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1.
SAGE Open Med ; 12: 20503121241271759, 2024.
Article in English | MEDLINE | ID: mdl-39206229

ABSTRACT

Objectives: We explored the perspectives of older veterans in Gerofit, a Department of Veteran Affairs (VA) supervised clinical exercise program, to understand the factors associated with participation and how the program supported personal health goals. Methods: Twenty semistructured interviews were conducted with active and inactive Gerofit participants. We used a hybrid inductive and deductive approach to thematic analysis of transcripts, with the latter informed by the Health Action Process Approach model of behavior change. Results: Active and inactive participants differed in their perspectives about how Gerofit impacted their progress toward meeting personal health goals. Active participants noted program features (e.g., schedule, staffing) as facilitators and suggested greater self-efficacy about program participation compared to inactive participants. Both groups perceived the camaraderie with other veterans as a facilitator. Conclusions: Exercise program features, including camaraderie, are important factors that affect the ability of older veterans to participate in exercise and achieve personal health goals.

2.
Article in English | MEDLINE | ID: mdl-39086259

ABSTRACT

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: Two-spirit, lesbian, gay, bisexual, transgender, and queer (2SLGBTQ+) people disproportionally experience health disparities, and hospital pharmacists, given their accessibility and expertise in medication management, are ideally positioned to provide care to this vulnerable population. This study investigated the barriers and facilitators faced by hospital pharmacists when providing care to 2SLGBTQ+ patients, with the goal of informing enhancement of quality care provided to these patients. METHODS: A mixed-methods triangulation design was utilized, comprising an online survey and qualitative interviews with Canadian hospital pharmacists. The survey used the lens of systemic oppression as a framework and assessed pharmacists' perceptions and knowledge. Survey data were analyzed using descriptive statistics, and interviews were analyzed using thematic analysis. RESULTS: A total of 129 individuals participated in the survey, and 15 participants were interviewed. Eleven themes were identified, and findings revealed a complex web of individual, interpersonal, and systemic barriers and facilitators. Pharmacists expressed a lack of proficiency and confidence in discussing 2SLGBTQ+ health topics, further compounded by an apprehension to engage and a fear of causing harm. Pharmacists desired support from their leadership teams and organizations in the form of access to resources, time to engage in training, and workplace environments that encourage discussions about 2SLGBTQ+ health. CONCLUSION: Hospital pharmacists in Canada are willing to provide inclusive care to 2SLGBTQ+ patients but face significant barriers. These findings highlight the need for comprehensive education, supportive workplace cultures, and accessible resources to address health disparities and improve care for 2SLGBTQ+ individuals.

3.
Am J Physiol Heart Circ Physiol ; 327(3): H601-H613, 2024 Sep 01.
Article in English | MEDLINE | ID: mdl-38995211

ABSTRACT

Nighttime blood pressure (BP) and BP dipping (daytime-nighttime BP) are prognostic for cardiovascular disease. When compared with other racial/ethnic groups, Black Americans exhibit elevated nighttime BP and attenuated BP dipping. Neighborhood deprivation may contribute to disparities in cardiovascular health, but its effects on resting and ambulatory BP patterns in young adults are unclear. Therefore, we examined associations between neighborhood deprivation with resting and nighttime BP and BP dipping in young Black and White adults. We recruited 19 Black and 28 White participants (23 males/24 females, 21 ± 1 yr, body mass index: 26 ± 4 kg/m2) for 24-h ambulatory BP monitoring. We assessed resting BP, nighttime BP, and BP dipping (absolute dip and nighttime:daytime BP ratio). We used the area deprivation index (ADI) to assess average neighborhood deprivation during early and mid-childhood and adolescence. When compared with White participants, Black participants exhibited higher resting systolic and diastolic BP (Ps ≤ 0.029), nighttime systolic BP (114 ± 9 vs. 108 ± 9 mmHg, P = 0.049), diastolic BP (63 ± 8 vs. 57 ± 7 mmHg, P = 0.010), and attenuated absolute systolic BP dipping (12 ± 5 vs. 9 ± 7 mmHg, P = 0.050). Black participants experienced greater average ADI scores compared with White participants [110 (10) vs. 97 (22), P = 0.002], and select ADI scores correlated with resting BP and some ambulatory BP measures. Within each race, select ADI scores correlated with some BP measures for Black participants, but there were no ADI and BP correlations for White participants. In conclusion, our findings suggest that neighborhood deprivation may contribute to higher resting BP and impaired ambulatory BP patterns in young adults warranting further investigation in larger cohorts.NEW & NOTEWORTHY We demonstrate that young Black adults exhibit higher resting blood pressure, nighttime blood pressure, and attenuated systolic blood pressure dipping compared with young White adults. Black adults were exposed to greater neighborhood deprivation, which demonstrated some associations with resting and ambulatory blood pressure. Our findings add to a growing body of literature indicating that neighborhood deprivation may contribute to increased blood pressure.


Subject(s)
Blood Pressure Monitoring, Ambulatory , Blood Pressure , Circadian Rhythm , Adolescent , Female , Humans , Male , Young Adult , Black or African American , Health Status Disparities , Hypertension/diagnosis , Hypertension/ethnology , Race Factors , Residence Characteristics , White
4.
Ecology ; 105(6): e4318, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38693703

ABSTRACT

SNAPSHOT USA is a multicontributor, long-term camera trap survey designed to survey mammals across the United States. Participants are recruited through community networks and directly through a website application (https://www.snapshot-usa.org/). The growing Snapshot dataset is useful, for example, for tracking wildlife population responses to land use, land cover, and climate changes across spatial and temporal scales. Here we present the SNAPSHOT USA 2021 dataset, the third national camera trap survey across the US. Data were collected across 109 camera trap arrays and included 1711 camera sites. The total effort equaled 71,519 camera trap nights and resulted in 172,507 sequences of animal observations. Sampling effort varied among camera trap arrays, with a minimum of 126 camera trap nights, a maximum of 3355 nights, a median 546 nights, and a mean 656 ± 431 nights. This third dataset comprises 51 camera trap arrays that were surveyed during 2019, 2020, and 2021, along with 71 camera trap arrays that were surveyed in 2020 and 2021. All raw data and accompanying metadata are stored on Wildlife Insights (https://www.wildlifeinsights.org/), and are publicly available upon acceptance of the data papers. SNAPSHOT USA aims to sample multiple ecoregions in the United States with adequate representation of each ecoregion according to its relative size. Currently, the relative density of camera trap arrays varies by an order of magnitude for the various ecoregions (0.22-5.9 arrays per 100,000 km2), emphasizing the need to increase sampling effort by further recruiting and retaining contributors. There are no copyright restrictions on these data. We request that authors cite this paper when using these data, or a subset of these data, for publication. Any use of trade, firm, or product names is for descriptive purposes only and does not imply endorsement by the US Government.


Subject(s)
Photography , United States , Animals , Mammals , Ecosystem
5.
Proc Natl Acad Sci U S A ; 121(16): e2400203121, 2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38598338

ABSTRACT

Viral outbreaks can cause widespread disruption, creating the need for diagnostic tools that provide high performance and sample versatility at the point of use with moderate complexity. Current gold standards such as PCR and rapid antigen tests fall short in one or more of these aspects. Here, we report a label-free and amplification-free nanopore sensor platform that overcomes these challenges via direct detection and quantification of viral RNA in clinical samples from a variety of biological fluids. The assay uses an optofluidic chip that combines optical waveguides with a fluidic channel and integrates a solid-state nanopore for sensing of individual biomolecules upon translocation through the pore. High specificity and low limit of detection are ensured by capturing RNA targets on microbeads and collecting them by optical trapping at the nanopore location where targets are released and rapidly detected. We use this device for longitudinal studies of the viral load progression for Zika and Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infections in marmoset and baboon animal models, respectively. The up to million-fold trapping-based target concentration enhancement enables amplification-free RNA quantification across the clinically relevant concentration range down to the assay limit of RT-qPCR as well as cases in which PCR failed. The assay operates across all relevant biofluids, including semen, urine, and whole blood for Zika and nasopharyngeal and throat swab, rectal swab, and bronchoalveolar lavage for SARS-CoV-2. The versatility, performance, simplicity, and potential for full microfluidic integration of the amplification-free nanopore assay points toward a unique approach to molecular diagnostics for nucleic acids, proteins, and other targets.


Subject(s)
Nanopores , Zika Virus Infection , Zika Virus , Animals , RNA, Viral/genetics , RNA, Viral/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Primates/genetics , Zika Virus/genetics , Sensitivity and Specificity , Nucleic Acid Amplification Techniques
6.
Soft Robot ; 11(4): 561-572, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38324015

ABSTRACT

Although soft robots show safer interactions with their environment than traditional robots, soft mechanisms and actuators still have significant potential for damage or degradation particularly during unmodeled contact. This article introduces a feedback strategy for safe soft actuator operation during control of a soft robot. To do so, a supervisory controller monitors actuator state and dynamically saturates control inputs to avoid conditions that could lead to physical damage. We prove that, under certain conditions, the supervisory controller is stable and verifiably safe. We then demonstrate completely onboard operation of the supervisory controller using a soft thermally actuated robot limb with embedded shape memory alloy actuators and sensing. Tests performed with the supervisor verify its theoretical properties and show stabilization of the robot limb's pose in free space. Finally, experiments show that our approach prevents overheating during contact, including environmental constraints and human touch, or when infeasible motions are commanded. This supervisory controller, and its ability to be executed with completely onboard sensing, has the potential to make soft robot actuators reliable enough for practical use.

7.
J Anim Ecol ; 93(2): 132-146, 2024 02.
Article in English | MEDLINE | ID: mdl-38213300

ABSTRACT

How animals use the diel period (24-h light-dark cycle) is of fundamental importance to understand their niche. While ecological and evolutionary literature abound with discussion of diel phenotypes (e.g. diurnal, nocturnal, crepuscular, cathemeral), they lack clear and explicit quantitative definitions. As such, inference can be confounded when evaluating hypotheses of animal diel niche switching or plasticity across studies because researchers may be operating under different definitions of diel phenotypes. We propose quantitative definitions of diel phenotypes using four alternative hypothesis sets (maximizing, traditional, general and selection) aimed at achieving different objectives. Each hypothesis set is composed of mutually exclusive hypotheses defined based on the activity probabilities in the three fundamental periods of light availability (twilight, daytime and night-time). We develop a Bayesian modelling framework that compares diel phenotype hypotheses using Bayes factors and estimates model parameters using a multinomial model with linear inequality constraints. Model comparison, parameter estimation and visualizing results can be done in the Diel.Niche R package. A simplified R Shiny web application is also available. We provide extensive simulation results to guide researchers on the power to discriminate among hypotheses for a range of sample sizes (10-1280). We also work through several examples of using data to make inferences on diel activity, and include online vignettes on how to use the Diel.Niche package. We demonstrate how our modelling framework complements other analyses, such as circular kernel density estimators and animal movement modelling. Our aim is to encourage standardization of the language of diel activity and bridge conceptual frameworks and hypotheses in diel research with data and models. Lastly, we hope more research focuses on the ecological and conservation importance of understanding how animals use diel time.


Subject(s)
Biological Evolution , Movement , Animals , Bayes Theorem
8.
Psychoneuroendocrinology ; 162: 106942, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38218000

ABSTRACT

Acute stress is known to influence performance on various task outcomes indicative of executive functioning (i.e., the top-down, goal-directed control of cognition and behavior). The most common interpretation of these effects is that stress influences control processes themselves. Another possibility, though, is that stress does not impair control per se, but instead alters the affective dynamics underlying the recruitment of control (e.g., reducing the extent to which making an error is aversive), resulting in less recruitment of control and thus poor performance. To date, however, no work has examined whether stress effects on executive function outcomes are driven by affective dynamics related to the recruitment of control. In the current study, we found that acute stress influenced-and cortisol responses related to-both executive control-related performance outcomes (e.g., post-error slowing) and control-related affective dynamics (e.g., negative affect following recruitment of control) in a modified Stroop task, but that these effects appeared to be independent of each other: The effects of stress on, and associations of cortisol with, control-related cognitive outcomes were not statistically mediated by task- or control-related affective dynamics. These results thus suggest that although stress influences affective dynamics underlying executive function, the effects of stress on executive function outcomes appear to be at least partially dependent on nonaffective processes, such as control processes themselves.


Subject(s)
Emotions , Hydrocortisone , Emotions/physiology , Cognition/physiology , Executive Function/physiology , Affect/physiology
9.
Am J Physiol Renal Physiol ; 326(1): F135-F142, 2024 01 01.
Article in English | MEDLINE | ID: mdl-37942539

ABSTRACT

Several human studies have used the mitochondrial antioxidant MitoQ. Recent in vitro data indicating that MitoQ may induce nephrotoxicity caused concern regarding the safety of MitoQ on the kidneys, but the doses were supraphysiological. Therefore, we sought to determine whether acute MitoQ elicits changes in urinary biomarkers associated with tubular injury in healthy adults with our hypothesis being there would be no changes. Using a randomized crossover design, 32 healthy adults (16 females and 16 males, 29 ± 11 yr old) consumed MitoQ (100-160 mg based on body mass) or placebo capsules. We obtained serum samples and a 4- to 6-h postcapsule consumption urine sample. We assessed creatinine clearance and urine kidney injury biomarkers including the chitinase 3-like-1 gene product YKL-40, kidney-injury marker-1, monocyte chemoattractant protein-1, epidermal growth factor, neutrophil gelatinase-associated lipocalin, interleukin-18, and uromodulin using multiplex assays. We used t tests, Wilcoxon tests, and Hotelling's T2 to assess global differences in urinary kidney injury markers between conditions. Acute MitoQ supplementation did not influence urine flow rate (P = 0.086, rrb = 0.39), creatinine clearance (P = 0.085, rrb = 0.42), or urinary kidney injury markers (T22,8 = 30.6, P = 0.121, univariate ps > 0.064). Using exploratory univariate analysis, MitoQ did not alter individual injury markers compared with placebo (e.g., placebo vs. MitoQ: YKL-40, 507 ± 241 vs. 442 ± 236 pg/min, P = 0.241; kidney injury molecule-1, 84.1 ± 43.2 vs. 76.2 ± 51.2 pg/min, P = 0.890; and neutrophil gelatinase-associated lipocalin, 10.8 ± 10.1 vs. 9.83 ± 8.06 ng/min, P = 0.609). In conclusion, although longer-term surveillance and data are needed in clinical populations, our findings suggest that acute high-dose MitoQ had no effect on urinary kidney injury markers in healthy adults.NEW & NOTEWORTHY We found acute high-dose mitochondria-targeted antioxidant (MitoQ) supplementation was not nephrotoxic and had no effect on markers of acute kidney injury in healthy adults. These findings can help bolster further confidence in the safety of MitoQ, particularly for future investigations seeking to examine the role of mitochondrial oxidative stress, via acute MitoQ supplementation, on various physiological outcomes.


Subject(s)
Acute Kidney Injury , Antioxidants , Male , Adult , Female , Humans , Lipocalin-2/metabolism , Cross-Over Studies , Chitinase-3-Like Protein 1/metabolism , Antioxidants/metabolism , Creatinine/metabolism , Kidney/metabolism , Acute Kidney Injury/chemically induced , Acute Kidney Injury/diagnosis , Biomarkers/urine
10.
Stress Health ; 40(1): e3272, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37222270

ABSTRACT

Writing about negative experiences can produce multiple benefits, including improvements in mental and emotional health. However, writing about negative experiences potentially be detrimental, as reliving and reexperiencing a negative memory can be painful. Although the emotional effects of writing about negative experiences are well established, the cognitive effects are less heavily explored, and no work to date has examined how writing about a stressful experience might influence episodic memory. We addressed this issue in the present study (N = 520) by having participants encode a list of 16 words that were organised around four semantic clusters, randomly assigning participants to write about an unresolved stressful experience (n = 263) or the events of the previous day (n = 257), and assessing their memory in a free recall task. Writing about a stressful experience did not influence overall memory performance; however, the stressful writing manipulation increased semantic clustering of information within memory for men, whereas the stressful writing manipulation did not influence semantic clustering of information within memory in women. Additionally, writing with more positive sentiment improved semantic clustering and reduced serial recall. These results provide evidence for unique sex differences in writing about stressful experiences and the role of sentiment in the effects of expressive writing.


Subject(s)
Emotions , Semantics , Female , Humans , Male , Cluster Analysis , Mental Recall , Writing
11.
Ann Plast Surg ; 91(6): 740-744, 2023 Dec 01.
Article in English | MEDLINE | ID: mdl-37962259

ABSTRACT

INTRODUCTION: Thrombocytosis, defined as a platelet count >400,000, has been implicated as a risk factor in free flap failure. Despite proposed mechanisms of pedicle thrombosis, recent studies have suggested that thrombocytosis has no effect on free tissue transfer viability. Risk factors that may compromise successful free tissue transfer should be understood and elucidated, with particular attention to thrombocytosis and its conflicting evidence in the literature. We hypothesize that thrombocytosis has no bearing on free flap success or the rates of pedicle thrombosis. METHODS: Our institution performed a retrospective chart review on all patients who underwent free flap reconstruction over the past 6 years. Patient demographics, medical history, type and location of free tissue transfer, preoperative platelets, postoperative platelets, and flap outcomes and complications (wound dehiscence, infection, hematoma, seroma, and need for blood transfusion) were recorded. Independent t test, Mann-Whitney U tests, χ2 test, and Fisher exact tests were used to determine P values to compare flap outcomes in patients with thrombocytosis (platelet count >400,000) and those with platelet counts less than 400,000. RESULTS: In our 502-patient cohort, 71 were found to have a platelet count >400,000 (35 preoperatively and 36 postoperatively) and 431 patients had platelet counts <400,000. There were 42 reconstructive failures (flap success rate of 91.6%) and 111 returns to the operating room (OR). For patients with postoperative thrombocytosis, 24 flaps returned to the OR (44.4%), whereas in patients without thrombocytosis, 87 flaps returned to the OR (19.4%; P < 0.001). In patients with postoperative thrombocytosis, 10 OR returns were due to pedicle venous thrombosis (18.5%), in comparison to 10 returns for venous thrombosis in those with normal platelets (2.2%; P < 0.001). There was a small difference in free flap success rates between those with postoperative thrombocytosis and normal platelets, 88.7% versus 92.11%; however, this was not statistically significant ( P = 0.71). The thrombocytosis group had a higher incidence of overall postoperative complications ( P = 0.002). CONCLUSIONS: Thrombocytosis has historically been cited as a risk factor for free flap reconstruction failure with recent conflicting evidence in the literature. In patients with postoperative thrombocytosis, we found an increased risk of venous thrombosis; however, this did not result in increased flap failure. There was an increase in postoperative complications, which corresponds with National Surgical Quality Improvement Program data reported in the literature. We suspect that thrombocytosis is not a harbinger of free flap failure but rather a marker for overall inflammation, which may confer a higher rate of venous thrombosis requiring reoperation and postoperative complications.


Subject(s)
Free Tissue Flaps , Thrombocytosis , Thrombosis , Venous Thrombosis , Humans , Retrospective Studies , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Postoperative Complications/surgery , Thrombocytosis/complications , Risk Factors , Thrombosis/etiology , Thrombosis/surgery , Venous Thrombosis/complications
12.
Proc Natl Acad Sci U S A ; 120(46): e2306580120, 2023 Nov 14.
Article in English | MEDLINE | ID: mdl-37931097

ABSTRACT

The transition from sessile suspension to active mobile detritus feeding in early echinoderms (c.a. 500 Mya) required sophisticated locomotion strategies. However, understanding locomotion adopted by extinct animals in the absence of trace fossils and modern analogues is extremely challenging. Here, we develop a biomimetic soft robot testbed with accompanying computational simulation to understand fundamental principles of locomotion in one of the most enigmatic mobile groups of early stalked echinoderms-pleurocystitids. We show that these Paleozoic echinoderms were likely able to move over the sea bottom by means of a muscular stem that pushed the animal forward (anteriorly). We also demonstrate that wide, sweeping gaits could have been the most effective for these echinoderms and that increasing stem length might have significantly increased velocity with minimal additional energy cost. The overall approach followed here, which we call "Paleobionics," is a nascent but rapidly developing research agenda in which robots are designed based on extinct organisms to generate insights in engineering and evolution.


Subject(s)
Robotics , Animals , Echinodermata , Locomotion , Gait , Computer Simulation
13.
Biomedicines ; 11(10)2023 Sep 25.
Article in English | MEDLINE | ID: mdl-37893004

ABSTRACT

Historically, cannabis has been valued for its pain-relieving, anti-inflammatory, and calming properties. Ancient civilizations like the Egyptians, Greeks, and Chinese medicines recognized their therapeutic potential. The discovery of the endocannabinoid system, which interacts with cannabis phytoconstituents, has scientifically explained how cannabis affects the human immune system, including the central nervous system (CNS). This review explores the evolving world of cannabis-based treatments, spotlighting its diverse applications. By researching current research and clinical studies, we probe into how cannabinoids like Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) help to manage conditions ranging from chronic pain, persistent inflammation, cancer, inflammatory bowel disease, and neurological disorders to even viral diseases such as Human Immunodeficiency virus (HIV), SARS-CoV-2. and the emerging monkeypox. The long-term recreational use of cannabis can develop into cannabis use disorder (CUD), and therefore, understanding the factors contributing to the development and maintenance of cannabis addiction, including genetic predisposition, neurobiological mechanisms, and environmental influences, will be timely. Shedding light on the adverse impacts of CUD underscores the importance of early intervention, effective treatment approaches, and public health initiatives to address this complex issue in an evolving landscape of cannabis policies and perceptions.

14.
Am J Physiol Heart Circ Physiol ; 325(6): H1418-H1429, 2023 12 01.
Article in English | MEDLINE | ID: mdl-37861651

ABSTRACT

Females typically exhibit lower blood pressure (BP) during exercise than males. However, recent findings indicate that adjusting for maximal strength attenuates sex differences in BP during isometric handgrip (HG) exercise and postexercise ischemia (PEI; metaboreflex isolation). In addition, body size is associated with HG strength but its contribution to sex differences in exercising BP is less appreciated. Therefore, the purpose of this study was to determine whether adjusting for strength and body size would attenuate sex differences in BP during HG and PEI. We obtained beat-to-beat BP in 110 participants (36 females, 74 males) who completed 2 min of isometric HG exercise at 40% of their maximal voluntary contraction followed by 3 min of PEI. In a subset (11 females, 17 males), we collected muscle sympathetic nerve activity (MSNA). Statistical analyses included independent t tests and mixed models (sex × time) with covariate adjustment for 40% HG force, height2, and body surface area. Females exhibited a lower absolute 40% HG force than male participants (Ps < 0.001). Females exhibited lower Δsystolic, Δdiastolic, and Δmean BPs during HG and PEI than males (e.g., PEI, Δsystolic BP, 15 ± 11 vs. 23 ± 14 mmHg; P = 0.004). After covariate adjustment, sex differences in BP responses were attenuated. There were no sex differences in MSNA. In a smaller strength-matched cohort, there was no sex × time interactions for BP responses (e.g., PEI systolic BP, P = 0.539; diastolic BP, P = 0.758). Our data indicate that sex differences in exercising BP responses are attenuated after adjusting for muscle strength and body size.NEW & NOTEWORTHY When compared with young males, females typically exhibit lower blood pressure (BP) during exercise. Adjusting for maximal strength attenuates sex differences in BP during isometric handgrip (HG) exercise and postexercise ischemia (PEI), but the contribution of body size is unknown. Novel findings include adjustments for muscle strength and body size attenuate sex differences in BP reactivity during exercise and PEI, and sex differences in body size contribute to HG strength differences.


Subject(s)
Hand Strength , Sex Characteristics , Humans , Male , Female , Young Adult , Hand Strength/physiology , Reflex , Blood Pressure/physiology , Sympathetic Nervous System , Ischemia , Body Size , Muscle, Skeletal/innervation , Heart Rate
15.
Protein Sci ; 32(11): e4792, 2023 11.
Article in English | MEDLINE | ID: mdl-37774136

ABSTRACT

Advances in computational tools for atomic model building are leading to accurate models of large molecular assemblies seen in electron microscopy, often at challenging resolutions of 3-4 Å. We describe new methods in the UCSF ChimeraX molecular modeling package that take advantage of machine-learning structure predictions, provide likelihood-based fitting in maps, and compute per-residue scores to identify modeling errors. Additional model-building tools assist analysis of mutations, post-translational modifications, and interactions with ligands. We present the latest ChimeraX model-building capabilities, including several community-developed extensions. ChimeraX is available free of charge for noncommercial use at https://www.rbvi.ucsf.edu/chimerax.


Subject(s)
Software , Cryoelectron Microscopy/methods , Likelihood Functions , Models, Molecular , Microscopy, Electron , Protein Conformation
16.
DNA (Basel) ; 3(3): 119-133, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37663147

ABSTRACT

DNA methyltransferase 1 (DNMT1) is the enzyme primarily responsible for propagation of the methylation pattern in cells. Mutations in DNMT1 have been linked to the development of adult-onset neurodegenerative disorders; these disease-associated mutations occur in the regulatory replication foci-targeting sequence (RFTS) domain of the protein. The RFTS domain is an endogenous inhibitor of DNMT1 activity that binds to the active site and prevents DNA binding. Here, we examine the impact of the disease-associated mutation A554V on normal RFTS-mediated inhibition of DNMT1. Wild-type and mutant proteins were expressed and purified to homogeneity for biochemical characterization. The mutation increased DNA binding affinity ~8-fold. In addition, the mutant enzyme exhibited increased DNA methylation activity. Circular dichroism (CD) spectroscopy revealed that the mutation does not significantly impact the secondary structure or relative thermal stability of the isolated RFTS domain. However, the mutation resulted in changes in the CD spectrum in the context of the larger protein; a decrease in relative thermal stability was also observed. Collectively, this evidence suggests that A554V disrupts normal RFTS-mediated autoinhibition of DNMT1, resulting in a hyperactive mutant enzyme. While the disease-associated mutation does not significantly impact the isolated RFTS domain, the mutation results in a weakening of the interdomain stabilizing interactions generating a more open, active conformation of DNMT1. Hyperactive mutant DNMT1 could be responsible for the increased DNA methylation observed in affected individuals.

17.
medRxiv ; 2023 Sep 12.
Article in English | MEDLINE | ID: mdl-37745604

ABSTRACT

Background: Ambulatory blood pressure (BP) monitoring measures nighttime BP and BP dipping, which are superior to in-clinic BP for predicting cardiovascular disease (CVD), the leading cause of death in America. Compared with other racial/ethnic groups, Black Americans exhibit elevated nighttime BP and attenuated BP dipping, including in young adulthood. Social determinants of health contribute to disparities in CVD risk, but the contribution of neighborhood deprivation on nighttime BP is unclear. Therefore, we examined associations between neighborhood deprivation with nighttime BP and BP dipping in young Black and White adults. Methods: We recruited 21 Black and 26 White participants (20 M/27 F, mean age: 21 years, body mass index: 25±4 kg/m2) for 24-hour ambulatory BP monitoring. We assessed nighttime BP and BP dipping (nighttime:daytime BP ratio). The area deprivation index (ADI) was used to measure neighborhood deprivation. Associations between ADI and ambulatory BP were examined. Results: Black participants exhibited higher nighttime diastolic BP compared with White participants (63±8 mmHg vs 58±7 mmHg, p=0.003), and attenuated BP dipping ratios for both systolic (0.92±0.06 vs 0.86±0.05, p=0.001) and diastolic BP (0.86±0.09 vs 0.78±0.08, p=0.007). Black participants experienced greater neighborhood deprivation compared with White participants (ADI scores: 110±8 vs 97±21, p<0.001), and ADI was associated with attenuated systolic BP dipping (ρ=0.342, p=0.019). Conclusions: Our findings suggest neighborhood deprivation may contribute to higher nighttime BP and attenuated BP dipping, which are prognostic of CVD, and more prevalent in Black adults. Targeted interventions to mitigate the effects of neighborhood deprivation may help to improve nighttime BP. Clinical Trial Registry: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04576338.

18.
Am J Clin Nutr ; 118(4): 822-833, 2023 10.
Article in English | MEDLINE | ID: mdl-37619651

ABSTRACT

BACKGROUND: Inadequate hydration is associated with cardiovascular and kidney disease morbidity and all-cause mortality. Compared with White individuals, Black individuals exhibit a higher prevalence of inadequate hydration, which may contribute to racial health disparities. However, the underlying reasons for these differences in hydration remain unclear. OBJECTIVE: This cross-sectional study aimed to investigate whether neighborhood deprivation contributes to racial differences in hydration status. METHODS: We assessed 24 Black and 30 White college students, measuring 24-hour urine osmolality, urine flow rate, urine specific gravity, and plasma copeptin concentration. Participants recorded their food and fluid intake for 3 d to assess total water intake from food and beverages. Neighborhood socioeconomic deprivation was measured using a tract-level Area Deprivation Index. RESULTS: Black participants exhibited higher urine osmolality (640 [314] compared with 440 [283] mOsm/kg H2O, respectively, P = 0.006) and lower urine flow rate (1.06 [0.65] compared with 1.71 [0.89] ml/min, respectively, P = 0.009) compared with White participants, indicating greater hypohydration among Black participants. Black participants reported lower total water intake from food and beverages than White participants (2.3 ± 0.7 compared with 3.5 ± 1.1 L/day, respectively, P < 0.01). Black participants exhibited higher copeptin than White participants (6.3 [3.1] compared with 4.5 [2.3] pmol/L, P = 0.046), and urine osmolality mediated 67% of the difference (P = 0.027). Black participants reported greater cumulative exposure to neighborhood deprivation during childhood (ages 0-18 y). Furthermore, neighborhood deprivation during childhood was associated with urine specific gravity (P = 0.031) and total water intake from food and beverages (P = 0.042) but did not mediate the racial differences in these measures. CONCLUSION: Our data suggest that compared with White young adults, Black young adults are hypohydrated and exhibit higher plasma copeptin concentration, and that greater neighborhood deprivation is associated with chronic underhydration irrespective of race. This trial was registered at clinicaltrials.gov as NCT04576338.


Subject(s)
Drinking , Urinalysis , Humans , Young Adult , Cross-Sectional Studies , Race Factors , Osmolar Concentration
19.
Cleft Palate Craniofac J ; : 10556656231193552, 2023 Aug 06.
Article in English | MEDLINE | ID: mdl-37545192

ABSTRACT

OBJECTIVE: Children with cleft lip and/or palate (CL/P) are at increased risk for Sleep Disordered Breathing (SDB), particularly Obstructive Sleep Apnea (OSA). At our institution, routine screening for SDB is performed using the Chevrin Pediatric Sleep Questionnaire (PSQ). This analysis is a practice audit looking at the outcomes of screening children with CL/P. DESIGN/SETTING/PATIENTS/PARTICIPANTS: A single-center, retrospective analysis was done of all non-syndromic patients with CL/P over the age of 36 months over a 4-year period. Children with known OSA were eliminated from analysis. MAIN OUTCOME MEASURES: Univariate logistic regression was used to assess predictors for SDB (PSQ score > 8) amongst various patient, disease, and treatment characteristics. Outcomes of those screened were tracked. RESULTS: Of the 239 patients in the study cohort, 43 (18%) had positive PSQs. These subjects were more likely to have class III dental occlusion with maxillary retrusion (OR = 2.65, 95% CI: 1.2-5.8, p = 0.02). There were no differences amongst age, type of cleft, Veau classification, BMI, or history of pharyngeal surgery. One third of the group did not complete recommended testing. Twenty-five subjects with positive sleep screening underwent subsequent polysomnography and 21 (84%) had OSA. CONCLUSION: Routine screening reveals a significant proportion of patients with CL/P with symptoms suggestive of OSA. While several patients did not complete confirmatory testing, those who completed a PSG had a high rate of identification of OSA. After excluding children with known OSA, patients with SDB are also likely to have class III dental occlusion and maxillary retrusion.

20.
Appetite ; 185: 106494, 2023 06 01.
Article in English | MEDLINE | ID: mdl-36805424

ABSTRACT

Eating behaviors in response to acute stressors are highly variable: whereas many individuals eat more following stressors, others eat less or show no change in food consumption. Understanding factors that predict individual differences in eating behaviors may help elucidate the psychosocial mechanisms underlying obesity, yet few experimental studies on this topic have been conducted to date. To address this issue, we conducted the present pre-registered study, where we investigated how lifetime stressor exposure moderates the extent to which eating expectancies enhance the learned association between stress-induced negative affect and snack intake. Participants were 44 women (30% non-White) between 18 and 50 years old (M = 27.9), with a mean body mass index of 25.6, who completed assessments of lifetime stressor exposure, eating behaviors, and eating expectancies (eating helps manage negative affect); in a subsequent visit, they were given snacks after an acute social stress task (TSST). The moderated moderation model (PROCESS model 3) yielded a significant three-way interaction. When eating expectancies were high, acute social stress-induced negative affect predicted greater M&M intake for women with very high total lifetime stressor exposure but less M&M intake for women with fewer lifetime stressors. These data thus highlight how lifetime stressor exposure interacts with eating expectancies and acute stress-induced negative affect to predict eating behavior. Replications in larger samples may help explain variability in stress-eating as well as how lifetime stressors contribute to obesity.


Subject(s)
Emotions , Feeding Behavior , Female , Humans , Adolescent , Young Adult , Adult , Middle Aged , Feeding Behavior/psychology , Obesity/psychology , Body Mass Index , Eating/psychology , Stress, Psychological/psychology
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