APOE Genotype Modulates Proton Magnetic Resonance Spectroscopy Metabolites in the Aging Brain

Background: Proton magnetic resonance spectroscopy (H-1-MRS) studies on healthy aging have reported inconsistent findings and have not systematically taken into account the possible modulatory effect of APOE genotype. We aimed to quantify brain metabolite changes in healthy subjects in relation to age and the presence of the APOE E4 genetic risk factor for Alzheimer\u27s disease. Additionally, we examined these measures in relation to cognition. Methods: We studied a cohort of 112 normal adults between 50 and 86 years old who were genotyped for APOE genetic polymorphism. Measurements of H-1-MRS metabolites were obtained in the posterior cingulate and precuneus region. Measures of general cognitive functioning, memory, executive function, semantic fluency, and speed of processing were also obtained. Results: General linear model analysis demonstrated that older APOE E4 carriers had significantly higher choline/creatine and myoinositol/creatine ratios than APOE E3 homozygotes. Structural equation modeling resulted in a model with an excellent goodness of fit and in which the APOE x age interaction and APOE status each had a significant effect on H-1-MRS metabolites (choline/creatine and myo-inositol/creatine). Furthermore, the APOE x age variable modulation of cognition was mediated by H-1-MRS metabolites. Conclusions: In a healthy aging normal population, choline/creatine and myo-inositol/creatine ratios were significantly increased in APOE E4 carriers, suggesting the presence of neuroinflammatory processes and greater membrane turnover in older carriers. Structural equation modeling analysis confirmed these possible neurodegenerative markers and also indicated the mediator role of these metabolites on cognitive performance among older APOE E4 carriers

Overview of the MOSAiC expedition: Physical oceanography

Arctic Ocean properties and processes are highly relevant to the regional and global coupled climate system, yet still scarcely observed, especially in winter. Team OCEAN conducted a full year of physical oceanography observations as part of the Multidisciplinary drifting Observatory for the Study of the Arctic Climate (MOSAiC), a drift with the Arctic sea ice from October 2019 to September 2020. An international team designed and implemented the program to characterize the Arctic Ocean system in unprecedented detail, from the seafloor to the air-sea ice-ocean interface, from sub-mesoscales to pan-Arctic. The oceanographic measurements were coordinated with the other teams to explore the ocean physics and linkages to the climate and ecosystem. This paper introduces the major components of the physical oceanography program and complements the other team overviews of the MOSAiC observational program. Team OCEAN’s sampling strategy was designed around hydrographic ship-, ice- and autonomous platform-based measurements to improve the understanding of regional circulation and mixing processes. Measurements were carried out both routinely, with a regular schedule, and in response to storms or opening leads. Here we present along-drift time series of hydrographic properties, allowing insights into the seasonal and regional evolution of the water column from winter in the Laptev Sea to early summer in Fram Strait: freshening of the surface, deepening of the mixed layer, increase in temperature and salinity of the Atlantic Water. We also highlight the presence of Canada Basin deep water intrusions and a surface meltwater layer in leads. MOSAiC most likely was the most comprehensive program ever conducted over the ice-covered Arctic Ocean. While data analysis and interpretation are ongoing, the acquired datasets will support a wide range of physical oceanography and multi-disciplinary research. They will provide a significant foundation for assessing and advancing modeling capabilities in the Arctic Ocean

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Open Data: Growing Up and Getting Specific

Open data has been given a lot of attention in the public. In some situation ‘open by default’ has become established as a core principle, whereas others argue about the limited results and the lack of robust studies demonstrating the value, and point to the risk that open data might turn out to be a short lived policy fad. This special issue contains a variety of research papers addressing this topic from different views and providing recent research results on open data. The papers in this issue deepen the understanding of open data and show that the subject of open data is moving from the general to the study of specifics. The special issue also includes invited papers presented at the first public meeting of the SharePSI project. Share-PSI 2.0 is the European network for the exchange of experience and ideas around implementing open data policies in the public sector.Engineering, Systems and ServicesTechnology, Policy and Managemen

A Midsummer Night's Dream Transcript : Guide

This post-production script of Russell T Davies' A Midsummer Night's Dream includes music, lighting, and camera cues, offering a comprehensive overview of the BBC TV adaptation. This post-production script of Russell T Davies' A Midsummer Night's Dream includes music, lighting, and camera cues, offering a comprehensive overview of the BBC TV adaptation. Description based on online resource; title from title screen (Digital Theatre+, viewed August 24, 2022

Developing Transdisciplinary Approaches to Sustainability Challenges: The Need to Model Socio-Environmental Systems in the Longue Durée

Human beings are an active component of every terrestrial ecosystem on Earth. Although our local impact on the evolution of these ecosystems has been undeniable and extensively documented, it remains unclear precisely how our activities are altering them, in part because ecosystems are dynamic systems structured by complex, non-linear feedback processes and cascading effects. We argue that it is only by studying human–environment interactions over timescales that greatly exceed the lifespan of any individual human (i.e., the deep past or longue durée), we can hope to fully understand such processes and their implications. In this article, we identify some of the key challenges faced in integrating long-term datasets with those of other areas of sustainability science, and suggest some useful ways forward. Specifically, we (a) highlight the potential of the historical sciences for sustainability science, (b) stress the need to integrate theoretical frameworks wherein humans are seen as inherently entangled with the environment, and (c) propose formal computational modelling as the ideal platform to overcome the challenges of transdisciplinary work across large, and multiple, geographical and temporal scales. Our goal is to provide a manifesto for an integrated scientific approach to the study of socio-ecological systems over the long term.Policy Analysi

The value of magnetic resonance spectroscopy in tumour imaging

Magnetic resonance (MR) imaging has a key role in the management of many childhood tumours. There is increasing interest in extending these investigations to MR techniques that give information on tumour biology in vivo. Magnetic resonance spectroscopy (MRS) is one such method and it provides information on tissue biochemistry. Promising results have been obtained from many preclinical and clinical studies, leading to an expectation that MRS will play a valuable clinical role. However, the role of MRS is not yet well defined and there is a paucity of data from multi-centre clinical trials. In this article we concentrate on MRS in paediatric oncology and provide some general guidance on current applications and outline areas that need to be developed further

First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial

Background Bisphosphonates reduce the risk of skeletal events in patients with malignant bone disease, and zoledronic acid has shown potential anticancer effects in preclinical and clinical studies. We aimed to establish whether bisphosphonates can affect clinical outcomes in patients with multiple myeloma. Methods Patients of age 18 years or older with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK. Computer-generated randomisation sequence was used to allocate patients equally, via an automated telephone service, to receive 4 mg zoledronic acid as an infusion every 3-4 weeks or 1600 mg oral clodronic acid daily. Patients also received intensive or non-intensive induction chemotherapy. No investigators, staff, or patients were masked to treatment allocation, and bisphosphonate and maintenance therapy continued at least until disease progression. The primary endpoints were overall survival, progression-free survival, and overall response rate. We assessed between-group differences with Cox proportional hazards models for progression-free survival and overall survival, and with logistic regression models for overall response rate. Analysis was by intention to treat. This trial is registered, number ISRCTN68454111. Findings 1970 patients were enrolled between May, 2003, and November, 2007, of whom 1960 were eligible for intention-to-treat analysis: 981 in the zoledronic acid group (555 on intensive chemotherapy, 426 on non-intensive chemotherapy); and 979 on clodronic acid (556 on intensive chemotherapy, 423 on non-intensive chemotherapy). The treatment cutoff was Oct 5,2009, with patients receiving bisphosphonates for a median of 350 days (IQR 137-632) before disease progression, with a median of 3.7 years' follow-up (IQR 2.9-4.7). Zoledronic acid reduced mortality by 16% (95% CI 4-26) versus clodronic acid (hazard ratio [HR] 0.84, 95% CI 0.74-0.96; p=0.0118), and extended median overall survival by 5.5 months (50.0 months, IQR 21.0 to not reached vs 44.5 months, IQR 16.5 to not reached; p=0.04). Zoledronic acid also significantly improved progression-free survival by 12% (95% CI 2-20) versus clodronic acid (HR 0.88, 95% CI 0.80-0.98; p=0.0179), and increased median progression-free survival by 2.0 months (19.5 months, IQR 9.0-33.0 vs 17.5 months, IQR 8.5-34.0; p=0.07). Rates of complete, very good partial, or partial response did not differ significantly between the zoledronic acid and clodronic acid groups for patients receiving intensive induction chemotherapy (432 patients [78%] vs 422 [76%]; p=0.43) or non-intensive induction chemotherapy (215 [50%] vs 195 [46%]; p=0.18). Both bisphosphonates were generally well tolerated, with similar occurrence of acute renal failure and treatment-emergent serious adverse events, but zoledronic acid was associated with higher rates of confirmed osteonecrosis of the jaw (35 [4%]) than was clodronic acid (3 [<1%]). Interpretation Consistent with the potential anticancer activity of zoledronic acid, overall survival improved independently of prevention of skeletal-related events, showing that zoledronic acid has treatment benefits beyond bone health. These findings support immediate treatment with zoledronic acid in patients with newly diagnosed multiple myeloma, not only for prevention of skeletal-related events, but also for potential antimyeloma benefits