proteins
Language	English
Publishing date	2021-10-08
Publishing country	United Arab Emirates
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2205170-3
ISSN	1875-5828 ; 1567-2050
ISSN (online)	1875-5828
ISSN	1567-2050
DOI	10.2174/1567205018666210422133547
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Article ; Online: Mitochondrial DNA oxidative mutations are elevated in Mexican American women potentially implicating Alzheimer's disease.

Reid, Danielle Marie / Barber, Robert C / Thorpe, Roland J / Sun, Jie / Zhou, Zhengyang / Phillips, Nicole R

npj aging

2022 Volume 8, Issue 1, Page(s) 2

Abstract: Mexican Americans (MAs) are the fastest-growing Hispanic population segment in the US; as this population increases in age, so will the societal burden of age-related diseases such as Alzheimer's disease (AD). Mitochondrial DNA (mtDNA) damage may be ... ...

Abstract	Mexican Americans (MAs) are the fastest-growing Hispanic population segment in the US; as this population increases in age, so will the societal burden of age-related diseases such as Alzheimer's disease (AD). Mitochondrial DNA (mtDNA) damage may be implicated in MA AD risk since metabolic comorbidities are more prevalent in this group. Oxidative damage to guanosine (8oxoG) is one of the most prevalent DNA lesions and a putative indicator of mitochondrial dysfunction. Testing blood samples from participants of the Texas Alzheimer's Research and Care Consortium, we found mtDNA 8oxoG mutational load to be significantly higher in MAs compared to non-Hispanic whites and that MA females are differentially affected. Furthermore, we identified specific mtDNA haplotypes that confer increased risk for oxidative damage and suggestive evidence that cognitive function may be related to 8oxoG burden. Our understanding of these phenomena will elucidate population- and sex-specific mechanisms of AD pathogenesis, informing the development of more precise interventions and therapeutic approaches for MAs with AD in the future.
Language	English
Publishing date	2022-04-04
Publishing country	England
Document type	Journal Article
ISSN	2731-6068
ISSN (online)	2731-6068
DOI	10.1038/s41514-022-00082-1
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Article ; Online: Characterisation of the serum cytokine profile in feline atopic skin syndrome.

Vargo, Cheryl / Gogal, Robert / Barber, James / Austel, Michaela / Banovic, Frane

Veterinary dermatology

2021 Volume 32, Issue 5, Page(s) 485–e133

Abstract: ... IL-8, C-C Motif Chemokine Ligand (CCL)5, CCL2 and CXCL12], as well as growth factors ...

Abstract	Background: Feline atopic skin syndrome (FASS) is a pruritic and inflammatory skin disease commonly encountered in cats. Three previous reports evaluated cytokine immune activation in cats diagnosed with feline allergic dermatitis. However, no significant upregulations were observed in allergic cats compared to healthy controls. Hypothesis/objective: To evaluate differences in the serum cytokine profile of cats diagnosed with FASS compared to healthy cats, and correlate serum markers with the extent of FASS skin disease using clinical scoring systems. Animals: Thirteen client-owned FASS cats and 12 healthy control cats. Methods and materials: Thirteen cytokine and chemokines from the serum of FASS cats and healthy controls were analysed using a commercially available feline-specific multiplex assay. Results: Patients with FASS had a significant increase in serum concentrations of interferon-gamma (IFN-γ), interleukin (IL)-2, IL-13 and IL-18. In addition, cytokine/chemokines involved in inflammation and chemotaxis [IL-8, C-C Motif Chemokine Ligand (CCL)5, CCL2 and CXCL12], as well as growth factors, stem cell factor and Fms-related tyrosine kinase 3 ligand (Flt3L), also were significantly elevated. A significant positive correlation (r = 0.64) between the serum levels of Flt3L and Scoring Feline Allergic Dermatitis (SCORFAD) score was observed. Conclusions: These results demonstrate the activation of a broad array of immune secretory cytokines in the serum of cats with FASS, which are largely associated with a mixed Th1 and Th2 inflammatory response along with specific growth factors. Further larger-sample studies are needed to assess the modulation of serum biomarkers in FASS by pharmacological/therapeutic interventions.
MeSH term(s)	Allergens ; Animals ; Cat Diseases ; Cats ; Cytokines ; Dermatitis, Atopic/veterinary ; Hypersensitivity/veterinary ; Skin
Chemical Substances	Allergens ; Cytokines
Language	English
Publishing date	2021-06-27
Publishing country	England
Document type	Journal Article
ZDB-ID	2011122-8
ISSN	1365-3164 ; 0959-4493
ISSN (online)	1365-3164
ISSN	0959-4493
DOI	10.1111/vde.12994
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Article ; Online: Driving following a diagnosis of dementia: Exploring the views and experiences of people with dementia-A UK survey.

Gouldsborough, Victoria / Fairmichael, Fergus / Davison, Christopher / Hetherington, Victoria / Barber, Robert

International journal of geriatric psychiatry

2023 Volume 38, Issue 2, Page(s) e5874

Abstract: Background: Driving cessation can be one of the adjustments made following a diagnosis of dementia. Little is known about the views and opinions of people living with dementia about this. The study aimed to gather a broad idea of the expectations, ... ...

Abstract	Background: Driving cessation can be one of the adjustments made following a diagnosis of dementia. Little is known about the views and opinions of people living with dementia about this. The study aimed to gather a broad idea of the expectations, impacts and the process of driving cessation from the perspective of those living with dementia. Methods: 138 people with dementia and 91 relatives/friends (on behalf of an individual with dementia) took part in an online questionnaire. Results: People living with dementia reported stopping driving following diagnosis can have negative psychological impacts particularly in relation to; feelings of isolation, depression, loss of freedom and feeling life isn't worth living. Age, gender and choice in the driving cessation process were related to the degree of negative experiences. Conclusions: The difficulties reported by people with dementia suggest a need to provide more structured post diagnostic support to aid decision making of driving continuation or cessation; with the view to reducing associated distress and enabling people with dementia to continue to live a meaningful life.
MeSH term(s)	Humans ; Dementia/diagnosis ; Dementia/psychology ; Automobile Driving/psychology ; United Kingdom
Language	English
Publishing date	2023-02-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	806736-3
ISSN	1099-1166 ; 0885-6230
ISSN (online)	1099-1166
ISSN	0885-6230
DOI	10.1002/gps.5874
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Article: Integrative Blood-Based Characterization of Oxidative Mitochondrial DNA Damage Variants Implicates Mexican Americans' Metabolic Risk for Developing Alzheimer's Disease.

Reid, Danielle Marie / Barber, Robert C / Jones, Harlan P / Thorpe, Roland J / Sun, Jie / Zhou, Zhengyang / Phillips, Nicole R

Research square

2023

Abstract: Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65+) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latinx population, due to their AD-related health ...

Abstract	Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65+) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latinx population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk. Our results show that 8oxoG levels in both buffy coat and plasma were significantly associated with population, sex, years of education, and reveal a potential association with AD. Furthermore, MAs are significantly burdened by mtDNA oxidative damage in both blood fractions, which may contribute to their metabolic vulnerability to developing AD.
Language	English
Publishing date	2023-03-24
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-2666242/v1
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Article ; Online: Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American's metabolic risk for developing Alzheimer's disease.

Reid, Danielle Marie / Barber, Robert C / Jones, Harlan P / Thorpe, Roland J / Sun, Jie / Zhou, Zhengyang / Phillips, Nicole R

Scientific reports

2023 Volume 13, Issue 1, Page(s) 14765

Abstract: Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related ... ...

Abstract	Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk. Our results show that 8oxoG levels in both buffy coat and plasma were significantly associated with population, sex, years of education, and reveal a potential association with AD. Furthermore, MAs are significantly burdened by mtDNA oxidative damage in both blood fractions, which may contribute to their metabolic vulnerability to developing AD.
MeSH term(s)	Aged ; Humans ; Alzheimer Disease/genetics ; DNA, Mitochondrial/genetics ; Guanine ; Mexican Americans/genetics ; Mitochondria/genetics ; Oxidative Stress/genetics ; DNA Damage/genetics ; White/genetics
Chemical Substances	DNA, Mitochondrial ; Guanine (5Z93L87A1R)
Language	English
Publishing date	2023-09-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-41190-6
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Article: A high quality, high molecular weight DNA extraction method for PacBio HiFi genome sequencing of recalcitrant plants.

Nishii, Kanae / Möller, Michael / Foster, Robert G / Forrest, Laura L / Kelso, Nathan / Barber, Sadie / Howard, Caroline / Hart, Michelle L

Plant methods

2023 Volume 19, Issue 1, Page(s) 41

Abstract: ... cells/nucleus lysis was achieved with 4 h at 58 °C. The obtained high quality and high molecular weight DNAs ...

Abstract	Background: PacBio HiFi sequencing provides highly accurate long-read sequencing datasets which are of great advantage for whole genome sequencing projects. One limitation of the method is the requirement for high quality, high molecular weight input DNA. This can be particularly challenging for plants that frequently contain common and species-specific secondary metabolites, which often interfere with downstream processes. Cape Primroses (genus Streptocarpus), are some of these recalcitrant plants and are selected here as material to develop a high quality, high molecular weight DNA extraction protocol for long read genome sequencing. Results: We developed a DNA extraction method for PacBio HiFi sequencing for Streptocarpus grandis and Streptocarpus kentaniensis. A CTAB lysis buffer was employed to avoid guanidine, and the traditional chloroform and phenol purification steps were replaced with pre-lysis sample washes. Best cells/nucleus lysis was achieved with 4 h at 58 °C. The obtained high quality and high molecular weight DNAs were tested in PacBio SMRTBell™ library preparations, which resulted in circular consensus sequencing (CCS) reads from 17 to 27 Gb per cell, and a read length N50 from 14 to 17 kbp. To evaluate the quality of the reads for whole genome sequencing, they were assembled with HiFiasm into draft genomes, with N50 = 49 Mb and 23 Mb, and L50 = 10 and 11. The longest contigs were 95 Mb and 57 Mb respectively, showing good contiguity as these are longer than the theoretical chromosome length (genome size/chromosome number) of 78 Mb and 55 Mb, for S. grandis and S. kentaniensis respectively. Conclusions: DNA extraction is a critical step towards obtaining a complete genome assembly. Our DNA extraction method here provided the required high quality, high molecular weight DNA for successful standard-input PacBio HiFi library preparation. The contigs from those reads showed a high contiguity, providing a good starting draft assembly towards obtaining a complete genome. The results obtained here were highly promising, and demonstrated that the DNA extraction method developed here is compatible with PacBio HiFi sequencing and suitable for de novo whole genome sequencing projects of plants.
Language	English
Publishing date	2023-04-29
Publishing country	England
Document type	Journal Article
ZDB-ID	2203723-8
ISSN	1746-4811
ISSN	1746-4811
DOI	10.1186/s13007-023-01009-x
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