Evolution of the Aging Brain Transcriptome and Synaptic Regulation

Alzheimer's disease and other neurodegenerative disorders of aging are characterized by clinical and pathological features that are relatively specific to humans. To obtain greater insight into how brain aging has evolved, we compared age-related gene expression changes in the cortex of humans, rhesus macaques, and mice on a genome-wide scale. A small subset of gene expression changes are conserved in all three species, including robust age-dependent upregulation of the neuroprotective gene apolipoprotein D (APOD) and downregulation of the synaptic cAMP signaling gene calcium/calmodulin-dependent protein kinase IV (CAMK4). However, analysis of gene ontology and cell type localization shows that humans and rhesus macaques have diverged from mice due to a dramatic increase in age-dependent repression of neuronal genes. Many of these age-regulated neuronal genes are associated with synaptic function. Notably, genes associated with GABA-ergic inhibitory function are robustly age-downregulated in humans but not in mice at the level of both mRNA and protein. Gene downregulation was not associated with overall neuronal or synaptic loss. Thus, repression of neuronal gene expression is a prominent and recently evolved feature of brain aging in humans and rhesus macaques that may alter neural networks and contribute to age-related cognitive changes

Survivability Is More Fundamental Than Evolvability

For a lineage to survive over long time periods, it must sometimes change. This has given rise to the term evolvability, meaning the tendency to produce adaptive variation. One lineage may be superior to another in terms of its current standing variation, or it may tend to produce more adaptive variation. However, evolutionary outcomes depend on more than standing variation and produced adaptive variation: deleterious variation also matters. Evolvability, as most commonly interpreted, is not predictive of evolutionary outcomes. Here, we define a predictive measure of the evolutionary success of a lineage that we call the k-survivability, defined as the probability that the lineage avoids extinction for k generations. We estimate the k-survivability using multiple experimental replicates. Because we measure evolutionary outcomes, the initial standing variation, the full spectrum of generated variation, and the heritability of that variation are all incorporated. Survivability also accounts for the decreased joint likelihood of extinction of sub-lineages when they 1) disperse in space, or 2) diversify in lifestyle. We illustrate measurement of survivability with in silico models, and suggest that it may also be measured in vivo using multiple longitudinal replicates. The k-survivability is a metric that enables the quantitative study of, for example, the evolution of 1) mutation rates, 2) dispersal mechanisms, 3) the genotype-phenotype map, and 4) sexual reproduction, in temporally and spatially fluctuating environments. Although these disparate phenomena evolve by well-understood microevolutionary rules, they are also subject to the macroevolutionary constraint of long-term survivability

Musculoskeletal disorders in shipyard industry: prevalence, health care use, and absenteeism

BACKGROUND: It is unclear whether the well-known risk factors for the occurrence of musculoskeletal disorders (MSD) also play an important role in the determining consequences of MSD in terms of sickness absence and health care use. METHODS: A cross-sectional study was conducted among 853 shipyard employees. Data were collected by questionnaire on physical and psychosocial workload, need for recovery, perceived general health, occurrence of musculoskeletal complaints, and health care use during the past year. Retrospective data on absenteeism were also available from the company register. RESULTS: In total, 37%, 22%, and 15% of employees reported complaints of low back, shoulder/neck, and hand/wrist during the past 12 months, respectively. Among all employees with at least one MSD, 27% visited a physician at least once and 20% took at least one period of sick leave. Various individual and work-related factors were associated with the occurrence of MSD. Health care use and absenteeism were strongest influenced by chronicity of musculoskeletal complaints and comorbidity with other musculoskeletal complaints and, to a lesser extent, by work-related factors. CONCLUSION: In programmes aimed at preventing the unfavourable consequences of MSD in terms of sickness absence and health care use it is important to identify the (individual) factors that determine the development of chronicity of complaints. These factors may differ from the well-know risk factors for the occurrence of MSD that are targeted in primary prevention

Minor psychiatric disorders among Brazilian ragpickers: a cross-sectional study

BACKGROUND: Ragpickers are informal workers who collect recyclable materials to earn a small wage. Their life and working conditions are extremely difficult. We examined minor psychiatric disorders (MPD) among a cohort of ragpickers in Pelotas, a city in southern Brazil. METHODS: Ragpickers were matched by sex, age, and years of schooling with a sample of non-ragpickers from the same poor neighborhoods. The cross-sectional study gathered data by interview on 990 individuals in 2004. MPD were assessed using a standard self-reporting questionnaire, the SRQ-20. RESULTS: The prevalence of MPD among ragpickers was 44.7%, higher than reported by neighborhood controls (33.6%; p < 0.001). MPD were more common among females, those of lower economic level, smokers and alcoholics. Among occupational characteristics, MPD prevalence was associated with frequent static postures, low job satisfaction and recent work accidents. CONCLUSION: Ragpickers more frequently report MPD than other poor workers living in the same neighborhoods, with many of the same life conditions. Improving the work lives of these precarious workers should address not only the physical hazards of their jobs but their mental and emotional health as well

Does spatial locative comprehension predict landmark-based navigation?

In the present study we investigated the role of spatial locative comprehension in learning and retrieving pathways when landmarks were available and when they were absent in a sample of typically developing 6- to 11-year-old children. Our results show that the more proficient children are in understanding spatial locatives the more they are able to learn pathways, retrieve them after a delay and represent them on a map when landmarks are present in the environment. These findings suggest that spatial language is crucial when individuals rely on sequences of landmarks to drive their navigation towards a given goal but that it is not involved when navigational representations based on the geometrical shape of the environment or the coding of body movements are sufficient for memorizing and recalling short pathways

SUMOylation and calcium signalling: potential roles in the brain and beyond

Small ubiquitin-like modi er (SUMO) conjugation (or SUMOylation) is a post-translational protein modi cation implicated in alterations to protein expression, localization and func- tion. Despite a number of nuclear roles for SUMO being well characterized, this process has only started to be explored in relation to membrane proteins, such as ion channels. Cal- cium ion (Ca2+) signalling is crucial for the normal functioning of cells and is also involved in the pathophysiological mechanisms underlying relevant neurological and cardiovascu- lar diseases. Intracellular Ca2+ levels are tightly regulated; at rest, most Ca2+ is retained in organelles, such as the sarcoplasmic reticulum, or in the extracellular space, whereas depolarization triggers a series of events leading to Ca2+ entry, followed by extrusion and reuptake. The mechanisms that maintain Ca2+ homoeostasis are candidates for modulation at the post-translational level. Here, we review the effects of protein SUMOylation, including Ca2+ channels, their proteome and other proteins associated with Ca2+ signalling, on vital cellular functions, such as neurotransmission within the central nervous system (CNS) and in additional systems, most prominently here, in the cardiac system

Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies

Objectives: The purpose of this document is to make the output of the International Working Group for Intravascular Optical Coherence Tomography (IWG-IVOCT) Standardization and Validation available to medical and scientific communities, through a peer-reviewed publication, in the interest of improving the diagnosis and treatment of patients with atherosclerosis, including coronary artery disease. Background: Intravascular optical coherence tomography (IVOCT) is a catheter-based modality that acquires images at a resolution of ∼10 μm, enabling visualization of blood vessel wall microstructure in vivo at an unprecedented level of detail. IVOCT devices are now commercially available worldwide, there is an active user base, and the interest in using this technology is growing. Incorporation of IVOCT in research and daily clinical practice can be facilitated by the development of uniform terminology and consensus-based standards on use of the technology, interpretation of the images, and reporting of IVOCT results. Methods: The IWG-IVOCT, comprising more than 260 academic and industry members from Asia, Europe, and the United States, formed in 2008 and convened on the topic of IVOCT standardization through a series of 9 national and international meetings. Results: Knowledge and recommendations from this group on key areas within the IVOCT field were assembled to generate this consensus document, authored by the Writing Committee, composed of academicians who have participated in meetings and/or writing of the text. Conclusions: This document may be broadly used as a standard reference regarding the current state of the IVOCT imaging modality, intended for researchers and clinicians who use IVOCT and analyze IVOCT data

Sex Differences in the Brain: A Whole Body Perspective

Most writing on sexual differentiation of the mammalian brain (including our own) considers just two organs: the gonads and the brain. This perspective, which leaves out all other body parts, misleads us in several ways. First, there is accumulating evidence that all organs are sexually differentiated, and that sex differences in peripheral organs affect the brain. We demonstrate this by reviewing examples involving sex differences in muscles, adipose tissue, the liver, immune system, gut, kidneys, bladder, and placenta that affect the nervous system and behavior. The second consequence of ignoring other organs when considering neural sex differences is that we are likely to miss the fact that some brain sex differences develop to compensate for differences in the internal environment (i.e., because male and female brains operate in different bodies, sex differences are required to make output/function more similar in the two sexes). We also consider evidence that sex differences in sensory systems cause male and female brains to perceive different information about the world; the two sexes are also perceived by the world differently and therefore exposed to differences in experience via treatment by others. Although the topic of sex differences in the brain is often seen as much more emotionally charged than studies of sex differences in other organs, the dichotomy is largely false. By putting the brain firmly back in the body, sex differences in the brain are predictable and can be more completely understood

Dynamic purine signaling and metabolism during neutrophil–endothelial interactions

During episodes of hypoxia and inflammation, polymorphonuclear leukocytes (PMN) move into underlying tissues by initially passing between endothelial cells that line the inner surface of blood vessels (transendothelial migration, TEM). TEM creates the potential for disturbances in vascular barrier and concomitant loss of extravascular fluid and resultant edema. Recent studies have demonstrated a crucial role for nucleotide metabolism and nucleoside signaling during inflammation. These studies have implicated multiple adenine nucleotides as endogenous tissue protective mechanisms invivo. Here, we review the functional components of vascular barrier, identify strategies for increasing nucleotide generation and nucleoside signaling, and discuss potential therapeutic targets to regulate the vascular barrier during inflammation