Mosaic loss of Y chromosome (LOY) is the most common somatic change that occurs in circulating white blood cells of older men. LOY in leukocytes is associated with increased risk for all-cause ...mortality and a range of common disease such as hematological and non-hematological cancer, Alzheimer's disease, and cardiovascular events. Recent genome-wide association studies identified up to 156 germline variants associated with risk of LOY. The objective of this study was to use these variants to calculate a novel polygenic risk score (PRS) for LOY, and to assess the predictive performance of this score in a large independent population of older men.
We calculated a PRS for LOY in 5131 men aged 70 years and older. Levels of LOY were estimated using microarrays and validated by whole genome sequencing. After adjusting for covariates, the PRS was a significant predictor of LOY (odds ratio OR = 1.74 per standard deviation of the PRS, 95% confidence intervals CI 1.62-1.86, p < 0.001). Men in the highest quintile of the PRS distribution had > fivefold higher risk of LOY than the lowest (OR = 5.05, 95% CI 4.05-6.32, p < 0.001). Adding the PRS to a LOY prediction model comprised of age, smoking and alcohol consumption significantly improved prediction (AUC = 0.628 CI 0.61-0.64 to 0.695 CI 0.67-0.71, p < 0.001).
Our results suggest that a PRS for LOY could become a useful tool for risk prediction and targeted intervention for common disease in men.
AMP-activated protein kinase (AMPK) coordinates cellular metabolism in response to energy demand as well as to a variety of stimuli. The AMPK β subunit acts as a scaffold for the α catalytic and γ ...regulatory subunits and targets the AMPK heterotrimer to glycogen. We have determined the structure of the AMPK β glycogen binding domain in complex with β-cyclodextrin. The structure reveals a carbohydrate binding pocket that consolidates all known aspects of carbohydrate binding observed in starch binding domains into one site, with extensive contact between several residues and five glucose units. β-cyclodextrin is held in a pincer-like grasp with two tryptophan residues cradling two β-cyclodextrin glucose units and a leucine residue piercing the β-cyclodextrin ring. Mutation of key β-cyclodextrin binding residues either partially or completely prevents the glycogen binding domain from binding glycogen. Modeling suggests that this binding pocket enables AMPK to interact with glycogen anywhere across the carbohydrate’s helical surface.
Thioredoxin‐interacting protein (TXNIP) is one of the six known α‐arrestins and has recently received considerable attention owing to its involvement in redox signalling and metabolism. Various ...stress stimuli such as high glucose, heat shock, UV, H2O2 and mechanical stress among others robustly induce the expression of TXNIP, resulting in the sequestration and inactivation of thioredoxin, which in turn leads to cellular oxidative stress. While TXNIP is the only α‐arrestin known to bind thioredoxin, TXNIP and two other α‐arrestins, Arrdc4 and Arrdc3, have been implicated in metabolism. Furthermore, owing to its roles in the pathologies of diabetes and cardiovascular disease, TXNIP is considered to be a promising drug target. Based on their amino‐acid sequences, TXNIP and the other α‐arrestins are remotely related to β‐arrestins. Here, the crystal structure of the N‐terminal domain of TXNIP is reported. It provides the first structural information on any of the α‐arrestins and reveals that although TXNIP adopts a β‐arrestin fold as predicted, it is structurally more similar to Vps26 proteins than to β‐arrestins, while sharing below 15% pairwise sequence identity with either.
Cancer treatment planning in older adults is complex and requires careful balancing of survival, quality of life benefits, and risk of treatment-related morbidity and toxicity. As a result, treatment ...selection in this cohort tends to differ from that for younger patients. However, there are very few studies describing cancer treatment patterns in older cohorts.
We used data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial and the ASPREE Cancer Treatment Substudy (ACTS) to describe cancer treatment patterns in older adults. We used a multivariate logistic regression model to identify factors affecting receipt of treatment.
Of 1893 eligible Australian and United States (US) participants with incident cancer, 1569 (81%) received some form of cancer treatment. Non-metastatic breast cancers most frequently received treatment (98%), while haematological malignancy received the lowest rates of treatment (60%). Factors associated with not receiving treatment were older age (OR 0.94, 95% CI 0.91-0.96), residence in the US (OR 0.34, 95% CI 0.22-0.54), smoking (OR 0.57, 95% CI 0.40-0.81), and diabetes (OR 0.56, 95% CI 0.39-0.80). After adjustment for treatment patterns in sex-specific cancers, sex did not impact receipt of treatment.
This study is one of the first describing cancer treatment patterns and factors affecting receipt of treatment across common cancer types in older adults. We found that most older adults with cancer received some form of cancer treatment, typically surgery or systemic therapy, although this varied by factors such as cancer type, age, sex, and country of residence.
The cholesterol-dependent cytolysins (CDCs), a superfamily of pore-forming toxins, are characterized by a conserved undecapeptide motif that is believed to be critical for membrane recognition by ...means of cholesterol. Intermedilysin (ILY), an unusual member of the CDCs, exhibits specificity for human cells and contains nonconservative substitutions in the motif. We show that the cellular specificity of ILY is based on its ability to specifically bind to human cells and does not involve some other feature of the CDC mechanism. Furthermore, cellular recognition by ILY appears to be encoded in domain 4 alone but does not involve the variant undecapeptide of ILY. We show that the undecapeptide is involved in the prepore-to-pore conversion of ILY and so demonstrate a direct connection between the structure of the undecapeptide and the prepore-to-pore transition. We have determined the crystal structure of ILY, which, when compared to the known structure of a prototypical CDC, suggests that the basic aspects of its 3D structure are likely to be conserved in all CDCs.
Cholesterol-dependent cytolysins (CDCs), a large family of bacterial toxins, are secreted as water-soluble monomers and yet are capable of generating oligomeric pores in membranes. Previous work has ...demonstrated that large scale structural rearrangements occur during this transition but the detailed mechanism by which these changes take place remains a puzzle. Despite evidence of structural and functional couplings between domains 3 and 4, the crystal structure of the CDC, perfringolysin O (PFO), shows the two domains do not make direct contact. Here, we present crystal structures of PFO that demonstrate movements of domain 4 are sufficient to trigger conformational changes that are transmitted through the molecule to the distant domain 3. These coupled movements result in a loss of many contacts between domain 3 and rest of the molecule that would eventually lead to the exposure of transmembrane regions in preparation for membrane insertion. The structures reveal a detailed molecular pathway that may be the basis for the allosteric transition that occurs on initial membrane binding leading to the exposure of membrane-spanning regions in a domain distant from the initial site of interaction.
ObjectiveGenetic variants that disrupt the function of the PCSK9 (proprotein convertase subtilisin kexin type 9) and APOB (apolipoprotein B)genes result in lower serum low-density lipoprotein ...cholesterol (LDL-C) levels and subsequently confer protection against coronary heart disease (CHD). The objective of this study was to measure the prevalence and selective advantage of such variants among healthy older individuals without a history of CHD.MethodsWe performed targeted sequencing of the PCSK9 and APOB genes in 13 131 healthy individuals without CHD aged 70 years or older enrolled into the ASPirin in Reducing Events in the Elderly trial. We detected variants in the PCSK9 and APOB genes with predicted loss-of-function. We associated variant carrier status with serum LDL-C and total cholesterol (TC) levels at the time of study enrolment, adjusting for statin use.ResultsWe detected 22 different rare PCSK9/APOB candidate variants with putative lipid-lowering effect, carried by 104 participants (carrier rate 1 in 126). Serum LDL-C and TC concentrations for rare PCSK9/APOB variant carriers were consistently lower than non-carriers. Rare variant carrier status was associated with 19.4 mg/dL (14.6%) lower LDL-C, compared with non-carriers (p≤0.001, adjusted for statin use). Statin prescriptions were less prevalent in rare variant carriers (16%) than non-carriers (35%). The more common PCSK9 R46L variant (rs11591147-T) was associated with 15.5 mg/dL (11.8%) lower LDL-C in heterozygotes, and 25.2 mg/dL (19.2%) lower LDL-C in homozygotes (both p≤0.001).ConclusionsLipid-lowering genetic variants are carried by healthy older individuals and contribute to CHD-free survival.Trial registration numberNCT01038583.
Mitochondrial DNA (mtDNA) encodes key proteins of the electron transfer chain (ETC), which produces ATP through oxidative phosphorylation (OXPHOS) and is essential for cells to perform specialised ...functions. Tumor-initiating cells use aerobic glycolysis, a combination of glycolysis and low levels of OXPHOS, to promote rapid cell proliferation and tumor growth. Glioblastoma multiforme (GBM) is an aggressively malignant brain tumor and mitochondria have been proposed to play a vital role in GBM tumorigenesis.
Using next generation sequencing and high resolution melt analysis, we identified a large number of mtDNA variants within coding and non-coding regions of GBM cell lines and predicted their disease-causing potential through in silico modeling. The frequency of variants was greatest in the D-loop and origin of light strand replication in non-coding regions. ND6 was the most susceptible coding gene to mutation whilst ND4 had the highest frequency of mutation. Both genes encode subunits of complex I of the ETC. These variants were not detected in unaffected brain samples and many have not been previously reported. Depletion of HSR-GBM1 cells to varying degrees of their mtDNA followed by transplantation into immunedeficient mice resulted in the repopulation of the same variants during tumorigenesis. Likewise, de novo variants identified in other GBM cell lines were also incorporated. Nevertheless, ND4 and ND6 were still the most affected genes. We confirmed the presence of these variants in high grade gliomas.
These novel variants contribute to GBM by rendering the ETC. partially dysfunctional. This restricts metabolism to anaerobic glycolysis and promotes cell proliferation.
Introduction. Objective and regular students’ knowledge monitoring in technical subjects can be implemented by means of special tests allowing for the required mastering level of the matter and the ...reliable consolidation of the acquired knowledge. Various aspects of the application of tests in the academic activity were considered.
Materials and methods. Tests used in practical studies should meet specific requirements, such as: validity, definiteness, simplicity, unambiguity, reliability. The identification of mastering levels makes it possible to “troubleshoot” and to improve the academic activity and the mastering degree of the competences by the students. Based on the assessment of the studying pattern of the forthcoming activity, one could point out four mastering levels of the subject matter. Level I tests include recognition, discrimination and classification. Level II tests monitor the mastering of the subject in the level of “reproduction” allowing for retrieval of information from the memory and its analysis, for routine assignment solutions. Level III tests impose special assignments challenging a student with quests for which no ready algorithms are catered, whereas the solutions found lead to obtaining of subjectively new information. Level IV tests reveal students’ capability to take decisions in new problematic situations, the solutions found, being a result of creative activity, are followed by obtaining of objectively new information.
Results. To establish an efficient system of monitoring tests in a certain subject, a number of basic prerequisites is required, such as a data base, a sample group of with the required number of assignments, at least 30 and maximum 70, a time limit in accordance with the required labor intensity, assessment of the assignments and its criteria, the output of the results.
Conclusions. If there is a required number of computers of at least one PC per two students, correctly arranged computer testing considerably reduces time demand of a monitoring event, increases the responsibility and the progress of the students, guarantees the objectiveness of the knowledge monitoring and helps to avoid conflicts.
Maleylacetoacetate isomerase (MAAI), a key enzyme in the metabolic degradation of phenylalanine and tyrosine, catalyzes the glutathione-dependent isomerization of maleylacetoacetate to ...fumarylacetoacetate. Deficiencies in enzymes along the degradation pathway lead to serious diseases including phenylketonuria, alkaptonuria, and the fatal disease, hereditary tyrosinemia type I. The structure of MAAI might prove useful in the design of inhibitors that could be used in the clinical management of the latter disease. Here we report the crystal structure of human MAAI at 1.9 Å resolution in complex with glutathione and a sulfate ion which mimics substrate binding. The enzyme has previously been shown to belong to the zeta class of the glutathione S-transferase (GST) superfamily based on limited sequence similarity. The structure of MAAI shows that it does adopt the GST canonical fold but with a number of functionally important differences. The structure provides insights into the molecular bases of the remarkable array of different reactions the enzyme is capable of performing including isomerization, oxygenation, dehalogenation, peroxidation, and transferase activity.
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