Background Aging-related inflammation is associated with chronic diseases and mortality. This study aimed to: 1) develop composite inflammaging metrics (CIMs) in UK biobank (UKB), and validate them in UKB and National Health and Nutrition Examination Survey (NHANES); 2) estimate mortality and CVD risk predictions of CIMs; 3) compare CIMs with single inflammatory blood biomarkers and conventional inflammatory indexes; 4) examine associations between lifestyles and CIMs. Methods We utilized algorithms including multiple linear regression, principal component analysis (PCA), allostatic load (AL), and Klemera and Doubal method (KDM), to develop four CIMs from five inflammatory blood biomarkers, using data of 438,321 adults (40-70 years) from UK Biobank (UKB). We validated these CIMs in UKB and 10,667 adults (20-84 years) from NHANES IV. We performed a parametric proportional hazard model based on Gompertz distribution to estimate CVD and mortality risk predictions of CIMs. Areas under receiver operating characteristic curves (AUCs) were calculated to compare the predictive abilities of CIMs. Multiple linear regression models were used to access associations between lifestyles and CIMs. Results With adjustment for age and sex, four CIMs were significantly associated with higher risks of all-cause mortality and incident CVD in UKB, among which CIMKDM outperformed the others (all-cause mortality: hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.46, 1.50; incident CVD: HR = 1.34, 95% CI = 1.33, 1.36). CIMKDM had the best discriminative ability for predicting 10-year survival and incident CVD in UKB (all-cause mortality: AUC = 0.728; incident CVD: AUC = 0.712). CIMs were responsive to lifestyle variables. For example, in UKB, compared to never smokers, current smokers had a significant increment in CIMKDM (coefficient = 0.30 SD, P < 0.001). Similar results were well validated in NHANES IV. Conclusions We developed and validated four novel CIMs that were predictive of mortality and CVD risk. CIMKDM outperformed the others and had the potential to be used in aging related preventive and intervention programs. Intervention programs targeting lifestyles could slow inflammaging and further reduce disease burden. | Make paid
It has long been suggested that environmental exposures (i.e., the exposome) play a dominant role in shaping trajectories of human aging and premature mortality. Here we aimed to quantify the contribution of the exposome and genome to aging and mortality. We conducted an exposome-wide analysis in the UK Biobank (n=492,567) to systematically identify exposures associated with mortality while accounting for exposure correlation and mismeasurement. We found that the exposome is a major mortality determinant irrespective of genetic disease risk via shaping distinct biological and multimorbidity patterns. We identified 41 independent exposures associated with mortality, and demonstrate that most identified exposures are associated with a common signature of age-related multimorbidity, aging biomarkers, and major cardiometabolic risk factors. Compared with age and sex, polygenic risk for 22 major diseases and aging phenotypes explained an additional 2% of mortality variation, whereas the exposome explained an additional 19%. While genetics explained the majority of variation in dementias and breast, prostate, and colorectal cancers, the exposome explained the majority of variation for diseases of the lung, heart, and liver. Our findings provide a comprehensive map of the contributions of environment and genetics to mortality and common age-related diseases. | Make paid
Purpose: Myopia has been considered a public health issue by the World Health Organization since 2015.The growing incidence of myopia worldwide, called the myopia epidemic, and its potential blinding complications in adulthood like cataract, glaucoma, retinal detachment and maculopathy, have been extensively published and discussed in peer review papers. Nonetheless, little information about Latin America is available. This study aims to detect the prevalence of myopia in southern Brazil, the biggest country of South America. Methods: A prospective cross sectional study recruited 330 public school children between 2019 and 2021, aged 5 to 20 years old. All children underwent a comprehensive eye examination and detailed lifestyle questionnaire. The Pearson correlation coefficient, Kruskal Wallys and the Chi-Square Test were used to assess simple correlations and associations between myopia and medical conditions, use of medications, ophthalmic history and family history of ocular conditions, besides demographics and lifestyle focused on screen time/day. Associations between the results of the ophthalmologic evaluation and all factors included in the questionnaire were analyzed using the Generalized Estimating Equation model (GEE). The prevalence of hyperopia and astigmatism were also assessed. Results: Total prevalence of myopia was 17.4% (CI 13.8 - 21.7%). Low myopia (-0.50D to -5.75D) comprised 15.2% (CI 11.9 - 19.3%) and high myopia (-6,00D or worse) was 2.1% (CI 1.1 - 4.1%). Relative risk of myopia for females was 1.6 (CI 1.00 - 2.57%) and each additional hour of screen time increased a childs chance of having myopia by 6.5%. The prevalence of hyperopia was 7,7% (CI 5.4 -10.9%) and of astigmatism, either myopic or hyperopic, was 25.6% (CI 21.4 - 30.2%). Conclusions: Brazil has always been considered a hyperopic country. These are the highest reported prevalences of myopia under cycloplegia and the first paper to present myopia as a more prevalent refractive error than hyperopia among Brazilian school children to date. | Make paid
Respiratory syncytial virus (RSV) infections and hospitalizations surged sharply in 2022 among young children. To assess whether COVID-19 contributed to this surge, we leveraged a real-time nation-wide US database of electronic health records (EHRs) using time series analysis from January 1, 2010 through January 31, 2023, and propensity-score matched cohort comparisons for children aged 0-5 years with or without prior COVID-19 infection. Seasonal patterns of medically attended RSV infections were significantly disrupted during the COVID-19 pandemic. The monthly incidence rate for first-time medically attended cases, most of which were severe RSV-associated diseases, reached a historical high rate of 2,182 cases per 1,0000,000 person-days in November 2022, corresponding to a related increase of 143% compared to expected peak rate (rate ratio: 2.43, 95% CI: 2.25-2.63). Among 228,940 children aged 0-5 years, the risk for first-time medically attended RSV during 10/2022-12/2022 was 6.40% for children with prior COVID-19 infection, higher than 4.30% for the matched children without COVID-19 (risk ratio or RR: 1.40, 95% CI: 1.27-1.55); and among 99,105 children aged 0-1 year, the overall risk was 7.90% for those with prior COVID-19 infection, higher than 5.64% for matched children without (RR: 1.40, 95% CI: 1.21-1.62). These data provide evidence that COVID-19 contributed to the 2022 surge of severe pediatric RSV cases. | Make paid
Background. Most analyses of excess mortality during the COVID-19 pandemic have employed aggregate data. Individual-level data from the largest integrated healthcare system in the US may enhance understanding of excess mortality. Methods. We performed an observational cohort study following patients receiving care from the Department of Veterans Affairs (VA) between 1 March 2018 and 28 February 2022. We estimated excess mortality on an absolute scale (i.e., excess mortality rates, number of excess deaths), and a relative scale by measuring the hazard ratio (HR) for mortality comparing pandemic and pre-pandemic periods, overall, and within demographic and clinical subgroups. Comorbidity burden and frailty were measured using the Charlson Comorbidity Index and Veterans Aging Cohort Study Index, respectively. Results. Of 5,905,747 patients, median age was 65.8 years and 91% were men. Overall, the excess mortality rate was 10.0 deaths/1000 person-years (PY), with a total of 103,164 excess deaths and pandemic HR of 1.25 (95% CI 1.25-1.26). Excess mortality rates were highest among the most frail patients (52.0/1000 PY) and those with the highest comorbidity burden (16.3/1000 PY). However, the largest relative mortality increases were observed among the least frail (HR 1.31, 95% CI 1.30-1.32) and those with the lowest comorbidity burden (HR 1.44, 95% CI 1.43-1.46). Conclusions. Individual-level data offered crucial clinical and operational insights into US excess mortality patterns during the COVID-19 pandemic. Notable differences emerged among clinical risk groups, emphasising the need for reporting excess mortality in both absolute and relative terms to inform resource allocation in future outbreaks. | Make paid
Insulin-mTOR signaling drives anabolic growth in organismal development, while its late-life antagonistic pleiotropy affects aging and compromises lifespan across animal phylogeny. Here we identify LPD-3 as a megaprotein that orchestrates the tempo of insulin-mTOR signaling during C. elegans aging. We find that an agonist insulin INS-7 is drastically over-produced and shortens lifespan in lpd-3 mutants, a C. elegans model of human Alkuraya-Ku[c]inskas syndrome. LPD-3 forms a bridge-like tunnel megaprotein to facilitate phospholipid trafficking to plasma membrane. Lipidomic profiling reveals increased abundance of hexaceramide species in lpd-3 mutants, accompanied by up-regulation of hexaceramide biosynthetic enzymes, including HYL-1 (Homolog of Yeast Longevity). Reducing HYL-1 activity decreases INS-7 levels and rescues the shortened lifespan of lpd-3 mutants through insulin receptor/DAF-2 and mTOR/LET-363. LPD-3 antagonizes SINH-1, a key mTORC2 component, and reduces protein abundance with age in wild type animals. We propose that LPD-3 acts as a megaprotein brake for aging and its age-dependent decline restricts lifespan through the sphingolipid-hexaceramide and insulin-mTOR pathways. | Make paid
Posttranslational modifications of epigenetic modifiers provide a flexible and timely mechanism for rapid adaptations to the dynamic environment of cancer cells. SIRT1 is an NAD+-dependent epigenetic modifier whose activity is classically associated with healthy aging and longevity, but its function in cancer is not well understood. Here, we reveal that 1a,25-dihydroxyvitamin D3 (1,25(OH)2D3, calcitriol), the active metabolite of vitamin D (VD), promotes SIRT1 activation through auto-deacetylation in human colon carcinoma cells, and identify lysine 610 as an essential driver of SIRT1 activity. Remarkably, our data show that the post-translational control of SIRT1 activity mediates the antiproliferative action of 1,25(OH)2D3. This effect is reproduced by the SIRT1 activator SRT1720, suggesting that SIRT1 activators may offer new therapeutic possibilities for colon cancer patients who are VD deficient or unresponsive. Moreover, this might be extrapolated to inflammation and other VD deficiency-associated and highly prevalent diseases in which SIRT1 plays a prominent role. | Make paid
Leaves are colonised by a complex mix of microbes, termed the leaf microbiota. Even though the leaf microbiota is increasingly recognised as an integral part of plant life and health, our understanding of its interactions with the plant host is still limited. Here, mature, axenically grown Arabidopsis thaliana plants were spray-inoculated with six diverse leaf-colonising bacteria. The transcriptomic changes in leaves were tracked over time and significant changes in ethylene marker (ARL2) expression were observed only two to four days after spray-inoculation. Whole transcriptome sequencing revealed that four days after inoculation, leaf transcriptional changes to colonisation by non-pathogenic and pathogenic bacteria differed in strength but not in the type of response. Inoculation of plants with different densities of the non-pathogenic bacterium Williamsia sp. Leaf354 showed that high bacterial titers caused disease phenotypes and led to severe transcriptional reprogramming with a strong focus on plant defence. An in silico epigenetic analysis of the data was congruent with the transcriptomic analysis. These findings suggest (1) that plant responses are not rapid after spray-inoculation, (2) that plant responses only differ in strength and (3) that plants respond to high titers of non-pathogenic bacteria with pathogen-like responses. Plain Language SummaryPlants are colonised by diverse bacteria affecting many aspects of plant life. Here we show that plants do not differentiate between different bacteria but measure their quantities to keep bacterial numbers in check. | Make paid
Visual categorization structures infants interactions with their environment. However, it is unknown when visual category representations emerge during the first year of life. Here we measured cortical representations of faces, limbs, corridors, characters, and cars using an electroencephalography (EEG) frequency-tagging paradigm in infants aged 3-4 months (N = 17), 4-6 months (N = 14), 6-8 months (N= 15), and 12-15 months (N = 15). We discovered a staggered development of category representations. Representations of faces emerge first, between 4-6 months and strengthen thereafter. Whereby representations for limbs, corridors, and characters emerge later, between 6-15 months. Not only do these data suggest that category representations are learned, but also that representations of everyday categories take different durations to develop. Thus, these findings necessitate a rethinking of the development of category representations in infancy and, have important implications for assessing atypical cortical development. | Make paid
While accumulated publications support the existence of neurogenesis in the adult human hippocampus, the homeostasis and developmental potentials of neural stem cells (NSCs) under different contexts remain unclear. Based on our generated single-nucleus atlas of the human hippocampus across neonatal, adult, aging and injury, we dissected the molecular heterogeneity and transcriptional dynamics of human hippocampal NSCs under different contexts. We further identified new specific neurogenic lineage markers that overcome the lack of specificity found in some well-known markers. Based on developmental trajectory and molecular signatures, we found that a subset of NSCs exhibit quiescent properties after birth, and most NSCs become deep quiescence during aging. Furthermore, certain deep quiescent NSCs are re-activated following stroke injury. Together, our findings provide valuable insights into the development, aging, and re-activation of the human hippocampal NSCs, and help to explain why adult hippocampal neurogenesis is infrequently observed in humans. | Make paid
DNA repair is essential for preserving genome integrity and ensuring cellular functionality and survival. Podocytes, post-mitotic glomerular epithelial cells, bear limited regenerative capacity, and their survival is indispensable to maintain the function of the kidney's filtration units. While podocyte depletion is a hallmark of the aging process and of many proteinuric kidney diseases, the underlying factors remain unclear. We investigated DNA repair in podocyte diseases by using a constitutive and an inducible podocyte-specific knockout mouse model for Ercc1, a multifunctional endonuclease cofactor involved in nucleotide excision repair (NER), interstrand crosslink (ICL) repair, and DNA double-strand break (DSB) repair. We assessed the consequences of Ercc1 loss in vivo, complemented by mechanistical in vitro studies of induced DNA damage in cultured podocytes. Furthermore, we characterized DNA damage-related alterations in mouse and human renal tissue of different ages as well as in patient biopsies with minimal change disease and focal segmental glomerulosclerosis. Podocyte-specific Ercc1 knockout resulted in accumulation of DNA damage with ensuing proteinuria, podocyte loss, glomerulosclerosis, renal insufficiency, and reduced lifespan. The response to genomic stress was different to the pattern reported in other cell types, as podocytes activated mTORC1 signaling upon DNA damage in vitro and in vivo. The induced mTORC1 activation was abrogated by inhibiting DNA damage response through DNA-PK and ATM kinases in vitro. Moreover, pharmacological inhibition of mTORC1 modulated the development of glomerulosclerosis in Ercc1-deficient mice. Perturbed DNA repair gene expression and genomic stress was also detected in podocytes of human focal segmental glomerulosclerosis, characterized by podocyte loss. Beyond that, DNA damage accumulation occurred in podocytes of healthy aging mice and humans. These findings reveal that genome maintenance is crucial for podocyte maintenance, linked to the mTORC1 pathway, and involved in the aging process as well as in the development of glomerulosclerosis, potentially serving as a therapeutic target in the future. | Make paid
Understanding how cognition and brain structure change across the lifespan is crucial for gaining insight into the healthy ageing process, as well as identifying early signs of neurodegenerative changes. In our recent prospective study of healthy ageing in midlife and older adults1, we compared the association of two cognitive batteries with age-related variability in brain morphology. Our findings revealed that online cognitive testing, which is more cost-effective, demonstrated comparable association to sulcal width as comprehensive in person assessment. In person cognitive testing shows a significantly stronger correlation with sulcal width when compared to online testing, although the difference is numerically minor. In addition, it was found that both cognitive assessment assays showed a more pronounced age-related decline in individuals with A{beta} burden. These findings suggest that online assessment is able to detect accelerated cognitive ageing comparably to the in-person assay in our preclinical sample, even in the early stages of A{beta} accumulation before significant structural brain changes occur. Taken together with their greater cost effectiveness, online cognitive testing could lead to more equitable early detection and intervention for neurodegenerative diseases. | Make paid
ObjectiveThe aim of this study was to investigate the determinants of not testing for HIV among young adult women aged 15-29 years in Papua New Guinea (PNG). Design and settingThe study used secondary data from the 2016-2018 PNG Demographic and Health Survey (PNGDHS), a nationally representative cross-sectional survey that utilised two-stage cluster sampling. Multivariate logistic regression with complex sample analysis was performed to assess the determinants of not testing for HIV. ParticipantsA total of 8,155 young adult women aged 15-29 years were included in the study. Outcome measureNot testing for HIV. ResultsThe prevalence of not testing for HIV was 71.8% (95% CI: 0.71-0.73). Young adult women who were never married (AOR: 4.9, 95% CI: 3.6-6.6), from rural areas (AOR: 2.0, 95% CI: 1.5-2.6), from poor wealth indices (AOR: 1.8, 95% CI: 1.3-2.5), who did not frequently read newspapers or magazines (AOR: 1.7, 95% CI: 1.3-2.1), who did not frequently listen to the radio (AOR: 1.5, 95% CI: 1.1-2.0), who had initiated sex before the age of 20 (AOR: 1.5, 95% CI: 1.1-1.9), and who had one sexual partner (AOR: 1.5, 95% CI: 1.2-2.0) had higher odds of not testing for HIV compared with their counterparts. ConclusionsOur study found that more than two-thirds of young women in PNG have never been tested for HIV. Socio-demographics, lack of exposure to media, having one sex partner, and not having had an STI in the past 12 months are associated with not testing for HIV. Multi-sectorial policy and programmatic approaches to strengthen community- and home-based testing to complement facility-based HIV services and overcome barriers associated with HIV testing among this population are necessary. Strengths and limitations of this studyO_LIThis study used the nationally representative large sample of young adult women aged 15-29 years from the 2016-2018 PNGDHS; thus, the findings are generalizable to the entire population of this age group. C_LIO_LIThe study provides much-needed data for strategic planning and programming to improve the health outcomes of young women in the country. C_LIO_LIThis is a cross-sectional study, and as such, it is not possible to make causal inferences. C_LIO_LIThe level of knowledge or awareness of where to get tested for HIV was not included in the analysis, and it remains unknown whether this variable contributes to the high proportion of young women who remain unaware of their HIV status. C_LIO_LIResponses to the questions from young women were self-reported, and this could have resulted in social desirability bias. C_LI | Make paid
Cervical lesions can be caused by pathogens, hormonal changes or by cervical injury. The recommended treatment in all cases is excision. Local re-epithelialization therapy should be initiated preoperatively and postoperatively. The present study assessed the post-market performance and tolerability of Cerviron ovules in the treatment and management of cervical lesions postoperatively. The study population included 345 participants aged 20-70 years with either a cervical lesion under treatment or with recent surgical removal of a cervical lesion. The degree of re-epithelialization of the cervical mucosa was improved in 73.17% of the patients evaluated during routine colposcopy exams and 92.73% of patients recorded no bleeding. When adding Cerviron either as monotherapy or in association with other antimicrobials in postoperative care of the cervical ectropion, improved postoperative outcomes such as reduced post-interventional bleeding, stimulation of the granulation tissue, and a superior quality of healing were observed. The study and its details are registered in www.clinicaltrials.gov under ID NCT05668806. | Make paid
Introduction: Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous condition with varied clinical and pathophysiologic characteristics. Although there is increasing evidence that COPD in low- and middle-income countries may have different clinical characteristics from that in high income countries, little is known about COPD phenotypes in these settings. We describe the clinical characteristics and risk factor profile of a COPD population in Uganda. Methods: We cross sectionally analyzed the baseline clinical characteristics of 323 COPD patients aged 30 years and above who were attending two national referral outpatient facilities in Kampala, Uganda between July 2019 and March 2021. Logistic regression was used to determine factors associated with spirometric disease severity. Results: The median age was 62 years; 51.1% females; 93.5% scored CAT >10; 63.8% mMRC >2; 71.8% had wheezing; 16.7% HIV positive; 20.4% had a history of pulmonary tuberculosis; 50% with blood eosinophilic count >3%, 51.7% had 3 or more exacerbations in the past year. Greater severity by GOLD stage was inversely related to age, (aOR=0.95, 95%CI=0.92, 0.97), and obesity compared to underweight (aOR=0.25, 95%CI=0.07, 0.82). Regarding clinical factors, more severe airflow obstruction was associated with SPO2<93% (aOR=3.79, 95%CI=2.05, 7.00), mMMRC[≥]2 (aOR=2.21, 95%CI=1.08, 4.53), and a history of severe exacerbations (aOR=2.64, 95%CI=1.32, 5.26). Conclusion: COPD patients in this population had specific characteristics and risk factor profiles including HIV and TB meriting tailored preventative approaches. Further studies are needed to better understand the pathophysiological mechanisms at play and the therapeutic implications of these findings. | Make paid
Products that combine liquid milk and date flesh are still minimal. Milk is an excellent source of protein and dates are a food ingredient that is rich in vitamins and minerals that are suitable for growth as well as phytochemical components which function to enhance the sensory properties of dates so that they can be used as a flavor enhancer in various dairy products such as cookies, yogurt, ice cream, and cakes. The purpose of this study was to create a vitamin D-enriched date milk product as an alternative nutritional supplement for preschool children aged 48-59 months. The study used a completely randomized design with three percentage addition of date flesh treatments, namely F1 (10%), F2 (15%), and F3 (20%). The results showed that the formulas significantly differed between the water, protein, and carbohydrate contents (P < 0.05). In contrast, the energy, ash, fat, zinc, iron, and calcium content were not statistically significant (P > 0.05). Kruskal-Wallis analysis product acceptance data showed only color and aroma attributes that were quite different between formulas (P < 0.05). In contrast, taste, thickness, mouthfeel, aftertaste, and overall characteristics were not statistically different (P > 0.05). Formula F2 (15%) was selected based on the hedonic rating and ranking tests. Formula F2 (15%) can be accepted quite well, with the percentage that consumes drinks without residue as much as 60% and those who can finish at least [1/2] portion of drinks as much as 93.3%. Keywords: Additional Food, Date Milk, Preschooler, Vitamin D Fortification | Make paid
Cervical lesions can be caused by pathogens, hormonal changes or by cervical injury. The recommended treatment in all cases is excision. Local re-epithelialization therapy should be initiated preoperatively and postoperatively. The present study assessed the post-market performance and tolerability of Cerviron ovules in the treatment and management of cervical lesions postoperatively. The study population included 345 participants aged 20-70 years with either a cervical lesion under treatment or with recent surgical removal of a cervical lesion. The degree of re-epithelialization of the cervical mucosa was improved in 73.17% of the patients evaluated during routine colposcopy exams and 92.73% of patients recorded no bleeding. When adding Cerviron either as monotherapy or in association with other antimicrobials in postoperative care of the cervical ectropion, improved postoperative outcomes such as reduced post-interventional bleeding, stimulation of the granulation tissue, and a superior quality of healing were observed. The study and its details are registered in www.clinicaltrials.gov under ID NCT05668806. | Make paid
Mitochondria are required for energy production and even give brown adipose tissue (BAT) its characteristic color due to their high iron content and abundance The physiological function and bioenergetic capacity of mitochondria are connected to the structure, folding, and organization of its inner-membrane cristae. During the aging process, mitochondrial dysfunction is observed, and the regulatory balance of mitochondrial dynamics is often disrupted, leading to increased mitochondrial fragmentation in aging cells. Therefore, we hypothesized that the morphological changes in BAT mitochondria and cristae observed across aging would reflect alterations to energy dynamics. We developed a quantitative three-dimensional (3D) electron microscopy approach to map cristae network organization in mouse BAT to test this hypothesis. Using this methodology, we investigated the 3D morphology of mitochondrial cristae in adult (3-month) and aged (2-year) murine BAT tissue via serial block face-scanning electron microscopy (SBF-SEM) and3D reconstruction software for manual segmentation, analysis, and quantification. Upon investigation, we found increases in mitochondrial volume, surface area, and complexity and decreased sphericity in aged BAT. Cristae examination revealed decreased cristae volume, perimeter, and complexity, with cristate appearing more heterogeneous. Overall, these data define the nature of the mitochondrial structure in BAT, showing loss of cristae definition across aging, suggesting alterations in functionality and bioactivity. | Make paid
The impact of host diversity on the genotypic and phenotypic evolution of broad-spectrum pathogens is a remaining issue. Here, we used populations of the plant pathogen Ralstonia pseudosolanacearum that were experimentally evolved on five types of host plants, either belonging to different botanical families or differing in their susceptibility or resistance to the pathogen. We investigated whether changes in transcriptomic profiles dissociated from genetic changes could occur during the process of host adaptation, and whether transcriptomic reprogramming was dependent on host type. Genomic and transcriptomic variations were established for 31 evolved clones that showed a better fitness in their experimental host than the ancestral clone. Few genomic polymorphisms were detected in these clones, but significant transcriptomic variations were observed, with a high number of differentially expressed genes (DEGs). In a very clear way, a group of genes belonging to the network of regulation of the bacterial virulence such as efpR, efpH or hrpB, among others, were deregulated in several independent evolutionary lineages and appeared to play a key role in the transcriptomic rewiring observed in evolved clones. A double hierarchical clustering based on the 400 top DEGs for each clone revealed two major patterns of gene deregulation that depend on host genotype, but not on host susceptibility or resistance to the pathogen. This work therefore highlights the existence of two major evolutionary paths that result in a significant reorganization of gene expression during adaptive evolution and underscore clusters of co-regulated genes associated to bacterial adaptation on different host lines. | Make paid
Unlike aged somatic cells, which exhibit a decline in molecular fidelity and eventually reach a state of replicative senescence, pluripotent stem cells can indefinitely replenish themselves while retaining full homeostatic capacity. The conferment of beneficial-pluripotency related traits via in vivo partial cellular reprogramming (IVPR) significantly extends lifespan and restores aging phenotypes in mouse models. Although the phases of cellular reprogramming are well characterized, details of the rejuvenation processes are poorly defined. To understand whether epigenetic reprogramming can ameliorate DNA damage, we created reprogrammable accelerated aging mouse model with an ERCC1 mutation. Importantly, using enhanced partial reprogramming by combining small molecules with the Yamanaka factors, we observed potent reversion of DNA damage, significant upregulation of multiple DNA damage repair processes, and restoration of the epigenetic clock. In addition, we present evidence that pharmacological inhibition of ALK5 and ALK2 receptors in TGFb pathway is able to phenocopy some benefits including epigenetic clock restoration suggesting a role in the mechanism of rejuvenation by partial reprogramming. | Make paid
Rationale: The transcription factor NRF2 is well recognized as a master regulator of antioxidant responses and cytoprotective genes. Previous studies showed that NRF2 protects mouse hearts during chronic hemodynamic overload at least in part by reducing oxidative stress. Evidence from other tissues suggests that NRF2 may modulate glucose intermediary metabolism but whether NRF2 has such effects in the heart is unclear. Objective: To investigate the role of NRF2 in regulating glucose intermediary metabolism and cardiac function during disease stress. Methods and Results: Cardiomyocyte-specific Keap1 knockout (csKeap1KO) mice, deficient in the endogenous inhibitor of NRF2, were used as a novel model of constitutively active NRF2 signaling. Targeted metabolomics and isotopomer analysis were employed in studies with 13C6-glucose in csKeap1KO and wild-type (WT) mice. Pharmacological and genetic approaches were utilized in neonatal rat ventricular cardiomyocytes (NRVM) to explore molecular mechanisms. We found that cardiac-specific activation of NRF2 upregulated key enzymes of the Pentose Phosphate Pathway (PPP), redirected glucose metabolism towards the PPP and protected the heart against pressure overload-induced cardiac dysfunction. In vitro, knockdown of Keap1 upregulated PPP enzymes and reduced cell death in NRVM subjected to chronic neurohumoral stimulation. These pro-survival effects were abolished by pharmacological inhibition of the PPP or silencing of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD). Knockdown of NRF2 in NRVM increased stress-induced DNA damage which was rescued by supplementing the cells with either NADPH or nucleosides, the two main products of the PPP. Activation of NRF2 also protected the heart against myocardial infarction-induced DNA damage, dysfunction, and adverse remodeling. Conclusions: These results indicate that NRF2 regulates cardiac metabolic reprogramming by stimulating the diversion of glucose into the PPP, thereby providing cardiac protection during stress by generating NADPH and providing nucleotides to prevent stress-induced DNA damage. | Make paid
Caloric restriction (CR) delays the onset of age-related changes and extends lifespan in most species, but how late in life organisms benefit from switching to a low-calorie (L) diet is unexplored. We transferred wild type male flies from a high- (H) to a L-calorie diet (HL) or vice versa (LH) at different times. Late-life HL shift immediately and profoundly reduces fly mortality rate to briefly lower rate than in flies on a constant L diet, and increases lifespan. Conversely, a LH shift increases mortality and hazard rate, which is temporarily higher than in flies aged on a H diet, and leads to shorter lifespan. Transcriptomic changes within 48 hours following diet shift uncover physiological adaptations to available nutrients. Unexpectedly, more abundant transcriptomic changes accompanied LH shift, including ribosome biogenesis, and promotion of growth, which likely contributes to higher mortality rate. Considering that the beneficial effects of CR on physiology and lifespan are conserved across many organisms, our findings suggest that CR interventions in older humans may counteract the detrimental effects of H diets even when initiated later in life. | Make paid
Walking humans often navigate complex, dynamically changing walking paths. To better understand falling risk, is critical that we first determine how older adults purposefully vary their steps in varying environments that challenge balance. Here, 20 young (21.7{+/-}2.6 yrs) and 18 older (71.6{+/-}6.0 yrs) healthy adults walked on a series of continuously-narrowing virtual paths. Participants could switch onto an "easier" path at any time. We applied our Goal Equivalent Manifold framework to quantify how healthy aging alters lateral stepping variability and underlying multi-objective regulation processes along these paths. We also computed participants' lateral stepping characteristics when they switched paths. All participants (but more so younger adults) reduced their lateral stepping variability to remain on the path. How participants varied their lateral steps as paths narrowed closely reflected their trading-off maintaining step width for lateral body position. Older adults exhibited consistent differences in the structure of their lateral stepping variability, which reflected their stronger regulation of step width compared to younger adults, presumably to afford balance. While older adults left the narrowing paths sooner, several of their lateral stepping characteristics remained similar to those of younger adults. While age did not degrade path walking performance per se, it did alter how participants balanced the competing stepping regulation processes that likely gave rise to age-altered lateral stepping variability. Thus, older adults used the flexibility afforded by multi-objective lateral stepping regulation in context-dependent ways to maintain highly adaptive stepping on complex, dynamically changing walking paths. | Make paid
Cancer-associated fibroblasts (CAFs) are key players of the tumor microenvironment (TME) involved in cancer initiation, progression, and resistance to therapy. These cells exhibit aggressive phenotypes affecting, among others, extracellular matrix remodeling, angiogenesis, immune system modulation, tumor growth, and proliferation. CAFs phenotypic changes appear to be associated with metabolic alterations, notably a reverse Warburg effect that may drive fibroblast transformation. However, its precise molecular mechanisms and regulatory drivers are still under investigation. Deciphering the reverse Warburg effect in breast CAFs may contribute to a better understanding of the interplay between TME and tumor cells, leading to new treatment strategies. In this regard, dynamic modeling approaches able to span multiple biological layers are essential to capture the emergent properties of various biological entities when complex and intertwined pathways are involved. This work presents the first hybrid large-scale computational model for breast CAFs covering major cellular signaling, gene regulation, and metabolic processes. It was generated by combining an asynchronous cell- and disease-specific regulatory Boolean model with a generic core metabolic network leveraging both data-driven and manual curation approaches. This model reproduces the experimentally observed reverse Warburg effect in breast CAFs and further identifies Hypoxia-Inducible Factor 1 (HIF-1) as its key molecular driver. Targeting HIF-1 as part of a TME-centered therapeutic strategy may prove beneficial in the treatment of breast cancer by addressing the reverse Warburg effect. Such findings in CAFs, considering our previously published results in rheumatoid arthritis synovial fibroblasts, point to a common HIF-1-driven metabolic reprogramming of fibroblasts in breast cancer and rheumatoid arthritis. All analyses are compiled and thoroughly annotated in Jupyter notebooks and R scripts available on a GitLab repository and a Zenodo permanent archive. | Make paid
Objective: This study aimed to investigate the incidence and predictors of MODS in a PICU in Ethiopia, with a focus on the association between traditional herbal medicine (THM) use and the risk of MODS. Methods: This was a single-center prospective cohort study conducted at a PICU in Ethiopia. The study enrolled eligible patients aged one month to 18 years admitted to the PICU during the study period. Data on demographic characteristics, medical history, clinical and laboratory data, and outcome measures using standard case record forms, physical examination, and patient document reviews. The predictors of MODS were assessed using Cox proportional hazards models, with a focus on the association between traditional herbal medicine use and the risk of MODS. Results: A total of 310 patients were included in the final analysis, with a median age of 48 months and a male-to-female ratio of 1.5:1. The proportion and incidence of MODS were 30.96% (95% CI:25.8, 36.6) and 7.71(95% CI: 6.10, 9.40) per 100-person-day observation respectively. Renal failure (17.74%), neurologic failure (15.16%), and heart failure (14.52%) were the leading organ failures identified. Nearly one-third of patients (32.9%) died in the PICU, of which 59.8% had MODS. The rate of mortality was higher in patients with MODS than in those without. The Cox proportional hazards model identified renal disease (AHR=6.32 (95%CI: 3.17,12.61)), intake of traditional herbal medication (AHR=2.45, 95% CI:1.29,4.65), modified Pediatric Index of Mortality 2 (mPIM 2) score (AHR=1.54 (95% CI: 1.38,1.71), and critical illness diagnoses (AHR=2.68 (95% CI: 1.77,4.07)) as predictors of MODS. Patients who used THM had a threefold increased risk of MODS (AHR) of 2.45 (95% CI: 1.29, 4.65). Conclusion: The incidence of MODS was high. Renal disease, THM use, mPIM 2 scores, and critical illness diagnoses were independent predictors of MODS. A threefold increase in the risk of MODS was seen in patients who used TMH. Healthcare providers should be aware of risks associated with THM, and educate caregivers about the potential harms of these products. Future studies with larger sample sizes and more comprehensive outcome measures are needed. | Make paid
Background: Diagnostic testing is essential for disease surveillance and test-trace-isolate efforts. Here, we aimed to investigate if residential area sociodemographic characteristics and test accessibility were associated with COVID-19 testing rates. Methods: We included information on 421 542 patient-initiated COVID-19 PCR tests from Uppsala County in Sweden from 24 June, 2020 to 9 February, 2022. Using Poisson regression analyses, we investigated whether the Care Need Index (CNI; median 1.0, IQR 0.8, 1.4), a composite measure of sociodemographic factors used in Sweden to allocate primary healthcare resources, was associated with aggregated COVID-19 daily testing rates after adjustments for community transmission. We further assessed if distance to the nearest testing station influenced testing. Lastly, we performed a difference-in-difference analysis of the opening of a testing station targeting a disadvantaged neighbourhood. Results: We observed that CNI, i.e. primary healthcare need, was negatively associated with COVID-19 testing rates in inhabitants aged 5-69 years. More pronounced differences were noted across younger age groups and in Uppsala City, with test rate ratios in children (5-14 years) ranging from 0.56 (95% CI 0.47-0.66) to 0.88 (95% CI 0.81-0.95) across the three pandemic waves. Longer distance to testing station was linked to lower testing rates, foremost in less densely populated areas. Furthermore, the opening of the targeted testing station was associated with increased testing, including twice as high testing rates in individuals aged 70-105, supporting an intervention effect. Conclusions: Ensuring accessible testing across all residential areas constitutes a promising tool to decrease differences and inequalities in testing. | Make paid
ObjectivesTo quantify healthcare resource utilisation (HCRU) and costs to the National Health Service (NHS) associated with acute COVID-19 in adults in England. DesignPopulation-based retrospective cohort study, using Clinical Practice Research Datalink (CPRD) Aurum primary care electronic medical records linked when available to Hospital Episode Statistics (HES) secondary care administrative data. SettingPatients registered to primary care practices in England. Population1,706,368 adults with a positive SARS-CoV-2 PCR or antigen test from August 2020 to January 2022 were included; 13,105 within the hospitalised cohort indexed between August 2020 and March 2021, and 1,693,263 within the primary care cohort indexed between August 2020 and January 2022. Main outcome measuresPrimary and secondary care HCRU and associated costs during the acute phase of COVID-19 ([≤]4 weeks following positive test), stratified by age group, risk of severe COVID-19 and immunocompromised status. ResultsAmong the hospitalised cohort, average total length of stay, as well as in critical care wards, was longer in older adults. Median healthcare cost per hospitalisation was higher in those aged 75 - 84 ({pound}8,942) and [≥]85 years ({pound}8,835) than in those aged <50 years ({pound}7,703). Whilst few (6.0%) patients in critical care required mechanical ventilation, its use was higher in older adults (50 - 74 years: 8.3%; <50 years: 4.3%). HCRU and associated costs were often greater in those at higher risk of severe COVID-19 when compared to the overall cohort, although minimal differences in HCRU were found across the three different high-risk definitions implemented. Among the primary care cohort, GP or nurse consultations were more frequent among older adults and the immunocompromised. ConclusionsCOVID-19 related hospitalisations in older adults, particularly critical care admissions, were the primary drivers of high resource use of COVID-19 in England. These findings may inform health policy decisions and resource allocation in the prevention and management of COVID-19. | Make paid
Regulation of lifespan by transcription factors has been well established. More recently a role for RNA binding proteins (RBPs) in regulating lifespan has also emerged. In both cases, a major challenge is to determine which regulatory targets are functionally responsible for the observed lifespan phenotype. We recently identified a pair of RBPs, exc-7/ELAVL and mbl-1/Muscleblind, which display synthetic (non-additive) lifespan defects: single mutants do not affect lifespan, but exc-7; mbl-1 double mutants have strongly reduced lifespan. Such a strong synthetic phenotype represented an opportunity to use transcriptomics to search for potential causative targets that are synthetically regulated. Focus on such genes would allow us to narrow our target search by ignoring the hundreds of genes altered only in single mutants, and provide a shortlist of synthetically-regulated candidate targets that might be responsible for the double mutant phenotype. We identified a small handful of genes synthetically dysregulated in double mutants and systematically tested each candidate gene for functional contribution to the exc-7; mbl-1 lifespan phenotype. We identified one such gene, the ion transporter nhx-6, which is highly upregulated in double mutants. Overexpression of nhx-6 causes reduced lifespan, and deletion of nhx-6 in an exc-7; mbl-1 background partially restores both lifespan and healthspan. Together, these results reveal that a pair of RBPs mediate lifespan in part by inhibiting expression of an ion transporter, and provide a template for how synthetic phenotypes (including lifespan) can be dissected at the transcriptomic level to reveal potential causative genes. | Make paid
Visual categorization structures infants' interactions with their environment. However, it is unknown when visual category representations emerge during the first year of life. Here we measured cortical representations of faces, limbs, corridors, characters, and cars using an electroencephalography (EEG) frequency-tagging paradigm in infants aged 3-4 months (N = 17), 4-6 months (N = 14), 6-8 months (N= 15), and 12-15 months (N = 15). We discovered a staggered development of category representations. Representations of faces emerge first, between 4-6 months and strengthen thereafter. Whereby representations for limbs, corridors, and characters emerge later, between 6-15 months. Not only do these data suggest that category representations are learned, but also that representations of everyday categories take different durations to develop. Thus, these findings necessitate a rethinking of the development of category representations in infancy and, have important implications for assessing atypical cortical development. | Make paid
Background and Aim: Osteoporotic fracture is a significant public health burden associated with increased mortality risk and substantial healthcare costs. Accurate and early identification of high-risk individuals and mitigation of their risks is a core part of the treatment and prevention of fractures. We aimed to introduce a digital tool called 'BONEcheck' for personalized bone health assessment. Methods: The development of BONEcheck primarily utilized data from the prospective population-based Dubbo Osteoporosis Epidemiology Study and the Danish Nationwide Registry. BONEcheck has 3 modules: input data, risk estimates, and risk context. Input variables include age, gender, prior fracture, fall incidence, bone mineral density (BMD), comorbidities, and genetic variants associated with BMD. By utilizing published methodologies, BONEcheck generates output related to the likelihood of fracture and its associated outcomes. The vocabulary utilized to convey risk estimation and management is tailored to individuals with a reading proficiency at level 8 or above. Results: The tool is designed for men and women aged 50 years and older who either have or have not sustained a fracture. Based on the input variables, BONEcheck estimates the probability of any fragility and hip fracture within 5 years, skeletal age, subsequent fracture, genetic risk score, and recommended interval for repeating BMD. The probability of fracture is shown in both numeric and human icon array formats. The risk is also presented in the context of treatment and management options based on Australian guidelines. Skeletal age was estimated as the sum of chronological age and years of life lost due to a fracture or exposure to risk factors that elevate mortality risk. In its entirety, BONEcheck is a system of algorithms translated into a single platform for personalized osteoporosis and fracture risk assessment. Conclusions: BONEcheck is a new system of algorithms that aims to offer not only fracture risk probability but also contextualize the efficacy of anti-fracture measures concerning the survival benefits. The tool can enable doctors and patients to engage in well-informed discussions and make decisions based on the patient's risk profile. Public access to BONEcheck is available via https://bonecheck.org and in Apple Store (iOS) and Google Play (Android). | Make paid