Microglia in Alzheimer's Disease: Exploring How Genetics and Phenotype Influence Risk

Research into the function of microglia has dramatically accelerated during the last few years, largely due to recent genetic findings implicating microglia in virtually every neurodegenerative disorder. In Alzheimer's disease (AD), a majority of risk loci discovered through genome-wide association studies were found in or near genes expressed most highly in microglia leading to the hypothesis that microglia play a much larger role in disease progression than previously thought. From this body of work produced in the last several years, we find that almost every function of microglia has been proposed to influence the progression of AD from altered phagocytosis and synaptic pruning to cytokine secretion and changes in trophic support. By studying key Alzheimer's risk genes such as TREM2, CD33, ABCA7, and MS4A6A, we will be able to distinguish true disease-modulatory pathways from the full range of microglial-related functions. To successfully carry out these experiments, more advanced microglial models are needed. Microglia are quite sensitive to their local environment, suggesting the need to more fully recapitulate an in vivo environment to study this highly plastic cell type. Likely only by combining the above approaches will the field fully elucidate the molecular pathways that regulate microglia and influence neurodegeneration, in turn uncovering potential new targets for future therapeutic development.     

Structural Instability and Emergence of the Biodiversity

In the framework of population dynamics, we start from the logistic equation describing the evolution of one species with limited food supply. A split device allows us to consider the population as two sub-populations x and y evolving analogously. The dynamical system has a one-parameter family of equilibria which is structurally unstable. Then small perturbations of the system (describing functional or ethological differentiations between the sub-species) lead in general to a new system involving a fast and a slow dynamics with a finite number of equilibria. In simple situations where the differentiation is clearly either an advantage or an inconvenience for one of the subspecies, the stable equilibrium amounts to extinction of the disadvantaged subspecies (elementary Darwinism). Oppositely more complex differentiations (involving both advantages and inconveniences) often lead to stable equilibria with well-defined non zero proportions of the sub-populations (preservation of the biodiversity). Other examples are concerned with symbiosis-like differentiations, leading to preservation, whereas the opposite case (mutual nuisances) has an unstable equilibrium and lead to extinction of one or the other subspecies according to the initial conditions. The case of a scission into three subspecies is more rich in consequences. In certain cases, predator-prey relations lead to auto-organization phenomena with stable diversity-preserving diversity. Cases of instability are also possible, leading to orbits tending towards a poly-cycle.This implies some kind of pseudo-extinction: this amounts to “pseudo-periodic-like” orbits with “pseudo-periods” larger and larger, tending to infinity; each pseudo-period contains parts where one of the sub-populations practically vanish. Other non-linear perturbations lead to stable orbits.     

Cardiovascular Disease Risk Models and Longitudinal Changes in Cognition: A Systematic Review

Background

Cardiovascular disease and its risk factors have consistently been associated with poor cognitive function and incident dementia. Whether cardiovascular disease prediction models, developed to predict an individual''s risk of future cardiovascular disease or stroke, are also informative for predicting risk of cognitive decline and dementia is not known.

Objective

The objective of this systematic review was to compare cohort studies examining the association between cardiovascular disease risk models and longitudinal changes in cognitive function or risk of incident cognitive impairment or dementia.

Materials and Methods

Medline, PsychINFO, and Embase were searched from inception to March 28, 2014. From 3,413 records initially screened, 21 were included.

Results

The association between numerous different cardiovascular disease risk models and cognitive outcomes has been tested, including Framingham and non-Framingham risk models. Five studies examined dementia as an outcome; fourteen studies examined cognitive decline or incident cognitive impairment as an outcome; and two studies examined both dementia and cognitive changes as outcomes. In all studies, higher cardiovascular disease risk scores were associated with cognitive changes or risk of dementia. Only four studies reported model prognostic performance indices, such as Area Under the Curve (AUC), for predicting incident dementia or cognitive impairment and these studies all examined non-Framingham Risk models (AUC range: 0.74 to 0.78).

Conclusions

Cardiovascular risk prediction models are associated with cognitive changes over time and risk of dementia. Such models are easily obtainable in clinical and research settings and may be useful for identifying individuals at high risk of future cognitive decline and dementia.     

Emergence of a Novel Avian Pox Disease in British Tit Species

Avian pox is a viral disease with a wide host range. In Great Britain, avian pox in birds of the Paridae family was first diagnosed in a great tit (Parus major) from south-east England in 2006. An increasing number of avian pox incidents in Paridae have been reported each year since, indicative of an emergent infection. Here, we utilise a database of opportunistic reports of garden bird mortality and morbidity to analyse spatial and temporal patterns of suspected avian pox throughout Great Britain, 2006–2010. Reports of affected Paridae (211 incidents) outnumbered reports in non-Paridae (91 incidents). The majority (90%) of Paridae incidents involved great tits. Paridae pox incidents were more likely to involve multiple individuals (77.3%) than were incidents in non-Paridae hosts (31.9%). Unlike the small wart-like lesions usually seen in non-Paridae with avian pox in Great Britain, lesions in Paridae were frequently large, often with an ulcerated surface and caseous core. Spatial analyses revealed strong clustering of suspected avian pox incidents involving Paridae hosts, but only weak, inconsistent clustering of incidents involving non-Paridae hosts. There was no spatial association between Paridae and non-Paridae incidents. We documented significant spatial spread of Paridae pox from an origin in south-east England; no spatial spread was evident for non-Paridae pox. For both host clades, there was an annual peak of reports in August/September. Sequencing of the avian poxvirus 4b core protein produced an identical viral sequence from each of 20 great tits tested from Great Britain. This sequence was identical to that from great tits from central Europe and Scandinavia. In contrast, sequence variation was evident amongst virus tested from 17 non-Paridae hosts of 5 species. Our findings show Paridae pox to be an emerging infectious disease in wild birds in Great Britain, apparently originating from viral incursion from central Europe or Scandinavia.     

Geography,Deer, and Host Biodiversity Shape the Pattern of Lyme Disease Emergence in the Thousand Islands Archipelago of Ontario,Canada

In the Thousand Islands region of eastern Ontario, Canada, Lyme disease is emerging as a serious health risk. The factors that influence Lyme disease risk, as measured by the number of blacklegged tick (Ixodes scapularis) vectors infected with Borrelia burgdorferi, are complex and vary across eastern North America. Despite study sites in the Thousand Islands being in close geographic proximity, host communities differed and both the abundance of ticks and the prevalence of B. burgdorferi infection in them varied among sites. Using this archipelago in a natural experiment, we examined the relative importance of various biotic and abiotic factors, including air temperature, vegetation, and host communities on Lyme disease risk in this zone of recent invasion. Deer abundance and temperature at ground level were positively associated with tick abundance, whereas the number of ticks in the environment, the prevalence of B. burgdorferi infection, and the number of infected nymphs all decreased with increasing distance from the United States, the presumed source of this new endemic population of ticks. Higher species richness was associated with a lower number of infected nymphs. However, the relative abundance of Peromyscus leucopus was an important factor in modulating the effects of species richness such that high biodiversity did not always reduce the number of nymphs or the prevalence of B. burgdorferi infection. Our study is one of the first to consider the interaction between the relative abundance of small mammal hosts and species richness in the analysis of the effects of biodiversity on disease risk, providing validation for theoretical models showing both dilution and amplification effects. Insights into the B. burgdorferi transmission cycle in this zone of recent invasion will also help in devising management strategies as this important vector-borne disease expands its range in North America.     

Control of River Blindness in West Africa: Case History of Biodiversity in a Disease Control Program

The elimination of river blindness (onchocerciasis) in West Africa has been one of the most successful public health and economic development programs yet conducted. Control was based on aerial application of insecticides to control the aquatic, larval stages of black flies in the Simulium damnosum complex and distribution of ivermectin-based drugs to reduce incidence of the filarial worm, Onchocerca volvulus, that may ultimately result in blindness. Control efforts were long-term (1974–2003), extensive (with as many as 50,000 km of river miles being treated weekly for 12 years or longer), and far-reaching (distribution of drugs to almost 7 million people in 11 West African countries). The challenges and success of the program were strongly related to biodiversity: the vector S. damnosum is actually a complex of several species and subspecies, which vary in their competence in disease transmission; the filarial worm O. volvulus has different forms that vary in their virulence and incidence of producing blindness in humans; maintenance of the biodiversity of the non-target riverine fauna was a prime concern of both the control program and the donor countries that supported it; the main insecticide used to control the black fly vector was derived from a bacterium Bacillus thuringensis israelensis; and the drug used in controlling the filarial worm was derived from a soil-dwelling Streptomyces fungus. Long-term biomonitoring studies indicate that environmental damage (e.g., loss of sensitive taxa) incurred was reversed when insecticide applications ceased.     

Local Scale Effects of Disease on Biodiversity

To date, ecologists and conservation biologists have focused much of their attention on the population and ecosystem effects of disease at regional scales and the role that diseases play in global species extinction. Far less research has been dedicated to identifying the effects that diseases can have on local scale species assemblages. We examined the role of infectious disease in structuring local biodiversity. Our intention was to illustrate how variable outcomes can occur by focusing on three case studies: the influence of chestnut blight on forest communities dominated by chestnut trees, the influence of red-spot disease on urchin barrens and kelp forests, and the influence of sylvatic plague on grassland communities inhabited by prairie dogs. Our findings reveal that at local scales infectious disease seems to play an important, though unpredictable, role in structuring species diversity. Through our case studies, we have shown that diseases can cause drastic population declines or local extirpations in keystone species, ecosystem engineers, and otherwise abundant species. These changes in local diversity may be very important, particularly when considered alongside potentially corresponding changes in community structure and function, and we believe that future efforts to understand the importance of disease to species diversity should have an increased focus on these local scales.     

Cross-Species Pathogen Transmission and Disease Emergence in Primates

Many of the most virulent emerging infectious diseases in humans, e.g., AIDS and Ebola, are zoonotic, having shifted from wildlife populations. Critical questions for predicting disease emergence are: (1) what determines when and where a disease will first cross from one species to another, and (2) which factors facilitate emergence after a successful host shift. In wild primates, infectious diseases most often are shared between species that are closely related and inhabit the same geographic region. Therefore, humans may be most vulnerable to diseases from the great apes, which include chimpanzees and gorillas, because these species represent our closest relatives. Geographic overlap may provide the opportunity for cross-species transmission, but successful infection and establishment will be determined by the biology of both the host and pathogen. We extrapolate the evolutionary relationship between pathogen sharing and divergence time between primate species to generate “hotspot” maps, highlighting regions where the risk of disease transfer between wild primates and from wild primates to humans is greatest. We find that central Africa and Amazonia are hotspots for cross-species transmission events between wild primates, due to a high diversity of closely related primate species. Hotspots of host shifts to humans will be most likely in the forests of central and west Africa, where humans come into frequent contact with their wild primate relatives. These areas also are likely to sustain a novel epidemic due to their rapidly growing human populations, close proximity to apes, and population centers with high density and contact rates among individuals.     

Insights into the Evolution and Emergence of a Novel Infectious Disease

Many zoonotic, novel infectious diseases in humans appear as sporadic infections with spatially and temporally restricted outbreaks, as seen with influenza A(H5N1). Adaptation is often a key factor for successfully establishing sustained human-to-human transmission. Here we use simple mathematical models to describe different adaptation scenarios with particular reference to spatial heterogeneity within the human population. We present analytical expressions for the probability of emergence per introduction, as well as the waiting time to a successful emergence event. Furthermore, we derive general analytical results for the statistical properties of emergence events, including the probability distribution of outbreak sizes. We compare our analytical results with a stochastic model, which has previously been studied computationally. Our results suggest that, for typical connection strengths between communities, spatial heterogeneity has only a weak effect on outbreak size distributions, and on the risk of emergence per introduction. For example, if or larger, any village connected to a large city by just ten commuters a day is, effectively, just a part of the city when considering the chances of emergence and the outbreak size distribution. We present empirical data on commuting patterns and show that the vast majority of communities for which such data are available are at least this well interconnected. For plausible parameter ranges, the effects of spatial heterogeneity are likely to be dominated by the evolutionary biology of host adaptation. We conclude by discussing implications for surveillance and control of emerging infections.     

Biodiversity: a lichenological perspective

Global biodiversity in lichens is discussed with respect to: areas of biodiversity, lichen biomass, food chains, nutrient cycling, carbon sinks, biomonitoring, climate change, conservation, and lichen identification. Examples of each topic are given, and areas for productive future research outlined.     

Effect of Climate Change on Lyme Disease Risk in North America

An understanding of the influence of climate change on Ixodes scapularis, the main vector of Lyme disease in North America, is a fundamental component in assessing changes in the spatial distribution of human risk for the disease. We used a climate suitability model of I. scapularis to examine the potential effects of global climate change on future Lyme disease risk in North America. A climate-based logistic model was first used to explain the current distribution of I. scapularis in North America. Climate-change scenarios were then applied to extrapolate the model in time and to forecast vector establishment. The spatially modeled relationship between I. scapularis presence and large-scale environmental data generated the current pattern of I. scapularis across North America with an accuracy of 89% (P < 0.0001). Extrapolation of the model revealed a significant expansion of I. scapularis north into Canada with an increase in suitable habitat of 213% by the 2080s. Climate change will also result in a retraction of the vector from the southern U.S. and movement into the central U.S. This report predicts the effect of climate change on Lyme disease risk and specifically forecasts the emergence of a tickborne infectious disease in Canada. Our modeling approach could thus be used to outline where future control strategies and prevention efforts need to be applied.     

植物化感作用与生物多样性

本文简要地阐释了化感作用的含义、基本特征以及作用机制,并结合生物多样性理论,综述了化感作用研究中化感物种的多样性、化感物质的多样性及其释放途径的多样性,具体讨论了化感作用对物种多样性、遗传多样性及生态系统多样性中的种群生态、协同进化、土壤生境、生态系统功能和生物入侵等方面的可能影响。文中提出了化感作用的利用、管理应与生物多样性保护相统一的看法,并指出对化感作用与生物多样性的关系以及相互影响机制进行本质的探索,特别是对植物化感作用的生态服务功能与价值评估与探讨,可为保护生物学和系统生态学提供理论基础,这也是今后工作开展的一个重要方向。     

Risk Analysis: Changes Needed from a Native American Perspective

The objective of this article is to help risk assessors and managers step back from paying sole attention to finer and finer detail (e.g., measuring nuances of a single chemical's biochemical action at the molecular level). As professionals, we must always remember that the higher service that risk assessment provides is to improve everyone's long-term well being and survival. It is especially important to note that there are many lessons all Americans should experience as early as possible. For instance, our Native American tribal members are taught from birth that we all live enmeshed within the environment, not isolated from it or superior to it. Our practical every day needs, including basic nutritional, spiritual, and economic needs, are all derived directly from a clean, functioning environment. In return, we must accept the fact that we are not masters or owners of the environment, and that we don't have dominion over ecological processes. Our relationship is best viewed as part of a human-eco-cultural system. The risks to this system as a whole must be reflected in new transparent system-level models that easily show the relationships among, and equality of, all of these elements. Transparent, user-friendly, system-level models must become standard tools in every risk assessors toolbox. Such models are being developed and have already made a difference. Tribal risk information, in particular, needs to be produced at the community and system level, must include eco-cultural metrics, and requires geospatial and temporal integration that most conventional models cannot accomplish. I expect that risk assessors, once enlightened, will insist that such models will become a required part of risk analysis in the near future.     

Beyond Disciplinary Boundaries: Leptospirosis as a Model of Incorporating Transdisciplinary Approaches to Understand Infectious Disease Emergence

Leptospirosis is a zoonotic infectious disease of global significance. Political, economic, demographic, ecologic, and other anthropogenically driven environmental changes have fueled the reemergence of this disease in industrialized and developing countries, and in both urban and rural settings. We argue that conventional disciplinary, even interdisciplinary, research methods are not sufficient to elucidate the complex mechanisms and causal relationships among the myriad factors responsible for infectious disease emergence. To address the significant gaps in the field of leptospirosis, an integrated research agenda is needed to guide successful public health remediation of the disease. Based on both working group analysis of literature and newly obtained information, we describe cross-disciplinary collaborative approaches that allow a novel approach to understand leptospirosis emergence with regard to mountain-to-sea ecosystems in Hawai‘i and other region-specific ecosystems. Leptospirosis research is a model for how complementary disciplines in the social, cultural, ecological, and biomedical sciences can optimally interact towards a higher understanding of emerging infectious diseases.     

Exploring Retrograde Trafficking: Mechanisms and Consequences in Cancer and Disease

Retrograde trafficking (RT) orchestrates the intracellular movement of cargo from the plasma membrane, endosomes, Golgi or endoplasmic reticulum (ER)–Golgi intermediate compartment (ERGIC) in an inward/ER-directed manner. RT works as the opposing movement to anterograde trafficking (outward secretion), and the two work together to maintain cellular homeostasis. This is achieved through maintaining cell polarity, retrieving proteins responsible for anterograde trafficking and redirecting proteins that become mis-localised. However, aberrant RT can alter the correct location of key proteins, and thus inhibit or indeed change their canonical function, potentially causing disease. This review highlights the recent advances in the understanding of how upregulation, downregulation or hijacking of RT impacts the localisation of key proteins in cancer and disease to drive progression. Cargoes impacted by aberrant RT are varied amongst maladies including neurodegenerative diseases, autoimmune diseases, bacterial and viral infections (including SARS-CoV-2), and cancer. As we explore the intricacies of RT, it becomes increasingly apparent that it holds significant potential as a target for future therapies to offer more effective interventions in a wide range of pathological conditions.