A primer on ageing studies in mice: Considerations, opportunities and limitations

One of the major challenges currently facing health care providers is an ageing population that is spending more time in ill-health. Many ageing individuals have multiple and complex needs which affect the ability to treat them effectively, which also has a significant impact on their own independence and quality of life. There are many aspects of testing interventions to improve health in old age in pre-clinical models; from breeding strategies to measurements of outcomes. Here we provide a brief overview of the major considerations to take into account in such studies and the limitations or challenges we face in these studies

Modelling age-related metabolic disorders in the mouse

Ageing can be characterised by a general decline in cellular function, which affects whole-body homoeostasis with metabolic dysfunction—a common hallmark of ageing. The identification and characterisation of the genetic pathways involved are paramount to the understanding of how we age and the development of therapeutic strategies for combating age-related disease. Furthermore, in addition to understanding the ageing process itself, we must understand the interactions ageing has with genetic variation that results in disease phenotypes. The use of model systems such as the mouse, which has a relatively short lifespan, rapid reproduction (resulting in a large number of offspring), well-characterised biology, a fully sequenced genome, and the availability of tools for genetic manipulation is essential for such studies. Here we review the relationship between ageing and metabolism and highlight the need for modelling these processes

With mouse age comes wisdom : a review and suggestions of relevant mouse models for age-related conditions

Ageing is a complex multifactorial process that results in many changes in physiological changes processes that ultimately increase susceptibility to a wide range of diseases. As such an ageing population is resulting in a pressing need for more and improved treatments across an assortment of diseases. Such treatments can come from a better understanding of the pathogenic pathways which, in turn, can be derived from models of disease. Therefore the more closely the model resembles the disease situation the more likely relevant the data will be that is generated from them. Here we review the state of knowledge of mouse models of a range of diseases and aspects of an ageing physiology that are all germane to ageing. We also give recommendations on the most common mouse models on their relevance to the clinical situations occurring in aged patients and look forward as to how research in ageing models can be carried out. As we continue to elucidate the pathophysiology of disease, often through mouse models, we also learn what is needed to refine these models. Such factors can include better models, reflecting the ageing patient population, or a better phenotypic understanding of existing models

Fibroblast growth factors 1 and 2 in cerebrospinal fluid are associated with HIV disease, methamphetamine use, and neurocognitive functioning.

BackgroundHuman immunodeficiency virus (HIV) and methamphetamine use commonly affect neurocognitive (NC) functioning. We evaluated the relationships between NC functioning and two fibroblast growth factors (FGFs) in volunteers who differed in HIV serostatus and methamphetamine dependence (MAD).MethodsA total of 100 volunteers were categorized into four groups based on HIV serostatus and MAD in the prior year. FGF-1 and FGF-2 were measured in cerebrospinal fluid by enzyme-linked immunosorbent assays along with two reference biomarkers (monocyte chemotactic protein [MCP]-1 and neopterin). Comprehensive NC testing was summarized by global and domain impairment ratings.ResultsSixty-three volunteers were HIV+ and 59 had a history of MAD. FGF-1, FGF-2, and both reference biomarkers differed by HIV and MAD status. For example, FGF-1 levels were lower in subjects who had either HIV or MAD than in HIV- and MAD- controls (P=0.003). Multivariable regression identified that global NC impairment was associated with an interaction between FGF-1 and FGF-2 (model R(2)=0.09, P=0.01): higher FGF-2 levels were only associated with neurocognitive impairment among subjects who had lower FGF-1 levels. Including other covariates in the model (including antidepressant use) strengthened the model (model R(2)=0.18, P=0.004) but did not weaken the association with FGF-1 and FGF-2. Lower FGF-1 levels were associated with impairment in five of seven cognitive domains, more than FGF-2, MCP-1, or neopterin.ConclusionThese findings provide in vivo support that HIV and MAD alter expression of FGFs, which may contribute to the NC abnormalities associated with these conditions. These cross-sectional findings cannot establish causality and the therapeutic benefits of recombinant FGF-1 need to be investigated

Sixteen years of Collaborative Learning through Active Sense-making in Physics (CLASP) at UC Davis

This paper describes our large reformed introductory physics course at UC Davis, which bioscience students have been taking since 1996. The central feature of this course is a focus on sense-making by the students during the five hours per week discussion/labs in which the students take part in activities emphasizing peer-peer discussions, argumentation, and presentations of ideas. The course differs in many fundamental ways from traditionally taught introductory physics courses. After discussing the unique features of CLASP and its implementation at UC Davis, various student outcome measures are presented showing increased performance by students who took the CLASP course compared to students who took a traditionally taught introductory physics course. Measures we use include upper-division GPAs, MCAT scores, FCI gains, and MPEX-II scores.Comment: Also submitted to American Journal of Physic

Quantifying microsatellite mutation rates from intestinal stem cell dynamics in Msh2-deficient murine epithelium

Microsatellite sequences have an enhanced susceptibility to mutation and can act as sentinels indicating elevated mutation rates and increased risk of cancer. The probability of mutant fixation within the intestinal epithelium is dictated by a combination of stem cell dynamics and mutation rate. Here we exploit this relationship to infer microsatellite mutation rates. First a sensitive, multiplexed and quantitative method for detecting somatic changes in microsatellite length was developed that allowed the parallel detection of mutant [CA]n sequences from hundreds of low-input tissue samples at up to 14 loci. The method was applied to colonic crypts in Mus musculus and enabled detection of mutant subclones down to 20% of the cellularity of the crypt (around 50 of 250 cells). By quantifying age-related increases in clone frequencies for multiple loci, microsatellite mutation rates in wild-type and Msh2- deficient epithelium were established. An average 388-fold increase in mutation per mitosis rate was observed in Msh2-deficient epithelium (2.4 x10-2) compared to wild- type epithelium (6.2 x10-5)

Contrasting longitudinal and cross-sectional relationships between insulin resistance and percentage of body fat, fitness, and physical activity in children - the LOOK study

Telford RD, Cunningham RB, Shaw JE, Dunstan DW, Lafferty ARA, Reynolds GJ, Hickman PE, Southcott E, Potter JM, Waring P, Telford RM. Contrasting longitudinal and cross-sectional relationships between insulin resistance and percentage of body fat, fitnes

Modification of an aggressive model of Alport Syndrome reveals early differences in disease pathogenesis due to genetic background

The link between mutations in collagen genes and the development of Alport Syndrome has been clearly established and a number of animal models, including knock-out mouse lines, have been developed that mirror disease observed in patients. However, it is clear from both patients and animal models that the progression of disease can vary greatly and can be modifed genetically. We have identifed a point mutation in Col4a4 in mice where disease is modifed by strain background, providing further evidence of the genetic modifcation of disease symptoms. Our results indicate that C57BL/6J is a protective background and postpones end stage renal failure from 7 weeks, as seen on a C3H background, to several months. We have identifed early diferences in disease progression, including expression of podocyte-specifc genes and podocyte morphology. In C57BL/6J mice podocyte efacement is delayed, prolonging normal renal function. The slower disease progression has allowed us to begin dissecting the pathogenesis of murine Alport Syndrome in detail. We fnd that there is evidence of diferential gene expression during disease on the two genetic backgrounds, and that disease diverges by 4 weeks of age. We also show that an infammatory response with increasing MCP-1 and KIM-1 levels precedes loss of renal function

Real‐world conservation planning for evolutionary diversity in the Kimberley, Australia, sidesteps uncertain taxonomy

Targeting phylogenetic diversity (PD) in systematic conservation planning is an efficient way to minimize losses across the Tree of Life. Considering representation of genetic diversity below and above species level, also allows robust analyses within systems where taxonomy is in flux. We use dense sampling of phylogeographic diversity for 11 lizard genera, to demonstrate how PD can be applied to a policy‐ready conservation planning problem. Our analysis bypasses named taxa, using genetic data directly to inform conservation decisions. We highlight areas that should be prioritized for ecological management, and also areas that would provide the greatest benefit if added to the multisector conservation estate. We provide a rigorous and effective approach to represent the spectrum of genetic and species diversity in conservation planning.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/145539/1/conl12438.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145539/2/conl12438-sup-0001-figureS1-S2.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145539/3/conl12438_am.pd

LHC Luminosity and energy upgrade: A Feasibility Study

We discuss a possible staged upgrade of the LHC and of its injectors, with a view to increasing the luminosity from the nominal 10**34 cm**-2s**-1 to 10**35 cm**-2s**-1 in each of the two high-luminosity experiments. We also consider possible scenarios for an upgrade to a proton beam energy of about 14 TeV. Starting from beam dynamics considerations and fundamental limitations of the hardware subsystems, we derive realistic requirements for the major components, such as superconducting magnets, cryogenic and RF systems, beam dump and vacuum. We also discuss a novel approach to the optimization of the collider performance, compatible with the beam-beam limit for high intensity proton bunches or long "super-bunches", and sketch a new design of the interaction regions, including an alternative beam crossing scheme. Finally we identify further studies required for an LHC performance upgrade and propose an R&D programm