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BackgroundSmartphone apps for heart rate variability (HRV) measurement have been extensively developed in the last decade. However, ultra–short-term HRV recordings taken by wearable devices have not been examined. ObjectiveThe aims of this study were the following: (1) to compare the validity and reliability of ultra–short-term and short-term HRV time-domain and frequency-domain variables in a novel smartphone app, Pulse Express Pro (PEP), and (2) to determine the agreement of HRV assessments between an electrocardiogram (ECG) and PEP. MethodsIn total, 60 healthy adults were recruited to participate in this study (mean age 22.3 years [SD 3.0 years], mean height 168.4 cm [SD 8.0 cm], mean body weight 64.2 kg [SD 11.5 kg]). A 5-minute resting HRV measurement was recorded via ECG and PEP in a sitting position. Standard deviation of normal R-R interval (SDNN), root mean square of successive R-R interval (RMSSD), proportion of NN50 divided by the total number of RR intervals (pNN50), normalized very-low–frequency power (nVLF), normalized low-frequency power (nLF), and normalized high-frequency power (nHF) were analyzed within 9 time segments of HRV recordings: 0-1 minute, 1-2 minutes, 2-3 minutes, 3-4 minutes, 4-5 minutes, 0-2 minutes, 0-3 minutes, 0-4 minutes, and 0-5 minutes (standard). Standardized differences (ES), intraclass correlation coefficients (ICC), and the Spearman product-moment correlation were used to compare the validity and reliability of each time segment to the standard measurement (0-5 minutes). Limits of agreement were assessed by using Bland-Altman plot analysis. ResultsCompared to standard measures in both ECG and PEP, pNN50, SDNN, and RMSSD variables showed trivial ES (0.8). The nVLF, nLF, and nHF demonstrated a variation of ES (from trivial to small effects, 0.01-0.40), ICC (from moderate to nearly perfect, 0.39-0.96), and Spearman correlation coefficient values (from moderate to nearly perfect, 0.40-0.96). Furthermore, the Bland-Altman plots showed relatively narrow values of mean difference between the ECG and PEP after consecutive 1-minute recordings for SDNN, RMSSD, and pNN50. Acceptable limits of agreement were found after consecutive 3-minute recordings for nLF and nHF. ConclusionsUsing the PEP app to facilitate a 1-minute ultra–short-term recording is suggested for time-domain HRV indices (SDNN, RMSSD, and pNN50) to interpret autonomic functions during stabilization. When using frequency-domain HRV indices (nLF and nHF) via the PEP app, a recording of at least 3 minutes is needed for accurate measurement.

ObjectivePhysical exercise may increase brain volume and cortical thickness in late adulthood. However, few studies have examined the possibility for exercise to influence brain morphology in women treated for breast cancer. We conducted a nested sub-study within a randomized clinical trial to examine whether 6 months of moderate-intensity aerobic exercise in postmenopausal women with early-stage breast cancer influences brain morphology.MethodsWe included twenty-eight postmenopausal women newly diagnosed with Stage 0-IIIa breast cancer (M age = 62.96 ± 5.40) who were randomized to either 45–60 min of supervised aerobic exercise 3 days/week (n = 16) or usual care (n = 12). Before beginning aromatase inhibitor aromatase inhibitor therapy, and the exercise intervention, and again at 6-month follow-up, volumetric and cortical thickness measures were derived from magnetic resonance imaging scans.ResultsThere were no significant intervention effects on brain volume and cortical thickness. However, greater average exercise intensity (%) during the intervention was associated with greater post-intervention cortical volume, mean cortical thickness, precentral gyrus thickness, and superior parietal thickness (all p < 0.05). Finally, total supervised exercise time was associated with higher precentral gyrus thickness after the intervention (p = 0.042, R2 = 0.263).ConclusionThe exercise intervention did not significantly affect brain volumes and cortical thickness compared to the control group. However, positive associations were found between exercise intensity and brain morphology changes after the 6-month intervention, indicating that exercise may reduce the vulnerability of the brain to the deleterious effects of breast cancer and its treatment.

Cell-free RNA from liquid biopsies can be analyzed to determine disease tissue of origin. We extend this concept to identify cell types of origin using the Tabula Sapiens transcriptomic cell atlas as well as individual tissue transcriptomic cell atlases in combination with the Human Protein Atlas RNA consensus dataset. We define cell type signature scores, which allow the inference of cell types that contribute to cell-free RNA for a variety of diseases.

Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression. Using multiple tissues from a single donor enabled identification of the clonal distribution of T cells between tissues, identification of the tissue-specific mutation rate in B cells, and analysis of the cell cycle state and proliferative potential of shared cell types across tissues. Cell type-specific RNA splicing was discovered and analyzed across tissues within an individual.

Abstract Senile plaque, composed of amyloid β protein (Aβ) aggregates, is a critical pathological feature in Alzheimer's disease (AD), leading to cognitive dysfunction. However, how Aβ aggregates exert age‐dependent toxicity and temporal cognitive dysfunction in APP/PS1 mice remains incompletely understood. In this study, we investigated AD pathogenesis and dynamic alterations in lysosomal pathways within the hippocampus of age‐gradient male mice using transcriptome sequencing, molecular biology assays, and histopathological analyses. We observed high levels of β‐amyloid precursor protein (APP) protein expression in the hippocampus at an early stage and age‐dependent Aβ deposition. Transcriptome sequencing revealed the enrichment of differential genes related to the lysosome pathway. Furthermore, the protein expression of ATP6V0d2 and CTSD associated with lysosomal functions exhibited dynamic changes with age, increasing in the early stage and decreasing later. Similar age‐dependent patterns were observed for the endosome function, autophagy pathway, and SGK1/FOXO3a pathway. Nissl and Golgi staining in the hippocampal region showed age‐dependent neuronal loss and synaptic damage, respectively. These findings clearly define the age‐gradient changes in the autophagy–lysosome system, the endosome/lysosome system, and the SGK1/FOXO3a pathway in the hippocampus of APP/PS1 mice, providing new perspectives and clues for understanding the possible mechanisms of AD, especially the transition from compensatory to decompensated state.

Objective To investigate the effects of mindfulness-based intervention on cognitive reappraisal, positive attentional bias and depression in army aviation maintenance personnel. Methods A total of 44 officers and soldiers of an army aviation brigade were selected by cluster sampling and then divided into intervention group (n=22) and control group (n=22).The intervention group received 2 hours'mindfulness intervention course once a week for 8 consecutive weeks, while the control group were given mental health education at same frequency and duration.Then the participants were assessed with self-compiled demographic scales, Five Facet Mindfulness Questionnaire (FFMQ), Emotion Regulation Questionnaire (ERQ), Attention to Positive and Negative Information Scale (APNIS), and Self-rating Depression Scale (SDS) before intervention (T1), at the end of the intervention (T2), and 1 month after the intervention (T3), respectively. Results There were no significant differences in the demographic data and psychological indicators between the 2 groups before training.After intervention, the scores of mindfulness level, cognitive reappraisal, positive attention bias and depression were significantly different between the 2 groups in terms of measurement time and group interaction (P < 0.05).The scores of mindfulness level and the cognitive reappraisal scores were greatly higher at T2 and T3 than T1(P < 0.01, P < 0.05), and the positive attention bias score at T2 was also notably higher than that of T1(P < 0.05) in the intervention group.In addition, no significant difference was observed in the depression score at the 3 time points in the intervention group, while in the control group, the score was obviously higher at T3 than T2 and T1(P < 0.05, P < 0.01). Conclusion Mindfulness-based intervention significantly improves the level of mindfulness, cognitive reappraisal and positive attentional bias, and relieves the impact of military training and management on depression of the army aviation officers and soldiers to a certain extent.

Background: Alcohol abuse, a prevalent global health issue, is associated with the onset of cognitive impairment and neurodegeneration. Actin filaments (F-actin) and microtubules (MTs) polymerized from monomeric globular actin (G-actin) and tubulin form the structural basis of the neuronal cytoskeleton. Precise regulation of the assembly and disassembly of these cytoskeletal proteins, and their dynamic balance, play a pivotal role in regulating neuronal morphology and function. Nevertheless, the effect of prolonged alcohol exposure on cytoskeleton dynamics is not fully understood. This study investigates the chronic effects of alcohol on cognitive ability, neuronal morphology and cytoskeleton dynamics in the mouse hippocampus. Methods: Mice were provided ad libitum access to 5% (v/v) alcohol in drinking water and were intragastrically administered 30% (v/v, 6.0 g/kg/day) alcohol for six weeks during adulthood. Cognitive functions were then evaluated using the Y maze, novel object recognition and Morris water maze tests. Hippocampal histomorphology was assessed through hematoxylin-eosin (HE) and Nissl staining. The polymerized and depolymerized states of actin cytoskeleton and microtubules were separated using two commercial assay kits and quantified by Western blot analysis. Results: Mice chronically exposed to alcohol exhibited significant deficits in spatial and recognition memory as evidenced by behavioral tests. Histological analysis revealed notable hippocampal damage and neuronal loss. Decreased ratios of F-actin/G-actin and MT/tubulin, along with reduced levels of polymerized F-actin and MTs, were found in the hippocampus of alcohol-treated mice. Conclusions: Our findings suggest that chronic alcohol consumption disrupted the assembly of the actin cytoskeleton and MTs in the hippocampus, potentially contributing to the cognitive deficits and pathological injury induced by chronic alcohol intoxication.

Introduction Physical activity (PA) has beneficial effects on brain health and cardiovascular disease (CVD) risk. Yet, we know little about whether PA-induced changes to physiological mediators of CVD risk influence brain health and whether benefits to brain health may also explain PA-induced improvements to CVD risk. This study combines neurobiological and peripheral physiological methods in the context of a randomised clinical trial to better understand the links between exercise, brain health and CVD risk.Methods and analysis In this 12-month trial, 130 healthy individuals between the ages of 26 and 58 will be randomly assigned to either: (1) moderate-intensity aerobic PA for 150 min/week or (2) a health information control group. Cardiovascular, neuroimaging and PA measurements will occur for both groups before and after the intervention. Primary outcomes include changes in (1) brain structural areas (ie, hippocampal volume); (2) systolic blood pressure (SBP) responses to functional MRI cognitive stressor tasks and (3) heart rate variability. The main secondary outcomes include changes in (1) brain activity, resting state connectivity, cortical thickness and cortical volume; (2) daily life SBP stress reactivity; (3) negative and positive affect; (4) baroreflex sensitivity; (5) pulse wave velocity; (6) endothelial function and (7) daily life positive and negative affect. Our results are expected to have both mechanistic and public health implications regarding brain–body interactions in the context of cardiovascular health.Ethics and dissemination Ethical approval has been obtained from the University of Pittsburgh Institutional Review Board (IRB ID: 19020218). This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule.Trial registration number NCT03841669.

Skeletal stem and progenitor cell populations are crucial for bone physiology. Characterization of these cell types remains restricted to heterogenous bulk populations with limited information on whether they are unique or overlap with previously characterized cell types. Here we show, through comprehensive functional and single-cell transcriptomic analyses, that postnatal long bones of mice contain at least two types of bone progenitors with bona fide skeletal stem cell (SSC) characteristics. An early osteochondral SSC (ocSSC) facilitates long bone growth and repair, while a second type, a perivascular SSC (pvSSC), co-emerges with long bone marrow and contributes to shape the hematopoietic stem cell niche and regenerative demand. We establish that pvSSCs, but not ocSSCs, are the origin of bone marrow adipose tissue. Lastly, we also provide insight into residual SSC heterogeneity as well as potential crosstalk between the two spatially distinct cell populations. These findings comprehensively address previously unappreciated shortcomings of SSC research.

Activation of the Hedgehog pathway may have therapeutic value for improved bone healing, taste receptor cell regeneration, and alleviation of colitis or other conditions. Systemic pathway activation, however, may be detrimental, and agents amenable to tissue targeting for therapeutic application have been lacking. We have developed an agonist, a conformation-specific nanobody against the Hedgehog receptor Patched1 (PTCH1). This nanobody potently activates the Hedgehog pathway in vitro and in vivo by stabilizing an alternative conformation of a Patched1 "switch helix," as revealed by our cryogenic electron microscopy structure. Nanobody-binding likely traps Patched in one stage of its transport cycle, thus preventing substrate movement through the Patched1 sterol conduit. Unlike the native Hedgehog ligand, this nanobody does not require lipid modifications for its activity, facilitating mechanistic studies of Hedgehog pathway activation and the engineering of pathway activating agents for therapeutic use. Our conformation-selective nanobody approach may be generally applicable to the study of other PTCH1 homologs.

Ageing is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death1. Despite rapid advances over recent years, many of the molecular and cellular processes that underlie the progressive loss of healthy physiology are poorly understood2. To gain a better insight into these processes, here we generate a single-cell transcriptomic atlas across the lifespan of Mus musculus that includes data from 23 tissues and organs. We found cell-specific changes occurring across multiple cell types and organs, as well as age-related changes in the cellular composition of different organs. Using single-cell transcriptomic data, we assessed cell-type-specific manifestations of different hallmarks of ageing-such as senescence3, genomic instability4 and changes in the immune system2. This transcriptomic atlas-which we denote Tabula Muris Senis, or 'Mouse Ageing Cell Atlas'-provides molecular information about how the most important hallmarks of ageing are reflected in a broad range of tissues and cell types.