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Nature Jul 2024
PubMed: 38961208
DOI: 10.1038/d41586-024-02107-z -
Nature Metabolism Jul 2024PAQR4 is an orphan receptor in the PAQR family with an unknown function in metabolism. Here, we identify a critical role of PAQR4 in maintaining adipose tissue function...
PAQR4 is an orphan receptor in the PAQR family with an unknown function in metabolism. Here, we identify a critical role of PAQR4 in maintaining adipose tissue function and whole-body metabolic health. We demonstrate that expression of Paqr4 specifically in adipocytes, in an inducible and reversible fashion, leads to partial lipodystrophy, hyperglycaemia and hyperinsulinaemia, which is ameliorated by wild-type adipose tissue transplants or leptin treatment. By contrast, deletion of Paqr4 in adipocytes improves healthy adipose remodelling and glucose homoeostasis in diet-induced obesity. Mechanistically, PAQR4 regulates ceramide levels by mediating the stability of ceramide synthases (CERS2 and CERS5) and, thus, their activities. Overactivation of the PQAR4-CERS axis causes ceramide accumulation and impairs adipose tissue function through suppressing adipogenesis and triggering adipocyte de-differentiation. Blocking de novo ceramide biosynthesis rescues PAQR4-induced metabolic defects. Collectively, our findings suggest a critical function of PAQR4 in regulating cellular ceramide homoeostasis and targeting PAQR4 offers an approach for the treatment of metabolic disorders.
PubMed: 38961186
DOI: 10.1038/s42255-024-01078-9 -
Scientific Reports Jul 2024Age-related changes in emotional processing are complex, with a bias toward positive information. However, the impact of aging on emotional responses in positive...
Age-related changes in emotional processing are complex, with a bias toward positive information. However, the impact of aging on emotional responses in positive everyday situations remains unclear. Virtual Reality (VR) has emerged as a promising tool for investigating emotional processing, offering a unique balance between ecological validity and experimental control. Yet, limited evidence exists regarding its efficacy to elicit positive emotions in older adults. Our study aimed to explore age-related differences in positive emotional responses to immersion in both social and nonsocial virtual emotional environments. We exposed 34 younger adults and 24 older adults to natural and social 360-degree video content through a low immersive computer screen and a highly immersive Head-Mounted Display, while recording participants' physiological reactions. Participants also provided self-report of their emotions and sense of presence. The findings support VR's efficacy in eliciting positive emotions in both younger and older adults, with age-related differences in emotional responses influenced by the specific video content rather than immersion level. These findings underscore the potential of VR as a valuable tool for examining age-related differences in emotional responses and developing VR applications to enhance emotional wellbeing across diverse user populations.
Topics: Humans; Emotions; Virtual Reality; Male; Female; Aged; Adult; Young Adult; Middle Aged; Aging; Age Factors
PubMed: 38961132
DOI: 10.1038/s41598-024-66119-5 -
Bone Research Jul 2024Bone marrow adipocytes (BMAds) affect bone homeostasis, but the mechanism remains unclear. Here, we showed that exercise inhibited PCNA clamp-associated factor (PCLAF)...
Bone marrow adipocytes (BMAds) affect bone homeostasis, but the mechanism remains unclear. Here, we showed that exercise inhibited PCNA clamp-associated factor (PCLAF) secretion from the bone marrow macrophages to inhibit BMAds senescence and thus alleviated skeletal aging. The genetic deletion of PCLAF in macrophages inhibited BMAds senescence and delayed skeletal aging. In contrast, the transplantation of PCLAF-mediated senescent BMAds into the bone marrow of healthy mice suppressed bone turnover. Mechanistically, PCLAF bound to the ADGRL2 receptor to inhibit AKT/mTOR signaling that triggered BMAds senescence and subsequently spread senescence among osteogenic and osteoclastic cells. Of note, we developed a PCLAF-neutralizing antibody and showed its therapeutic effects on skeletal health in old mice. Together, these findings identify PCLAF as an inducer of BMAds senescence and provide a promising way to treat age-related osteoporosis.
Topics: Animals; Adipocytes; Cellular Senescence; Mice; Aging; Mice, Inbred C57BL; Bone Marrow Cells; Bone and Bones; Male; Osteogenesis; Signal Transduction; Macrophages
PubMed: 38961077
DOI: 10.1038/s41413-024-00337-5 -
Nature Communications Jul 2024DNA methylation plays an important role in various biological processes, including cell differentiation, ageing, and cancer development. The most important methylation...
DNA methylation plays an important role in various biological processes, including cell differentiation, ageing, and cancer development. The most important methylation in mammals is 5-methylcytosine mostly occurring in the context of CpG dinucleotides. Sequencing methods such as whole-genome bisulfite sequencing successfully detect 5-methylcytosine DNA modifications. However, they suffer from the serious drawbacks of short read lengths and might introduce an amplification bias. Here we present Rockfish, a deep learning algorithm that significantly improves read-level 5-methylcytosine detection by using Nanopore sequencing. Rockfish is compared with other methods based on Nanopore sequencing on R9.4.1 and R10.4.1 datasets. There is an increase in the single-base accuracy and the F1 measure of up to 5 percentage points on R.9.4.1 datasets, and up to 0.82 percentage points on R10.4.1 datasets. Moreover, Rockfish shows a high correlation with whole-genome bisulfite sequencing, requires lower read depth, and achieves higher confidence in biologically important regions such as CpG-rich promoters while being computationally efficient. Its superior performance in human and mouse samples highlights its versatility for studying 5-methylcytosine methylation across varied organisms and diseases. Finally, its adaptable architecture ensures compatibility with new versions of pores and chemistry as well as modification types.
Topics: 5-Methylcytosine; Nanopore Sequencing; DNA Methylation; Animals; Mice; Humans; CpG Islands; Deep Learning; Algorithms; Sequence Analysis, DNA; Whole Genome Sequencing; Sulfites
PubMed: 38961062
DOI: 10.1038/s41467-024-49847-0 -
Clinical Rheumatology Jul 2024The burden of osteoarthritis (OA) is rapidly increasing with population aging, but there are still no approved disease-modifying drugs available. Accumulating evidence... (Review)
Review
The burden of osteoarthritis (OA) is rapidly increasing with population aging, but there are still no approved disease-modifying drugs available. Accumulating evidence has shown that OA is a heterogeneous disease with multiple phenotypes, and it is unlikely to respond to one-size-fits-all treatments. Inflammation is recognized as an important phenotype of OA and is associated with worse pain and joint deterioration. Therefore, it is believed that anti-inflammatory treatments may be more effective for OA with an inflammatory phenotype. In this review, we summarized clinical trials that evaluated anti-inflammatory treatments for OA and discussed whether these treatments are more effective in inflammatory OA phenotypes compared to general OA patients.
PubMed: 38961031
DOI: 10.1007/s10067-024-07042-y -
Quality of Life Research : An... Jul 2024To identify utility-based patient-reported outcome measures (PROMs) for assessing health-related quality of life (HRQoL) in cardiac rehabilitation and secondary... (Review)
Review
PURPOSE
To identify utility-based patient-reported outcome measures (PROMs) for assessing health-related quality of life (HRQoL) in cardiac rehabilitation and secondary prevention programs (CR) and appraise existing evidence on their measurement properties. Secondly, to link their items to the International Classification of Functioning Disability and Health (ICF) and the International Consortium of Health Outcome Measures (ICHOM) domains for cardiovascular disease (CVD).
METHODS
Eight databases were searched. The review followed the COSMIN and JBI guidelines for measurement properties systematic reviews and PRISMA 2020 reporting guidelines. Non-experimental and observational empirical studies of patients ≥ 18 years of age with CVD undergoing CR and assessed quality of life (QoL) or HRQoL using utility-based PROMs or one accompanied by health state utilities were included.
RESULTS
Nine PROMs were identified with evidence on measurement properties for three measures: the German translations of SF-12, EQ-5D-5L, and MacNew heart disease HRQoL questionnaire. There was moderate quality evidence for responsiveness and hypothesis testing of the SF-12 and EQ-5D-5L, and high-quality evidence for responsiveness and hypothesis testing for the MacNew. All items of SF-12 and EQ-5D were linked to ICF categories, but four items of the MacNew were not classified or defined. All the PROM domains were mapped onto similar constructs from the ICHOM global sets.
CONCLUSION
Three utility-based PROMs validated in CR were identified: the German versions of the EQ-5D and SF-12 and the MacNew questionnaire. These PROMs are linked to a breadth of ICF categories and all ICHOM global sets. Additional validation studies of PROMs in CR are required.
PubMed: 38961008
DOI: 10.1007/s11136-024-03657-5 -
Osteoporosis International : a Journal... Jul 2024Task Force on 'Clinical Algorithms for Fracture Risk' commissioned by the American Society for Bone and Mineral Research (ASBMR) Professional Practice Committee has...
Task Force on 'Clinical Algorithms for Fracture Risk' commissioned by the American Society for Bone and Mineral Research (ASBMR) Professional Practice Committee has recommended that FRAX® models in the US do not include adjustment for race and ethnicity. This position paper finds that an agnostic model would unfairly discriminate against the Black, Asian and Hispanic communities and recommends the retention of ethnic and race-specific FRAX models for the US, preferably with updated data on fracture and death hazards. In contrast, the use of intervention thresholds based on a fixed bone mineral density unfairly discriminates against the Black, Asian and Hispanic communities in the US. This position of the Working Group on Epidemiology and Quality of Life of the International Osteoporosis Foundation (IOF) is endorsed both by the IOF and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).
PubMed: 38960982
DOI: 10.1007/s00198-024-07162-w -
Analytical and Bioanalytical Chemistry Jul 2024From organs to subcellular organelles, trace element (TE) homeostasis is fundamental for many physiological processes. While often overlooked in early stages, manifested...
From organs to subcellular organelles, trace element (TE) homeostasis is fundamental for many physiological processes. While often overlooked in early stages, manifested TE disbalance can have severe health consequences, particularly in the context of aging or pathological conditions. Monitoring TE concentrations at the mitochondrial level could identify organelle-specific imbalances, contributing to targeted diagnostics and a healthier aging process. However, mitochondria isolation from frozen tissue is challenging, as it poses the risk of TE losses from the organelles due to cryodamage, but would significantly ease routine laboratory work. To address this, a novel method to isolate an enriched mitochondria fraction (EMF) from frozen tissue was adapted from already established protocols. Validation of manganese (Mn), iron (Fe), and copper (Cu) quantification via inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) showed sufficiently low quantification limits for EMF TE analysis. Successful mitochondrial enrichment from frozen liver samples was confirmed via immunoblots and transmission electron microscopy (TEM) revealed sufficient structural integrity of the EMFs. No significant differences in EMF TEs between frozen and fresh tissue were evident for Mn and Cu and only slight decreases in EMF Fe. Consequently, EMF TEs were highly comparable for isolates from both tissue states. In application, this method effectively detected dietary differences in EMF Fe of a murine feeding study and identified the disease status in a Wilson disease rat model based on drastically increased EMF Cu. In summary, the present method is suitable for future applications, facilitating sample storage and high-throughput analyses of mitochondrial TEs.
PubMed: 38960940
DOI: 10.1007/s00216-024-05400-y -
Physiological Reports Jul 2024High tissue sodium accumulation and intermuscular adipose tissue (IMAT) are associated with aging, type 2 diabetes, and chronic kidney disease. In this study, we aim to...
BACKGROUND AND AIMS
High tissue sodium accumulation and intermuscular adipose tissue (IMAT) are associated with aging, type 2 diabetes, and chronic kidney disease. In this study, we aim to investigate whether high lower-extremity tissue sodium accumulation relates to IMAT quantity and whether systemic inflammatory mediators and adipocytokines contribute to such association.
METHODS
Tissue sodium content and IMAT accumulation (percentage of IMAT area to muscle area) were measured in 83 healthy individuals using sodium imaging (Na-MRI) and proton (1H-MRI) imaging of the calf. Insulin sensitivity was assessed by glucose disposal rate (GDR) measured with the hyperinsulinemic-euglycemic clamp.
RESULTS
Median (interquartile range) muscle and skin sodium contents were 16.6 (14.9, 19.0) and 12.6 (10.9, 16.7) mmol/L, respectively. Median IMAT was 3.69 (2.80, 5.37) %. In models adjusted for age, sex, BMI, GDR, adiponectin, and high-sensitivity C-reactive protein, increasing tissue sodium content was significantly associated with higher IMAT quantity (p = 0.018 and 0.032 for muscle and skin tissue sodium, respectively). In subgroup analysis stratified by sex, skin sodium was significantly associated with IMAT only among men. In interaction analysis, the association between skin sodium and IMAT was greater with increasing levels of high-sensitivity C-reactive protein and interleukin-6 (p for interaction = 0.022 and 0.006, respectively).
CONCLUSIONS
Leg muscle and skin sodium are associated with IMAT quantity among healthy individuals. The relationship between skin sodium and IMAT may be mediated by systemic inflammation.
Topics: Humans; Male; Female; Adipose Tissue; Adult; Sodium; Muscle, Skeletal; Middle Aged; Skin; Insulin Resistance; Magnetic Resonance Imaging
PubMed: 38960895
DOI: 10.14814/phy2.16127