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Scientific Reports Oct 2023Heart rate (HR) is a crucial physiological signal that can be used to monitor health and fitness. Traditional methods for measuring HR require wearable devices, which...
Heart rate (HR) is a crucial physiological signal that can be used to monitor health and fitness. Traditional methods for measuring HR require wearable devices, which can be inconvenient or uncomfortable, especially during sleep and meditation. Noncontact HR detection methods employing microwave radar can be a promising alternative. However, the existing approaches in the literature usually use high-gain antennas and require the sensor to face the user's chest or back, making them difficult to integrate into a portable device and unsuitable for sleep and meditation tracking applications. This study presents a novel approach for noncontact HR detection using a miniaturized Soli radar chip embedded in a portable device (Google Nest Hub). The chip has a [Formula: see text] dimension and can be easily integrated into various devices. The proposed approach utilizes advanced signal processing and machine learning techniques to extract HRs from radar signals. The approach is validated on a sleep dataset (62 users, 498 h) and a meditation dataset (114 users, 1131 min). The approach achieves a mean absolute error (MAE) of 1.69 bpm and a mean absolute percentage error (MAPE) of [Formula: see text] on the sleep dataset. On the meditation dataset, the approach achieves an MAE of 1.05 bpm and a MAPE of [Formula: see text]. The recall rates for the two datasets are [Formula: see text] and [Formula: see text], respectively. This study represents the first application of the noncontact HR detection technology to sleep and meditation tracking, offering a promising alternative to wearable devices for HR monitoring during sleep and meditation.
Topics: Humans; Heart Rate; Meditation; Sleep; Monitoring, Physiologic; Heart Rate Determination
PubMed: 37865634
DOI: 10.1038/s41598-023-44714-2 -
Canadian Journal of Physiology and... May 2024Cardiovascular disease (CVD) is the leading cause of death in women. After menopause, sex-specific and gender-specific factors may play an important role in increasing...
Cardiovascular disease (CVD) is the leading cause of death in women. After menopause, sex-specific and gender-specific factors may play an important role in increasing CVD risk, with changes in sex hormones, body fat distribution, lipid and metabolic profile, and structural and functional vascular modifications. Premature and early-onset menopause are detrimental to cardiovascular health due to the early cessation of the protective effect of endogenous estrogen. An independent association of menopause with an increased risk of CVD has been documented in early menopause (<45 years). Sex-related differences are relevant in pharmacokinetics and pharmacodynamics; different enzyme formations, drug compatibility, efficacy, and side effects vary for different sexes. Despite some progress in sex and gender research in CVD, disparities remain. Menopausal hormone therapy (MHT) is available at midlife for symptoms of menopause and may impact CVD risk. Taken early, MHT may reduce CVD morbimortality. However, this is balanced againts the risk of increased thrombosis. This paper reviews physiologic changes that contribute to cardiovascular risk in postmenopausal women and discusses clinical implications. Specifically, it explores the atheroprotective effects of estrogen and menopausal hormone therapy and the associations between menopause with lipid levels, hypertension, body composition, and diabetes for women at midlife and beyond.
PubMed: 38739947
DOI: 10.1139/cjpp-2023-0468 -
Science Advances Sep 2023Increasing the therapeutic potential and reducing the side effects of U.S. Food and Drug Administration-approved glucagon-like peptide-1 receptor (GLP-1R) agonists used...
Increasing the therapeutic potential and reducing the side effects of U.S. Food and Drug Administration-approved glucagon-like peptide-1 receptor (GLP-1R) agonists used to treat obesity require complete characterization of the central mechanisms that mediate both the food intake-suppressive and illness-like effects of GLP-1R signaling. Our studies, in the rat, demonstrate that GLP-1Rs in the locus coeruleus (LC) are pharmacologically and physiologically relevant for food intake control. Furthermore, agonism of LC GLP-1Rs induces illness-like behaviors, and antagonism of LC GLP-1Rs can attenuate GLP-1R-mediated nausea. Electrophysiological and behavioral pharmacology data support a role for LC GLP-1Rs expressed on presynaptic glutamatergic terminals in the control of feeding and malaise. Collectively, our work establishes the LC as a site of action for GLP-1 signaling and extends our understanding of the GLP-1 signaling mechanism necessary for the development of improved obesity pharmacotherapies.
Topics: United States; Animals; Rats; Appetite Depressants; Locus Coeruleus; Obesity; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Nausea
PubMed: 37729419
DOI: 10.1126/sciadv.adh0980 -
Pharmaceutics Oct 2023Regulatory agencies worldwide expect that clinical pharmacokinetic drug-drug interactions (DDIs) between an investigational new drug and other drugs should be conducted...
Regulatory agencies worldwide expect that clinical pharmacokinetic drug-drug interactions (DDIs) between an investigational new drug and other drugs should be conducted during drug development as part of an adequate assessment of the drug's safety and efficacy. However, it is neither time nor cost efficient to test all possible DDI scenarios clinically. Phenytoin is classified by the Food and Drug Administration as a strong clinical index inducer of CYP3A4, and a moderate sensitive substrate of CYP2C9. A physiologically based pharmacokinetic (PBPK) platform model was developed using GastroPlus to assess DDIs with phenytoin acting as the victim (CYP2C9, CYP2C19) or perpetrator (CYP3A4). Pharmacokinetic data were obtained from 15 different studies in healthy subjects. The PBPK model of phenytoin explains the contribution of CYP2C9 and CYP2C19 to the formation of 5-(4'-hydroxyphenyl)-5-phenylhydantoin. Furthermore, it accurately recapitulated phenytoin exposure after single and multiple intravenous and oral doses/formulations ranging from 248 to 900 mg, the dose-dependent nonlinearity and the magnitude of the effect of food on phenytoin pharmacokinetics. Once developed and verified, the model was used to characterize and predict phenytoin DDIs with fluconazole, omeprazole and itraconazole, i.e., simulated/observed DDI AUC ratio ranging from 0.89 to 1.25. This study supports the utility of the PBPK approach in informing drug development.
PubMed: 37896246
DOI: 10.3390/pharmaceutics15102486 -
Arthritis Research & Therapy May 2024Rheumatoid arthritis (RA) related interstitial lung disease (ILD) impacts on the treatment strategy and its prognosis in patients with RA. However, the relationship...
OBJECTIVES
Rheumatoid arthritis (RA) related interstitial lung disease (ILD) impacts on the treatment strategy and its prognosis in patients with RA. However, the relationship between RA disease activity and the severity of comorbid ILD has not been fully investigated. This study aimed to investigate the impact of RA disease activity on the severity of comorbid ILD in detail based on currently established visual scoring method along with physiological severity.
METHODS
Consecutive patients with RA visiting to our Rheumatology Centre between December 2020 and December 2023 were analysed. The radiological severity of ILD was evaluated by averaging the extent of the combined lesion of ground glass opacity, reticulation and honeycombing in 5% increments in six representative high-resolution computed tomography slices ranging from 0% (no involvement) to 100% (all lung fields affected) according to Goh and Walsh's method. Associations between the radiological and physiological severity of ILD and patients' features were investigated using linear regression analysis.
RESULTS
Among 124 patients (32 men, 92 women), the median age was 70 years, and the median disease duration was 2.92 years. Radiological severity of ILD was 0% (without ILD) in 107 (86.2%), ILD with extent < 10% in nine (7.2%), ILD with extent ≥10% and < 20% in three (2.4%), ILD with extent ≥20% in five (4.0%). Both disease activity score (DAS)28-erythrocyte sedimentation rate (ESR) (standardized coefficient = 0.199, P = 0.03) and rheumatoid factor titre (standardized coefficient = 0.247, P = 0.01) were significantly associated with the radiological quantitative severity of ILD in multivariate analysis adjusted for age, sex, disease duration, smoking status and anti-citrullinated peptide antibody titre. DAS28-ESR was significantly associated with forced vital capacity% predicted (standardized coefficient = -0.230, P = 0.047).
CONCLUSIONS
Disease activity of RA was significantly associated with the severity of RA-ILD both radiologically and physiologically.
Topics: Humans; Arthritis, Rheumatoid; Lung Diseases, Interstitial; Male; Female; Aged; Middle Aged; Severity of Illness Index; Tomography, X-Ray Computed; Retrospective Studies; Aged, 80 and over
PubMed: 38704556
DOI: 10.1186/s13075-024-03333-6 -
Current Opinion in Neurobiology Dec 2023The study of the hippocampal code is gaining momentum. While the physiological approach targets the contribution of individual cells as determined by genetic,... (Review)
Review
The study of the hippocampal code is gaining momentum. While the physiological approach targets the contribution of individual cells as determined by genetic, biophysical and circuit factors, the field pushes for a population dynamic approach that considers the representation of behavioural variables by a large number of neurons. In this alternative framework, neuronal activity is projected into low-dimensional manifolds. These manifolds can reveal the structure of population representations, but their physiological interpretation is challenging. Here, we review the recent literature and propose that integrating information regarding behavioral traits, local field potential oscillations and cell-type-specificity into neural manifolds offers strategies to make them interpretable at the physiological level.
Topics: Hippocampus; Neurons; Nerve Net; Population Dynamics
PubMed: 37898015
DOI: 10.1016/j.conb.2023.102800 -
Aging and Disease Dec 2023Physiologically aged lungs are prone to senescence-associated pulmonary diseases (SAPD). This study aimed to determine the mechanism and subtype of aged T cells...
Physiologically aged lungs are prone to senescence-associated pulmonary diseases (SAPD). This study aimed to determine the mechanism and subtype of aged T cells affecting alveolar type II epithelial (AT2) cells, which promote the pathogenesis of senescence-associated pulmonary fibrosis (SAPF). Cell proportions, the relationship between SAPD and T cells, and the aging- and senescence-associated secretory phenotype (SASP) of T cells between young and aged mice were analyzed using lung single-cell transcriptomics. SAPD was monitored by markers of AT2 cells and found to be induced by T cells. Furthermore, IFNγ signaling pathways were activated and cell senescence, SASP, and T cell activation were shown in aged lungs. Physiological aging led to pulmonary dysfunction and TGF-β1/IL-11/MEK/ERK (TIME) signaling-mediated SAPF, which was induced by senescence and SASP of aged T cells. Especially, IFNγ was produced by the accumulated CD4+ effector memory T (T) cells in the aged lung. This study also found that physiological aging increased pulmonary CD4+ T cells, IFNγ was produced mainly by CD4+ T cells, and pulmonary cells had increased responsiveness to IFNγ signaling. Specific regulon activity was increased in T cell subclusters. IFNγ transcriptionally regulated by IRF1 in CD4+ T cells promoted the epithelial-to-mesenchymal transition by activating TIME signaling and cell senescence of AT2 cells with aging. Accumulated IRF1+CD4+ T produced IFNγ in lung with aging and anti-IRF1 primary antibody treatment inhibited the expression of IFNγ. Aging might drive T cell differentiation toward helper T cells with developmental trajectories and enhance cell interactions of pulmonary T cells with other surrounding cells. Thus, IFNγ transcribed by IRF1 in CD4+ effector memory T cells promotes SAPF. IFNγ produced by CD4+ T cells in physiologically aged lungs could be a therapeutic target for preventing SAPF.
PubMed: 37199578
DOI: 10.14336/AD.2023.0320 -
The Journal of Biological Chemistry Oct 2023Point mutations in leucine-rich repeat kinase 2 (LRRK2) cause Parkinson's disease and augment LRRK2's kinase activity. However, cellular pathways that endogenously...
Point mutations in leucine-rich repeat kinase 2 (LRRK2) cause Parkinson's disease and augment LRRK2's kinase activity. However, cellular pathways that endogenously enhance LRRK2 kinase function have not been identified. While overexpressed Rab29 draws LRRK2 to Golgi membranes to increase LRRK2 kinase activity, there is little evidence that endogenous Rab29 performs this function under physiological conditions. Here, we identify Rab38 as a novel physiologic regulator of LRRK2 in melanocytes. In mouse melanocytes, which express high levels of Rab38, Rab32, and Rab29, knockdown (or CRISPR knockout) of Rab38, but not Rab32 or Rab29, decreases phosphorylation of multiple LRRK2 substrates, including Rab10 and Rab12, by both endogenous LRRK2 and exogenous Parkinson's disease-mutant LRRK2. In B16-F10 mouse melanoma cells, Rab38 drives LRRK2 membrane association and overexpressed kinase-active LRRK2 shows striking pericentriolar recruitment, which is dependent on the presence of endogenous Rab38 but not Rab32 or Rab29. Consistently, knockdown or mutation of BLOC-3, the guanine nucleotide exchange factor for Rab38 and Rab32, inhibits Rab38's regulation of LRRK2. Deletion or mutation of LRRK2's Rab38-binding site in the N-terminal armadillo domain decreases LRRK2 membrane association, pericentriolar recruitment, and ability to phosphorylate Rab10. In sum, our data identify Rab38 as a physiologic regulator of LRRK2 function and lend support to a model in which LRRK2 plays a central role in Rab GTPase coordination of vesicular trafficking.
Topics: Animals; Mice; Golgi Apparatus; Guanine Nucleotide Exchange Factors; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Melanocytes; Mutation; Parkinson Disease; Phosphorylation; rab GTP-Binding Proteins; HEK293 Cells; Humans; Gene Expression; Protein Domains; Protein Binding; Intracellular Membranes
PubMed: 37625589
DOI: 10.1016/j.jbc.2023.105192 -
Journal of Crohn's & Colitis Jul 2023Crohn's disease [CD] is a major subtype of inflammatory bowel diseases [IBD] with increasing incidence and prevalence. Results of studies using available small and large...
BACKGROUND AND AIMS
Crohn's disease [CD] is a major subtype of inflammatory bowel diseases [IBD] with increasing incidence and prevalence. Results of studies using available small and large animal models are often poorly translatable to patients, and few CD models show small intestinal pathology. Due to its similarities to humans, the pig has emerged as a highly suitable translational disease model, particularly for testing novel nutritional and technological interventions. Our goal was to develop a physiologically relevant porcine CD model to facilitate translation of findings and interventions towards the clinic.
METHODS
We generated pigs bearing a 93-bp deletion of the adenosine-uracil-rich element [ARE] and a constitutive-decay element within the 3' untranslated region of the TNF gene. Comparative analysis of physiological, molecular, histological and microbial characteristics was performed between wild-type, TNFΔARE/+ and TNFΔARE/ΔARE animals. Alterations in the microbiome were compared to the TNFΔARE mouse model and IBD patients.
RESULTS
TNF ΔARE pigs recapitulate major characteristics of human CD, including ulcerative transmural ileocolitis, increased abundance of proinflammatory cytokines, immune cell infiltration and dysbiotic microbial communities. 16S rRNA gene amplicon sequencing revealed enrichment in members belonging to Megasphaera, Campylobacter, Desulfovibrio, Alistipes and Lachnoclostridum in faecal or mucosa-associated bacteria compared to wild-type littermates. Principal components analysis clustering with a subset of TNFΔARE/+ mice and human IBD patients suggests microbial similarity based on disease severity.
CONCLUSIONS
We demonstrate that the TNFΔARE pig resembles a CD-like ileocolitis pathophenotype recapitulating human disease. The ability to conduct long-term studies and test novel surgical procedures and dietary interventions in a physiologically relevant model will benefit future translational IBD research studies.
Topics: Humans; Animals; Mice; Swine; Crohn Disease; RNA, Ribosomal, 16S; Tumor Necrosis Factor-alpha; Ileitis; Inflammatory Bowel Diseases
PubMed: 36821422
DOI: 10.1093/ecco-jcc/jjad034