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Using a decade of administrative data from the Government of Canada, we provide fresh analysis of the composition and distribution of staff most formally associated with policy work, the Economics and Social Science (EC) classification. Comparative analysis across unit levels including 'ministerial departments' and central agencies, as well as non-standard organizations support but clarify the nature of the uneven distribution of policy analytical capacity across government. We demonstrate a dramatic increase in not only the overall complement of EC staff over time, particularly since 2017, but also significant growth at senior levels while junior EC staff have remained stable or declined. The findings also point to new dynamics related to the pace, orientation, and distribution of policy analytical capacity as governments gain, lose, and exercise that capacity often in the face of tough choices about how, where, and when to deploy policy resources. A partir d'une decennie de donnees administratives du gouvernement du Canada, nous formulons une nouvelle analyse de la composition et de la repartition du personnel le plus formellement associe au travail d'elaboration des politiques, la classification Economique et services de sciences sociales (EC). L'analyse comparative entre les differents niveaux d'unites, y compris les << ministeres >> et les organismes centraux, ainsi que les organismes non conventionnels, soutient mais clarifie la nature de la repartition inegale de la capacite d'analyse des politiques dans l'ensemble du gouvernement. Nous prouvons une augmentation spectaculaire non seulement de l'effectif global du personnel d'EC au fil du temps, en particulier depuis 2017, mais egalement une forte croissance au niveau des hauts dirigeants, tandis que le personnel subalterne d'EC est reste stable ou a diminue. Les resultats suggerent aussi de nouvelles dynamiques liees au rythme, a l'orientation et a la distribution de la capacite de formulation et d'analyse des politiques alors que les gouvernements gagnent, perdent et exercent cette capacite, souvent compte tenu des choix difficiles sur comment, ou et quand deployer les ressources politiques., INTRODUCTION Governments around the world are struggling with a variety of policy issues. Some are emergent like Covid-19 while others like economic productivity, social equality, and healthcare are longstanding. Part [...]

Concerns of a decline in public service policy capacity coupled with evolving policy advisory systems have seen public services seek to reform their policy capacity and practices. This article examines the flagship policy modernisation initiatives launched by the Australian, Canadian, British, and New Zealand governments. Comparative analysis reveals a shared emphasis on overarching objectives, but important differences in their design, how they are embedded within the public service, and their comprehensiveness. The New Zealand and British initiatives are found to be the most comprehensive and stable, while the Canadian and Australian approaches suffer from repeated reinvention exercises and resource and leadership precarity. An examination of these initiatives also provides new insights into understanding the trade‐offs and tensions around how these initiatives aim to address public service policymaking and effective advisory system participation. Points for practitioners: The public service's role within advisory systems is evolving and needs to be carefully reconsidered.Senior officials need to get serious about effectively scoping reform initiatives and being clearer about the trade‐offs associated with broad or more targeted approaches.Initiatives are drastically under‐resourced even in the best of scenarios. Governments and senior officials need to step up and invest in sustainable and well‐institutionalised initiatives.Practitioners will need to be creative about how and where they can access tools and approaches to improve their policymaking in cases where governments continue to under‐resource policy modernisation. [ABSTRACT FROM AUTHOR]

This document is an editorial titled "The role and mechanism of metabolic dysfunction in the development of neurodegenerative disease." It discusses the intersection of metabolic dysfunction and neurodegenerative diseases, such as Alzheimer's disease. The editorial highlights several research studies that provide insights into how metabolic processes influence the development and progression of these diseases. The studies examine the effects of diet-induced obesity, genetic risk factors, metabolic alterations in astrocytes, and the role of microRNAs in obstructive sleep apnea and its associated metabolic complications. The editorial emphasizes the importance of a comprehensive approach to understanding and managing neurodegenerative disorders, integrating insights from various disciplines. It suggests that interventions targeting metabolic health could have significant impacts on the prevention and management of these diseases. [Extracted from the article]

This article provides fresh empirical insights into the evolving nature of policy analytical capacity in Australia, Britain, Canada, and New Zealand. We argue for a focus on the formal policy staff employed in government to provide greater conceptual clarity and empirical purchase regarding specific types of policy analytical resources linked to capacity. Using ten years of administrative data we chart the evolution of the size, composition, and distribution of formal public service policy staff in these cases. We find, contrary to expectations, that formal policy staff have increased in all four cases. Comparative analysis reveals not only uneven staffing capacity across government organizations, but also important developments in the seniority and distribution of staff in “analysts” and “managers” classifications. The findings are used to generate country profiles that demonstrate more nuanced patterns of policy analytical capacity change over time. The findings also raise important questions about shortcomings in how governments track and classify their policy staff, and their ability to effectively manage policy analytical resources in policy making. [ABSTRACT FROM AUTHOR]

This exploratory article examines the contemporary state of formal government policy staff in Australia, Britain, Canada, and New Zealand, contributing to the ongoing research seeking to understand the policy capacity of governments. It analyzes the size, composition, and distribution of the countries' formal policy staff across government units. Comparative analysis reveals significant differences in the basic organizing approaches used to categorize policy staff as well as important differences in their numbers, composition, and distribution across government units. While uneven distributions characterize all four cases, there is significant variance in where staff work, their seniority, and functional classifications as "analysts" or "managers". The analysis provides fresh insights into the nature and availability of policy analytical capacity within these governments. It also underscores major gaps in how governments collect and make available basic data on their policy staff, which raises questions about their ability to effectively manage and deploy those staff. [ABSTRACT FROM AUTHOR]

Inhibition of either the insulin-like or target of rapamycin (TOR) pathways in the nematode Caenorhabditis elegans extends life span. Here, we demonstrate that starvation and inhibition of the C. elegans insulin receptor homolog (daf-2) elicits a daf-16-dependent up-regulation of a mitochondrial superoxide dismutase (sod-3). We also find that although heat and oxidative stress result in nuclear localization of the DAF-16 protein, these stressors do not activate a SOD-3 reporter, suggesting that nuclear localization alone may not be sufficient for transcriptional activation of DAF-16. We show that inhibition of either TOR activity or key components of the cognate translational machinery (eIF-4G and EIF-2B homologs) increases life span by both daf-16-dependent and -independent mechanisms. Finally, we demonstrate that at least one nematode hexokinase is localized to the mitochondria. We propose that the increased life spans conferred by alterations in both the TOR and insulin-like pathways function by inappropriately activating food-deprivation pathways.

A study was conducted on the stability of a plasmid-borne 94-base pair palindromic insertion incorporated in the yeast plasmid beta-galactose gene. The inverted repeat, which had a poly GT sequence, exhibited instability in Saccharomyces cerevisiae and displayed a minimal deletion frequency of approximately 10(super -4) per mitotic division. All deletions were found to involve an interaction between two 5-base pair repeat flanking the inverted repeat. Results also indicated that a rad52 mutation did not influence both the deletion rate and the deletion type.

Abstract Background To examine the effect of genetic variation in APOE, IDE and IL1B on the response to induced ketosis in the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) in subjects with mild to moderate Alzheimer's disease (AD). Methods Genotype effects on ADAS-Cog scores from a randomized, double-blind, placebo-controlled study in mild to moderate AD were examined by an overall two way analysis of variance. In addition, interactions with the carriage status of the epsilon 4 allele of the APOE gene (APOE4) were examined. Results Significant differences in response to induced ketosis were found among non-carriers of putative gain-of-function polymorphisms in rs1143627 and rs16944 in the IL1B gene and among variants of the polymorphism rs2251101 in the IDE gene. Significant differences were found among non-carriers of the APOE4 gene, with notable improvement among the E3/E3 genotype group. Conclusions Variants in APOE, IL1B and IDE may influence the cognitive response to induced ketosis in patients with mild to moderate AD. Trial registration This trial was registered with ClinicalTrials.gov, registry number NCT00142805.

Abstract Background Alzheimer's disease (AD) is characterized by early and region-specific declines in cerebral glucose metabolism. Ketone bodies are produced by the body during glucose deprivation and are metabolized by the brain. An oral ketogenic compound, AC-1202, was tested in subjects with probable AD to examine if ketosis could improve cognitive performance. Methods Daily administration of AC-1202 was evaluated in 152 subjects diagnosed with mild to moderate AD in a US-based, 90-day, randomized, double-blind, placebo-controlled, parallel-group study. Subjects were on a normal diet and continued taking approved AD medications. Primary cognitive end points were mean change from Baseline in the AD Assessment Scale-Cognitive subscale (ADAS-Cog), and global scores in the AD Cooperative Study – Clinical Global Impression of Change (ADCS-CGIC). AC-1202 was compared to Placebo in several population groups, including: intention-to-treat (ITT), per protocol, and dosage compliant groups. Results were also stratified by APOE4 carriage status (a predefined analysis based on the epsilon 4 (E4) variant of the apolipoprotein E gene). This trial was registered with ClinicalTrials.gov, registry number NCT00142805, information available at http://clinicaltrials.gov/ct2/show/NCT00142805 Results AC-1202 significantly elevated a serum ketone body (β-hydroxybutyrate) 2 hours after administration when compared to Placebo. In each of the population groups, a significant difference was found between AC-1202 and Placebo in mean change from Baseline in ADAS-Cog score on Day 45: 1.9 point difference, p = 0.0235 in ITT; 2.53 point difference, p = 0.0324 in per protocol; 2.6 point difference, p = 0.0215 in dosage compliant. Among participants who did not carry the APOE4 allele (E4(-)), a significant difference was found between AC-1202 and Placebo in mean change from Baseline in ADAS-Cog score on Day 45 and Day 90. In the ITT population, E4(-) participants (N = 55) administered AC-1202 had a significant 4.77 point difference in mean change from Baseline in ADAS-Cog scores at Day 45 (p = 0.0005) and a 3.36 point difference at Day 90 (p = 0.0148) compared to Placebo. In the per protocol population, E4(-) participants receiving AC-1202 (N = 37) differed from placebo by 5.73 points at Day 45 (p = 0.0027) and by 4.39 points at Day 90 (p = 0.0143). In the dosage compliant population, E4(-) participants receiving AC-1202 differed from placebo by 6.26 points at Day 45 (p = 0.0011, N = 38) and 5.33 points at Day 90 (p = 0.0063, N = 35). Furthermore, a significant pharmacologic response was observed between serum β-hydroxybutyrate levels and change in ADAS-Cog scores in E4(-) subjects at Day 90 (p = 0.008). Adverse events occurred more frequently in AC-1202 subjects, were primarily restricted to the gastrointestinal system, and were mainly mild to moderate in severity and transient in nature. Conclusion AC-1202 rapidly elevated serum ketone bodies in AD patients and resulted in significant differences in ADAS-Cog scores compared to the Placebo. Effects were most notable in APOE4(-) subjects who were dosage compliant.

Abstract Background Alzheimer's disease (AD) is a progressive neurodegenerative disorder that primarily strikes the elderly. Studies in both humans and animal models have linked the consumption of cholesterol and saturated fats with amyloid-β (Aβ) deposition and development of AD. Yet, these studies did not examine high fat diets in combination with reduced carbohydrate intake. Here we tested the effect of a high saturated fat/low carbohydrate diet on a transgenic mouse model of AD. Results Starting at three months of age, two groups of female transgenic mice carrying the "London" APP mutation (APP/V717I) were fed either, a standard diet (SD) composed of high carbohydrate/low fat chow, or a ketogenic diet (KD) composed of very low carbohydrate/high saturated fat chow for 43 days. Animals fed the KD exhibited greatly elevated serum ketone body levels, as measured by β-hydroxybutyrate (3.85 ± 2.6 mM), compared to SD fed animals (0.29 ± 0.06 mM). In addition, animals fed the KD lost body weight (SD 22.2 ± 0.6 g vs. KD 17.5 ± 1.4 g, p = 0.0067). In contrast to earlier studies, the brief KD feeding regime significantly reduced total brain Aβ levels by approximately 25%. Despite changes in ketone levels, body weight, and Aβ levels, the KD diet did not alter behavioral measures. Conclusion Previous studies have suggested that diets rich in cholesterol and saturated fats increased the deposition of Aβ and the risk of developing AD. Here we demonstrate that a diet rich in saturated fats and low in carbohydrates can actually reduce levels of Aβ. Therefore, dietary strategies aimed at reducing Aβ levels should take into account interactions of dietary components and the metabolic outcomes, in particular, levels of carbohydrates, total calories, and presence of ketone bodies should be considered.