Plant genome evolution in the genus Eucalyptus is driven by structural rearrangements that promote sequence divergence.

Genomes have a highly organized architecture (nonrandom organization of functional and nonfunctional genetic elements within chromosomes) that is essential for many biological functions, particularly gene expression and reproduction. Despite the need to conserve genome architecture, a high level of structural variation has been observed within species. As species separate and diverge, genome architecture also diverges, becoming increasingly poorly conserved as divergence time increases. However, within plant genomes, the processes of genome architecture divergence are not well described. Here we use long-read sequencing and de novo assembly of 33 phylogenetically diverse, wild and naturally evolving Eucalyptus species, covering 1-50 million years of diverging genome evolution to measure genome architectural conservation and describe architectural divergence. The investigation of these genomes revealed that following lineage divergence, genome architecture is highly fragmented by rearrangements. As genomes continue to diverge, the accumulation of mutations and the subsequent divergence beyond recognition of rearrangements become the primary driver of genome divergence. The loss of syntenic regions also contribute to genome divergence but at a slower pace than that of rearrangements. We hypothesize that duplications and translocations are potentially the greatest contributors to Eucalyptus genome divergence.

Small molecules disaggregate alpha-synuclein and prevent seeding from patient brain-derived fibrils.

The amyloid aggregation of alpha-synuclein within the brain is associated with the pathogenesis of Parkinson's disease (PD) and other related synucleinopathies, including multiple system atrophy (MSA). Alpha-synuclein aggregates are a major therapeutic target for treatment of these diseases. We identify two small molecules capable of disassembling preformed alpha-synuclein fibrils. The compounds, termed CNS-11 and CNS-11g, disaggregate recombinant alpha-synuclein fibrils in vitro, prevent the intracellular seeded aggregation of alpha-synuclein fibrils, and mitigate alpha-synuclein fibril cytotoxicity in neuronal cells. Furthermore, we demonstrate that both compounds disassemble fibrils extracted from MSA patient brains and prevent their intracellular seeding. They also reduce in vivo alpha-synuclein aggregates in C. elegans. Both compounds also penetrate brain tissue in mice. A molecular dynamics-based computational model suggests the compounds may exert their disaggregating effects on the N terminus of the fibril core. These compounds appear to be promising therapeutic leads for targeting alpha-synuclein for the treatment of synucleinopathies.

Structure-based design of nanobodies that inhibit seeding of Alzheimer's patient-extracted tau fibrils.

Despite much effort, antibody therapies for Alzheimer's disease (AD) have shown limited efficacy. Challenges to the rational design of effective antibodies include the difficulty of achieving specific affinity to critical targets, poor expression, and antibody aggregation caused by buried charges and unstructured loops. To overcome these challenges, we grafted previously determined sequences of fibril-capping amyloid inhibitors onto a camel heavy chain antibody scaffold. These sequences were designed to cap fibrils of tau, known to form the neurofibrillary tangles of AD, thereby preventing fibril elongation. The nanobodies grafted with capping inhibitors blocked tau aggregation in biosensor cells seeded with postmortem brain extracts from AD and progressive supranuclear palsy (PSP) patients. The tau capping nanobody inhibitors also blocked seeding by recombinant tau oligomers. Another challenge to the design of effective antibodies is their poor blood-brain barrier (BBB) penetration. In this study, we also designed a bispecific nanobody composed of a nanobody that targets a receptor on the BBB and a tau capping nanobody inhibitor, conjoined by a flexible linker. We provide evidence that the bispecific nanobody improved BBB penetration over the tau capping inhibitor alone after intravenous administration in mice. Our results suggest that the design of synthetic antibodies that target sequences that drive protein aggregation may be a promising approach to inhibit the prion-like seeding of tau and other proteins involved in AD and related proteinopathies.

Dietary Vitamin K1 Intake and Incident Aortic Valve Stenosis.

BACKGROUND: Leaflet calcification contributes to the development and progression of aortic valve stenosis. Vitamin K activates inhibitors of vascular calcification and may modulate inflammation and skeletal bone loss. Therefore, we aimed to determine whether higher dietary intakes of vitamin K1 are associated with a lower incidence of aortic stenosis. METHODS: In the Danish Diet, Cancer and Health study, participants aged 50 to 64 years completed a 192-item food frequency questionnaire at baseline, from which habitual intakes of vitamin K1 were estimated. Participants were prospectively followed using linkage to nationwide registers to determine incident aortic valve stenosis (primary outcome) and aortic stenosis with subsequent complications (aortic valve replacement, heart failure, or cardiovascular disease-related mortality; secondary outcome). RESULTS: In 55 545 participants who were followed for a maximum of 21.5 years, 1085 were diagnosed with aortic stenosis and 615 were identified as having subsequent complications. Participants in the highest quintile of vitamin K1 intake had a 23% lower risk of aortic stenosis (hazard ratio, 0.77 [95% CI, 0.63-0.94]) and a 27% lower risk of aortic stenosis with subsequent complications (hazard ratio, 0.73 [95% CI, 0.56-0.95]), compared with participants in the lowest quintile after adjusting for demographics and cardiovascular risk factors. CONCLUSIONS: In this study, a high intake of vitamin K1-rich foods was associated with a lower incidence of aortic stenosis and a lower risk of aortic stenosis with subsequent complications.

De novo designed protein inhibitors of amyloid aggregation and seeding.

Neurodegenerative diseases are characterized by the pathologic accumulation of aggregated proteins. Known as amyloid, these fibrillar aggregates include proteins such as tau and amyloid-ß (Aß) in Alzheimer's disease (AD) and alpha-synuclein (αSyn) in Parkinson's disease (PD). The development and spread of amyloid fibrils within the brain correlates with disease onset and progression, and inhibiting amyloid formation is a possible route toward therapeutic development. Recent advances have enabled the determination of amyloid fibril structures to atomic-level resolution, improving the possibility of structure-based inhibitor design. In this work, we use these amyloid structures to design inhibitors that bind to the ends of fibrils, "capping" them so as to prevent further growth. Using de novo protein design, we develop a library of miniprotein inhibitors of 35 to 48 residues that target the amyloid structures of tau, Aß, and αSyn. Biophysical characterization of top in silico designed inhibitors shows they form stable folds, have no sequence similarity to naturally occurring proteins, and specifically prevent the aggregation of their targeted amyloid-prone proteins in vitro. The inhibitors also prevent the seeded aggregation and toxicity of fibrils in cells. In vivo evaluation reveals their ability to reduce aggregation and rescue motor deficits in Caenorhabditis elegans models of PD and AD.

Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. PURPOSE: To clarify associations of sex hormones with these outcomes. DATA SOURCES: Systematic literature review to July 2019, with bridge searches to March 2024. STUDY SELECTION: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. DATA EXTRACTION: Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. DATA SYNTHESIS: Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. LIMITATIONS: Observational study design, heterogeneity among studies, and imputation of missing data. CONCLUSION: Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Genomic determinants, architecture, and constraints in drought-related traits in Corymbia calophylla.

BACKGROUND: Drought adaptation is critical to many tree species persisting under climate change, however our knowledge of the genetic basis for trees to adapt to drought is limited. This knowledge gap impedes our fundamental understanding of drought response and application to forest production and conservation. To improve our understanding of the genomic determinants, architecture, and trait constraints, we assembled a reference genome and detected ~ 6.5 M variants in 432 phenotyped individuals for the foundational tree Corymbia calophylla. RESULTS: We found 273 genomic variants determining traits with moderate heritability (h2SNP = 0.26-0.64). Significant variants were predominantly in gene regulatory elements distributed among several haplotype blocks across all chromosomes. Furthermore, traits were constrained by frequent epistatic and pleiotropic interactions. CONCLUSIONS: Our results on the genetic basis for drought traits in Corymbia calophylla have several implications for the ability to adapt to climate change: (1) drought related traits are controlled by complex genomic architectures with large haplotypes, epistatic, and pleiotropic interactions; (2) the most significant variants determining drought related traits occurred in regulatory regions; and (3) models incorporating epistatic interactions increase trait predictions. Our findings indicate that despite moderate heritability drought traits are likely constrained by complex genomic architecture potentially limiting trees response to climate change.

Excess Deaths Associated with Rheumatic Heart Disease, Australia, 2013-2017.

During 2013-2017, the mortality rate ratio for rheumatic heart disease among Indigenous versus non-Indigenous persons in Australia was 15.9, reflecting health inequity. Using excess mortality methods, we found that deaths associated with rheumatic heart disease among Indigenous Australians were probably substantially undercounted, affecting accuracy of calculations based solely on Australian Bureau of Statistics data.

Vitamin D status and cognitive performance in community-dwelling adults: A dose-response meta-analysis of observational studies.

Low vitamin D status is linked with poorer cognition in adults while findings in relation to high levels are mixed.We performed a systematic review and meta-analyses to examine dose-response associations between 25-hydroxyvitamin D (25OHD) levelsand cognitive performance in community-dwelling adults. Thirty-eight observational studies were included in dose-response meta-analyses. Positive, nonlinear associations were identified between baseline25OHD levels and global cognition incross-sectional and longitudinal analyses, and for performance in memory and executive function in longitudinal analyses. When restricted to studies involving older adults, thepattern emerged forspecific domains in cross-sectional analyses. Poorer performance was associated with low 25OHD levels, while a sharp improvement was associated withlevels up to 60-70 nM/L. Further improvement was observed only for longitudinal global cognition. Our findings support the association between low vitamin D and poorer cognition and suggest levels of at least 60 nM/L are associated with better cognition during ageing.

Exertional heat stroke causes long-term skeletal muscle epigenetic reprogramming, altered gene expression, and impaired satellite cell function in mice.

The effect of exertional heat stroke (EHS) exposure on skeletal muscles is incompletely understood. Muscle weakness is an early symptom of EHS but is not considered a major target of multiorgan injury. Previously, in a preclinical mouse model of EHS, we observed the vulnerability of limb muscles to a second EHS exposure, suggesting hidden processes contributing to declines in muscle resilience. Here, we evaluated the possible molecular origins of EHS-induced declines in muscle resilience. Female C57BL/6 mice [total n = 56; 28/condition, i.e., EHS and exercise control (EXC)] underwent forced wheel running at 37.5°C/40% relative humidity until symptom limitation (unconsciousness). EXC mice exercised identically at room temperature (22-23°C). After 1 mo of recovery, the following were assessed: 1) specific force and caffeine-induced contracture in soleus (SOL) and extensor digitorum longus (EDL) muscles; 2) transcriptome and DNA methylome responses in gastrocnemius (GAST); and 3) primary satellite cell function (proliferation and differentiation). There were no differences in specific force in either SOL or EDL from EXC. Only EHS solei exhibited lower caffeine sensitivity. EHS GAST exhibited higher RNA expression of genes encoding structural proteins of slow fibers, heat shock proteins, and myogenesis. A total of ∼2,500 differentially methylated regions of DNA that could potentially affect many cell functions were identified. Primary satellite cells exhibited suppressed proliferation rates but normal differentiation responses. Results demonstrate long-term changes in skeletal muscles 1 mo after EHS that could contribute to declines in muscle resilience. Skeletal muscle may join other, more recognized tissues considered vulnerable to long-term effects of EHS.NEW & NOTEWORTHY Exertional heat stroke (EHS) in mice induces long-term molecular and functional changes in limb muscle that could reflect a loss of "resilience" to further stress. The phenotype was characterized by altered caffeine sensitivity and suppressed satellite cell proliferative potential. This was accompanied by changes in gene expression and DNA methylation consistent with ongoing muscle remodeling and stress adaptation. We propose that EHS may induce a prolonged vulnerability of skeletal muscle to further stress or injury.

A further update on mortality and morbidity in patients with very low hemoglobin levels who decline blood transfusion.

BACKGROUND: In the past two decades, researchers have published mortality and morbidity rates in patients with very low hemoglobin levels declining blood transfusion. The clinical knowledge and tools available for the management of patients who decline transfusions have grown since these publications. The aim of our study was to provide a further update on outcomes associated with severe anemia in these patients. STUDY DESIGN AND METHODS: A retrospective observational study of patients declining allogeneic blood transfusions with nadir hemoglobin levels ≤8 g/dL treated at The Institute for Blood Management, HELIOS Klinikum Gotha, Germany. Outcomes were in-hospital mortality within 30 days and composite morbidity or mortality, with morbidity events defined as acute myocardial infarction, cardiac failure, wound infection, arrhythmia, and pneumonia. RESULTS: Between June 2008 and June 2021, The Institute for Blood Management treated 2841 admissions of which 159 (5.6%) recorded nadir hemoglobin levels ≤8 g/dL. Of these, five (3.1%) patients died in hospital within 30 days, including four (4.8%) patients admitted for surgical procedures and one (1.4%) medical admission. There was a significant increase in the unadjusted proportion of composite morbidity or mortality events with severity of nadir hemoglobin, with each gram decrease in hemoglobin associated with a 1.48 (95% confidence interval = 1.05-2.09; p = .025) times increase. CONCLUSION: Our comparatively lower proportion of patients reaching hemoglobin levels ≤8 g/dL and lower mortality rates suggest outcomes in patients with severe anemia is modifiable with the application of current patient blood management and bloodless medicine and surgery strategies.

Longitudinal effects of dog ownership, dog acquisition, and dog loss on children's movement behaviours: findings from the PLAYCE cohort study.

INTRODUCTION: Regular physical activity is important for children's physical and mental health, yet many children do not achieve recommended amounts of physical activity. Dog ownership has been associated with increased physical activity in children, however, there have been no longitudinal studies examining this relationship. This study used data from the Play Spaces and Environments for Children's Physical Activity (PLAYCE) cohort study to examine the longitudinal effects of dog ownership status on children's movement behaviours. METHODS: Change in dog ownership from preschool (wave 1, age 2-5) to fulltime school (wave 2, age 5-7) was used as a natural experiment with four distinct dog ownership groups: continuing non-dog owners (n = 307), continuing dog owners (n = 204), dog acquired (n = 58), and dog loss (n = 31; total n = 600). Daily movement behaviours, including physical activity, sedentary time, sleep, and screen time, were measured using accelerometry and parent-report surveys. Differences between groups over time and by sex were tested using linear mixed effects regression models. RESULTS: Girls who acquired a dog increased their light intensity activities and games by 52.0 min/day (95%CI 7.9, 96.0) and girls who lost a dog decreased their light intensity activities and games by 62.1 min/day (95%CI -119.3, -4.9) compared to no change among non-dog owners. Girls and boys who acquired a dog increased their unstructured physical activity by 6.8 (95%CI 3.2, 10.3) and 7.1 (95%CI 3.9, 10.3) occasions/week, compared to no changes among non-dog owners. Girls and boys who lost a dog reduced their unstructured physical activity by 10.2 (95%CI -15.0, -5.3) and 7.7 (95%CI -12.0, -3.5) occasions/week. Girls who lost a dog decreased their total physical activity by 46.3 min/day (95%CI -107.5, 14.8) compared to no change among non-dog owners. Continuing dog ownership was typically not associated with movement behaviours. Dog ownership group was not associated with changes in sleep and had mixed associations with screen time. CONCLUSION: The positive influence of dog ownership on children's physical activity begins in early childhood and differs by child sex. Further research should examine the specific contributions dog-facilitated physical activity makes to children's overall physical activity, including the intensity and duration of dog walking and play.

Factors Associated With Circulating Sex Hormones in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements. PURPOSE: To clarify factors associated with variations in sex hormone concentrations. DATA SOURCES: Systematic literature searches (to July 2019). STUDY SELECTION: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry. DATA EXTRACTION: Individual participant data (IPD) (9 studies; n = 21 074) and aggregate data (2 studies; n = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted. DATA SYNTHESIS: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years. LIMITATION: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data. CONCLUSION: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Young children's use of blue spaces and the impact on their health, development and environmental awareness: A qualitative study from parents' perspectives.

ISSUE ADDRESSED: This study examined how families with young children access and use different types of blue spaces and the health and development benefits, and potential negative effects. METHODS: Parents(n = 25) of young children across four coastal communities in Western Australia were recruited via purposive sampling to participate in interviews. A generic qualitative study design grounded in the pragmatism paradigm was utilised. RESULTS: Beaches were the most frequently used blue space for families all year around, however families did not necessarily attend their closest beach. This appears due to certain beach features making them more or less attractive for use regardless of the distance from home. Parents perceived blue spaces as health promoting due to the increased physical activity children did in and around these spaces. They also reported blue spaces could be positive for child development, contributing to the development of identity. Blue spaces were also perceived to promote children's environmental awareness and environmentally friendly behaviours. However, blue spaces could also be potentially risky environments for families with young children. CONCLUSIONS: The findings highlight blue spaces are an important setting for supporting children's health, development and environmental consciousness. SO WHAT?: It is important to protect natural outdoor environments such as blue spaces for future generations. The findings can be used by governments and policy makers to improve the quality (features and amenities) of blue spaces and positively impact how often families (including those with dogs) use blue spaces and the benefits they experience.

Bioinformatic identification of previously unrecognized amyloidogenic proteins.

Low-complexity domains (LCDs) of proteins have been shown to self-associate, and pathogenic mutations within these domains often drive the proteins into amyloid aggregation associated with disease. These domains may be especially susceptible to amyloidogenic mutations because they are commonly intrinsically disordered and function in self-association. The question therefore arises whether a search for pathogenic mutations in LCDs of the human proteome can lead to identification of other proteins associated with amyloid disease. Here, we take a computational approach to identify documented pathogenic mutations within LCDs that may favor amyloid formation. Using this approach, we identify numerous known amyloidogenic mutations, including several such mutations within proteins previously unidentified as amyloidogenic. Among the latter group, we focus on two mutations within the TRK-fused gene protein (TFG), known to play roles in protein secretion and innate immunity, which are associated with two different peripheral neuropathies. We show that both mutations increase the propensity of TFG to form amyloid fibrils. We therefore conclude that TFG is a novel amyloid protein and propose that the diseases associated with its mutant forms may be amyloidoses.

Chronic mitochondria antioxidant treatment in older adults alters the circulating milieu to improve endothelial cell function and mitochondrial oxidative stress.

Excessive reactive oxygen species production by mitochondria (mtROS) is a key contributor to age-related vascular endothelial dysfunction. We recently showed in a crossover design, placebo-controlled clinical trial in older adults that 6 wk of treatment with the mitochondria-targeted antioxidant (MitoQ) improved endothelial function, as measured by nitric oxide (NO)-mediated endothelium-dependent dilation (EDD), by lowering mtROS and was associated with reduced circulating levels of oxidized low-density lipoprotein (oxLDL). Here, we conducted an ancillary analysis using plasma samples from our clinical trial to determine if MitoQ treatment-mediated changes in the "circulating milieu" (plasma) contribute to improvements in endothelial function and the mechanisms involved. With the use of an ex vivo model of endothelial function, acetylcholine-stimulated NO production was quantified in human aortic endothelial cells (HAECs) exposed to plasma collected after chronic MitoQ and placebo supplementation in 19 older adults (67 ± 1 yr; 11 females). We also assessed the influence of plasma on endothelial cell (EC) mtROS bioactivity and the role of lower circulating oxLDL in plasma-mediated changes. NO production was ∼25% higher (P = 0.0002) and mtROS bioactivity was ∼25% lower (P = 0.003) in HAECs exposed to plasma collected from subjects after MitoQ treatment versus placebo. Improvements in NO production ex vivo and NO-mediated EDD in vivo with MitoQ were correlated (r = 0.4683; P = 0.0431). Increasing oxLDL in plasma collected after MitoQ to placebo levels abolished MitoQ treatment effects on NO production and mtROS bioactivity, whereas inhibition of endogenous oxLDL binding to its lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) prevented these effects. These findings provide novel insight into the mechanisms by which MitoQ treatment improves endothelial function in older adults.NEW & NOTEWORTHY Chronic supplementation with a mitochondria-targeted antioxidant (MitoQ) improves vascular endothelial function in older adults, but the mechanisms of action are incompletely understood. Here, we show that MitoQ supplementation leads to changes in the circulating milieu (plasma), including reductions in oxidized low-density lipoprotein that enhance nitric oxide production and reduce mitochondrial oxidative stress in endothelial cells. These findings provide new information regarding the mechanisms by which MitoQ improves age-related endothelial dysfunction.

Interspecies genome divergence is predominantly due to frequent small scale rearrangements in Eucalyptus.

Synteny, the ordering of sequences within homologous chromosomes, must be maintained within the genomes of sexually reproducing species for the sharing of alleles and production of viable, reproducing offspring. However, when the genomes of closely related species are compared, a loss of synteny is often observed. Unequal homologous recombination is the primary mechanism behind synteny loss, occurring more often in transposon rich regions, and resulting in the formation of chromosomal rearrangements. To examine patterns of synteny among three closely related, interbreeding, and wild Eucalyptus species, we assembled their genomes using long-read DNA sequencing and de novo assembly. We identify syntenic and rearranged regions between these genomes and estimate that ~48% of our genomes remain syntenic while ~36% is rearranged. We observed that rearrangements highly fragment microsynteny. Our results suggest that synteny between these species is primarily lost through small-scale rearrangements, not through sequence loss, gain, or sequence divergence. Further examination of identified rearrangements suggests that rearrangements may be altering the phenotypes of Eucalyptus species. Our study also underscores that the use of single reference genomes in genomic variation studies could lead to reference bias, especially given the scale at which we show potentially adaptive loci have highly diverged, deleted, duplicated and/or rearranged. This study provides an unbiased framework to look at potential speciation and adaptive loci among a rapidly radiating foundation species of woodland trees that are free from selective breeding seen in most crop species.

Performance of Urinary Phenyl-γ-Valerolactones as Biomarkers of Dietary Flavan-3-ol Exposure.

BACKGROUND: Phenyl-γ-valerolactones (PVLs) have been identified as biomarkers of dietary flavan-3-ol exposure, although their utility requires further characterization. OBJECTIVES: We investigated the performance of a range of PVLs as biomarkers indicative of flavan-3-ol intake. METHODS: We report the results of 2 companion studies: a 5-way randomized crossover trial (RCT) and an observational cross-sectional study. In the RCT (World Health Organization, Universal Trial Number: U1111-1236-7988), 16 healthy participants consumed flavan-3-ol-rich interventions (of apple, cocoa, black tea, green tea, or water [control]) for 1 d each. First morning void samples and 24-h urine samples were collected with diet standardized throughout. For each participant, 1 intervention period was extended (to 2 d) to monitor PVL kinetics after repeat exposure. In the cross-sectional study, 86 healthy participants collected 24-h urine samples, and concurrent weighed food diaries from which flavan-3-ol consumption was estimated using Phenol-Explorer. A panel of 10 urinary PVLs was quantified using liquid chromatography tandem mass spectrometry. RESULTS: In both studies, 2 urinary PVLs [5-(3'-hydroxyphenyl)-γ-valerolactone-4'-sulfate and putatively identified 5-(4'-hydroxyphenyl)-γ-valerolactone-3'-glucuronide] were the principal compounds excreted (>75%). In the RCT, the sum of these PVLs was significantly higher than the water (control) after each intervention; individually, there was a shift from sulfation toward glucuronidation as the total excretion of PVLs increased across the different interventions. In the extended RCT intervention period, no accumulation of these PVLs was observed after consecutive days of treatment, and after withdrawal of treatment on the third day, there was a return toward negligible PVL excretion. All results were consistent, whether compounds were measured in 24-h urine or first morning void samples. In the observational study, the sum of the principal PVLs correlated dose dependently (Rs = 0.37; P = 0.0004) with dietary flavan-3-ol intake, with similar associations for each individually. CONCLUSIONS: Urinary 5-(3'-hydroxyphenyl)-γ-valerolactone-4'-sulfate and putatively identified 5-(4'-hydroxyphenyl)-γ-valerolactone-3'-glucuronide are recommended biomarkers for dietary flavan-3-ol exposure.

Higher Habitual Dietary Intakes of Flavanols and Anthocyanins Differentially Associate with Lower Incidence of Ischemic Stroke Subtypes-A Follow-Up Analysis.

BACKGROUND: We previously reported that habitual consumption of dietary flavanol oligomers + polymers and anthocyanins is associated with a lower risk of ischemic stroke. However, no studies have investigated their relationship with ischemic stroke subtypes. OBJECTIVES: In this follow-up analysis, we aimed to examine the association of flavanol oligomers + polymers and anthocyanin intake with ischemic stroke subtypes, including the following: 1) large-artery atherosclerosis, 2) cardioembolism, 3) small-vessel occlusion, 4) other determined etiology, and 5) undetermined etiology. METHODS: Participants (n = 55,094) from the Danish Diet, Cancer, and Health Study were followed up for <16 y for first-time ischemic stroke events, which were classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Intakes of flavanol oligomers + polymers and anthocyanins were calculated from food frequency questionnaires using the Phenol-Explorer database, and their relationships with ischemic stroke subtypes were investigated using restricted cubic splines within Cox proportional hazards models. After multivariable adjustment, higher habitual intakes (quintile 5 compared with quintile 1) of flavanol oligomers + polymers and anthocyanins were associated with a lower risk of specific ischemic stroke subtypes, including large-artery atherosclerosis [flavanol oligomers + polymers, hazard ratio {HR} (95% confidence interval {CI}): 0.64 (0.47, 0.87)], cardioembolism [anthocyanins, HR (95% CI): 0.45 (0.25, 0.82)], and small-vessel occlusion [flavanol oligomers + polymers, HR (95% CI): 0.65 (0.54, 0.80); anthocyanins, HR (95% CI): 0.79 (0.64, 0.97)], but not stroke of other determined or undetermined etiology. CONCLUSIONS: Higher habitual intakes of flavanols and anthocyanins are differentially associated with a lower risk of ischemic stroke from atherosclerosis and/or cardioembolism but not with other subtypes.