UW Supplementation with AP39 Improves Liver Viability Following Static Cold Storage.

Static cold storage of donor livers at 4°C incompletely arrests metabolism, ultimately leading to decreases in ATP levels, oxidative stress, cell death, and organ failure. Hydrogen Sulfide (H 2 S) is an endogenously produced gas, previously demonstrated to reduce oxidative stress, reduce ATP depletion, and protect from ischemia and reperfusion injury. H 2 S is difficult to administer due to its rapid release curve, resulting in cellular death at high concentrations. AP39, a mitochondrially targeted, slow-release H 2 S donor, has been shown to reduce ischemia-reperfusion injury in hearts and kidneys. Thus, we investigated whether the addition of AP39 during 3-day static cold storage can improve liver graft viability. At the end of storage, livers underwent six hours of acellular normothermic machine perfusion, a model of transplantation. During simulated transplantation, livers stored with AP39 showed reduced resistance, reduced cellular damage (ALT and AST), and reduced apoptosis. Additionally, bile production and glucose, as well as energy charge were improved by the addition of AP39. These results indicate that AP39 supplementation improves liver viability during static cold storage.

ATP-dependent citrate lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling of the Heart.

Background: Metabolic remodeling is a hallmark of the failing heart. Oncometabolic stress during cancer increases the activity and abundance of the ATP-dependent citrate lyase (ACL, Acly ), which promotes histone acetylation and cardiac adaptation. ACL is critical for the de novo synthesis of lipids, but how these metabolic alterations contribute to cardiac structural and functional changes remains unclear. Methods: We utilized human heart tissue samples from healthy donor hearts and patients with hypertrophic cardiomyopathy. Further, we used CRISPR/Cas9 gene editing to inactivate Acly in cardiomyocytes of MyH6-Cas9 mice. In vivo, positron emission tomography and ex vivo stable isotope tracer labeling were used to quantify metabolic flux changes in response to the loss of ACL. We conducted a multi-omics analysis using RNA-sequencing and mass spectrometry-based metabolomics and proteomics. Experimental data were integrated into computational modeling using the metabolic network CardioNet to identify significantly dysregulated metabolic processes at a systems level. Results: Here, we show that in mice, ACL drives metabolic adaptation in the heart to sustain contractile function, histone acetylation, and lipid modulation. Notably, we show that loss of ACL increases glucose oxidation while maintaining fatty acid oxidation. Ex vivo isotope tracing experiments revealed a reduced efflux of glucose-derived citrate from the mitochondria into the cytosol, confirming that citrate is required for reductive metabolism in the heart. We demonstrate that YAP inactivation facilitates ACL deficiency. Computational flux analysis and integrative multi-omics analysis indicate that loss of ACL induces alternative isocitrate dehydrogenase 1 flux to compensate. Conclusions: This study mechanistically delineates how cardiac metabolism compensates for suppressed citrate metabolism in response to ACL loss and uncovers metabolic vulnerabilities in the heart.

Genetic modifiers of somatic expansion and clinical phenotypes in Huntington's disease reveal shared and tissue-specific effects.

Huntington's disease (HD), due to expansion of a CAG repeat in HTT , is representative of a growing number of disorders involving somatically unstable short tandem repeats. We find that overlapping and distinct genetic modifiers of clinical landmarks and somatic expansion in blood DNA reveal an underlying complexity and cell-type specificity to the mismatch repair-related processes that influence disease timing. Differential capture of non-DNA-repair gene modifiers by multiple measures of cognitive and motor dysfunction argues additionally for cell-type specificity of pathogenic processes. Beyond trans modifiers, differential effects are also illustrated at HTT by a 5'-UTR variant that promotes somatic expansion in blood without influencing clinical HD, while, even after correcting for uninterrupted CAG length, a synonymous sequence change at the end of the CAG repeat dramatically hastens onset of motor signs without increasing somatic expansion. Our findings are directly relevant to therapeutic suppression of somatic expansion in HD and related disorders and provide a route to define the individual neuronal cell types that contribute to different HD clinical phenotypes.

Hydroxyurea to prevent brain injury in children with sickle cell disease (HU Prevent)-A randomized, placebo-controlled phase II feasibility/pilot study.

Central nervous system (CNS) injury is common in sickle cell disease (SCD) and occurs early in life. Hydroxyurea is safe and efficacious for treatment of SCD, but high-quality evidence from randomized trials to estimate its neuroprotective effect is scant. HU Prevent was a randomized (1:1), double-blind, phase II feasibility/pilot trial of dose-escalated hydroxyurea vs. placebo for the primary prevention of CNS injury in children with HbSS or HbS-ß0-thalassemia subtypes of SCD age 12-48 months with normal neurological examination, MRI of the brain, and cerebral blood flow velocity. We hypothesized that hydroxyurea would reduce by 50% the incidence of CNS injury. Two outcomes were compared: primary-a composite of silent cerebral infarction, elevated cerebral blood flow velocity, transient ischemic attack, or stroke; secondary-a weighted score estimating the risk of suffering the consequences of stroke (the Stroke Consequences Risk Score-SCRS), based on the same outcome events. Six participants were randomized to each group. One participant in the hydroxyurea group had a primary outcome vs. four in the placebo group (incidence rate ratio [90% CI] 0.216 [0.009, 1.66], p = .2914) (~80% reduction in the hydroxyurea group). The mean SCRS score was 0.078 (SD 0.174) in the hydroxyurea group, 0.312 (SD 0.174) in the placebo group, p = .072, below the p-value of .10 often used to justify subsequent phase III investigations. Serious adverse events related to study procedures occurred in 3/41 MRIs performed, all related to sedation. These results suggest that hydroxyurea may have profound neuroprotective effect in children with SCD and support a definitive phase III study to encourage the early use of hydroxyurea in all infants with SCD.

An adjustable acoustic metamaterial cell using a magnetic membrane for tunable resonance.

Acoustic metamaterials are growing in popularity for sound applications including noise control. Despite this, there remain significant challenges associated with the fabrication of these materials for the sub-100 Hz regime, because acoustic metamaterials for such frequencies typically require sub-mm scale features to control sound waves. Advances in additive manufacturing technologies have provided practical methods for rapid fabrication of acoustic metamaterials. However, there is a relatively high sensitivity of their resonant characteristics to sub-mm deviations in geometry, pushing the limits of additive manufacturing. One way of overcoming this is via active control of device resonance. Here, an acoustic metamaterial cell with adjustable resonance is demonstrated for the sub-100 Hz regime. A functionally superparamagnetic membrane-devised to facilitate the fabrication process by eliminating magnetic poling requirements-is engineered using stereolithography, and its mechanical and acoustic properties are experimentally measured using laser Doppler vibrometry and electret microphone testing, with a mathematical model developed to predict the cell response. It is demonstrated that an adjustable magnetic acoustic metamaterial can be fabricated at ultra-subwavelength dimensions ( ≤ λ /77.5), exhibiting adjustable resonance from 88.73 to 86.63 Hz. It is anticipated that this research will drive new innovations in adjustable metamaterials, including wider frequency ranges.

Prediction of Listeria monocytogenes Clonal Complexes from Multilocus Variable Number Tandem Repeat Analysis Patterns Using a Machine Learning Approach.

Multilocus variable number tandem repeat analysis (MLVA) is a molecular subtyping technique that remains useful for those without the resources to access whole genome sequencing for the tracking and tracing of bacterial contaminants. Unlike techniques such as multilocus sequence typing (MLST) and pulsed-field gel electrophoresis, MLVA did not emerge as a standardized subtyping method for Listeria monocytogenes, and as a result, there is no reference database of virulent or food-associated MLVA subtypes as there is for MLST-based clonal complexes (CCs). Having previously shown the close congruence of a 5-loci MLVA scheme with MLST, a predictive model was created using the XGBoost machine learning (ML) technique, which enabled the prediction of CCs from MLVA patterns with ∼85% (±4%) accuracy. As well as validating the model on existing data, a straightforward update protocol was simulated for if and when previously unseen subtypes might arise. This article illustrates how ML techniques can be applied with elementary coding skills to add value to previous-generation molecular subtyping data in-built food processing environments.

Developing and Investigating a Nanovibration Intervention for the Prevention/Reversal of Bone Loss Following Spinal Cord Injury.

Osteoporosis disrupts the fine-tuned balance between bone formation and resorption, leading to reductions in bone quantity and quality and ultimately increasing fracture risk. Prevention and treatment of osteoporotic fractures is essential for reductions in mortality, morbidity, and the economic burden, particularly considering the aging global population. Extreme bone loss that mimics time-accelerated osteoporosis develops in the paralyzed limbs following complete spinal cord injury (SCI). In vitro nanoscale vibration (1 kHz, 30 or 90 nm amplitude) has been shown to drive differentiation of mesenchymal stem cells toward osteoblast-like phenotypes, enhancing osteogenesis and inhibiting osteoclastogenesis simultaneously. Here, we develop and characterize a wearable device designed to deliver and monitor continuous nanoamplitude vibration to the hindlimb long bones of rats with complete SCI. We investigate whether a clinically feasible dose of nanovibration (two 2 h/day, 5 days/week for 6 weeks) is effective at reversing the established SCI-induced osteoporosis. Laser interferometry and finite element analysis confirmed transmission of nanovibration into the bone, and microcomputed tomography and serum bone formation and resorption markers assessed effectiveness. The intervention did not reverse SCI-induced osteoporosis. However, serum analysis indicated an elevated concentration of the bone formation marker procollagen type 1 N-terminal propeptide (P1NP) in rats receiving 40 nm amplitude nanovibration, suggesting increased synthesis of type 1 collagen, the major organic component of bone. Therefore, enhanced doses of nanovibrational stimulus may yet prove beneficial in attenuating/reversing osteoporosis, particularly in less severe forms of osteoporosis.

Quaternion-Based Attitude Estimation of an Aircraft Model Using Computer Vision.

Investigating aircraft flight dynamics often requires dynamic wind tunnel testing. This paper proposes a non-contact, off-board instrumentation method using vision-based techniques. The method utilises a sequential process of Harris corner detection, Kanade-Lucas-Tomasi tracking, and quaternions to identify the Euler angles from a pair of cameras, one with a side view and the other with a top view. The method validation involves simulating a 3D CAD model for rotational motion with a single degree-of-freedom. The numerical analysis quantifies the results, while the proposed approach is analysed analytically. This approach results in a 45.41% enhancement in accuracy over an earlier direction cosine matrix method. Specifically, the quaternion-based method achieves root mean square errors of 0.0101 rad/s, 0.0361 rad/s, and 0.0036 rad/s for the dynamic measurements of roll rate, pitch rate, and yaw rate, respectively. Notably, the method exhibits a 98.08% accuracy for the pitch rate. These results highlight the performance of quaternion-based attitude estimation in dynamic wind tunnel testing. Furthermore, an extended Kalman filter is applied to integrate the generated on-board instrumentation data (inertial measurement unit, potentiometer gimbal) and the results of the proposed vision-based method. The extended Kalman filter state estimation achieves root mean square errors of 0.0090 rad/s, 0.0262 rad/s, and 0.0034 rad/s for the dynamic measurements of roll rate, pitch rate, and yaw rate, respectively. This method exhibits an improved accuracy of 98.61% for the estimation of pitch rate, indicating its higher efficiency over the standalone implementation of the direction cosine method for dynamic wind tunnel testing.

Billed advance care planning visits may be occurring among older adults with high risk of mortality.

CONTEXT: Advance care planning (ACP) is a process that helps people prepare to make decisions about their future medical care. OBJECTIVES: We sought to understand who was received billed ACP visits and measure the association with health care utilization, cost, and mortality. METHODS: We used a randomly sampled 20 % cohort of Medicare fee-for-service (FFS) beneficiaries' files to conduct a retrospective cohort study. Beneficiaries with a billed ACP visit were matched to controls using a 2-stage propensity score matching process that included assigning a pseudo-ACP visit date for controls. Outcomes included healthcare utilization, mortality, and total medical cost per month. We used descriptive statistics for univariate analysis and fit multilevel logistic regression, multilevel linear regression, or Cox regression models. RESULTS: We identified 183,513 beneficiaries who received any billed ACP visit and 550,539 matched controls. Of those who had a ACP visit, the mean age was 76.5 years and high-risk comorbidities were common: 16 % dementia, 10 % congestive heart failure, 10 % cancer. Beneficiaries who had an ACP visit had slightly more health care utilization than controls. Beneficiaries who had an ACP visit were more likely to die (3.1% vs. 1.0 %, p < 0.01, OR=3.0, 95 %CI 2.9-3.2) in the unadjusted and adjusted analyses compared to matched controls. Total monthly medical costs were 33 % higher among beneficiaries who had an ACP visit. CONCLUSION: Our results suggest that ACP visits may be preferentially utilized amongst individuals with higher risk of mortality. There may be an opportunity to increase ACP visits among older adults at lower risk for mortality. KEY MESSAGE: This article suggests that ACP visits are likely targeted to older adults with a higher risk of mortality than those at lower risk of mortality suggesting an opportunity to reach people before they are facing end-of-life decisions.

Examining the Role of Aguas Frescas in Assessment of Sugary-Drink Intake among Mexican and Mexican American Adults.

BACKGROUND: Aguas frescas are Mexican drinks that are typically made with water, sugar, and fruit. Aguas frescas may be a significant component of sugary-drink intake among Mexican and Mexican-American (MA) adults. However, it is unclear whether survey respondents report aguas frescas consumption when it is not specifically queried in standardized beverage frequency instruments. OBJECTIVES: This study examined the prevalence of aguas frescas consumption, the sociodemographic correlates of aguas frescas intake, and how specifically querying aguas frescas intake affects sugary-drink estimates among Mexican and MA adults. METHODS: Cross-sectional, online surveys were conducted in 2021 with 5377 Mexican and 3073 MA adults as part of the International Food Policy Study. Past 7-d consumption of sugar-sweetened beverages (SSBs), sugary drinks, and aguas frescas were assessed along with relevant covariates. Weighted analyses included logistic and linear regression, including models with correlation structure. RESULTS: An estimated 61.7% of Mexican and 28.7% of MA adults consumed aguas frescas. In Mexico, consumption was associated with females, low education, perceiving oneself as having about the right weight, being good to excellent health, and consuming an unhealthy amount of sugary drinks. For MAs, intake was associated with being younger, speaking Spanish, and perceiving oneself as being underweight or about the right weight. Among Mexican adults who consumed aguas frescas but did not report them unless specifically queried, the volume of SSB intake was 67.9% higher for females and 64.3% higher for males when aguas frescas were included. Among MAs, SSB intake was 56.9% higher for females and 44.1% higher for males. Most participants (79.9%-85.2%) remained in the same sugary-drink tertiles when including compared with excluding aguas frescas. CONCLUSIONS: Aguas frescas should be queried during beverage intake assessments, as they contribute a nontrivial amount of added sugars to the diets of many Mexican and MA adults.

Identification of genetic modifiers of Huntington's disease somatic CAG repeat instability by in vivo CRISPR-Cas9 genome editing.

Huntington's disease (HD), one of >50 inherited repeat expansion disorders (Depienne and Mandel, 2021), is a dominantly-inherited neurodegenerative disease caused by a CAG expansion in HTT (The Huntington's Disease Collaborative Research Group, 1993). Inherited CAG repeat length is the primary determinant of age of onset, with human genetic studies underscoring that the property driving disease is the CAG length-dependent propensity of the repeat to further expand in brain (Swami et al ., 2009; GeM-HD, 2015; Hensman Moss et al ., 2017; Ciosi et al ., 2019; GeM-HD, 2019; Hong et al ., 2021). Routes to slowing somatic CAG expansion therefore hold great promise for disease-modifying therapies. Several DNA repair genes, notably in the mismatch repair (MMR) pathway, modify somatic expansion in HD mouse models (Wheeler and Dion, 2021). To identify novel modifiers of somatic expansion, we have used CRISPR-Cas9 editing in HD knock-in mice to enable in vivo screening of expansion-modifier candidates at scale. This has included testing of HD onset modifier genes emerging from human genome-wide association studies (GWAS), as well as interactions between modifier genes, thereby providing new insight into pathways underlying CAG expansion and potential therapeutic targets.

Framingham Stroke Risk Profile Score and White Matter Disease Progression.

OBJECTIVES: To evaluate the relationship between Framingham Stroke Risk Profile (FSRP) score and rate of white matter hyperintensity (WMH) progression and cognition. METHODS: Consecutive patients enrolled in the Mayo Clinic Florida Familial Cerebrovascular Diseases Registry (2011-2020) with 2 brain-MRI scans at least 1 year apart were included. The primary outcome was annual change in WMH volume (cm3/year) stratified as fast versus slow (above vs. below median). Cognition was assessed using a Mini-Mental State Exam (MMSE, 0-30). FSRP score (0 to 8) was calculated by summing the presence of age 65 years or older, smoking, systolic blood pressure greater than 130 mmHg, diabetes, coronary disease, atrial fibrillation, left ventricular hypertrophy, and antihypertensive medication use. Linear and logistic regression analyses were performed to examine the association between FSRP and WMH progression, and cognition. RESULTS: In all, 207 patients were included, with a mean age of 60±16 y and 54.6% female. FSRP scores risk distribution was: 31.9% scored 0 to 1, 36.7% scored 2 to 3, and 31.4% scored ≥4. The baseline WMH volume was 9.6 cm3 (IQR: 3.3-28.4 cm3), and the annual rate of WMH progression was 0.9 cm3/year (IQR: 0.1 to 3.1 cm3/year). A higher FSRP score was associated with fast WMH progression (odds ratio, 1.45; 95% CI: 1.22-1.72; P<0.001) and a lower MMSE score (23.6 vs. 27.1; P<0.001). There was a dose-dependent relationship between higher FSRP score and fast WMH progression (odds ratios, 2.20, 4.64, 7.86, 8.03 for FSRP scores 1, 2, 3, and ≥4, respectively; trend P<0.001). CONCLUSIONS: This study demonstrated an association between higher FSRP scores and accelerated WMH progression, as well as lower cognition.

The lipid side of unfolded protein response.

Although our current knowledge of the molecular crosstalk between the ER stress, the unfolded protein response (UPR), and lipid homeostasis remains limited, there is increasing evidence that dysregulation of either protein or lipid homeostasis profoundly affects the other. Most research regarding UPR signaling in human diseases has focused on the causes and consequences of disrupted protein folding. The UPR itself consists of very complex pathways that function to not only maintain protein homeostasis, but just as importantly, modulate lipid biogenesis to allow the ER to adjust and promote cell survival. Lipid dysregulation is known to activate many aspects of the UPR, but the complexity of this crosstalk remains a major research barrier. ER lipid disequilibrium and lipotoxicity are known to be important contributors to numerous human pathologies, including insulin resistance, liver disease, cardiovascular diseases, neurodegenerative diseases, and cancer. Despite their medical significance and continuous research, however, the molecular mechanisms that modulate lipid synthesis during ER stress conditions, and their impact on cell fate decisions, remain poorly understood. Here we summarize the current view on crosstalk and connections between altered lipid metabolism, ER stress, and the UPR.

Telomeres and the Rate of Living: Linking Biological Clocks of Senescence.

AbstractTwo prominent theories of aging, one based on telomere dynamics and the other on mass-specific energy flux, propose biological time clocks of senescence. The relationship between these two theories, and the biological clocks proposed by each, remains unclear. Here, we examine the relationships between telomere shortening rate, mass-specific metabolic rate, and lifespan among vertebrates (mammals, birds, fishes). Results show that telomere shortening rate increases linearly with mass-specific metabolic rate and decreases nonlinearly with increasing body mass in the same way as mass-specific metabolic rate. Results also show that both telomere shortening rate and mass-specific metabolic rate are similarly related to lifespan and that both strongly predict differences in lifespan, although the slopes of the relationships are less than linear. On average, then, telomeres shorten a fixed amount per unit of mass-specific energy flux. So the mitotic clock of telomere shortening and the energetics-based clock described by metabolic rate can be viewed as alternative measures of the same biological clock. These two processes may be linked, we speculate, through the process of cell division.

USE OF VISCOELASTIC COAGULATION TESTING IN MEGACHIROPTERA (PTEROPUS HYPOMELANUS AND PTEROPUS VAMPYRUS) REVEALS HIGH VARIABILITY IN CLOT KINETICS.

Megachiroptera is a mammalian suborder that includes old world fruit bats. Common clinical problems among captive Megachiroptera, such as liver disease (e.g., iron storage disease), kidney disease (e.g., protein-losing nephropathy), and heart disease (e.g., dilated cardiomyopathy), carry elevated risk for hemostatic derangements. The assessment of viscoelastic coagulation assays, however, has not yet been reported in bats. The main objective of the study was to describe viscoelastography data using the Viscoelastic Coagulation Monitor (VCM) Vet in captive large flying foxes (Pteropus vampyrus) (n = 20) and variable flying foxes (Pteropus hypomelanus) (n = 10). Additional objectives were to compare viscoelastic and clotting parameters (1) between healthy P. vampyrus and P. hypomelanus bats and (2) between untreated bats and those treated with meloxicam or aspirin, and (3) to examine relationships between activated partial thromboplastin time (aPTT) and potentially homologous viscoelastic parameters clotting time (CT) and clot formation time (CFT). The results showed marked variability among clinically normal bats. The intrinsic pathway, as measured by aPTT, had prolonged times compared with most terrestrial mammals, but similar times to birds, marine mammals, and sea turtles. A search of P. vampyrus genome found stop codons present in two exons of the factor XI gene; alterations in factor XI expression would be expected to alter intrinsic coagulation. Because of the high variability, no statistically significant findings were noted in the secondary objectives. Correlation between aPTT and CT or CFT was not strong (rs = 0.406 or 0.192, respectively). The results from this study suggest that clot kinetics vary widely among Megachiroptera when using the VCM Vet with untreated blood. A prolonged intrinsic coagulation pathway, as has been found in other megachiropteran species, and activation of the extrinsic coagulation pathway during venipuncture may be responsible for the inconsistent results.

NOVEL SIMPLEXVIRUS (SIMPLEXVIRUS DOLICHOTINEALPHA1) ASSOCIATED WITH FATALITY IN FOUR PATAGONIAN MARA (DOLICHOTIS PATAGONUM).

Four of seven Patagonian maras (Dolichotis patagonum) at a zoological institution developed acute neurologic signs that progressed to tetraparesis and death. All affected were young adult females (10 mon-5 yr old) that presented over 11 d. Clinical signs were rapidly progressive and unresponsive to supportive therapies. Two of the four individuals were found deceased 4 d after hospitalization. Two individuals were euthanized due to poor prognosis and decline after 6 and 8 d, respectively. Simultaneously, an additional mara developed mild and self-resolving clinical signs, including a kyphotic gait and paraparesis. On gross examination, there were widespread petechiae and ecchymoses of the skeletal muscle, myocardium, skin, pericardium, urinary bladder mucosa, and spinal cord. On histopathology, all animals had necrotizing myelitis and rhombencephalitis, with intranuclear viral inclusions in three individuals. Electron microscopy confirmed herpesviral replication and assembly complexes in neurons and oligodendrocytes. Consensus PCR performed on spinal cord, brainstem, or cerebellum revealed a novel Simplexvirus most closely related to Simplexvirus leporidalpha 4. The virus was amplified and sequenced and is referred to as Simplexvirus dolichotinealpha1. It is unknown whether this virus is endemic in Patagonian mara or whether it represents an aberrant host species. Clinicians should be aware of this virus and its potential to cause severe, rapidly progressive, life-threatening disease in this species.

SCHIZANGIELLA INFECTIONS IN AN EASTERN RATSNAKE (PANTHEROPHIS ALLEGHANIENSIS) AND A TIMBER RATTLESNAKE (CROTALUS HORRIDUS).

This report describes Schizangiella infections in colubrid and viperid snakes. A captive eastern ratsnake (Pantherophis alleghaniensis) was presented for a large intraoral mass associated with the mandible. The mass was debulked and histologic examination revealed severe, granulomatous stomatitis with intralesional fungi exhibiting morphologic features consistent with Schizangiella serpentis. PCR and sequencing of affected tissues confirmed S. serpentis. Because of declining health, the ratsnake was euthanized and postmortem examination identified a disseminated S. serpentis infection involving the skeletal musculature, lung, kidney, mesentery, and mandible. A wild-caught timber rattlesnake (Crotalus horridus) was presented for cutaneous lesions, weakness, and lethargy and later died. Postmortem examination revealed a mass-like structure in the esophagus characterized by high numbers of Schizangiella-like fungi associated with extensive granulomatous inflammation; the snake also had cutaneous mycosis suggestive of ophidiomycosis. This is the first report to document the unique morphologic features of S. serpentis in tissues and the presentation of schizangiellosis in snakes. Schizangiellosis should be considered as a differential diagnosis for nodular lesions involving the oral cavity and/or the gastrointestinal tract of snakes.

Mitochondrial microRNA profiles are altered in thirteen-lined ground squirrels (Ictidomys tridecemlineatus) during hibernation.

Thirteen-lined ground squirrels (TLGS) are obligate hibernators that cycle between torpor (low metabolic rate and body temperature) and interbout euthermia (IBE; typical euthermic body temperature and metabolism) from late autumn to spring. Many physiological changes occur throughout hibernation, including a reduction in liver mitochondrial metabolism during torpor, which is reversed during arousal to interbout euthermia. Nuclear-encoded microRNA (small post-transcriptional regulator molecules) differ in abundance throughout TLGS hibernation and have been shown to regulate mitochondrial gene expression in mammalian cell culture (where they are referred to as mitomiRs). This study characterized differences in mitomiR profiles from TLGS liver mitochondria isolated during summer, torpor, and IBE, and predicted their mitochondrial targets. Using small RNA sequencing, differentially abundant mitomiRs were identified between hibernation states and, using qPCR analysis we quantified expression of predicted mitochondrial mRNA targets. Most differences in mitomiR abundances were seasonal (i.e. between summer and winter) with only one mitomiR differentially abundant between IBE and torpor. Multiple factor analysis revealed three clusters divided by hibernation states, where clustering was predominantly driven by mitomiR abundances. Nine of these differentially abundant mitomiRs had predicted mitochondrial RNA targets, including subunits of electron transfer system complexes I and IV, 12S rRNA and two tRNAs. Overall, mitomiRs were predicted to suppress expression of their mitochondrial targets and may have some involvement in regulating protein translation in mitochondria. This study found differences in mitomiR abundances between seasons and hibernation states of TLGS and suggests potential mechanisms in regulating the mitochondrial electron transfer system.

Fatherhood and Cardiovascular Health, Disease, and Mortality: Associations From the Multi-Ethnic Study of Atherosclerosis.

Introduction: Emerging literature links fatherhood to men's health but lacks comprehensive assessment of health outcomes, especially among multiethnic populations. This study's objective was to evaluate the associations of fatherhood (age at onset and status) with cardiovascular health scores, incident cardiovascular disease, cardiovascular disease death, and all-cause mortality, examining differences by race/ethnicity. Methods: The study sample included men from Multi-Ethnic Study of Atherosclerosis, prospective cohort study that enrolled adults aged 45-84 years without known cardiovascular disease at baseline. Cardiovascular health was defined using the American Heart Association's Life's Essential 8 scores (0-100), excluding sleep (cardiovascular health score). Results: In this sample of 2,814 men, mean age at cardiovascular health assessment was 62.2 years, 82% were fathers, 24% self-identified as Black, 13% self-identified Chinese, 22% self-identified Hispanic, and 41% self-identified White. Fathers who were aged <20 years and 20-24 years at their oldest child's birth had worse overall cardiovascular health than fathers who were aged >35 years (adjusted mean score of 61.1 vs 64.7 [p=0.01] and 61.0 vs 64.7 [p<0.001], respectively). Fathers had worse overall cardiovascular health (adjusted mean score of 63.2 vs 64.7, p=0.03) and more nicotine exposure (63.1 vs 66.6, p=0.04) than nonfathers. In age-adjusted models, fathers overall (hazard ratio=0.82; 95% CI=0.69, 0.98) and Black fathers (hazard ratio=0.73; 95% CI=0.53, 0.999) had a lower rate of all-cause mortality rate than nonfathers, but these associations were no longer significant in fully adjusted models. Conclusions: Fatherhood is a social determinant of health, and understanding its influence may provide opportunities to improve men's health, particularly among men of color.