This study aimed to develop a classification model predicting incident bipolar disorder (BD) cases in young adults within a 5-year interval, using sociodemographic and clinical features from a large cohort study. We analyzed 1,091 individuals without BD, aged 18 to 24 years at baseline, and used the XGBoost algorithm with feature selection and oversampling methods. Forty-nine individuals (4.49%) received a BD diagnosis five years later. The best model had an acceptable performance (test AUC: 0.786, 95% CI: 0.686-0.887) and included ten features: feeling of worthlessness, sadness, current depressive episode, self-reported stress, self-confidence, lifetime cocaine use, socioeconomic status, sex frequency, romantic relationship, and tachylalia. We performed a permutation test with 10,000 permutations that showed the AUC from the built model is significantly better than random classifiers. The results provide insights into BD as a latent phenomenon, as depression is its typical initial manifestation. Future studies could monitor subjects during other developmental stages and investigate risk populations to improve BD characterization. Furthermore, the usage of digital health data, biological, and neuropsychological information and also neuroimaging can help in the rise of new predictive models. | Make paid
BACKGROUND, Alcohol Minimum Unit Pricing (MUP) was introduced in Scotland in May 2018. Existing evidence suggests MUP can reduce alcohol consumption in the general population, but there is little research about its impact on vulnerable groups. This qualitative study aimed to explore experiences of MUP among people with experience of homelessness. METHODS We conducted qualitative semi-structured interviews with a purposive sample of 46 people with current or recent experience of homelessness who were current drinkers when MUP was introduced. Participants (30 men and 16 women) were aged 21 to 73 years. Interviews focused on views and experiences of MUP. Data were analysed using thematic analysis. RESULTS People with experience of homelessness were aware of MUP but it was accorded low priority in their hierarchy of concerns. Reported impacts varied. Some participants reduced their drinking, or moved away from drinking strong white cider in line with policy intentions. Others were unaffected because the cost of their preferred drink (usually wine, vodka or beer) did not change substantially. A minority reported increased involvement in begging. Wider personal, relational and social factors also played an important role in participant responses to MUP. CONCLUSION Our findings suggest that MUP worked as intended for some people with experience of homelessness, while a minority reported negative consequences. Our findings highlight the importance of considering the impact of population level health policies on marginalised groups. Policymakers in Scotland, and elsewhere, need to consider wider contextual factors that affect responses to MUP in people with experience of homelessness. It is important to invest further in secure housing and appropriate support services for people with experience of homelessness who consume alcohol, and implement and evaluate harm reduction initiatives such as managed alcohol programmes. | Make paid
Ageing is the greatest global healthcare challenge, as it underlies age-related functional decline and is the primary risk factor for a range of common diseases, including neurodegenerative conditions such as Alzheimer's disease (AD). However, the molecular mechanisms defining chronological age versus biological age, and how these underlie AD pathogenesis, are not well understood. The objective of this study was to integrate common human genetic variation associated with human lifespan or AD from Genome-Wide Association Studies (GWAS) with co-expression networks altered with age in the central nervous system, to gain insights into the biological processes which connect ageing with AD and lifespan. Initially, we identified common genetic variation in the human population associated with lifespan and AD by performing a gene-based association study using GWAS data. We also identified preserved co-expression networks associated with age in the brains of C57BL/6J mice from bulk and single-cell RNA-sequencing (RNA-seq) data, and in the brains of humans from bulk RNA-seq data. We then intersected the human gene-level common variation with these co-expression networks, representing the different cell types and processes of the brain. We found that genetic variation associated with AD was enriched in both microglial and oligodendrocytic bulk RNA-seq gene networks, which show increased expression with ageing in the human hippocampus, in contrast to synaptic networks which decreased with age. Further, longevity-associated genetic variation was modestly enriched in a single-cell gene network expressed by homeostatic microglia. Finally, we performed a transcriptome-wide association study (TWAS), to identify and confirm new risk genes associated with ageing that show variant-dependent changes in gene expression. In addition to validating known ageing-related genes such as APOE and FOXO3, we found that Caspase 8 (CASP8) and APOC1 show genetic variation associated with longevity. We observed that variants contributing to ageing and AD balance different aspects of microglial function suggesting that ageing-related processes affect multiple cell types in the brain. Specifically, changes in homeostatic microglia are associated with lifespan, and allele-dependent expression changes in age-related genes control microglial activation and myelination influencing the risk of developing AD. We identified putative molecular drivers of these genetic networks, as well as module genes whose expression in relevant human tissues are significantly associated with AD-risk or longevity, and may drive "inflammageing." Our study also shows allele-dependent expression changes with ageing for genes classically involved in neurodegeneration, including MAPT and HTT, and demonstrates that PSEN1 is a prominent member/hub of an age-dependent expression network. In conclusion, this work provides new insights into cellular processes associated with ageing in the brain, and how these may contribute to the resilience of the brain against ageing or AD-risk. Our findings have important implications for developing markers indicating the physiological age and pre-pathological state of the brain, and provide new targets for therapeutic intervention. | Make paid
A wealth of research has investigated the effects of bilingualism on cognition, especially on executive function. Developmental studies reveal different cognitive profiles between monolinguals and bilinguals in (audio-)visual attention tasks, which might stem from their attention allocation differences. Yet, whether such distinction exists in the auditory domain alone is unknown. In this study, we compared differences in auditory attention, measured by standardized tests, between monolingual and bilingual children. A comprehensive literature search was conducted in three electronic databases: OVID Medline, OVID PsycInfo, and EBSCO CINAHL. Empirical studies using standardized tests to assess auditory attention in monolingual and bilingual participants aged less than 18 years were included. Among the 20 studies identified, we performed a meta-analysis and found that test measure (accuracy vs. response times) was significantly related to differences in effect sizes whereas other factors (e.g., participant age, stimulus type) were not. Specifically, studies reporting accuracy observed a marginal bilingual advantage (g = 0.10), but those reporting response times indicated a small monolingual benefit (g = -0.34). Therefore, there was little difference between monolingual and bilingual children's performance on standardized auditory attention tests. We also found that studies tend to include a wide variety of bilingual children but report limited language background information of the participants. This, unfortunately, limits the potential theoretical contributions of the reviewed studies. Recommendations to improve the quality of future research are discussed. | Make paid
Healthy mitochondria are critical for reproduction. During aging, both reproductive fitness and mitochondrial homeostasis decline. Mitochondrial metabolism and dynamics are key factors in supporting mitochondrial homeostasis. However, how they are coupled to control reproductive health remains unclear. We report that mitochondrial GTP metabolism acts through mitochondrial dynamics factors to regulate reproductive aging. We discovered that germline-only inactivation of GTP- but not ATP-specific succinyl-CoA synthetase (SCS), promotes reproductive longevity in Caenorhabditis elegans. We further revealed an age-associated increase in mitochondrial clustering surrounding oocyte nuclei, which is attenuated by the GTP-specific SCS inactivation. Germline-only induction of mitochondrial fission factors sufficiently promotes mitochondrial dispersion and reproductive longevity. Moreover, we discovered that bacterial inputs affect mitochondrial GTP and dynamics factors to modulate reproductive aging. These results demonstrate the significance of mitochondrial GTP metabolism in regulating oocyte mitochondrial homeostasis and reproductive longevity and reveal mitochondrial fission induction as an effective strategy to improve reproductive health. | Make paid
Telomeres play central roles in senescence, aging and chromosome integrity. Using ONT long read sequencing we have assembled the genomes of the three most devastating plant-parasitic nematodes at unparalleled contiguity. The telomeric repeat (TTAGGC)n, evolutionarily conserved in nematodes, was not found in these genomes. Furthermore, no evidence for a telomerase enzyme or for orthologs of C. elegans telomere-associated proteins could be found. Instead, we identified species-specific complex repeated patterns mostly present at one end of contigs. Similarly to known telomeric repeats, these patterns were G-rich, oriented and transcribed. Using FISH we confirmed these repeats were present at one single end of chromosomes in M. incognita. The discovery of a new kind of telomeric repeat in these species highlights the evolutionary diversity of chromosome protection systems despite their central roles and opens new perspectives towards the development of more specific control methods against these pests. | Make paid
Telomeres play central roles in senescence, aging and chromosome integrity. Using ONT long read sequencing we have assembled the genomes of the three most devastating plant-parasitic nematodes at unparalleled contiguity. The telomeric repeat (TTAGGC)n, evolutionarily conserved in nematodes, was not found in these genomes. Furthermore, no evidence for a telomerase enzyme or for orthologs of C. elegans telomere-associated proteins could be found. Instead, we identified species-specific complex repeated patterns mostly present at one end of contigs. Similarly to known telomeric repeats, these patterns were G-rich, oriented and transcribed. Using FISH we confirmed these repeats were present at one single end of chromosomes in M. incognita. The discovery of a new kind of telomeric repeat in these species highlights the evolutionary diversity of chromosome protection systems despite their central roles and opens new perspectives towards the development of more specific control methods against these pests. | Make paid
Cerebral ischemia triggers a powerful inflammatory reaction involving both peripheral leukocytes and brain resident cells. Recent evidence indicates that their differentiation into a variety of functional phenotypes contributes to both tissue injury and repair. However, the temporal dynamics and diversity of post-stroke immune cell subsets remain poorly understood. To address these limitations, we performed a longitudinal single-cell transcriptomic study of both brain and mouse blood to obtain a composite picture of brain-infiltrating leukocytes, circulating leukocytes, microglia and endothelium diversity over the ischemic/reperfusion time. Brain cells and blood leukocytes isolated from mice 2 or 14 days after transient middle cerebral artery occlusion or sham surgery were purified by FACS sorting and processed for droplet-based single-cell transcriptomics. The analysis revealed a strong divergence of post-ischemic microglia, macrophages, and neutrophils over time, while such diversity was less evident in dendritic cells, B, T and NK cells. Conversely, brain endothelial cells and brain associated-macrophages showed altered transcriptomic signatures at 2 days post-stroke, but low divergence from sham at day 14. Pseudotime trajectory inference predicted the in-situ longitudinal progression of monocyte-derived macrophages from their blood precursors into day 2 and day 14 phenotypes, while microglia phenotypes at these two time points were not connected. In contrast to monocyte-derived macrophages, neutrophils were predicted to be continuously de-novo recruited from the blood. Brain single-cell transcriptomics from both female and male aged mice did not show major changes in respect to young mice, but aged and young brains differed in their immune cell composition. Furthermore, blood leukocyte analysis also revealed altered transcriptomes after stroke. However, brain-infiltrating leukocytes displayed higher transcriptomic divergence than their circulating counterparts, indicating that phenotypic diversification into cellular subsets occurs within the brain in the early and the recovery phase of ischemic stroke. In addition, this resource report contains a searchable database https://anratherlab.shinyapps.io/strokevis/ to allow user-friendly access to our data. The StrokeVis tool constitutes a comprehensive gene expression atlas that can be interrogated at the gene and cell type level to explore the transcriptional changes of endothelial and immune cell subsets from mouse brain and blood after stroke. | Make paid
When yeast cells are exposed to nutrient-limiting conditions, they undergo transcriptional and translational reprogramming that results in the remodeling of metabolite utilization and organelle architecture. Organelle membranes and contacts also undergo structural and functional alterations. In the budding yeast Saccharomyces cerevisiae, regulated expression of Uip4 is shown to be a critical effector of nuclear shape and function, particularly during the stationary phase. In this work, we demonstrate that the absence of UIP4 affects the morphology of multiple other organelles including mitochondria, endoplasmic reticulum, vacuole and the distribution of lipid droplets. The results show that modulating carbon source, nitrogen availability and cellular energy state impact Uip4 expression. This expression of Uip4 is controlled by the transcription factor Msn2, downstream of Sch9 signaling pathway. Cells lacking Uip4 have poor survival in the stationary phase of the growth cycle. These cellular changes are concomitant with dysregulation of the global lipidome profile and aberrant organelle interaction. We propose that the dynamic and regulated expression of Uip4 is required to maintain lipid homeostasis and organelle architecture which is ultimately required to survive in nutrient-limiting conditions such as stationary phase. | Make paid
Transcription factors (TFs) play key roles in regulating the differentiation and function of stem cells, including muscle satellite cells (MuSCs), a resident stem cell population responsible for postnatal regeneration of the skeletal muscle. Sox11 belongs to the Sry-related HMG-box (SOX) family of TFs that play diverse roles in stem cell behavior and tissue specification. Analysis of single-cell RNA-sequencing (scRNA-seq) datasets identify a specific enrichment of Sox11 mRNA in differentiating but not quiescent MuSCs. Consistent with the scRNA-seq data, Sox11 levels increase during differentiation of murine primary myoblasts in vitro. scRNA-seq data comparing muscle regeneration in young and old mice further demonstrate that Sox11 expression is reduced in aged MuSCs. Age-related decline of Sox11 expression is associated with reduced chromatin contacts within the topologically associated domains. Unexpectedly, Myod1Cre-driven deletion of Sox11 in embryonic myoblasts has no effects on muscle development and growth, resulting in apparently healthy muscles that regenerate normally. Pax7CreER or Rosa26CreER driven (MuSC-specific or global) deletion of Sox11 in adult mice similarly has no effects on MuSC differentiation or muscle regeneration. These results identify Sox11 as a novel myogenic differentiation marker with reduced expression in quiescent and aged MuSCs, but the specific function of Sox11 in myogenesis remain to be elucidated. | Make paid
Model-guided DNA sequence design can accelerate the reprogramming of living cells. It allows us to engineer more complex biological systems by removing the need to physically assemble and test each potential design. While mechanistic models of gene expression have seen some success in supporting this goal, data-centric, deep learning-based approaches often provide more accurate predictions. This accuracy, however, comes at a cost - a lack of generalisation across genetic and experimental contexts, which has limited their wider use outside the context in which they were trained. Here, we address this issue by demonstrating how a simple transfer learning procedure can effectively tune a pre-trained deep learning model to predict protein translation rate from 5' untranslated region sequence (5'UTR) for diverse contexts in Escherichia coli using a small number of new measurements. This allows for important model features learnt from expensive massively parallel reporter assays to be easily transferred to new settings. By releasing our trained deep learning model and complementary calibration procedure, this study acts as a starting point for continually refined model-based sequence design that builds on previous knowledge and future experimental efforts. | Make paid
Pancreatic cancer is a heterogeneous disease with distinct subtypes. Here, we investigated candidate driver genes of the highly aggressive basal-like/squamous molecular subtype of pancreatic ductal adenocarcinoma (PDAC). Integrative transcriptomic analyses identified the upregulated serine/cysteine protease inhibitor, SERPINB3 (squamous cell carcinoma antigen 1, SCCA1) in basal-like/squamous PDAC using discovery and validation approaches. Upregulation of SERPINB3 associated with decreased patient survival and a transcriptome profile indicative of the basal-like/squamous subtype. In human PDAC cell lines, SERPINB3 transgene expression enhanced their invasion capability. Moreover, upregulated expression of SERPINB3 in AsPC-1 cells resulted in enhanced lung metastasis in an orthotopic xenograft model. Molecular analysis of the primary tumor xenografts indicated activation of pathways related to metastasis, increased oxidative damage, and angiogenesis when SERPINB3 was upregulated. Furthermore, metabolomic analysis, using patient cohorts and PDAC cell lines showed a distinct metabolic pattern closely associated with both SERPINB3 and the basal-like/squamous subtype, which included upregulation of carnitine/acylcarnitine, amino acid, glutathione, and purine metabolic pathways, and glycolysis. Further RNA-seq and metabolomic analyses indicated that SERPINB3 may potentially induce the basal-like/squamous subtype and metabolic reprogramming through MYC activation. Taken together, our findings identified SERPINB3 as a candidate marker gene for the basal-like/squamous subtype, which may contribute to the disease aggressiveness in this subtype of PDAC. | Make paid
Auditory complications are potential side effects from childhood cancer treatment. Yet, limited evidence exists about the impact of auditory complications--particularly tinnitus--on health-related quality of life (HRQoL) among childhood cancer survivors (CCS). We determined the prevalence of hearing loss and tinnitus in the large European PanCareLIFE cohort of CCS and examined its effect on HRQoL. We included CCS from four European countries who were diagnosed at age [≤] 18 years; survived [≥] 5 years; and aged 25-44 years at study. We assessed HRQoL (Short Form 36), hearing loss, and tinnitus using questionnaires. We used multivariable linear regression to examine associations between these two auditory complications and HRQoL adjusting for socio-demographic and clinical factors. Our study population consisted of 6,318 CCS (53% female; median age at cancer diagnosis 9 years interquartile range [IQR] 5-13 years) with median age at survey of 31 years (IQR 28-35 years). Prevalence was 7.5% (confidence interval [CI]: 6.9-8.2) for hearing loss and 7.6% (CI: 6.4-9.0) for tinnitus. CCS with hearing loss had impaired physical (coefficient [coef.] -4.3, CI: -7.0 to -1.6) and mental (coef. -3.2, CI: -5.5 to -0.8) HRQoL when compared with CCS with normal hearing. Tinnitus was also associated with impaired physical (coef. -8.2, CI: -11.8 to -4.7) and mental (coef. -5.9, CI: -8.8 to -3.1) HRQoL. We observed the lowest HRQoL among CCS with both hearing loss and tinnitus. Our findings indicate timely treatment of hearing loss and tinnitus may contribute to quality of life of survivors. | Make paid
Background. The 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. Methods. We 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. Results. PLS 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. Conclusions. Transdiagnostic 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
The ability of a third dose of the Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine to stimulate immune responses against subvariants, including Omicron BA.1, has not been assessed in New Zealand populations. Unlike many overseas populations, New Zealanders were largely infection naive at the time they were boosted. This adult cohort of 298 participants, oversampled for at-risk populations, was composed of 29% M[a]ori and 28% Pacific peoples, with 40% of the population aged 55+. A significant proportion of the cohort was obese and presented with at least one comorbidity. Sera were collected 28 days and 6 months post second vaccination and 28 days post third vaccination. SARS-CoV-2 anti-S IgG titres and neutralising capacity using surrogate viral neutralisation assays against variants of concern, including Omicron BA.1, were investigated. The incidence of SARS-CoV-2 infection, within our cohort, prior to third vaccination was very low (<6%). This study found a third vaccine significantly increased the mean SARS-CoV-2 anti-S IgG titres, for every demographic subgroup, by a minimum of 1.5-fold compared to titres after two doses. Diabetic participants experienced a greater increase (~4-fold) in antibody titres after their third vaccination, compared to non-diabetics (increase of ~2-fold). This corrected for the deficiency in antibody titres within diabetic participants which was observed following two doses. A third dose also induced a neutralising response against Omicron variant BA.1, which was absent after two doses. This neutralising response improved regardless of age, BMI, ethnicity, or diabetes status. Participants aged >75 years consistently had the lowest SARS-CoV-2 anti-S IgG titres at each timepoint, however experienced the greatest improvement after three doses compared to younger participants. This study shows that in the absence of prior SARS-CoV-2 infection, a third Pfizer-BioNTech BNT162b2 vaccine enhances immunogenicity, including against Omicron BA.1, in a cohort representative of at-risk groups in the adult New Zealand population. | Make paid
Abstract Background Bivalent BA.1 booster vaccines were offered to adults aged 50 years and older and clinically vulnerable individuals as part of the autumn COVID-19 booster vaccination programme 2022 in England. Methods A test-negative case-control study was used to estimate the duration of protection of the monovalent vaccines against hospitalisation as compared to those unvaccinated. In addition, the incremental VE of the bivalent BA.1 booster vaccines was estimated relative to those with waned immunity where the last dose was at least 6 months prior amongst those aged 50 years and older. Findings The protection conferred by the monovalent vaccines was well maintained long-term: absolute VE against hospitalisation amongst those aged 65 years and older who had received at least 3 doses plateaued from 6 months after the last dose at around 50%. Incremental VE (in addition to the protection from earlier vaccines) of the bivalent BA.1 boosters against hospitalisation peaked at 53.0% (95% C.I.; 47.9-57.5%) (equivalent to an absolute VE of approximately 75%) before waning to around 35.9% (95% C.I.; 31.4-40.1%) after 10 or more weeks. Interpretation This study provides evidence of the long-term duration of protection of the monovalent vaccines, suggesting individuals at lower risk of severe disease who did not receive a booster in autumn 2022 may not require regular re-vaccination. Furthermore, this study finds good evidence that the bivalent BA.1 booster vaccines are highly effective against hospitalisation amongst those aged 50 years and older with the sub-lineages of Omicron present in the autumn/winter of 2022 in England. Funding None. | Make paid
Aging compromises hematopoietic and immune system functions, making elderly individuals especially susceptible to hematopoietic failure, infections and tumor development and thus representing an important medical target for a broad range of diseases. During aging, hematopoietic stem cells (HSCs) lose their blood reconstitution capability and commit preferentially toward myeloid lineage (myeloid-bias). These processes are accompanied by an aberrant accumulation of mitochondria in HSCs. The administration of the mitophagy-inducer Urolithin-A re-establishes the correct mitochondrial homeostasis in HSCs and completely restores the blood reconstitution capability of old HSCs. Moreover, Urolithin-A supplemented food restores lymphoid compartments, boosts HSCs function and improves the immune response to viral infection in old mice. Altogether our results demonstrate that targeting mitophagy reverts aging phenotype in the hematopoietic and immune system. | Make paid
Alzheimer's disease (AD) is the leading cause of dementia in individuals over 65 in the U.S. Prevalence is projected to double by 2050, but current treatments cannot stop the progression of AD. Treatments administered before severe cognitive decline may be effective; identification of biomarkers for preclinical and prodromal stages of AD is therefore imperative. Cerebral blood flow (CBF) is a potential early biomarker for AD; generally, older adults with AD have decreased CBF compared to normally aging peers. Characterization should include the relationships between CBF and AD risk factors and pathologies. We assessed the relationships between CBF quantified by arterial spin labeled MRI, hypertension, APOE {epsilon}4, and tau and amyloid PET in 77 older adults: cognitively normal, subjective cognitive decline, and mild cognitive impairment. Tau and amyloid aggregation were related to altered CBF, and some of these relationships were dependent on hypertension or APOE {epsilon}4 status. Our findings suggest a complex relationship between risk factors, AD pathologies, and CBF that warrants future studies of CBF as a potential early biomarker for AD. | Make paid
Objective: Recently, we demonstrated cholesterol accelerating colorectal cancer (CRC) progression via squalene epoxidase (SQLE) reduction, activating the {beta}-catenin oncogenic pathway while downregulating the p53 pathway, mediated by the inhibition of GSK3{beta} activity (GSK3{beta}pS9). However, the interrelationship between cholesterol increase and CRC progression with aging has never been determined. Design: We utilized case data from public databases and human specimens to assess the relationship between cholesterol accumulation and CRC progression with aging. Digital image analysis-machine learning with multiplex fluorescence-immunohistochemistry evaluated the effects of SQLE, p53WT, p53MT, and GSK3{beta}pS9 (hereafter candidates) on the survival of CRC patients. Also, the prognostic and diagnostic abilities were assessed by a time-dependent receiver operating characteristic (timeROC) and a ROC curve with and without the discriminant score for the candidates as a single or whole, respectively. Results: We found an accumulation of cholesterol and cholesteryl ester in tissues with aging, which led to the acceleration of CRC progression through substantial decreases of SQLE, p53WT, p53MT, expressions and inhibition of GSK3{beta}pS9 activity in advanced CRCs. Retrospective studies demonstrated that SQLE significantly impacted the shortened progression-free survival of the population with progressive pathological severity and high CRC risk beyond the age of 50. Clinical assays further showed the excellent prognostic and diagnostic abilities of SQLE and GSK3{beta}pS9 but also the substantial diagnostic potential of the combined candidate for the aged high-risk CRC population. Conclusion: We provide new insights into the relationship between cholesterol increase and CRC progression with aging and identify valuable biomarkers for aged populations with high-risk CRC. | Make paid
Sleep-wake regulating circuits are affected during prodromal stages in the pathological progression of both Alzheimer's disease (AD) and Parkinson's disease (PD). Assessment of 24-hour rhythm impairment may serve as an early indicator of disease and cognitive decline. Our objective was to determine whether objective markers of 24-hour activity are associated with subsequent development of AD, PD, and cognitive decline. This longitudinal study obtained UK Biobank data from 82,829 individuals with valid accelerometer data (collected from June 2013 to January 2016) out of 103,671 eligible adults aged 40 to 79 years with a mean (+/-SD) follow-up of 6.8 (+/-0.9) years. AD and PD diagnoses were ascertained through September 2021, with data analysis conducted March to November 2022. The outcomes were accelerometer-derived measures of 24-hour activity (derived by cosinor, nonparametric, and functional principal component methods), incident AD and PD diagnosis (obtained through hospitalization or primary care records), longitudinal tests of cognitive function, and demographic characteristics. 82,829 participants consisted of 46,683 women (56%) and 36,146 men (44%) with a mean (+/-SD) age of 62.0 (+/-7.8) years at the time of actigraphy data collection. During the follow-up period, 191 individuals converted to AD (0.2%) and 266 to PD (0.3%). After adjusting for covariates, interdaily stability, a measure of regularity, (hazard ratio [HR] per SD increase 1.24, 95% confidence interval [CI] 1.04-1.47), diurnal amplitude (HR 0.77, CI 0.64-0.93), mesor (mean activity; HR 0.73, CI 0.56-0.95), and activity during most active 10 hours (HR 0.73, CI 0.59-0.91), were each associated with an increased risk of AD. Diurnal amplitude (HR 0.28, CI 0.23-0.34), mesor (HR 0.12, CI 0.10-0.16), activity during least active 5 hours (HR 0.24, CI 0.08-0.68), and activity during most active 10 hours (HR 0.20, CI 0.16-0.25), were associated with an increased risk of PD. Several measures were additionally predictive of longitudinal cognitive test performance. In this community-based longitudinal study, objective measures of 24-hour activity were associated with elevated risk of AD, PD, and accelerated cognitive decline, suggesting actigraphy-estimated 24-hour rhythm integrity may serve as a scalable early marker of neurodegenerative disease. | Make paid
ABSTRACT Purpose: To use a genome-wide polygenic risk score for hand grip strength (PRS HGS) to investigate whether the muscle strength genotype predicts the most common age related noncommunicable diseases, survival from acute adverse health events, and all cause mortality. Methods: This study consisted of 342 443 Finnish biobank participants from FinnGen Data Freeze 10 (53% women) aged 40 to 108 with combined genotype and health registry data. Associations were explored with a linear or Cox proportional hazards regression models. Results: A higher PRS HGS predicted a lower body mass index (BMI) ({beta} = -0.112 kg/m2, standard error (SE) = 0.017, P = 1.69 x 10-11) in women but not in men ({beta} = 0.004 kg/m2, P = 0.768, sex by PRS HGS interaction: P = 2.12 x 10-07). In all participants, a higher PRS HGS was associated with a lower risk for obesity diagnosis (hazard ratio 0.94, 95% confidence interval 0.93 to 0.95), type 2 diabetes (0.95, 0.94 to 0.96), ischemic heart diseases (0.97, 0.96 to 0.97), hypertension (0.97, 0.96 to 0.97), stroke (0.97, 0.96 to 0.98), asthma (0.94, 0.93 to 0.95), chronic obstructive pulmonary disease (0.94, 0.92 to 0.95), polyarthrosis (0.90, 0.88 to 0.92), knee arthrosis (0.98, 0.97 to 0.99), rheumatoid arthritis (0.95, 0.94 to 0.97), osteoporosis (0.95, 0.93 to 0.97), falls (0.98, 0.98 to 0.99), depression (0.95, 0.94 to 0.96), and vascular dementia (0.93, 0.89 to 0.96). In women only, a higher PRS predicted a lower hazard for any dementia (0.94, 0.92 to 0.96) and Alzheimer's disease (0.96, 0.93 to 0.98). Participants with a higher PRS HGS had a decreased risk of cardiovascular (0.96, 0.95 to 0.98) and all cause mortality (0.97, 0.96 to 0.98). However, the predictive value of the PRS HGS for mortality was not pronounced after adverse acute health events compared to the non-diseased period. Conclusions: The genotype that supports higher muscle strength protects against many future health adversities. Further research is needed to investigate whether or how a favourable lifestyle modifies this intrinsic capacity to resist diseases, and if the impacts of lifestyle behaviour on health differ due to polygenic risk. Keywords: genetics, muscle strength, risk, prediction, noncommunicable diseases, FinnGen | Make paid
Toxoplasma gondii is an obligate intracellular parasite whose tachyzoite form causes disease via a lytic growth cycle. Its metabolic and cellular pathways are primarily designed to ensure parasite survival within a host cell. But during its lytic cycle tachyzoites are exposed to the extracellular milieu and prolonged exposure requires activation of stress response pathways that include reprogramming the parasite proteome. Regulation of protein synthesis is therefore important for extracellular survival. We previously reported that in extracellularly stressed parasites that the elongation phase of protein synthesis is negatively regulated by the Toxoplasma oxygen sensing protein, PhyB. PhyB acts by promoting the activity of elongation factor eEF2, which is a GTPase that catalyzes the transfer of the peptidyl-tRNA from the A site to the P site of the ribosome. In the absence of PhyB, eEF2 is hyper-phosphorylated, which inhibits eEF2 from interacting with the ribosome. eEF2 kinases are atypical calcium-dependent kinases and BLAST analyses revealed the parasite kinase, CDPK3, as the most highly homologous to the Saccharomyces cerevisiae eEF2 kinase, RCK2. In parasites exposed to extracellular stress, loss of CDPK3 leads to decreased eEF2 phosphorylation and enhanced rates of elongation. Furthermore, co-immunoprecipitation studies revealed that CDPK3 and eEF2 interact in stressed parasites. Since CDPK3 and eEF2 normally localize to the plasma membrane and cytosol, respectively, we investigated how the two can interact. We report that under stress conditions that CDPK3 is not N-myristoylated likely leading to its cytoplasmic localization. In summary, we have identified a novel function for CDPK3 as the first protozoan extracellular-stress induced eEF2 kinase. | Make paid
Age-related decline in episodic memory performance is a well-replicated finding across numerous studies. Recent studies focusing on aging and individual differences found that the Big Five personality trait Openness to Experience is associated with better episodic memory performance in older adults, but the associated neural mechanisms are largely unclear. Here we investigated the relationship between Openness and memory network function in a sample of 352 participants (143 older adults, 50-80 years; 209 young adults, 18-35 years). Participants underwent functional magnetic resonance imaging (fMRI) during a visual memory encoding task. Functional memory brain-network integrity was assessed using the SAME scores (similarity of activations during memory encoding), which reflect the similarity of a participants memory network activity compared to prototypical fMRI activity patterns of young adults. Openness was assessed using the NEO Five Factor Inventory (NEO-FFI). Older vs. young adults showed lower memory performance and higher deviation of fMRI activity patterns (i.e., lower SAME scores). Specifically in older adults, high Openness was associated with better memory performance, and mediation analysis showed that this relationship was partially mediated by higher SAME scores. Our results suggest that trait Openness may constitute a protective factor in cognitive aging by better preservation of the brains memory network. | Make paid
Background: Information regarding the prevalence and etiologies of complete atrioventricular block (CAVB) in younger patients is scarce. We aimed to investigate the potential causes for non-iatrogenic CAVB, the prevalence of CAVB without an identified etiology, the utilization of guidelines-recommended advanced imaging modalities in adults presenting with an early-onset CAVB of unidentified etiology, as well as to identify the predictors for cardiac implantable electronic device (CIED) insertion. Methods: Using the National Inpatient Sample (NIS) database, we identified patients aged 18-60 hospitalized with non-iatrogenic CAVB in the US between 2015 (last quarter)-2019. Baseline demographics, clinical characteristics, potential etiologies for CAVB, advanced imaging utilization as well as outcomes including the need for temporary cardiac pacing (TCP) and CIED implantation were analyzed. Multivariable logistic regression models were used to identify predictors of CIED implantation. Results: An estimated total of 14,495 patients aged 18-60 with non-iatrogenic CAVB were identified. The mean age was 51 years, 60% were males and 3,050 (21%) had documentation of a prior conduction disorder. Eleven percent of the patients had a diagnosis of syncope and 6% suffered from a cardiac arrest. Two third of the patients (9,735, 67%) had no identified etiology for CAVB, of whom 8,205 (84%) were implanted with a permanent pacemaker (PPM), 180 patients (2%) with an implantable cardioverter-defibrillator (ICD), and 295 patients (3%) with a cardiac resynchronization therapy device. Only 40 patients (0.3%) underwent advanced imaging during their hospitalization. In multivariate analyses, older age [adjusted OR 1.046 (1.04-1.05), p<0.001] and the need for TCP [adjusted OR 1.543 (1.29-1.84), p<0.001], emerged as predictors for PPM implantation. Cardiac arrest [adjusted OR 2.786 (1.69-4.58), p<0.001] and younger age [adjusted OR 0.98 (0.96-0.99), p=0.02], were associated with ICD implantation. 185 patients (1.3%) died during their hospitalization. Conclusion: The majority of patients, hospitalized in the US for non-iatrogenic early-onset CAVB, had no identified etiology for their conduction disease. Despite the current US and European guidelines recommendation, advanced imaging prior to CIED implantation was under-utilized in this patient population. | Make paid
Oleocanthal and oleacein are olive oil phenolic compounds with well known anti-inflammatory and anti-oxidant properties. The main evidence, however, is provided by experimental studies. Few human clinical trials have examined the health benefits of olive oils rich in these polyphenols. Our aim was to assess the health properties of rich oleocanthal and oleacein extra virgin olive oil (EVOO), compared to those of common olive oil (OO), in people with prediabetes and obesity. This was a randomised, double-blind, crossover trial done in people aged 40-65 years with obesity (BMI 30-40 kg/m2) and prediabetes (HbA1c 5.7-6.4%). The intervention consisted in substituting for 1 month the oil used for food, both raw and cooked, by EVOO or OO. No hypocaloric diet or changes in physical activity were recommended. The primary outcome was the inflammatory status. Secondary outcomes were the oxidative status, body weight, metabolic status and lipid profile. An ANCOVA model adjusted for age, sex and treatment administration sequence was used for the statistical analysis. 91 patients were enrolled (33 men and 58 women) and finished the trial. A decrease in interferon-{gamma} was observed after EVOO treatment, reaching inter-treatment differences (P=0.041). Total antioxidant status increased and lipid and organic hydroperoxides decreased after EVOO treatment, the changes reaching significance compared to OO treatment (P<0.05). Decreases in weight, BMI and blood glucose (p<0.05) were found after treatment with EVOO and not with OO. In conclusion, treatment with EVOO rich in oleocanthal and oleacein differentially improved oxidative and inflammatory status in people with obesity and prediabetes | Make paid
Vaccination remains the primary strategy for ending the COVID-19 pandemic. However, vaccination rates are still low in low-income countries. The primary goal of this study was to describe the status of COVID-19 vaccine acceptance and hesitancy among women in Guinea and to identify associated predictors. We conducted a cross-sectional study in five Guinean cities (Conakry, Mamou, Kindia, Kankan and N'zerekore) across the four natural regions between Mar 22 and Aug 25 2021. Participants aged 18 were randomly recruited from the healthcare workers (HCWs) and the general population (GP). We used multivariate logistic regression to identify facilitators and barriers to acceptance of COVID-19 vaccination and a classification and regression tree (CART) to extract the profile of predictors. We included 2,208 women among the HCWs and 1,121 in the GP. Most HCWs (63%) were already vaccinated, compared to only 28% of GP. The main factors associated with acceptance of a COVID-19 vaccine in the HCWs were an absence of pregnancy ORA = 4.46 [CI95%: 3.08, 6.52] and positive subjective norms ORA = 2.34 [CI95%: 1.92, 2.84]. Regarding the GP, the main factors were the ability to receive the vaccine ORA = 5.20 [CI95%: 3.45, 8.01] and being adult ORA = 2.25 [CI95%: 1.34, 3.79] associated with acceptance of vaccination. Vaccination rates were higher in the HCWs. Favourable subjective norms and ability to receive the vaccine were facilitators of acceptance of COVID-19 vaccination, while youth and pregnancy were barriers to the approval of the COVID-19 vaccine. | Make paid
ABSTRACT Background: Post-stroke aphasia is a common but intractable sequela which still needs new and more effective treatments. Evidence from follow-ups after contralateral seventh cervical nerve transfer surgery indicated that nerve transection leads to immediate language improvements in patients with right post stroke aphasia. Objective: Through a prospective cohort design, this study aims to prove that C7 neurotomy at the intervertebral foramen (NC7) combined with a 3-week intensive speech and language therapy (iSLT) can improve the language function in post-stroke aphasia patients. Methods: In this study, patients aged over 18 years old and had been diagnosed with post-stroke aphasia for 1 year or longer were included. Primary outcomes were the change in the ability to retrieve personally relevant words in Boston Naming Test (BNT) with follow-up assessment after three weeks' iSLT post operatively. As well as several secondary outcome measures including the Western Aphasia Battery (WAB), daily communication abilities (measured by the Communication Activities of Daily Living Third Edition [CADL 3]) and Fugl-Meyer of upper limb part (UEFM). Results: The average increase of BNT score was 11.2 points from baseline to 3 weeks post operatively (P=0.001, 95%CI: 8.1-14.1). The WAB and CADL-3 assessment showed 9.4, 10.4 points increasing in average (P<0.005, 95%CI: 4.6 to 14.1; P<0.001, 95%CI:6.7 to 14.1) from baseline to 4-week follow-up, respectively. The mean difference from baseline to 3 weeks post-operatively in UEFM score decreased 0.8 points (95% CI: -3.2 to 1.6; p<0.405). Conclusions: NC7 plus iSLT significantly improved the language function in patients with post-stroke aphasia, and did not significantly affect the motor function of the right limb. The mechanism of this surgery needs to be further explored. | Make paid
Background: While endovascular thrombectomy (EVT) is considered as the most effective treatment for a select group of patients with acute ischemic stroke and large vessel occlusion, its safety and efficacy in older patients are still debated especially in read-world settings. This study reports outcomes of EVT in acute ischemic stroke patients aged 90 and older in our community hospital setting. Methods: Data between January 2018 and December 2022 were aggregated for all acute ischemic stroke patients with aged 90 and older at the time of EVT. Thirty-one patients met the criteria and were included in this report. The data valuables included, but are not limited to, demographics, stroke risk factors, thrombolysis in cerebral infarction (TICI), modified Rankin Scale (mRS), and NIH Stroke Scale (NIHSS). Results: All 31 patients had improvement in TICI scale. One had symptomatic intracranial hemorrhage after EVT not related to the procedure, but likely on the basis of reperfusion breakthrough. Three patients expired prior to their discharge from non-stroke related causes. Of remaining 28, four expired, six went into hospice care, and four lost to follow-up by 30-days post DC. Of six hospice cases, one expired by 90-day post DC, and additional three were lost to follow-up. Given this data, 20/27 (74%) survived to 30 days and 16/24 (67%) to 90 days. For their NIHSS symptomatic categories, 15/28 (54%) patients improved, 10/28 (36%) remained the same, and 3/28 (11%) declined. For mRS, at 30-days post DC, 7/24 (30%) patients showed improvement, 7/24 (30%) remained the same, and 10/24 (40%) declined. At 90-days post DC, 7/21 (33%) showed improvement from DC, 4/21 (19%) remained the same, and 10/21 (48%) declined. Conclusions: While a larger cohort study is necessary, our report supports the safety and efficacy of EVT in this patient aged 90 and older in a real-world setting. | Make paid
Objective: Recently, we demonstrated cholesterol accelerating colorectal cancer (CRC) progression via squalene epoxidase (SQLE) reduction, activating the {beta}-catenin oncogenic pathway while downregulating the p53 pathway, mediated by the inhibition of GSK3{beta} activity (GSK3{beta}pS9). However, the interrelationship between cholesterol increase and CRC progression with aging has never been determined. Design: We utilized case data from public databases and human specimens to assess the relationship between cholesterol accumulation and CRC progression with aging. Digital image analysis-machine learning with multiplex fluorescence-immunohistochemistry evaluated the effects of SQLE, p53WT, p53MT, and GSK3{beta}pS9 (hereafter candidates) on the survival of CRC patients. Also, the prognostic and diagnostic abilities were assessed by a time-dependent receiver operating characteristic (timeROC) and a ROC curve with and without the discriminant score for the candidates as a single or whole, respectively. Results: We found an accumulation of cholesterol and cholesteryl ester in tissues with aging, which led to the acceleration of CRC progression through substantial decreases of SQLE, p53WT, p53MT, expressions and inhibition of GSK3{beta}pS9 activity in advanced CRCs. Retrospective studies demonstrated that SQLE significantly impacted the shortened progression-free survival of the population with progressive pathological severity and high CRC risk beyond the age of 50. Clinical assays further showed the excellent prognostic and diagnostic abilities of SQLE and GSK3{beta}pS9 but also the substantial diagnostic potential of the combined candidate for the aged high-risk CRC population. Conclusion: We provide new insights into the relationship between cholesterol increase and CRC progression with aging and identify valuable biomarkers for aged populations with high-risk CRC. | Make paid
Aging is a complex process influenced by a wide range of environmental and molecular factors. Despite this complexity, individuals tend to age in highly similar ways, leading to the question of what drives this convergence. Recent research, including my own discoveries, suggests that the length of transcript molecules plays a crucial role in age-dependent changes to the transcriptome. Drawing inspiration from the road trip analogy of cellular transcription, I propose that a non-linear scaling law drives convergence towards specific pleiotropic phenotypes in biological aging. This scaling law is based on the notion that molecular changes observed during aging may reflect unspecific damage to cellular physiology. By validating this hypothesis, I can improve our understanding of biological aging and identify new candidate compounds for anti-aging interventions, as well as re-identify one known intervention. This work has actionable implications for improving human health and extending lifespans. | Make paid