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NPJ Microgravity Jun 2024The participation of women in space programs of increasing flight duration requires research of their reproductive system from the perspective of subsequent childbearing...
The participation of women in space programs of increasing flight duration requires research of their reproductive system from the perspective of subsequent childbearing and healthy aging. For the first time, we present hormonal and structural data on the dynamics of recovery after a 157-day space flight in a woman of reproductive age. There were no clinically significant changes in the reproductive system, but detailed analysis shows that weightlessness leads to an increase in the proportion of early antral follicles and granulosa cells in large antral follicles. Returning to Earth's gravity reduces the number and diameter of early antral follicles.
PubMed: 38909072
DOI: 10.1038/s41526-024-00413-4 -
Cell Death Discovery Jun 2024The physiological quantum of stress-inducible transcriptional protein, Lens Epithelium-Derived Growth Factor (LEDGF), is vital for the maintenance of cellular...
The physiological quantum of stress-inducible transcriptional protein, Lens Epithelium-Derived Growth Factor (LEDGF), is vital for the maintenance of cellular physiology. Erratic epigenetic reprogramming in response to oxidative stress or with advancing age is found to be a major cause in the gene silencing, leading to pathobiologies. Using aging human (h) eye lens/lens epithelial cells (LECs) coupled with redox-active Peroxiredoxin 6 (Prdx6)-deficient (Prdx6) mLECs as model systems, herein, we showed that in aging/oxidative stress, the human LEDGF gene was regulated by unique methylation patterns of CGs nucleotides within and around the Sp1 binding site(s) of CpG island of the LEDGF promoter (-170 to -27nts). The process caused the repression of LEDGF and its target, Hsp27, resulting in reactive oxygen species (ROS) amplification and cellular insults. This phenomenon was opposed to the unmethylated promoter in LECs. Clinically, we observed that the loss of LEDGF in the Prdx6 mLECs or aging lenses/LECs, correlating with increased expression of DNMT1, DNMT3a, and DNMT3b along with the methyl CpG binding protein 2 (MeCP2). Upon oxidative stress, the expression of these molecules was increased with the dramatic reduction in LEDGF expression. While demethylating agent, 5-Aza deoxycytidine (5-AzaC) transposed the aberrant methylation status, and revived LEDGF and Hsp27 expression. Mechanistically, the chloramphenicol acetyltransferase (CAT) reporter gene driven by the LEDGF promoter (-170/ + 35) and ChIP assays uncovered that 5-AzaC acted on GC/Sp1 sites to release LEDGF transcription. The data argued, for the first time, that de novo methylation of CGs around and within Sp1 sites of the CpG island directly disrupted Sp1 activity, which ensued in LEDGF repression and its biological functions. The findings should improve our understanding of cellular insults-associated with aberrant DNMTs-mediated LEDGF's activity, and can offer strategies for therapeutic intervention to halt aging/oxidative stress-induced abnormalities.
PubMed: 38909054
DOI: 10.1038/s41420-024-02076-2 -
Nature Communications Jun 2024DNA double-strand breaks are repaired by multiple pathways, including non-homologous end-joining (NHEJ) and microhomology-mediated end-joining (MMEJ). The balance of...
DNA double-strand breaks are repaired by multiple pathways, including non-homologous end-joining (NHEJ) and microhomology-mediated end-joining (MMEJ). The balance of these pathways is dependent on the local chromatin context, but the underlying mechanisms are poorly understood. By combining knockout screening with a dual MMEJ:NHEJ reporter inserted in 19 different chromatin environments, we identified dozens of DNA repair proteins that modulate pathway balance dependent on the local chromatin state. Proteins that favor NHEJ mostly synergize with euchromatin, while proteins that favor MMEJ generally synergize with distinct types of heterochromatin. Examples of the former are BRCA2 and POLL, and of the latter the FANC complex and ATM. Moreover, in a diversity of human cancer types, loss of several of these proteins alters the distribution of pathway-specific mutations between heterochromatin and euchromatin. Together, these results uncover a complex network of proteins that regulate MMEJ:NHEJ balance in a chromatin context-dependent manner.
Topics: DNA Breaks, Double-Stranded; Humans; DNA End-Joining Repair; Chromatin; Heterochromatin; Euchromatin; BRCA2 Protein; Ataxia Telangiectasia Mutated Proteins; DNA Repair
PubMed: 38909016
DOI: 10.1038/s41467-024-49232-x -
BMJ Open Jun 2024Generation Scotland (GS) is a large family-based cohort study established as a longitudinal resource for research into the genetic, lifestyle and environmental...
PURPOSE
Generation Scotland (GS) is a large family-based cohort study established as a longitudinal resource for research into the genetic, lifestyle and environmental determinants of physical and mental health. It comprises extensive genetic, sociodemographic and clinical data from volunteers in Scotland.
PARTICIPANTS
A total of 24 084 adult participants, including 5501 families, were recruited between 2006 and 2011. Within the cohort, 59% (approximately 14 209) are women, with an average age at recruitment of 49 years. Participants completed a health questionnaire and attended an in-person clinic visit, where detailed baseline data were collected on lifestyle information, cognitive function, personality traits and mental and physical health. Genotype array data are available for 20 026 (83%) participants, and blood-based DNA methylation (DNAm) data for 18 869 (78%) participants. Linkage to routine National Health Service datasets has been possible for 93% (n=22 402) of the cohort, creating a longitudinal resource that includes primary care, hospital attendance, prescription and mortality records. Multimodal brain imaging is available in 1069 individuals.
FINDINGS TO DATE
GS has been widely used by researchers across the world to study the genetic and environmental basis of common complex diseases. Over 350 peer-reviewed papers have been published using GS data, contributing to research areas such as ageing, cancer, cardiovascular disease and mental health. Recontact studies have built on the GS cohort to collect additional prospective data to study chronic pain, major depressive disorder and COVID-19.
FUTURE PLANS
To create a larger, richer, longitudinal resource, 'Next Generation Scotland' launched in May 2022 to expand the existing cohort by a target of 20 000 additional volunteers, now including anyone aged 12+ years. New participants complete online consent and questionnaires and provide postal saliva samples, from which genotype and salivary DNAm array data will be generated. The latest cohort information and how to access data can be found on the GS website (www.generationscotland.org).
Topics: Humans; Scotland; Female; Male; Longitudinal Studies; Middle Aged; Adult; Family Health; Life Style; Aged; Young Adult; COVID-19; DNA Methylation; Mental Health; Health Status; Adolescent; SARS-CoV-2
PubMed: 38908846
DOI: 10.1136/bmjopen-2024-084719 -
Free Radical Biology & Medicine Jun 2024The skin is made up of different layers with various gradients, which maintain a complex microenvironment, particularly in terms of oxygen levels. However, all types of... (Review)
Review
The skin is made up of different layers with various gradients, which maintain a complex microenvironment, particularly in terms of oxygen levels. However, all types of skin cells are cultured in conventional incubators that do not reproduce physiological oxygen levels. Instead, they are cultured at atmospheric oxygen levels, a condition that is far removed from physiology and may lead to the generation of free radicals known to induce skin ageing. This review aims to summarize the current literature on the effect of physiological oxygen levels on skin cells, highlight the shortcomings of current in vitro models, and demonstrate the importance of respecting skin oxygen levels. We begin by clarifying the terminology used about oxygen levels and describe the specific distribution of oxygen in the skin. We review and discuss how skin cells adapt their oxygen consumption and metabolism to oxygen levels environment, as well as the changes that are induced, particularly, their redox state, life cycle and functions. We examine the effects of oxygen on both simple culture models and more complex reconstructed skin models. Finally, we present the implications of oxygen modulation for a more therapeutic approach.
PubMed: 38908804
DOI: 10.1016/j.freeradbiomed.2024.06.015 -
Free Radical Biology & Medicine Jun 2024Oxygen is essential for aerobic life on earth but it is also the origin of harmful reactive oxygen species (ROS). Ubiquinone is par excellence the endogenous cellular...
Oxygen is essential for aerobic life on earth but it is also the origin of harmful reactive oxygen species (ROS). Ubiquinone is par excellence the endogenous cellular antioxidant, but a very hydrophobic one. Because of that, other molecules have been envisaged, such as idebenone (IDE) and mitoquinone (MTQ), molecules having the same redox active benzoquinone moiety but higher solubility. We have used molecular dynamics to determine the location and interaction of these molecules, both in their oxidized and reduced forms, with membrane lipids in a membrane similar to that of the mitochondria. Both IDE and reduced IDE (IDOL) are situated near the membrane interface, whereas both MTQ and reduced MTQ (MTQOL) locate in a position adjacent to the phospholipid hydrocarbon chains. The quinone moieties of both ubiquinone 10 (UQ10) and reduced UQ10 (UQOL10) in contraposition to the same moieties of IDE, IDOL, MTQ and MTQOL, located near the membrane interphase, whereas the isoprenoid chains remained at the middle of the hydrocarbon chains. These molecules do not aggregate and their functional quinone moieties are located in the membrane at different depths but near the hydrophobic phospholipid chains whereby protecting them from ROS harmful effects.
PubMed: 38908803
DOI: 10.1016/j.freeradbiomed.2024.06.017 -
Journal of the American Medical... Jun 2024Most quality indicators (QIs) currently used in nursing homes reflect the care delivered by the entire multidisciplinary team and are not specific for medical...
Most quality indicators (QIs) currently used in nursing homes reflect the care delivered by the entire multidisciplinary team and are not specific for medical practitioners. International experts have proposed a set of QIs that specifically reflect the quality of medical care in nursing homes. The objective of the Delphi study described here was to compile a set of actionable QIs tailored for medical practitioners working within Dutch nursing homes. This was achieved through the evaluation of 15 existing national QIs and 35 international QIs by a panel of medical practitioners, comprising medical specialists, nurse practitioners, and physician assistants, who are working in Dutch nursing homes. Panelists rated each QI on (1) level of direct control by medical practitioners and (2) its relevance to the quality of medical care. QIs progressing to subsequent rounds required panel agreement on both direct control (≥70% ≥3 points on a 4-point scale) and relevance (≥70% ≥8 on a 10-point scale). In the last round, each panelist selected the 5 most relevant QIs and arranged them in order of importance. These top 5 rankings were converted into points for an overall final ranking. There was consensus on 42 QIs being under the control of medical practitioners, and 21 of these QIs were considered relevant for quality of care. Most of the 21 QIs originated from the international QI set. This finding supports the transferability of the internationally developed QIs to the Dutch nursing home context and provides opportunities to compare the quality of medical care in nursing homes across countries. In the final ranking, the QI related to new medication prescriptions received the highest rating, followed by 3 QIs related to advance care planning. Future research should focus on evaluating the feasibility of measuring the selected QIs and assessing their measurement properties before implementing them in professional learning and quality improvement initiatives for medical practitioners in nursing homes.
PubMed: 38908400
DOI: 10.1016/j.jamda.2024.105089 -
Pathology, Research and Practice Jun 2024Cancer-associated fibroblasts (CAFs) are a heterogeneous population of fibroblasts with various features in the cancer stroma and have been reported to influence cancer...
Cancer-associated fibroblasts (CAFs) are a heterogeneous population of fibroblasts with various features in the cancer stroma and have been reported to influence cancer progression through cell-cell interactions in various types of malignancies, including lung adenocarcinoma (LUAD). Dipeptidyl peptidase 4 (DPP4) is a transmembrane protein with serine protease activity and is involved in the progression of tumors, metabolic diseases, and autoimmune diseases. In the present study, we focused on the role of DPP4-positive CAFs in LUAD. Immunohistochemistry revealed that 38 of 89 LUAD patients showed DPP4 expression in the fibrous stroma, and patients harboring DPP4-positive CAFs were more often male, had a higher Brinkman index, and had a higher Ki-67 labeling index of tumor cells than those with DPP4-negative CAFs. DPP4-positivity was associated with the expression of other CAF markers, α-SMA, periostin, and podoplanin, as well as a cellular senescence marker, p16. In the in vitro study, conditioned media collected from pulmonary fibroblast (OUS-11, HPF, and HPF-C)-induced overexpression of DPP4 significantly promoted the proliferation of LUAD cells (A549 and PC-9) and increased the expression levels of MCP-1, IL-8, IL-6, and GCSF in the media compared to those in controls. In addition, OUS-11 overexpression in DPP4 overexpression increased periostin expression. In conclusion, DPP4-positive CAFs could promote lung adenocarcinoma cell growth by producing soluble factors, and DPP4 inhibition may inhibit cancer progression.
PubMed: 38908333
DOI: 10.1016/j.prp.2024.155418 -
The Journal of Nutrition, Health & Aging Jun 2024There is a lack of consensus about the operationalization of vitality, which is one of the intrinsic capacity (IC) domains. In particular, no study has investigated...
BACKGROUND
There is a lack of consensus about the operationalization of vitality, which is one of the intrinsic capacity (IC) domains. In particular, no study has investigated whether cardiorespiratory fitness (CRF) can be considered a vitality indicator.
OBJECTIVE
To examine whether vitality is the upstream domain of IC, and establish the validity of CRF as a vitality indicator, using maximal oxygen consumption (VO max) as a representative.
METHODS
561 older adults from a longitudinal cohort study were included. Variables under consideration were VO max, other IC domains, instrumental activities of daily living (IADL), and handgrip strength, which was considered an already validated indicator of vitality. Using handgrip strength as the reference point, path analyses were performed to examine whether VO max followed a similar hierarchical structure in predicting change in IADL difficulty through other IC domains.
RESULTS
The mean age of the participants was 75.5 years. The path model in which vitality was measured by VO max demonstrated adequate fit, which was similar to the model in which vitality was measured by handgrip strength. Regarding the path coefficients, the model using VO max demonstrated significant total and indirect effects. Notably, the indirect effect was due to the locomotor domain (standardized coefficient = -0.148, p < .001), but not the cognitive or psychological domain.
CONCLUSION
Vitality is the upstream domain of IC. VO max can be considered an indicator to operationalize the vitality concept.
PubMed: 38908298
DOI: 10.1016/j.jnha.2024.100300 -
The Journal of Nutrition, Health & Aging Jun 2024An age-dependent normative values of calf circumference (CC) has been recently proposed as an accessible proxy for muscle mass. However, its usefulness to estimate...
BACKGROUND
An age-dependent normative values of calf circumference (CC) has been recently proposed as an accessible proxy for muscle mass. However, its usefulness to estimate sarcopenia has not been assessed. The objectives of the present study were to determine if the substitution of the classical way to assess muscle mass by these values have enough diagnostic accuracy and prognostic value among older adults living in the community.
METHODS
Data from the Toledo Study of Healthy Ageing (TSHA) were used. CC was measured using an anthropometric tape. We used two age-groups CC cut-off points: the TSHA CC median and the one proposed in the Longevity Check-up 7+ (Lookup 7+) project. Sarcopenia was defined based on the European Working Group on Sarcopenia in Older People (EWGSOP2), the Foundation for the National Institutes of Health (FNIH), and FNIH criteria standardized for our population (sFNIH). Frailty (according to the Frailty Phenotype and the Frailty Trait Scale-5) and disability (Katz index) were assessed at baseline and follow-up. Mortality and first hospitalization were also recorded. Logistic (incident frailty and worsening disability) and Cox (mortality and hospitalization) regressions were performed. Diagnostic accuracy was assessed through Kappa index, AUCs, positive and negative predictive values. Predictive ability was assessed through AUCs and integrated AUCs (IAUCs).
RESULTS
1531 participants (74.8 ± 5.8 years; 45.6% men) were included in the analysis. Prevalence rates of sarcopenia were 22.7% (sFNIH), 15.0% (FNIH), and 13.9% (EWGSOP2). Using TSHA-based cut-points of CC, the prevalence of sarcopenia was 16.8% (sFNIH), 11.0% (FNIH), and 11.5% (EWGSOP2). According to LC7+-based CC cut-off points, sarcopenia prevalence was 17.6% (sFNIH), 11.9% (FNIH), and 12.4% (EWGSOP2). CC cut-off points showed low-to-moderate agreement (Kappa Index values between 0.49 and 0.69) with appendicular lean mass for the evaluation of sarcopenia. Sarcopenia identified by Lookup 7+ and TSHA CC cut-off points was associated with the adverse events examined, with similar AUCs and IAUCs than original sarcopenia definitions, and were lost after adjustment by baseline frailty, except when the original EWGSOP2 definition was used.
CONCLUSIONS
Using normalized values of CC as a criteria of muscle mass shows moderate agreement with classical criteria for diagnosing sarcopenia and offer similar predictive value in community-dwelling older adults.
PubMed: 38908297
DOI: 10.1016/j.jnha.2024.100290