The twenties are typically considered the prime reproductive years for women. However, in today's modern world, many women are choosing to delay family planning, resulting in an increase in females in their forties seeking fertility treatment. Although in vitro fertilization (IVF) with donated oocytes and preimplantation genetic testing may help to address the impact of maternal age, the success rate for IVF treatment in this age group is still significantly lower. While endometrial changes, such as abnormal endometrial thickness, inflammatory background, and altered hormone response signaling, are associated with aging, little is known about the molecular features of endometrial aging and their impact on the ability to support embryo implantation. To better understand age-specific changes, we performed endometrial transcriptome profiling of young and advanced-age females, undergoing hormonal replacement therapy (HRT) before frozen embryo transfer, followed by immunohistology analysis and single-cell-based deconvolution. Here, we identified 491 differentially expressed genes pointing to the effect of aging on decidualization, cell signaling, inflammation and endometrial receptivity. Our results indicate that p16INK4a may be involved in cellular senescence and the suppression of metabolic and inflammatory processes essential for endometrial preparation for embryo implantation. We have also shown that the proportion of ciliated cells along with ciliary processes is affected by endometrial aging. These findings have important implications for future strategies aimed at improving infertility treatment in women of advanced reproductive age. | Make paid
Skin aging is of immense societal and, thus, scientific interest. Because mechanics play a critical role in skin's function, a plethora of studies have investigated age-induced changes in skin mechanics. Nonetheless, much remains to be learned about the mechanics of aging skin. This is especially true when considering sex as a biological variable. In our work, we set out to answer some of these questions using mice as a model system. Specifically, we combined mechanical testing, histology, collagen assays, and two-photon microscopy to identify age- and sex-dependent changes in skin mechanics and to relate them to structural, microstructural, and compositional factors. Our work revealed that skin stiffness, thickness, and collagen content all decreased with age and were sex dependent. Interestingly, sex differences in stiffness were age induced. We hope our findings not only further our fundamental understanding of skin aging but also highlight both age and sex as important variables when conducting studies on skin mechanics. | Make paid
The naked mole-rat Heterocephalus glaber is a eusocial mammal exhibiting extreme longevity (37-year lifespan), extraordinary resistance to hypoxia and absence of cardiovascular disease. To identify the mechanisms behind these exceptional traits, RNAseq and metabolomics of cardiac tissue from naked mole-rats was compared to other African mole-rat genera. We identified metabolic and genetic adaptations unique to naked mole-rats including elevated glycogen, thus enabling glycolytic ATP generation during cardiac ischemia. Elevated normoxic expression of HIF-1 was observed while downstream hypoxia responsive-genes were down regulated, suggesting adaptation to low oxygen environments. Naked mole-rat hearts showed reduced succinate build-up during ischemia and negligible tissue damage following ischemia-reperfusion injury. These adaptive evolutionary traits reflect a unique hypoxic and eusocial lifestyle that collectively may contribute to their longevity and health span. | Make paid
Squamous cell carcinoma has been attributed to chronic schistosomiasis and is the predominant type of bladder cancer in schistosomiasis endemic areas. The aim of this study was to assess early promoter DNA methylation in selected genes implicated in schistosomiasis associated bladder cancer (SABC). A total of 161 urine samples were collected from school aged children in Eggua Community of Ogun State and examined by microscopy for Schistosoma haematobium eggs. From this sample, a subset of 34 (21.1%) urine samples positive for S. haematobium eggs and 22 formalin fixed paraffin-embedded bladder cancer tissues obtained from the University College Hospital Ibadan, were subjected to DNA isolation and bisulfite DNA conversion. Quantitative methylation specific PCR was used to determine the methylation status of APC, RAR{beta}2, RASSF1A and TIMP3 in the samples. Methylation in APC, RAR{beta}2, RASSF1A and TIMP3 was observed in 24(70.6%), 18(52.9%), 15(44.1%) and 8(23.5%) of the positive urine samples respectively and in 7(31.8%), 13(59.1%), 17(77.3%) and 8(36.4%) of bladder cancer tissues respectively. APC, RAR{beta}2 and RASSF1A were 5-fold, 2-fold and 27-fold downregulated respectively in positive urine samples and 9-fold, 3-fold and 15-fold downregulated respectively in the bladder cancer tissues. The odds of promoter methylation in RAR{beta}2 (OR: 1.133) were likely even with light infection. Gene promoter DNA methylation in tumour suppressor genes was observed in schistosomiasis cases. Hence, DNA methylation may occur during active Schistosoma haematobium in children. This result may serve as an early non-invasive biomarker to detect and hint at the risk of developing SABC later in life. | Make paid
MicroRNAs (miRNAs) regulate gene expression by base-pairing to target sequences in messenger RNAs (mRNAs) and recruiting factors that induce translational repression and mRNA decay. In animals, nucleotides 2-8 at the 5' end of the miRNA, called the seed region, are often necessary and sometimes sufficient for functional target interactions. MiRNAs that contain identical seed sequences are grouped into families where individual members have the potential to share targets and act redundantly. A rare exception seemed to be the miR-238/239ab family in Caenorhabditis elegans, as previous work indicated that loss of miR-238 reduced lifespan while deletion of the miR-239ab locus resulted in enhanced longevity and thermal stress resistance. Here, we re-examined these potentially opposing roles using new strains that individually disrupt each miRNA sister. We confirmed that loss of miR-238 is associated with a shortened lifespan but could detect no longevity or stress phenotypes in animals lacking miR-239a or miR-239b, individually or in combination. Additionally, dozens of genes were mis-regulated in miR-238 mutants but almost no gene expression changes were detected in either miR-239a or miR-239b mutants compared to wild type animals. We present evidence that the lack of redundancy between miR-238 and miR-239ab is independent of their sequence differences; miR-239a or miR-239b could substitute for the longevity role of miR-238 when expressed from the miR-238 locus. Altogether, these studies disqualify miR-239ab as negative regulators of aging and demonstrate that expression, not sequence, dictates the specific role of miR-238 in promoting longevity. | Make paid
Robotic exoskeletons can provide powered locomotor assistance and rehabilitation to persons with mobility impairments due to aging and/or physical disabilities. Here we present the preliminary development and systems integration of T-BLUE - a modular, bilateral robotic hip-knee exoskeleton with 3D-printed backdriveable actuators. We retrofitted commercially available passive postoperative orthoses with open-source 3D-printed actuators to minimize cost and improve accessibility. The actuators are of quasi-direct drive design with high-torque density brushless DC motors and low gearing (15:1 transmission ratio) for low output impedance and high backdrivability, therein allowing for energy-efficient and dynamic human-robot physical interaction and legged locomotion. The modular design allows the exoskeleton to be customized and adapted to different users (e.g., persons with lateral vs. bilateral mobility impairments) and different hip-knee joint configurations. The goals of this preliminary study were to describe our experience with regards to the repeatability of the open-source 3D-printed actuators in engineering practice and the feasibility of integrating the actuators into wearable robotics hardware. This qualitative research serves as a first step towards using the robotic exoskeleton to support the development and testing of novel controller designs and rehabilitation protocols for different locomotor activities of daily living. We are especially interested in populations that could benefit from partial locomotor assistance such as older adults and/or persons with osteoarthritis. Future research will involve benchtop testing to quantitatively evaluate the actuator performance in terms of dynamics and energy-efficiency. | Make paid
Frontotemporal lobar degeneration (FTLD) includes a heterogeneous group of disorders pathologically characterized by the degeneration of the frontal and temporal lobes. In addition to major genetic contributors of FTLD such as mutations in MAPT, GRN, and C9orf72, recent work has identified several epigenetic modifications including significant differential DNA methylation in DLX1, and OTUD4 loci. As aging remains to be one of the major risk factors for FTLD, we investigated the presence of accelerated epigenetic aging in FTLD compared to controls. We calculated epigenetic age in both peripheral blood and brain tissues of multiple FTLD subtypes using several DNA methylation clocks, i.e., DNAmClockMulti, DNAmClockHannum, DNAmClockCortical, GrimAge and PhenoAge, and determined age acceleration and its association with different cellular proportions and clinical traits. Significant epigenetic age acceleration was observed in the peripheral blood of both frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP) patients compared to controls with DNAmClockHannum, even after accounting for confounding factors. A similar trend was observed with both DNAmClockMulti and DNAmClockCortical in post-mortem frontal cortex tissue of PSP patients and in FTLD cases harboring GRN mutations. Our findings support that increased epigenetic age acceleration in the peripheral blood could be an indicator for PSP and to a smaller extent, FTD. | Make paid
Sound information is transmitted from the cochlea to the brain mainly by type I spiral ganglion neurons (SGNs), which consist of different subtypes with distinct physiological properties and selective expression of molecular markers. It remains unclear how these SGN subtypes distribute along the tonotopic axis, and how the distribution pattern changes during aging that might underlie age-related hearing loss (ARHL). We investigated these questions using immunohistochemistry in three age groups of CBA/CaJ mice of either sex, including 2-5 months (young), 17-19 months (middle-age), and 28-32 months (old). Mouse cochleae were cryo-sectioned and triple-stained using antibodies against Tuj1, calretinin (CR) and calbindin (CB), which are reportedly expressed in all type I, subtype Ia, and subtype Ib SGNs, respectively. Labeled SGNs were classified into four groups based on the expression pattern of stained markers, including CR+ (subtype Ia), CB+ (subtype Ib), CR+CB+ (dual-labeled Ia/Ib), and CR-CB- (subtype Ic) neurons. The distribution of these SGN groups was analyzed in the apex, middle, and base regions of the cochleae. It showed that the prevalence of subtype Ia, Ib and dual-labeled Ia/Ib SGNs are high in the apex and low in the base. In contrast, the distribution pattern is reversed in Ic SGNs. Such frequency-dependent distribution is largely maintained during aging except for a preferential reduction of Ic SGNs, especially in the base. These findings suggest that sound processing of different frequencies involves distinct combinations of SGN subtypes, and the age-dependent loss of Ic SGNs in the base may especially impact high-frequency hearing during ARHL. | Make paid
Parasites with complex lifecycles are known to manipulate the phenotype of their intermediate hosts to increase the probability of transmission to their definitive hosts. Anomotaenia brevis, a cestode that uses Temnothorax nylanderi ants as intermediate hosts, extends the lifespan of these hosts several fold and changes their behaviour, morphology, and colouration. The mechanisms behind these changes are unknown, as is whether the increased longevity is achieved through manipulation of the parasite. Here we show that the prolonged lifespan of infected ants is probably due to the secretion of antioxidants and possibly novel substances by the parasite. These parasitic proteins make up a substantial portion of the host haemolymph proteome, and thioredoxin peroxidase and superoxide dismutase, two antioxidants, exhibited the highest abundances among them. The largest part of the secreted proteins could not be annotated, indicating they are either novel or severely altered during recent coevolution to function in host manipulation. We found not only secreted proteins, but also shifts in the host proteome, in particular an overabundance of vitellogenin-like A in infected ants, a protein that regulates division of labour in Temnothorax ants, which fits the observed behavioural changes. Our results thus point at two different strategies that are likely employed by this parasite to manipulate its host - by secretion of proteins with immediate influence on the host's phenotype and by altering the host's translational activity. Our results reveal the intricate molecular interplay required to influence host phenotype and shed light on potential signalling pathways and genes. | Make paid
HRas is an important node that controls cellular signaling, proliferation, and differentiation. Mutants of HRas (e.g., the constitutively active HRas V12) can be oncogenic, and can also inhibit myoblast differentiation. The C-terminal cysteines of HRas (Cys181 and Cys184) serve as substrates for intra-cellular reversible palmitoylation and de-palmitoylation reactions, which control its subcellular distribution. The relationship between the C-terminal cysteines of HRas, its intracellular distribution, and its cellular activity has remained unclear. Understanding this relationship has important implications for targeting HRas in pathogenic states where it is activated. In this study, we show that a mutation in the C-terminal of HRas, C181S, is sufficient to cause increased levels of HRas V12 in the Golgi, decreased HRas V12-driven Akt and Erk signaling and reverse the ability of HRas V12 to inhibit myoblast differentiation. This demonstrates the importance of C- terminal cysteines in controlling HRas V12. It has been previously shown that Cys184 can also be irreversibly modified by an electrophilic prostaglandin lipid 15d-PGJ2. This lipid is released by senescent cells as a part of senescence-associated secretory phenotype (SASP). In this study, we show that 15d-PGJ2 is secreted by senescent myoblasts formed by treatment with Doxorubicin. We also show that 15d-PGJ2 causes decreased levels of HRas within Golgi, activates Erk signaling (but not Akt signaling), and inhibits differentiation of C2C12 myoblasts in an HRas Cys184-dependent fashion. Chemotherapeutics such as Doxorubicin drive senescence and loss of skeletal muscle homeostasis in cancer patients. This study suggests that targeting the senescence-derived synthesis of 15-PGJ2 might be a target to promote muscle homeostasis after chemotherapy. | Make paid
Glaucoma is a leading cause of irreversible blindness, with advanced age being the single most significant risk factor. However, the mechanisms underlying the relationship between aging and glaucoma remain unclear. Genome wide association studies (GWAS) have successfully identified genetic variants strongly associated with increased glaucoma risk. Understanding how these variants function in pathogenesis is crucial for translating genetic associations into molecular mechanisms and, ultimately, clinical applications. The chromosome 9p21.3 locus is among the most replicated glaucoma risk loci discovered by GWAS. Nonetheless, the absence of protein-coding genes in the locus makes interpreting the disease association challenging, leaving the causal variant and molecular mechanism elusive. In this study, we report the identification of a functional glaucoma risk variant, rs6475604. By employing computational and experimental methods, we demonstrated that rs6475604 resides in a repressive regulatory element. Risk allele of rs6475604 disrupts the binding of YY1, a transcription factor known to repress the expression of a neighboring gene in 9p21.3, p16INK4A, which plays a crucial role in cellular senescence and aging. These findings suggest that the glaucoma disease variant contributes to accelerated senescence, providing a molecular link between glaucoma risk and an essential cellular mechanism for human aging. | Make paid
Programmed cell death (apoptosis) is a homeostasis program of animal tissues designed to remove cells that are unwanted or are damaged by physiological insults. To assess the functional role of apoptosis we have studied the consequences of subjecting Drosophila epithelial cells defective in apoptosis to stress or genetic perturbations that normally cause massive cell death. We find that many of those cells acquire persistent activity of the JNK pathway, which drives them into senescent status, characterized by arrest of cell division, cell hypertrophy, Senescent Associated Beta-gal activity (SA-Beta-gal), ROS production, Senescent Associated Secretory Phenotype (SASP) and migratory behaviour. We have identified two classes of senescent cells in the wing disc: 1) those that localize to the appendage part of the disc, express the upd, wg and dpp signaling genes and generate tumour overgrowths, and 2) those located in the thoracic region do not express wg and dpp nor they induce tumour overgrowths. Whether to become tumorigenic or non-tumorigenic depends on the original identity of the cell prior to the transformation. We also find that the p53 gene contributes to senescence by enhancing the activity of JNK. | Make paid
In this ageing society, sarcopenia as a geriatric condition that can have significant negative impacts on an individual's quality of life. Sarcopenia is a kind of aged syndrome associated with loss of muscle mass and function, which may lead to falls, fractures, gait disorders or even mortality. There are multiple ways to diagnose sarcopenia, such as using Magnetic resonance imaging (MRI), Dual-energy X-ray absorptiometry (DEXA) and Bioelectrical impedance analysis (BIA) etc. to calculate muscle mass; using handgrip or sit-to-stand to measure muscle strength; using short physical performance battery (SPPB), gait, and 5-time sit-to-stand to evaluate physical performance. In this work, we use two IMUs worn on subjects to record their sit-to-stand motion, and then used several machine learning models to diagnose the severity of sarcopenia of the subjects. We recruited 53 elderly subjects in total for this work. The youngest subject is 65 years old and the oldest is 84 years old. Their average age is 70 years old. Among these 53 subjects, there are 12 healthy ones and 41 sarcopenia patients with different severity. The subject is instructed to do the single sit-to-stand (STS) three times, and two IMUs attached to the subject's waist and thigh transfer the data to a computer by Bluetooth. We separated the STS motion process into 4 phases based on the angle and angular velocity, extracted a total of 510 features for motion analytics. These features were futher analyzed by sequential feature selection with 5 different machine learning models (SVM, KNN, decision tree, LDA, and multilayer perceptron). With our proposed methodology, all 53 subjects could be classified as healthy or having sarcopenia with risk level 1, 2, or 3. The best accuracy to distinguish the healthy or sarcopenia subjects is 98.32%, and the best results to distinguish sarcopenia risk levels from 0 (healthy) to 3 (most severe) is 90.44%. | Make paid
Alzheimers disease (AD) is an age-related neurodegenerative disease that affects over 6 million adults each year. As individuals age, their cells do not repair themselves which leads to proliferation arrest known as senescence. In the nervous system, astrocyte senescence has been associated with neuroinflammation and other AD processes. Thus, studying senescence may be a unique approach to understanding AD pathology. This study looks at the correlation between SCN9A, a novel gene target, and AD. Results suggest SCN9A may be a potential diagnostic marker for AD. A model was created with an 80%+ accuracy rate in predicting AD. Overall, this study suggests SCN9A plays a large role in neurodegeneration and treating AD. | Make paid
Objective To classify older adults with multiple long term conditions (MLTC) in clusters based on accumulating conditions as trajectories over time, characterise clusters and quantify associations between derived clusters and all-cause mortality. Design We conducted a retrospective cohort study using the English Longitudinal Study of Ageing (ELSA) over nine years (n=15,091 aged 50 years and older). Group-based trajectory modelling was used to classify people into MLTC clusters based on accumulating conditions over time. Derived clusters were used to quantify the associations between MLTC trajectory memberships, sociodemographic characteristics, and all-cause mortality. Five distinct clusters of MLTC of trajectories were identified and characterised as: "no-LTC" (18.57%), "single-LTC" (31.21%), "evolving MLTC" (28.82%), "moderate MLTC" (17.12%) and "high-MLTC" (7.27%). Increasing age was increasingly associated with an increased number of MLTC. Female sex (aOR = 1.13; 95%CI 1.01 to 1.27) and ethnic minority (aOR = 2.04; 95%CI 1.40 to 3.00) were associated with the "moderate-MLTC" and "high-MLTC" clusters respectively. Higher education and paid employment were associated with lower likelihood of progression over time towards an increased number of MLTC. All clusters had higher all-cause mortality than the "no-LTC" cluster. Conclusions The development of MLTC and the increase in the number of conditions over time follow distinct trajectories. These are determined by non-modifiable (age, sex, ethnicity) and modifiable factors (education and employment). Stratifying risk through clustering will enable practitioners to identify older adults with a higher likelihood of worsening MLTC over time to tailor effective interventions. | Make paid
Objective: To investigate the mortality risk linked to prescription of different anti-diabetic medication classes. Design: Prospective population-based study. Setting UK Biobank. Participants: 410 389 of the 502 536 participants in UK Biobank with covariate data, clinical and prescription records were included in the analyses, 43 610 of which had been diagnosed type 2 diabetes (T2D). A nearest neighbour covariate matching (NNCM) algorithm based on covariates with relevant effects on survival was applied to match cohorts of anti-diabetic medication class users to minimally differing control cohorts, either with a T2D diagnosis or without. Kaplan Meier estimates and Cox proportional models were used to evaluate survival differences and hazard ratio between drug classes and controls. Main outcome measures: All-cause mortality and causes of death. Results: 13667 (3.3%) individuals died during a median of 12.2 years of follow-up. After applying NNCM, participants with T2D on metformin (average hazard ratio 0.39, 95% confidence interval 0.31 to 0.49) or SGLT2I (average hazard ratio 0.58, 95% confidence interval 0.36 to 0.93) have an increased survival probability compared to matched individuals with T2D. When compared to matched individuals without T2D, the survival probability of individuals with T2D increases only if prescribed SGLT2I (average hazard ratio 0.31, 95% confidence interval 0.19 to 0.51). NNCM-based analysis of matched individuals with T2D on both SGLT2I and metformin versus metformin only reveals increased survival in the presence of SGLT2I (average hazard ratio 0.29, 95% confidence interval 0.09 to 0.91), also when compared to matched identical individuals without T2D (average hazard ratio 0.05, 95% confidence interval 0.01 to 0.19). All the other anti-diabetic drugs analyzed are either detrimental in prolonging lifespan (insulin, thiazolidinediones, and sulfonylureas), or have no effect (DPP4 inhibitors and GLP1 receptor agonists). Conclusion: The use of the current first-line anti-diabetic treatment, metformin, or sodium-glucose cotransporter 2 inhibitors (SGLT2I) increases the survival probability compared to matched individuals with diabetes using other anti-diabetic drugs. Only individuals on SGLT2I experience increased survival when compared to individuals without T2D. | Make paid
Objectives: Age is the strongest risk factor of Giant Cell Arteritis (GCA), implying a possible pathogenetic role of cellular senescence. To address this question, we applied an established senescence specific multi-marker algorithm in tissue artery biopsies (TABs) of GCA patients. Methods: Seventy five positive TABs from GCA patients and 22 negative from patients with Polymyalgia Rheumatica (PMR) were retrospectively retrieved and analyzed. Senescent cells and their histologic origin were identified with specific cellular markers; IL-6 and MMP-9 were investigated as components of the senescent associated secretory phenotype (SASP) by triple co-staining. GCA or PMR artery culture supernatants were applied to primary skin fibroblasts with or without IL-6 blocking agent to explore the induction of IL-6 associated cellular senescence. Results: Senescent cells were mainly present in GCA arteries at higher proportion compared to PMR (9.50% vs 2.66% respectively, p<0.0001) and were mainly originated from fibroblasts, macrophages and endothelial cells. IL-6 was expressed by senescent fibroblasts and macrophages while MMP-9 by fibroblasts only. IL-6 positive senescent cells were associated with the extension of vascular inflammation (adventitial limited disease vs transmural inflammation: 10.02% vs 4.37% respectively, p<0.0001). GCA but not PMR artery culture supernatant could induce IL-6-associated senescence that was partially inhibited by IL-6 blockade. Conclusions: Senescent cells with inflammatory phenotype are present in GCA arteries and are associated with the tissue inflammatory bulk. These findings might suggest a potential implication in disease pathogenesis by perpetuating inflammation and affecting vascular remodeling via IL-6 dependent mechanisms. | Make paid
Faithful transcription of eukaryotic genes by RNA polymerase II (Pol II) is essential for proper cell function. Nevertheless, the integrity of the DNA template of Pol II is continuously challenged by different sources of DNA damage, such as UV-light, that impede transcription. When unresolved, these transcription-blocking lesions (TBLs) can cause cellular dysfunction, senescence and apoptosis, eventually resulting in DNA damage-induced aging. Cells counteract these deleterious effects by Transcription-Coupled Nucleotide Excision Repair (TC-NER), which specifically removes TBLs, thereby safeguarding transcription. TC-NER initiation relies on the concerted actions of the CSB, CSA and UVSSA proteins, and loss of either of these factors results in a complete TC-NER deficiency. Although their TC-NER defect is similar, UVSSA loss results in UV-Sensitive Syndrome (UVSS), with only mild phenotypes like freckling and photosensitivity, while loss of CSA or CSB activity results in the severe Cockayne Syndrome (CS), characterized by premature aging, progressive neurodegeneration and mental retardation. Thus far the underlying mechanism for these striking differences in phenotypes remains unclear. Using live-cell imaging approaches, here we show that in TC-NER proficient cells lesion-stalled Pol II is swiftly resolved by repair of the TBL. However, in CSA and CSB knockout (KO) cells, elongating Pol II remains chromatin-bound. This lesion-stalled Pol II will obstruct other DNA transacting processes and will also shield the damage from repair by alternative pathways. In contrast, in UVSSA KO cells, Pol II is removed from the TBL by VCP-mediated proteasomal degradation, thereby, allowing alternative repair mechanisms to remove the TBL. | Make paid
The process of aging is a complex phenomenon that involves a progressive decline in physiological functions required for survival and fertility. To better understand the mechanisms underlying this process, the scientific community has utilized several tools. Among them, mitochondrial DNA has emerged as a crucial factor in biological aging, given that mitochondrial dysfunction is thought to significantly contribute to this phenomenon. Additionally, Drosophila melanogaster has proven to be a valuable model organism for studying aging thanks to its low cost, capacity to generate large populations, and ease of genetic manipulation and tissue dissection. Moreover, graph theory has been employed to understand the dynamic changes in gene expression patterns associated with aging and to investigate the interactions between aging and aging-related diseases. In this study, we have integrated these approaches to examine the patterns of gene co-expression in Drosophila melanogaster at various stages of development. By applying graph-theory techniques, we have identified modules of co-expressing genes, highlighting those that contain a significantly high number of mitochondrial genes. We found important mitochondrial genes involved in aging and age-related diseases in Drosophila melanogaster, including UQCR-C1, ND-B17.2, ND-20, and Pdhb. Our findings shed light on the role of mitochondrial genes in the aging process and demonstrate the utility of Drosophila melanogaster as a model organism and graph theory in aging research. | Make paid
Cell type-specific gene expression patterns are outputs of transcriptional gene regulatory networks (GRNs) that connect transcription factors and signaling proteins to target genes. Single-cell technologies such as single cell RNA-sequencing (scRNA-seq) and single cell Assay for Transposase-Accessible Chromatin using sequencing (scATAC-seq), can examine cell-type specific gene regulation at unprecedented detail. However, current approaches to infer cell type-specific GRNs are limited in their ability to integrate scRNA-seq and scATAC-seq measurements and to model network dynamics on a cell lineage. To address this challenge, we have developed single-cell Multi-Task Network Inference (scMTNI), a multi-task learning framework to infer the GRN for each cell type on a lineage from scRNA-seq and scATAC-seq data. Using simulated and real datasets, we show that scMTNI is a broadly applicable framework for linear and branching lineages that accurately infers GRN dynamics and identifies key regulators of fate transitions for diverse processes such as cellular reprogramming and differentiation. | Make paid
The cuticle constitutes the outermost defensive barrier of most land plants. It comprises a polymeric matrix - cutin, surrounded by soluble waxes. Moreover, the cuticle constitutes the first line of defence against pathogen invasion, while also protecting the plant from many abiotic stresses. Aliphatic monomers in cutin have been suggested to act as immune elicitors in plants. This study analyses the potential of tomato cutin oligomers to act as damage-associated molecular patterns (DAMPs) able to induce a rapid immune response in the model plant Arabidopsis. Cutin oligomeric mixtures led to Ca2+ influx and MAPK activation in Arabidopsis. Comparable responses were measured for cutin, which was also able to induce a reactive oxygen species (ROS) burst. Furthermore, treatment of Arabidopsis with cutin oligomers resulted in a unique transcriptional reprogramming profile, having many archetypal features of pattern-triggered immunity (PTI). Targeted spectroscopic and spectrometric analyses of the cutin oligomers suggest that the elicitors compounds consist mostly of two up to three 10,16-dihydroxy-hexadecanoic acid monomers linked together through ester bonds. This study demonstrates that cutin breakdown products can act as DAMPs; a novel class of elicitors deserving further characterization. | Make paid
Cellular senescence is a conserved biological process essential for embryonic development, tissue remodeling, repair, and a key regulator of aging. Senescence also plays a crucial role in cancer, though this role can be tumor-suppressive or tumor-promoting, depending on the genetic context and the microenvironment. The highly heterogeneous, dynamic, and context-dependent nature of senescence-associated features and the relatively small numbers of senescent cells in tissues makes in vivo mechanistic studies of senescence challenging. As a result, which senescence-associated features are observed in which disease contexts and how they contribute to disease phenotypes remain largely unknown. Similarly, the specific mechanisms by which various senescence-inducing signals are integrated in vivo to induce senescence and why some cells become senescent while their immediate neighbors do not are unclear. Here, we identify a small number of cells that exhibit multiple features of senescence in a genetically complex model of intestinal transformation we recently established in the developing Drosophila larval hindgut epithelium. We demonstrate that these cells emerge in response to concurrent activation of AKT, JNK, and DNA damage response pathways within transformed tissue. Eliminating senescent cells, genetically or by treatment with senolytic compounds, reduces overgrowth and improves survival. We find that this tumor-promoting role is mediated by Drosophila macrophages recruited to the transformed tissue by senescent cells, which results in non-autonomous activation of JNK signaling within the transformed epithelium. These findings emphasize complex cell-cell interactions underlying epithelial transformation and identify senescent cell-macrophage interactions as a potential druggable node in cancer. | Make paid
Background: Post-coronary artery shunt remains one of the most frequently used revascularization in emergency. Aims: Asses the role of age advancement in the incidence rate of post coronary artery shunt complications. Objectives: Aging is a pathophysiological process that experience every living cell and starts from the early period of development, before even born. Materials and methods: Retrospective analysis of the 290 patients who underwent coronary artery bypass graft from the Mordovia republic hospital for the period of 2017-2021. The results of the descriptive statistics demonstrated age dependent complications. Therefore, the sample subdivided into two groups, first group 126 patients (mean age: min; max, 55.21:41.00;60.00) and the second group 163 (M age: min; max, 66.11: 61.00; 80.00). For statistical analysis, we used the T test, one-way ANOVA test, and Pearson correlation test by using the Statistica 12 programme. Results: Post-CABG arrythmia developed in elderly patients, t-value -2.51307, p<0.012528. Subsequently, post-CABG arrythmia increased ICU and total hospitalisation days, t value -5.83306, p< 0.000000; t-value -4.02907, p< 0.000072, respectively. Elderly people are at higher risk of psychosis after CABG surgery, t value 2.69885, p <0.007379. psychosis significantly increases hospitalisation days in the ICU, t-value 3.86094, p < 0.000140. Postoperative stroke occurs more frequently in elderly people, t-value 2.087585, p < 0.037736. Subsequently, postoperative stroke increases the ICU hospitalization days, t-value 3.409293, p <0.000747. The number of ITAs used is less in the elderly people, t-value 2.41992, p < 0.016145. In terms of correlation, exist a direct association between age and ICU / total hospitalization days/number of complications, r= 0.189046, 0.141415, 0.138565; respectively. Conclusions: The number of complications is determined by age increase, CPB time, aortic cross-clamp time, the days of hospitalization in the ICU and total hospitalization days. Elderly people undergoing CABG are at higher risk of psychosis, arrythmia, longer total and ICU hospitalization days, and stroke. Others: Total hospitalization days depend on the presence of arrythmia, which is commonly seen in elderly patients > 63 years old. | Make paid
Trachoma, caused by ocular Chlamydia trachomatis infection, is targeted for global elimination as a public health problem by 2030. To provide evidence for use of antibodies to monitor C. trachomatis transmission, we collated IgG responses to Pgp3 antigen, PCR positivity, and clinical observations from 19,811 children aged 1-9 years in 14 populations. We demonstrate that age-seroprevalence curves consistently shift along a gradient of transmission intensity: rising steeply in populations with high levels of infection and active trachoma and becoming flat in populations near elimination. Seroprevalence (range: 0-54%) and seroconversion rates (range: 0-15 per 100 person-years) correlate with PCR prevalence (r: 0.87, 95% CI: 0.57, 0.97). A seroprevalence threshold of 13.5% (seroconversion rate 2.75 per 100 person-years) identifies clusters with any PCR-identified infection at high sensitivity (>90%) and moderate specificity (69-75%). Antibody responses in young children provide a robust, generalizable approach to monitor population progress toward and beyond trachoma elimination. | Make paid
Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown and to date no genetic mechanisms for AKI have been established. Clonal hematopoiesis of indeterminate potential (CHIP) is a recently recognized biological mechanism conferring risk of several chronic aging diseases including cardiovascular disease, pulmonary disease and liver disease. In CHIP, blood stem cells acquire mutations in myeloid cancer driver genes such as DNMT3A, TET2, ASXL1 and JAK2 and the myeloid progeny of these mutated cells contribute to end-organ damage through inflammatory dysregulation. We sought to establish whether CHIP causes acute kidney injury (AKI). To address this question, we first evaluated associations with incident AKI events in three population-based epidemiology cohorts (N = 442,153). We found that CHIP was associated with a greater risk of AKI (adjusted HR 1.26, 95% CI: 1.19-1.34, p<0.0001), which was more pronounced in patients with AKI requiring dialysis (adjusted HR 1.65, 95% CI: 1.24-2.20, p=0.001). The risk was particularly high in the subset of individuals where CHIP was driven by mutations in genes other than DNMT3A (HR: 1.49, 95% CI: 1.37-1.61, p<0.0001). We then examined the association between CHIP and recovery from AKI in the ASSESS-AKI cohort and identified that non-DNMT3A CHIP was more common among those with a non-resolving pattern of injury (HR 2.3, 95% CI: 1.14-4.64, p = 0.03). To gain mechanistic insight, we evaluated the role of Tet2-CHIP to AKI in ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO) mouse models. In both models, we observed more severe AKI and greater post-AKI kidney fibrosis in Tet2-CHIP mice. Kidney macrophage infiltration was markedly increased in Tet2-CHIP mice and Tet2-CHIP mutant renal macrophages displayed greater pro-inflammatory responses. In summary, this work establishes CHIP as a genetic mechanism conferring risk of AKI and impaired kidney function recovery following AKI via an aberrant inflammatory response in CHIP-derived renal macrophages. | Make paid
The coronavirus disease 2019 (COVID-19) pandemic and the measures taken by authorities to control its spread had altered human behavior and mobility patterns in an unprecedented way. However, it remains unclear whether the population response to a COVID-19 outbreak varies within a city or among demographic groups. Here we utilized passively recorded cellular signaling data at a spatial resolution of 1km x 1km for over 5 million users and epidemiological surveillance data collected during the SARS-CoV-2 Omicron BA.2 outbreak from February to June 2022 in Shanghai, China, to investigate the heterogeneous response of different segments of the population at the within-city level and examine its relationship with the actual risk of infection. Changes in behavior were spatially heterogenous within the city and population groups, and associated with both the infection incidence and adopted interventions. We also found that males and individuals aged 30-59 years old traveled more frequently, traveled longer distances, and their communities were more connected; the same groups were also associated with the highest SARS-CoV-2 incidence. Our results highlight the heterogeneous behavioral change of the Shanghai population to the SARS-CoV-2 Omicron BA.2 outbreak and the its effect on the heterogenous spread of COVID-19, both spatially and demographically. These findings could be instrumental for the design of targeted interventions for the control and mitigation of future outbreaks of COVID-19 and, more broadly, of respiratory pathogens. | Make paid
The increased prevalence of obesity is due to a decreased level of physical activity and increased intake of fast food. Furthermore, obesity among children and adolescent is a risk factor for life-threatening conditions including cardiovascular diseases (CVD), Cardio-metabolic disorders, type 2 diabetes mellitus, hypertension, cancer and reproductive disorders. The aim of this study is to describe the determinants of obesity. A cross-sectional study was conducted on a total of 377 adolescents aged 13 to 20 years from 16 secondary schools in Thulamela Municipality, Vhembe District Limpopo Province, South Africa. Information about socio-demographic characteristics, household income, disease family history, and level of education of parents was obtained using a self-administered questionnaire. Anthropometric measurements such as weight, height and waist circumference were taken by trained field workers and body mass index (BMI), and the waist-hip ratio were determined. Biochemical measurements and clinical assessment were done by a professional nurse following standard procedures. The prevalence of obesity is 22.2% in males and 32.6% in females by abdominal obesity by (waist circumference), whilst 11.1% (males) and 28.3% (females) by waist to hip ratio (WHR). Gender ({beta}=0.32, p=0.018, 95%CI); age ({beta}=1.28, p=0.015, 95%CI); source of income ({beta}=3.25, p=0.008, 95%CI) and systolic blood pressure ({beta}=1.04, p=0.01, 95%CI) were associated with obesity. Overweight and obesity were more prevalent in females than in males in Thulamela municipality. There is a need to bring up children and adolescents in a health-promoting environment in an effort to reverse and stop the increasing trend of overweight and obesity. | Make paid
Background: Pulse pressure (PP) and mean arterial pressure (MAP) have been well-established as markers of cardiovascular risk in clinical settings. We aimed to determine the impact of cannabis use on both PP and MAP in U.S. adults and to assess the modifying role of sex. Methods: We abstracted data from the 2009 to 2018 National Health and Nutrition Examination survey (NHANES). Cannabis use was assessed by NHANES professionals in adults aged 18 to 59 years by using computer-assisted self-interviews. We defined PP as the difference between systolic and diastolic BP, and MAP as diastolic BP plus one third of PP. We used multivariable linear models to estimate the covariates-adjusted associations and assessed effect modification by including sexxexposure interaction terms into the model. Results: The mean age of the study population (n=8,942) was 35.0{+/-}11.9 years, with 51% female (n=4,551). Mean{+/-}SD PP and MAP were 46{+/-}13 mm Hg and 82{+/-}13 mm Hg, respectively. We found a significant interaction between sex and cannabis use in relation to PP (P=0.0878) and no interaction when modeling MAP (P=0.2084). The mean difference of PP between cannabis users and never-users increased with the frequency of use per week, being +4.5 mm Hg (P=0.0004) in those who reported 1 use/week, +4.9 mm Hg (P<0.0001) for 2-3 uses/week and +4.9 mm Hg (P<0.0001) for [≥] 4 uses/week. In females, only those who reported [≥] 4 uses/week showed a higher PP (+3.1 mm Hg; P=0.0050) compared with never-users. Conclusions: In US adults aged 18 to 59 years, cannabis use is associated with widening of PP in males. | Make paid
Objective: The present study sought to determine the cochlear frequency regions represented by Audtory Brainstem Responses (ABRs) obtained using the high-pass noise/derived response (HP/DR) technique. Design: Broadband noise sufficient to mask the ABR to 50 dB nHL clicks was HP filtered (96 dB/oct) at 8000, 4000, 2000, 1000 and 500 Hz. Mixed with the clicks and high-pass noise masker was narrowband noise. Three DR bands, denoted by the upper and lower high-pass noise frequencies, were obtained: DR4000-2000, DR2000-1000, and DR1000-500. Study sample: Ten adults with normal hearing, aged 19-27 years (mean age: 22.4 years), were recruited from the community. Results: Frequencies contributing to each DR were determined from the wave V percent amplitude (or latency shift) vs narrowband masker frequency profiles (relative to a no-narrowband-noise condition). Overall, results indicate derived band center frequencies were closer to the lower HP cutoff frequencies for DR4000-2000 and DR2000-1000, and approximately halfway between the lower HP cutoff and the geometric mean of the two HP frequencies for DR1000-500, with bandwidths of 0.5-1 octave in width. Conclusions: These results confirm the validity of the HP/DR technique for assessing narrow cochlear regions ([≤]1.0 octave wide), with center frequencies within [1/2]-octave of the lower HP cutoff frequency. | Make paid
Background Some researchers have highlighted the need to integrate spirituality into the definition of health, as they have found a positive relationship between spirituality and quality of life (QoL). Hence, we aim to ascertain the effect of spirituality on mental health and QoL in older people residing in Kumejima Town in Japan. Methods We conducted an interview-based survey between September 2010 and 2011 on people residing in Kumejima Town aged 65 years or older. The scale used was The Spirituality Health Scale for the Elderly. The survey includes items on basic attributes (e.g., age, sex); physical, mental, and social health; spirituality; and quality of life. The analysis was conducted on a causal structure model in which spirituality is a distinct item influencing QoL (Model 1) and a causal structure model in which spirituality poses direct and indirect effects on QoL (Model 2). For each model, we reported the goodness-of-fit in terms of the goodness-of-fit index (GFI), adjusted goodness-of-fit index (AGFI), comparative fit index (CFI), and root mean square error of approximation (RMSEA). To compare the models, we used the Akaike information criterion (AIC). Results The total number of participants was 338, of whom 72.5% were female. The average age and its standard deviation were 77.2 {+/-} 6.4 years. We presented a comparison of the results of the analysis of Model 1 and Model 2, with the results favoring Model 2. Also, Model 2 was superior to Model 1 in terms of the AIC, where the value of the AIC is 313.67 for Model 2 compared to 330.48 for Model 1. Conclusion This study was able to show the possibility of preventing a decline in QoL until death by building up spiritual health. However, further studies are required to further investigate these outcomes in the wider population (Japanese and other nationalities) and with some focus on male participants. | Make paid