The human structural brain network, or connectome, has a rich-club organization with a small number of brain regions showing high network connectivity, called hubs. Hubs are centrally located in the network, energy costly, and critical for human cognition. Aging has been associated with changes in brain structure, function, and cognitive decline, such as processing speed. At a molecular level, the aging process is a progressive accumulation of oxidative damage, which leads to subsequent energy depletion in the neuron and causes cell death. However, it is still unclear how age affects hub connections in the human connectome. The current study aims to address this research gap by utilizing a novel measure of structural connectivity strength, fiber bundle capacity (FBC), which is derived from Constrained Spherical Deconvolution (CSD) modeling of white-matter fiber bundles. FBC represents the capacity of a fiber bundle to transfer information and is a less biased measure for quantifying connection strength within biological pathways. We found that hubs exhibit longer-distance connections and higher metabolic rates compared to peripheral brain regions, suggesting that hubs are biologically costly. Although the landscape of structural hubs was relatively age-invariant, there were wide-spread age effects on FBC in the connectome. Critically, these age effects were larger in connections within hub compared to peripheral brain connections. These findings were supported by both a cross-sectional sample with wide age-range (N=137) and a longitudinal sample across 5 years (N=83). Moreover, our results demonstrated that associations between FBC and processing speed were more concentrated in hub connections than chance level, and FBC in hub connections mediated the age-effects on processing speed. Overall, our findings indicate that structural connections of hubs, which demonstrate greater energy demands, are particular vulnerable to aging. The vulnerability may contribute to age-related impairments in processing speed among older adults. | Make paid
Interplay between metabolism and chromatin signaling have been implicated in cancer initiation and progression. However, whether and how metabolic reprogramming in tumors generates specific epigenetic vulnerabilities remain unclear. Lung adenocarcinoma (LUAD) tumors frequently harbor mutations that cause aberrant activation of the NRF2 antioxidant pathway and drive aggressive and chemo-resistant disease. We performed a chromatin-focused CRISPR screen and report that NRF2 activation sensitized LUAD cells to genetic and chemical inhibition of class I histone deacetylases (HDAC). This association was consistently observed across cultured cells, syngeneic mouse models and patient-derived xenografts. HDAC inhibition causes genome-wide increases in histone H4 acetylation (H4ac) at intergenic regions, but also drives re-targeting of H4ac reader protein BRD4 away from promoters with high H4ac levels and transcriptional downregulation of corresponding genes. Integrative epigenomic, transcriptomic and metabolomic analysis demonstrates that these chromatin changes are associated with reduced flux into amino acid metabolism and de novo nucleotide synthesis pathways that are preferentially required for the survival of NRF2-active cancer cells. Together, our findings suggest that metabolic alterations such as NRF2 activation could serve as biomarkers for effective repurposing of HDAC inhibitors to treat solid tumors. | Make paid
Translation elongation is essential for maintaining cellular proteostasis, and alterations in the translational landscape are associated with a range of diseases. Ribosome profiling allows detailed measurement of translation at genome scale. However, it remains unclear how to disentangle biological variations from technical artifacts and identify sequence determinant of translation dysregulation. Here we present Riboformer, a deep learning-based framework for modeling context-dependent changes in translation dynamics. Riboformer leverages the transformer architecture to accurately predict ribosome densities at codon resolution. It corrects experimental artifacts in previously unseen datasets, reveals subtle differences in synonymous codon translation and uncovers a bottleneck in protein synthesis. Further, we show that Riboformer can be combined with in silico mutagenesis analysis to identify sequence motifs that contribute to ribosome stalling across various biological contexts, including aging and viral infection. Our tool offers a context-aware and interpretable approach for standardizing ribosome profiling datasets and elucidating the regulatory basis of translation kinetics. | Make paid
This brief report examines the trends in health and dietary disparities by economic status among elderly individuals in Japan from 2004 to 2014 with subjective measures. The study design utilized a repeated cross-sectional approach, using data from the Survey of Attitudes among the Elderly toward Daily Life in 2004 and 2014. Logistic regression analysis was performed with subjective economic status, survey year, and their interactions as independent variables, and self-rated health, dietary satisfaction, and intake of balanced meals as dependent variables. The results revealed that disparities in self-rated health, dietary satisfaction, and intake of a balanced meal were present due to economic status. Furthermore, the disparities in self-rated health, dietary satisfaction, and balanced meal intake by economic status remained unchanged from 2004 to 2014 (p for interaction [≥] 0.05). The findings were consistent in sensitivity analyses conducted on those aged 75 and older, as well as on long-term care insurance recipients. | Make paid
Gain-of-function mutations in STING1, which encodes the Stimulator of Interferon Gene (STING), result in a severe autoinflammatory disease termed STING-associated vasculopathy with onset in infancy (SAVI). Although elevated type I interferon (IFN) production is thought to be the leading cause of the symptoms observed in patients, STING can induce a set of pathways, which roles in the onset and severity of SAVI, remain to be elucidated. To address this point, we compared a single-cell RNA sequencing (scRNA-seq) dataset of peripheral blood mononuclear cells (PBMCs) from SAVI patients to a dataset of healthy PBMCs treated with recombinant IFN-beta. We revealed a loss of mucosal associated invariant T cells and CD56bright natural killer cells in SAVI patients, not observed in IFN-beta-treated PBMC. Patients T cells present markers of early activation, associated with markers of senescence and apoptosis. Inferring cell-to-cell communication from scRNA-seq predicted monocytes as potential drivers of this T cell phenotype. Furthermore, scRNA-seq clustering identified a patient-specific subset of monocytes, expressing a strong integrated stress response (ISR), and high CCL3, CCL4 and IL-6. It also pinpointed to a patient with lower ISR, allowing us to identify a secondary mutation in PERK, recently shown to be activated by STING to trigger the ISR. Finally, based on the identification of this patient-specific subset of monocytes and the exploration of IFN-beta stimulated PBMCs from healthy donors, we developed a strategy to propose a transcriptomic signature specific of STING activation and independent of type I IFN response. Altogether, these results provide a deeper understanding of SAVI at the cellular and molecular levels. | Make paid
The development of aging is associated with the disruption of key cellular processes manifested as well-established hallmarks of aging. Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) have no stable tertiary structure that provide them a power to be configurable hubs in signaling cascades and regulate many processes, potentially including those related to aging. There is a need to clarify the roles of IDPs/IDRs in aging. The dataset of 1624 aging-related proteins was collected from established aging databases and experimental studies. There is a noticeable presence of IDPs/IDRs, accounting for about 36% of the aging-related dataset, which is comparable to the disorder content of the whole human proteome (about 40%). A Gene Ontology analysis of the our Aging proteome reveals an abundance of IDPs/IDRs in one-third of aging-associated processes, especially in genome regulation. Signaling pathways associated with aging also contain IDPs/IDRs on different hierarchical levels. Protein-protein interaction network analysis showed that IDPs present in different clusters associated with different aging hallmarks. Protein cluster with IDPs enrichment and high liquid-liquid phase separation (LLPS) probability has 'nuclear' localization and DNA-associated functions, related to aging hallmarks: genomic instability, telomere attrition, epigenetic alterations, stem cells exhaustion. Some IDPs related to aging with high LLPS propensity were identified as 'dangerous' based on the prediction of their propensity to aggregation. Overall, our analyses indicate that IDPs/IDRs play significant roles in aging-associated processes, particularly in the regulation of DNA functioning. IDP aggregation, which can lead to loss-of-function and toxicity, could be critically harmful to the cell. A structure-based analysis of aging and the identification of proteins that are particularly susceptible to disturbances can enhance our understanding of the molecular mechanisms of aging and open up new avenues for slowing it down. | 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
Objective: Surgery for spinal deformity has the potential to improve pain, disability, function, self image, and mental health. These surgeries carry significant risk and require careful selection, optimization, and risk assessment. Epigenetic clocks are age estimation tools derived by measuring methylation patterns of specific DNA regions. The study of biological age in the adult deformity population has the potential to shed insight on the molecular basis of frailty and improve current risk assessment tools. Methods: Adult patients undergoing deformity surgery were prospectively enrolled. Preoperative whole blood was used to assess epigenetic age and telomere length. DNA methylation patterns were quantified and processed to extract 4 principal component (PC) based epigenetic age clocks (PC Horvath, PC Hannum, PC PhenoAge, and PC GrimAge) and the instantaneous pace of aging (DunedinPACE). Telomere length was assessed using both qPCR (T/S ratio) and methylation-based telomere estimator (PC DNAmTL). Patient demographic and surgical data included age, BMI, American Society of Anesthesiology (ASA) classification, and Charlson Comorbidity Index (CCI), Adult Spinal Deformity Frailty Index (ASDFI), Edmonton Frail Score (EFS), Oswestry Disability Index (ODI), and Scoliosis Research Society 22r (SRS22). Medical or surgical complications within 90 days of surgery were collected. Spearman correlations and log odd ratios derived from linear regression analyses, adjusted for gender and BMI, were performed. Results: Eighty-six patients were enrolled with mean age of 65 years and 46 women (54%). All patients underwent a posterior fusion with a mean of 11 levels fused and 35 3 column osteotomies (41%). Among epigenetic clocks, DunedinPACE showed a significant association with ASDFI, EFS, ASDFI, and SRS22, a higher pace of aging was associated with worse frailty and disability scores. PC PhenoAge showed significant associations with EFS, ASDFI, and ODI. PC GrimAge showed significant associations with EFS and ASD-FI. Among telomere measurements, PC DNAmTL was associated with CCI. There was a significant association between increased pace of aging by DunedinPACE and postoperative complications. Conclusions: DunedinPACE showed significant associations with markers of frailty (EFS, ASDFI), disability (ODI, SRS22), and postoperative complications. These data suggest a role for aging biomarkers as components of surgical risk assessment. Integrating biological age into current risk calculators may improve their accuracy and provide valuable information for patients, surgeons, and payers. | Make paid
This brief report examines the trends in health and dietary disparities by economic status among elderly individuals in Japan from 2004 to 2014 with subjective measures. The study design utilized a repeated cross-sectional approach, using data from the Survey of Attitudes among the Elderly toward Daily Life in 2004 and 2014. Logistic regression analysis was performed with subjective economic status, survey year, and their interactions as independent variables, and self-rated health, dietary satisfaction, and intake of balanced meals as dependent variables. The results revealed that disparities in self-rated health, dietary satisfaction, and intake of a balanced meal were present due to economic status. Furthermore, the disparities in self-rated health, dietary satisfaction, and balanced meal intake by economic status remained unchanged from 2004 to 2014 (p for interaction [≥] 0.05). The findings were consistent in sensitivity analyses conducted on those aged 75 and older, as well as on long-term care insurance recipients. | Make paid
Monkeypox virus (MPXV), an orthopox virus endemic to West and western Central Africa, is the etiological agent of Monkeypox (Mpox) disease. While the recent global outbreak has been fuelled primarily through human-to-human contact, primary transmission in endemic areas is most likely through contact with reservoir host species with secondary transmission to caregivers and close relatives. Prior to the year 2022, Ghana had not reported any human cases of Mpox, however, the 2003 Mpox outbreak in the US was initiated by rodents that were exported from Ghana. This preliminary study was done to determine the seroprevalence of Mpox after about 40 years of global eradication and discontinuation of smallpox vaccination in Ghana. ELISA was conducted on a total of 1507 archived sera collected prior to 2022 from the 16 regions of Ghana and 281 samples collected from clinical patients and their contacts to detect the presence of anti-monkeypox IgG antibodies. The overall seroprevalence of the mpox virus estimated by the study was 29% (526/1788). People living in rural communities were also found to be 0.62 times [95% CI:0.47 - 0.81, p=0.001] more likely to be exposed to the virus which explains the seroprevalence of participants from the Upper West region having a 71% (12/17). Participants younger than 35 accounted for 66% (1185/1788) of the samples tested and were considered unvaccinated with the smallpox vaccine. The odds of monkeypox exposure in participants aged >19years, between 20-29 years and 30-39 years were higher compared to other age groups (aOR 1.89: 95% CI 1.23 - 2.91, p=0.004), (aOR 2.04: 95% CI 1.30 - 3.21, p=0.002) and (aOR 1.89: 95% CI 1.19 - 3.01, p=0.007) respectively. The study results indicate a fairly high seroprevalence suggesting existing MPXV circulation, especially among unvaccinated people living in the rural part of Ghana. | Make paid
Introduction: Over the past decade, 15 high-priority countries in eastern and southern Africa have promoted voluntary medical male circucmsion for HIV and STI prevention. Despite male circumcision prevalence in Uganda nearly doubling from 26% in 2011 to 43% in 2016, it remained below the target level by 2020. Little is known about perceived norms of male circumcision and their association with circumcision uptake among men. Methods: We conducted a cross-sectional study targeting all adult residents across eight villages in Rwampara District, southwestern Uganda in 2020-2022. We compared what men and women thought was the adult male circumcision prevalence within their village (perceived norm: >50% (most), 10% to <50% (some), <10%, (few), or do not know) to the aggregated prevalence of circumcision as reported by men aged <50 years. We used a modified multivariable Poisson regression model to estimate the association between perceived norms about male circumcision uptake and personal circumcision status among men. Results: Overall, 167 (38%) men < 50 years old were circumcised (and 27% of all men were circumcised). Among all 1566 participants (91% response rate), 189 (27%) men and 177 (20%) women underestimated the male circumcision prevalence, thinking that few men in their own village had been circumcised. Additionally, 10% of men and 25% of women reported not knowing the prevalence. Men who underestimated the prevalence were less likely to be circumcised (aRR = 0.51, 95% CI 0.37 to 0.83) compared to those who thought that some village men were circumcised, adjusting for perceived personal risk of HIV, whether any same-household women thought most men were circumcised, and other sociodemographic factors. Conclusions: Across eight villages, a quarter of the population underestimated the local prevalence of male circumcision. Men who underestimated circumcision uptake were less likely to be circumcised. Future research should evaluate norms-based approaches to promoting male circumcision uptake. Strategies may include disseminating messages about the increasing prevalence of adult male circumcision uptake in Uganda and providing personalized normative feedback to men who underestimated local rates about how uptake is greater than they thought. | Make paid
Background: Stroke is one of the commonest cause of seizures and epilepsy and is the leading cause of epilepsy over the age of 60 (1, 2). Post-stroke seizures and epilepsy are associated with increased mortality, disability and recurrent hospital admissions (3, 4). Seizures occurring in the immediate aftermath of the acute stroke can complicate a patient's stroke diagnosis and management or can even go undiagnosed resulting in increased risk of mortality, disability and hospital readmissions. There is limited evidence on detection, observation, diagnosis and management of early post-stroke seizures as part of acute stroke treatment. Objectives: The objective of this series of scoping reviews is to map the extent and type of literature in relation to in-hospital early post-stroke seizures. For this paper, the specific objectives relate to the clinical methods used in the bedside identification and observation, usually performed by nurses, of early post-stroke seizures (EPSS) in adults being treated and managed for acute stroke. Eligibility criteria: Participants included adults aged 18 years or older with acute ischaemic stroke or primary intracerebral haemorrhage and a diagnosis, or suspected diagnosis, of post-stroke seizures whilst receiving hospital care for their acute stroke. Sources of evidence: Medline, CINAHL, Embase, and the Cochrane Library databases were searched, including papers published up to October 2021, limited to English language. A broad range of published literature was selected comprising of primary research, including case studies/case reports, conference abstracts, systematic reviews/meta-analyses, clinical guidelines and consensus statements. Reference lists of included studies were also searched. Charting methods: A data charting table was developed by the reviewers, with key information selected for included articles. Findings have been aggregated to an overview of extent and type of evidence and identify gaps in evidence. Results: We included two research papers, two clinical guidelines and four discussion papers. There was limited literature on clinical methods used to identify and observe acute stroke patients for seizures. We found no evaluation of different methods aimed at recognising and observing EPSS, and subsequently recommendations lacking detail and consensus on clinical processes. Conclusion: Early post-stroke seizures are important to diagnose due to associated increases in post-stroke complications, mortality, disability and recurrent hospital admissions. Whilst the diagnostic challenge of EPSS is recognised, there is a need for research looking into how to improve the identification and observation of seizure activity in acute stroke settings. | Make paid
BackgroundThe complex interplay between functional brain network maturation and psychopathology during development remains elusive. In pursuit of the structure of psychopathology and its underlying neurobiological mechanisms, mapping of both shared and unique functional connectivity patterns in developmental clinical populations is needed. MethodsWe investigated shared associations between resting-state functional brain network patterns and psychopathology in children and adolescents aged 5-21 from the Healthy Brain Network study (n = 1880, 62% male). Specifically, we used partial least squares (PLS) to identify latent variables (LV) between functional connectivity and a) symptom scores, and b) diagnostic information. In addition, we investigated associations between functional connectivity and each diagnosis specifically, controlling for other diagnosis categories. ResultsPLS identified several statistically significant LVs between functional brain networks and symptoms, mapping onto the psychopathology hierarchy. The first LV, explaining most covariance in functional connectivity, resembled a general psychopathology factor (r=.69, p=.01). This LV implicated weaker connectivity between the salience network and limbic and visual network. The next four LVs entailed externalisation-internalisation, neurodevelopmental, somatoform, and detachment (r=.69, p=.038; r=.70, p=.012; r=.69, p=.031; r=68, p=.012, r=.65, p=.005, respectively), all associated with distinct patterns of functional connectivity. Another PLS with diagnostic data revealed one significant LV (r=.69, p=.009), resembling a cross-diagnostic case-control pattern. This diagnostic LV entailed stronger connectivity between the limbic and visual network, in addition to weaker connectivity within the somatomotor network. The disorder-specific PLS identified a unique connectivity pattern for autism spectrum disorder (ASD) (r=.67, p=.012), implicating weaker connectivity within the somatomotor network and salience network. ConclusionsTransdiagnostic and symptom-based dimensions of psychopathology map onto to the functional networks of the brain during childhood and adolescence, while ASD was the only diagnostic category to exhibit a specific connectivity pattern. This finding supports dimensional and transdiagnostic classifications of psychopathology. | Make paid
Background: Brain age prediction algorithms using structural magnetic resonance imaging (MRI) aim to assess the biological age of the human brain. The difference between a person's chronological age and the estimated brain age is thought to reflect deviations from a normal aging trajectory, indicating a slower, or accelerated, biological aging process. Several pre-trained software packages for predicting brain age are publicly available. In this study, we perform a head-to-head comparison of such packages with respect to 1) predictive accuracy, 2) test-retest reliability, and 3) the ability to track age progression over time. Methods: We evaluated the six brain age prediction packages: brainageR, DeepBrainNet, brainage, ENIGMA, pyment, and mccqrnn. The accuracy and test-retest reliability were assessed on MRI data from 372 healthy people aged between 18.4 and 86.2 years (mean 38.7 {+/-} 17.5 years). Results: All packages showed significant correlations between predicted brain age and chronological age (r = 0.66 to 0.97, p < 0.001), with pyment displaying the strongest correlation. The mean absolute error was between 3.56 (pyment) and 9.54 years (ENIGMA). brainageR, pyment, and mccqrnn were superior in terms of reliability (ICC values between 0.94 - 0.98), as well as predicting age progression over a longer time span. Conclusion: Of the six packages, pyment and brainageR consistently showed the highest accuracy and test-retest reliability. | Make paid
To identify functional differences between vertebrate clathrin light chains (CLCa or CLCb), phenotypes of mice lacking genes encoding either isoform were characterised. Mice without CLCa displayed 50% neonatal mortality, reduced body weight, reduced fertility, and ~40% of aged females developed uterine pyometra. Mice lacking CLCb displayed a less severe weight reduction phenotype compared to those lacking CLCa, and had no survival or reproductive system defects. Analysis of female mice lacking CLCa that developed pyometra revealed ectopic expression of epithelial differentiation markers (FOXA2 and K14) and a reduced number of endometrial glands, indicating defects in the luminal epithelium. Defects in lumen formation and polarity of epithelial cysts derived from uterine or gut cell lines were also observed when either CLCa or CLCb were depleted, with more severe effects from CLCa depletion. In cysts, the CLC isoforms had different distributions relative to each other, while they converge in tissue. Together, these findings suggest differential and cooperative roles for CLC isoforms in epithelial lumen formation, with a dominant function for CLCa. | Make paid
Objectives: To compare the association between cardiorespiratory fitness (CRF) and cut-point-free accelerometer metrics (intensity gradient [IG] and average acceleration [AvAcc]) to that with traditional metrics in healthy adults aged 20 to 89 years and patients with heart failure, and 2) provide age-, sex-, and CRF-related reference values for healthy adults. Methods: In the COmPLETE study, 463 healthy adults and 67 patients with heart failure wore GENEActiv accelerometers on their non-dominant wrist and underwent cardiopulmonary exercise testing. Cut-point-free (IG: distribution of intensity of activity across the day; AvAcc: proxy of volume of activity) and traditional (moderate-to-vigorous and vigorous activity) metrics were generated. The 'rawacceleration' application was developed to translate findings into clinical practice. Results: IG and AvAcc yield complementary information on PA with both IG (p=0.009) and AvAcc (p<0.001) independently associated with CRF in healthy individuals. Only IG was independently associated with CRF in patients with heart failure (p=0.043). The best cut-point-free and cut-point-based model had similar predictive value for CRF in both cohorts. However, unlike traditional metrics, IG and AvAcc are comparable across populations and the most commonly used accelerometers. We produced age- and sex-specific reference values and percentile curves for IG, AvAcc, moderate-to-vigorous, and vigorous activity for healthy adults. Conclusions: IG and AvAcc are strongly associated with CRF and, thus, indirectly with the risk of non-communicable diseases and mortality in healthy adults and patients with heart failure. Our reference values enhance the utility of cut-point-free metrics and facilitate their interpretation. Trial registration: This study was registered on clinicaltrials.gov (NCT03986892). | Make paid
Aging is a complex process with interindividual variability, which can be measured by aging biological clocks. Aging clocks are machine-learning algorithms guided by biological information and associated with mortality risk and a wide range of health outcomes. One of these aging clocks are transcriptomic clocks, which uses gene expression data to predict biological age; however, their functional role is unknown. Here, we profiled two transcriptomic clocks (RNAAgeCalc and knowledge-based deep neural network clock) in a large dataset of human postmortem prefrontal cortex (PFC) samples. We identified that deep-learning transcriptomic clock outperforms RNAAgeCalc to predict transcriptomic age in the PFC. We identified associations of transcriptomic clocks with psychiatric-related traits. Further, we applied system biology algorithms to identify common gene networks among both clocks and performed pathways enrichment analyses to assess its functionality and prioritize genes involved in the aging processes. Identified gene networks showed enrichment for diseases of signal transduction by growth factor receptors and second messengers pathways. We also observed enrichment of genome-wide signals of mental and physical health outcomes and identified genes previously associated with human brain aging. Our findings suggest a link between transcriptomic aging and health disorders, including psychiatric traits. Further, it reveals functional genes within the human PFC that may play an important role in aging processes and health risk. | Make paid
Background and Aims: Previous trials evaluating remote ischaemic preconditioning in children undergoing cardiac surgery showed mixed results. We sought to determine whether adequately delivered bilateral preconditioning is cardioprotective in young children, with or without cyanosis, undergoing surgery. Methods: Prospective, double-blind, randomised controlled trial at two UK centres. Children aged 3-36 months undergoing tetralogy of Fallot repair or ventricular septal defect closure were randomised in a 1:1 ratio to receive either bilateral preconditioning or sham intervention. Participants were followed up until hospital discharge or 30 days. The primary outcome was area under the curve for high-sensitivity troponin-T in the first 24 hours after surgery, analysed by intention-to-treat. Right atrial biopsies were obtained in selected patients. Trial registration: ISRCTN12923441. Results: Between 24 October 2016 and 8 December 2020, 120 eligible children were randomised to receive either bilateral preconditioning (n=60) or sham intervention (n=60). Participants had a median age of 7 months and 42 (35%) were female. The primary outcome, area under the curve for hs-troponin-T was higher in the preconditioning group (mean: 70.0+/-50.9microg/L/hr, n=56) than in controls (mean: 55.6+/-30.1microg/L/hr, n=58), p=0.04. Sub-group analyses did not show a differential treatment effect by oxygen saturations (pinteraction=0.25) but showed evidence of differential treatment effect by underlying defect (pinteraction=0.04). Myocardial metabolism, quantified in atrial biopsies, and secondary outcomes were not different between randomised groups. Conclusions: Bilateral remote ischemic preconditioning does not attenuate myocardial injury in children undergoing surgical repair for congenital heart defects, and there was evidence of potential harm in unstented tetralogy of Fallot. | Make paid
Abstract Background: Major depressive disorder affects mental well-being and accelerates DNA methylation age, a marker of biological aging. Subclinical depressive symptoms and DNA methylation aging have not been explored. Objective: To assess the cross-sectional association between depressive symptoms and accelerated DNA methylation aging among United States adults over age 50. Methods: We included 3,793 participants from the 2016 wave of the Health and Retirement Study. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression scale and operationalized as high versus low/no. Blood DNA methylation GrimAge was regressed on chronologic age to obtain acceleration. Multiple linear regression assessed the relationship between high depressive symptoms and GrimAge acceleration, controlling for demographic factors, health behaviors, and cell type proportions. We investigated sex and race/ethnicity stratified associations. Results: Participants were 42% male, 14% had high depressive symptoms, 44% had accelerated GrimAge, and were mean age 70 years. In our fully adjusted model, those with high depressive symptoms had 0.40 (95%CI: 0.06, 0.73) years accelerated GrimAge, compared to those with low/no depressive symptoms. The association between depressive symptoms and GrimAge acceleration was larger in male participants (P = 0.04). Conclusion: Higher depressive symptoms were associated with accelerated DNA methylation age among older adults. Keywords: Epigenetic clock, DNA methylation age, epigenetic age acceleration, depressive symptoms, epidemiology, older adults | Make paid
In the last decade, there has been an emergence of scrub typhus in many parts of India. In Mizoram, North-East India, there has been a steep increase in scrub typhus and other rickettsial infections in the last 5 years. As part of the public health response, the Mizoram Government has integrated screening (by rapid immunochromatographic test and/or Weil-Felix test) and line listing of scrub typhus and other rickettsial infections across all its health settings, a first in India. From 2018-22 (study period), 22914 cases were reported; of these, 19651 were positive for scrub typhus. Aizawl district is the worst affected, with 10580 cases (46.17%). The average incidence rate of rickettsial infections is 3.54 cases per 1000 persons-year, and the case fatality rate is 0.35. Patients with eschar (aOR=2.5, p<0.05), construction workers (aOR=17.9, p<0.05), and children aged 10 and below (aOR=5.4, p<0.05) have higher odds of death due to rickettsial infections. | Make paid
Background: It is crucial to understand the differences in dengue seroprevalence rates in different regions in Sri Lanka to understand the burden of infection to plan dengue vaccination programmes. Methods: age stratified seroprevalence rates were assessed in 5208 children, aged 10 to 19 years, in nine districts representing the nine provinces in Sri Lanka. A stratified multi-stage cluster was used to select 146 schools representing each district. Probability proportionate to the size (PPS) sampling technique based on the age distribution of general population and the urbanicity in each district was used to select the number of clusters to be enrolled for the study from each district. Findings: The overall dengue seroprevalence rates in children was 24.8%, with the highest rates reported from Trincomalee (54.3%) and the lowest rates from Badulla (14.2%), which is a high altitude estate area. There was a weak but positive correlation between the dengue antibody positivity rates and age in districts which had seroprevalence rates of >25%, while there was no increase in antibody titres with age in the other districts. While the seroprevalence rates was significantly higher in urban areas (35.8%) compared to rural (23.2%) and estate areas (9.4%), there was no association with seropositivity rates with population density (Spearmans r=- 0.01, p=0.98), in each district. Interpretation: The seroprevalence rates in many districts were <25% and the rates were very different to those reported from Colombo. Therefore, it would be important to take into account these differences when rolling out dengue vaccines in Sri Lanka. | Make paid
At the end of 2009, due to the increase in primary resistance to isoniazid, the Brazilian Ministry of Health established changes in the treatment regimen for tuberculosis. The changes included the addition of ethambutol as the fourth drug in the intensive treatment phase and the integration of the four drugs into fixed-dose combination tablets. The introduction of fixed combination doses also led to changes in the dosage of isoniazid and pyrazinamide in the intensive and maintenance phases. Objective: To estimate the effect of changing the tuberculosis treatment regimen on all-cause mortality and, secondly, outcomes such as mortality due to tuberculosis, cure, and loss to follow-up. Methods: We compared the cohorts of people diagnosed with tuberculosis from 2008 to 2013, aged ten years or older, who started treatment for tuberculosis in Brazil before and after the change in the regimen adopted in 2009 (n: 145528 vs. 161264). Data were extracted from the Notifiable Diseases (Sinan) and Mortality (SIM) information systems. The missing data were imputed, and the effects were estimated using multilevel logistic models, with the state as the aggregation cluster. A directed acyclic graph guided the selection of covariates. Results: The current (modified) regimen was not associated with significant changes in all-cause mortality (Relative Risk [RR]: 1.01; 95% confidence interval [95%CI]: 0.98 - 1.04), or tuberculosis mortality (RR: 0.98; 95%CI: 0.95 - 1.02). For cure, when transfers and missing outcome data (MOD) were considered an absence of outcome, there were no differences between treatments. When they were assumed as cured or imputed, the cure was less frequent in the current treatment. When transfers and MOD were imputed or considered an absence of loss to follow-up, the latter was more frequent in the current treatment. There were no differences in loss to follow-up between treatments when transfers and MOD were interpreted as that outcome. Conclusion: The implementation of the modified treatment regimen was not associated with increased mortality in tuberculosis patients. Although there was a lower record of cures and a higher frequency of loss to follow-up during the second period, the sensitivity analysis indicated that a reduction in transfers and unknown outcomes could explain these associations. | Make paid
Background: Vaccines have substantially mitigated the disproportional impact of SARS-CoV-2 on the high morbidity and mortality experienced by nursing home residents. However, variation in vaccine efficacy, immune senescence and waning immunity all undermine vaccine effectiveness over time. The introduction of the bivalent vaccine in September 2022 aimed to counter this increasing susceptibility and consequences of breakthrough infection, however data on the durability and protection of the vaccine are limited. We evaluated the durability of immunity and protection after the first bivalent vaccination to SARS-CoV-2 in nursing home residents. Methods: For the immunologic evaluation, community nursing home volunteers agreed to serial blood sampling before, at two weeks, three and six months after each vaccination for antibodies to spike protein and pseudovirus neutralization activity over time. Concurrent clinical outcomes were evaluated by reviewing electronic health record data from residents living in Veterans Administration managed nursing home units. Residents without recent infection but prior vaccination to SARS-CoV-2 were followed over time beginning with administration of the newly available bivalent vaccine using a target trial emulation (TTE) approach; TTE compared time to breakthrough infection, hospitalization and death between those who did and did not receive the bivalent vaccine. Results: We evaluated antibodies in 650 nursing home residents; 452 had data available following a first monovalent booster, 257 following a second monovalent booster and 321 following a bivalent vaccine. We found a rise in BA.5 neutralization activity from the first and second monovalent boosters through the bivalent vaccination regardless of prior SARS-CoV-2 history. Titers declined at three and six months after the bivalent vaccination but generally exceeded those at three months compared to either prior boost. BA.5 neutralization titers six months after the bivalent vaccination were diminished but had detectable levels in 80% of infection-naive and 100% of prior infected individuals. TTE evaluated 5903 unique subjects, of whom 2235 received the bivalent boost. TTE demonstrated 39% or greater reduction in risk of infection, hospitalization or death at four months following the bivalent boost. Conclusion: Immunologic results mirrored those of the TTE and suggest bivalent vaccination added substantial protection for up to six months after bivalent vaccination with notable exceptions. However, the level of protection declined over this period, and by six months may open a window of added vulnerability to infection before the next updated vaccine becomes available. We strongly agree with the CDC recommendation that those who have not received a bivalent vaccination receive that now and these results support a second bivalent booster for those at greatest risk which includes many nursing home residents. | Make paid
Leaf senescence is an essential physiological process related to grain yield potential and nutritional quality. Green leaf duration (GLD) after anthesis directly reflects the leaf senescence process and exhibits large genotypic differences in common wheat; however, the underlying gene regulatory mechanism is still lacking up to now. Here, we report TaNAM-A1 as the causal gene of major loci qGLD-6A for GLD during grain filling by map-based cloning. The role of TaNAM-A1 in regulating leaf senescence, spike length, and grain size was proved by transgenic assay and TILLING mutants analyses. Furthermore, the functional divergences among TaNAM-A1 three haplotypes were systematically evaluated. Wheat varieties with TaNAM-A1d (containing two mutations in CDS of TaNAM-A1) had longer GLD and advantages in yield-related traits than those with the wild type TaNAM-A1a. All three haplotypes were functional in transactivating the expression of genes involved in macromolecular degradation and mineral nutrient remobilization, with TaNAM-A1a the strongest activity and TaNAM-A1d the weakest. TaNAM-A1 modulates the expression of TaNAC016-3A and TaNAC-S-7A to trigger senescence initiation. TaNAC016-3A enhances TaNAM-A1 transcriptional activation ability by protein-protein interaction. Our study provides new insights into fine-tuning the leaf functional period and grain yield formation for wheat breeding under different geographical climatic conditions. | Make paid
Human mesenchymal stem cells (hMSCs) are multipotent cells that can differentiate into adipocytes, chondrocytes and osteoblasts. Due to their differentiation potential, hMSCs are among the most frequently used cells for therapeutic applications in tissue engineering and regenerative medicine. However, the number of cells obtained through isolation alone is insufficient for hMSC-based therapies and basic research, necessitating their in-vitro expansion. Conventionally, this is often carried out on rigid surfaces such as tissue culture petriplates (TCPs). However, during in-vitro expansion, hMSCs lose their proliferative ability and multilineage differentiation potential, making them unsuitable for clinical use. Although multiple approaches have been tried to maintain hMSC stemness over prolonged expansion, finding a suitable culture system to achieve this remains an unmet need. Recently, few research groups including ours have shown that hMSCs maintain their stemness over long passages when cultured on soft substrate. In addition, it has been shown that hMSCs cultured on soft substrates have more condensed chromatin and lower levels of histone acetylation compared to those cultured on stiff substrates. It has also been shown that condensing/decondensing chromatin by deacetylation/acetylation can delay/hasten replicative senescence in hMSCs during long-term expansion on TCPs. However, how chromatin condensation/decondensation influences nuclear morphology and DNA damage - which are strongly related to the onset of senescence and cancer - is still not known. To answer this question, here we cultured hMSCs for long duration (P4-P11) in presence of epigenetic modifiers histone acetyltransferase inhibitor (HATi) which promotes chromatin condensation by preventing histone acetylation and histone deacetylase inhibitor (HDACi) which promotes chromatin decondensation and investigated their effect on various nuclear markers related to senescence and cancer. We have found that consistent acetylation causes severe nuclear abnormalities whereas chromatin condensation by deacetylation helps in safeguarding nucleus from damages caused by in-vitro expansion. | Make paid
HnRNP A3 is a protein that binds the age-related increase element (AIE) of blood coagulation factor IX (FIX) and that plays critical roles in age-related gene expression, likely through an epigenetic mechanism as yet unidentified. In a previous study, we found that Ser359 phosphorylated hnRNP A3 proteins do not bind to the AIE of FIX although both unphosphorylated and Ser359 phosphorylated hnRNP proteins exist in the liver. In the present study, to explore the relationship between hnRNP A3 and FIX, we examined the age-related expression pattern of 14 single spots of hnRNP A3 detected by 2DE and subsequent MALDI-TOF/TOF/MS analyses in mouse liver. We found that the level of all four Ser359 phosphorylated hnRNP A3 proteins increased with age (from 1-21 months), while the 10 unphosphorylated hnRNP A3 proteins showed various expression patterns with age. We then examined the functional role of hnRNP A3 in FIX expression using siRNA knockdown technology targeting the hnRNP A3 gene in aged mice (12-17 months old). Inhibition of hnRNP A3 expression induced an increase in the circulating FIX level in aged mice. These results suggested that hnRNP A3 inhibits age-related FIX protein expression and that age-dependent modification of hnRNP A3, including its phosphorylation at Ser359, might be involved in the age-dependent increase in FIX expression in vivo. | Make paid
The development of aging is associated with the disruption of key cellular processes manifested as well-established hallmarks of aging. Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) have no stable tertiary structure that provide them a power to be configurable hubs in signaling cascades and regulate many processes, potentially including those related to aging. There is a need to clarify the roles of IDPs/IDRs in aging. The dataset of 1624 aging-related proteins was collected from established aging databases and experimental studies. There is a noticeable presence of IDPs/IDRs, accounting for about 36% of the aging-related dataset, which is comparable to the disorder content of the whole human proteome (about 40%). A Gene Ontology analysis of the our Aging proteome reveals an abundance of IDPs/IDRs in one-third of aging-associated processes, especially in genome regulation. Signaling pathways associated with aging also contain IDPs/IDRs on different hierarchical levels. Protein-protein interaction network analysis showed that IDPs present in different clusters associated with different aging hallmarks. Protein cluster with IDPs enrichment and high liquid-liquid phase separation (LLPS) probability has 'nuclear' localization and DNA-associated functions, related to aging hallmarks: genomic instability, telomere attrition, epigenetic alterations, stem cells exhaustion. Some IDPs related to aging with high LLPS propensity were identified as 'dangerous' based on the prediction of their propensity to aggregation. Overall, our analyses indicate that IDPs/IDRs play significant roles in aging-associated processes, particularly in the regulation of DNA functioning. IDP aggregation, which can lead to loss-of-function and toxicity, could be critically harmful to the cell. A structure-based analysis of aging and the identification of proteins that are particularly susceptible to disturbances can enhance our understanding of the molecular mechanisms of aging and open up new avenues for slowing it down. | Make paid
Inflammatory cytokines released by the synovium after trauma disturb the gene regulatory network and have been implicated in the pathophysiology of osteoarthritis. A mechanistic understanding of how aging perturbs this process can help identify novel interventions. Here, we introduced network paradigms to simulate cytokine-mediated pathological communication between the synovium and cartilage. Cartilage-specific network analysis of injured young and aged murine knees revealed aberrant matrix remodeling as a transcriptomic response unique to aged knees displaying accelerated cartilage degradation. Next, network-based cytokine inference with pharmacological manipulation uncovered IL6 family member, Oncostatin M, as a driver for the aberrant matrix remodeling. By implementing a phenotypic drug discovery approach, we identified that the activation of Oncostatin M recapitulated inflammation phenotype of knee osteoarthritis and highlighted high-value targets for drug development and repurposing. These findings offer translational opportunities targeting the inflammation-driven osteoarthritis phenotype. | Make paid
Aging is associated with a number of physiologic changes including perturbed circadian rhythms; however, mechanisms by which rhythms are altered remain unknown. To test the idea that circulating factors mediate age-dependent changes in peripheral rhythms, we compared the ability of human serum from young and old individuals to synchronize circadian rhythms in culture. We collected blood from apparently healthy young (age 25-30) and old (age 70-76) individuals and used the serum to synchronize cultured fibroblasts. We found that young and old sera are equally competent at driving robust ~24h oscillations of a luciferase reporter driven by clock gene promoter. However, cyclic gene expression is affected, such that young and old sera drive cycling of different genes. While genes involved in the cell cycle and transcription/translation remain rhythmic in both conditions, genes identified by STRING and IPA analyses as associated with oxidative phosphorylation and Alzheimer's Disease lose rhythmicity in the aged condition. Also, the expression of cycling genes associated with cholesterol biosynthesis increases in the cells entrained with old serum. We did not observe a global difference in the distribution of phase between groups, but find that peak expression of several clock controlled genes (PER3, NR1D1, NR1D2, CRY1, CRY2, and TEF) lags in the cells synchronized with old serum. Taken together, these findings demonstrate that age-dependent blood-borne factors affect peripheral circadian rhythms in cells and have the potential to impact health and disease via maintaining or disrupting rhythms respectively. | Make paid
Purpose: A high number of circulating neutrophils is a poor prognostic factor for breast cancer, where evidence of bone marrow cancer-dependent priming is found. However, how early this priming is detectable remains unclear. Patients and Methods: Here, we investigate changes in circulating neutrophils from newly diagnosed breast cancer patients before any therapeutic interventions. To do this, we assessed their lifespan and their broader intracellular kinase network activation states by using the Pamgene Kinome assay which measures the activity of neutrophil kinases. Results: We found sub-type specific L-selectin (CD62L) changes in circulating neutrophils as well as perturbations in their overall global kinase activity. Strikingly, breast cancer patients of different subtypes (HR+, HER2+, triple negative) exhibited distinct neutrophil kinase activity patterns indicating that quantifiable perturbations can be detected in circulating neutrophils from early breast cancer patients, that are sensitive to both hormonal and HER-2 status. We also detected an increase in neutrophils lifespan in cancer patients, independently of tumour subtype. Conclusions: Our results suggest that the tumour-specific kinase activation patterns in circulating neutrophils may be used in conjunction with other markers to identify patients with cancer from those harbouring only benign lesions of the breast. Given the important role neutrophil in breast cancer progression, the significance of this sub-type of specific priming warrants further investigation. | Make paid