综述:靶向淀粉样蛋白的阿尔茨海默病药物研究进展

淀粉样蛋白级联假说是阐释阿尔茨海默病(Alzheimer's disease,AD)发病机制的主要学说之一,即脑内过量的β-淀粉样蛋白(β-amyloid,Aβ)是促发AD的核心因素．因此,靶向Aβ形成、聚集和清除等关键环节的药物开发是目前药物研究的热点．但近年来AD新药临床试验屡屡失败,至今尚未得到一种切实有效的治疗药物．淀粉样蛋白级联假说的局限性和痴呆期患者疾病进程的难以逆转,可能是临床试验反复失败的两个主要原因．借助AD早期诊断技术的发展,将药物干预的时间窗口前移,重视痴呆前期病理机制与治疗的研究,可能是研制延缓AD发生和发展有效药物的新途径．     

Simple criteria for finding (nearly) optimal vaccination strategies

Strategies for best controlling the spread of the diseases with limited vaccine available are explored. I use influenza as a representative disease in point. The model describes the dynamics of influenza spread among multiple groups that have different risks and activity levels. I define a core group consisting of individuals with occupations that brings them in contact with many other people in a day. These occupations may include service industries, teachers, health care, and government workers, to name a few. High-risk individuals are those as typically designated for: children under 5 and adults over 50, people with weakened immune systems as well as emergency and health care personnel. Under certain conditions, shifting vaccination resources away from the high-risk group to the high-activity group will result in improved herd immunity in both the high-risk group and the population as whole. This results in more high-risk people protected even though less of them are being vaccinated, with the obvious implications that current vaccination policies may be far less then optimal. I show that the criteria for the optimal strategy can be derived from simple expressions gleaned from the expression for the basic reproductive number.     

Two-stage designs for gene-disease association studies

The goal of this article is to describe a two-stage design that maximizes the power to detect gene-disease associations when the principal design constraint is the total cost, represented by the total number of gene evaluations rather than the total number of individuals. In the first stage, all genes of interest are evaluated on a subset of individuals. The most promising genes are then evaluated on additional subjects in the second stage. This will eliminate wastage of resources on genes unlikely to be associated with disease based on the results of the first stage. We consider the case where the genes are correlated and the case where the genes are independent. Using simulation results, it is shown that, as a general guideline when the genes are independent or when the correlation is small, utilizing 75% of the resources in stage 1 to screen all the markers and evaluating the most promising 10% of the markers with the remaining resources provides near-optimal power for a broad range of parametric configurations. This translates to screening all the markers on approximately one quarter of the required sample size in stage 1.     

Copy number variation in Fayoumi and Leghorn chickens analyzed using array comparative genomic hybridization

Copy number variation refers to regions along chromosomes that harbor a type of structural variation, such as duplications or deletions. Copy number variants (CNVs) play a role in many important traits as well as in genetic diversity. Previous analyses of chickens using array comparative genomic hybridizations or single‐nucleotide polymorphism chip assays have been performed on various breeds and genetic lines to discover CNVs. In this study, we assessed individuals from two highly inbred (inbreeding coefficiency > 99.99%) lines, Leghorn G‐B2 and Fayoumi M15.2, to discover novel CNVs in chickens. These lines have been previously studied for disease resistance, and to our knowledge, this represents the first global assessment of CNVs in the Fayoumi breed. Genomic DNA from individuals was examined using the Agilent chicken 244 K comparative genomic hybridization array and quantitative PCR. We identified a total of 273 CNVs overall, with 112 CNVs being novel and not previously reported. Quantitative PCR using the standard curve method validated a subset of our array data. Through enrichment analysis of genes within CNV regions, we observed multiple chromosomes, terms and pathways that were significantly enriched, largely dealing with the major histocompatibility complex and immune responsiveness. Using an additional round of computational and statistical analysis with a different bioinformatic pipeline, we identified 43 CNVs among these as high‐confidence regions, 14 of which were found to be novel. We further compared and contrasted individuals of the two inbred lines to discover regions that have a significant difference in copy number between lines. A total of 40 regions had significant deletions or duplications between the lines. Gene Ontology analysis of genomic regions containing CNVs between lines also was performed. This between‐line candidate CNV list will be useful in studies with these two unique genetic lines, which may harbor variations that underlie quantitative trait loci for disease resistance and other important traits. Through the global discovery of novel CNVs in chicken, these data also provide resources for further genetic and functional genomics studies.     

Extreme‐phenotype genome‐wide association study (XP‐GWAS): a method for identifying trait‐associated variants by sequencing pools of individuals selected from a diversity panel

Although approaches for performing genome‐wide association studies (GWAS) are well developed, conventional GWAS requires high‐density genotyping of large numbers of individuals from a diversity panel. Here we report a method for performing GWAS that does not require genotyping of large numbers of individuals. Instead XP‐GWAS (extreme‐phenotype GWAS) relies on genotyping pools of individuals from a diversity panel that have extreme phenotypes. This analysis measures allele frequencies in the extreme pools, enabling discovery of associations between genetic variants and traits of interest. This method was evaluated in maize (Zea mays) using the well‐characterized kernel row number trait, which was selected to enable comparisons between the results of XP‐GWAS and conventional GWAS. An exome‐sequencing strategy was used to focus sequencing resources on genes and their flanking regions. A total of 0.94 million variants were identified and served as evaluation markers; comparisons among pools showed that 145 of these variants were statistically associated with the kernel row number phenotype. These trait‐associated variants were significantly enriched in regions identified by conventional GWAS. XP‐GWAS was able to resolve several linked QTL and detect trait‐associated variants within a single gene under a QTL peak. XP‐GWAS is expected to be particularly valuable for detecting genes or alleles responsible for quantitative variation in species for which extensive genotyping resources are not available, such as wild progenitors of crops, orphan crops, and other poorly characterized species such as those of ecological interest.     

Aggression and Welfare in a Common Aquarium Fish,the Midas Cichlid

Many species of fishes are aggressive when placed in small aquaria. Aggression can negatively affect the welfare of those individuals toward whom it is directed. Animals may behave aggressively in order to defend resources such as food, shelter, mates, and offspring. The decision to defend depends on the distribution of resources and on ecological factors such as number of competitors, amount of available space, and amount of habitat complexity. This study tested the effects of these factors on aggression in a common aquarium fish, the Midas cichlid (Amphilophus citrinellus). The study found that time spent behaving aggressively was not associated with small-scale differences in group size or available space. Aggression was significantly lower in a large aquarium with a complex habitat. Aquaria of sizes typically used in the companion animal (pet) hobby did not provide optimal welfare for cichlids housed with aggressive conspecifics. The public should be aware that this and similar species require larger aquaria with complex habitat, which elicit more natural behavior.     

Dynamic health policies for controlling the spread of emerging infections: influenza as an example

The recent appearance and spread of novel infectious pathogens provide motivation for using models as tools to guide public health decision-making. Here we describe a modeling approach for developing dynamic health policies that allow for adaptive decision-making as new data become available during an epidemic. In contrast to static health policies which have generally been selected by comparing the performance of a limited number of pre-determined sequences of interventions within simulation or mathematical models, dynamic health policies produce "real-time" recommendations for the choice of the best current intervention based on the observable state of the epidemic. Using cumulative real-time data for disease spread coupled with current information about resource availability, these policies provide recommendations for interventions that optimally utilize available resources to preserve the overall health of the population. We illustrate the design and implementation of a dynamic health policy for the control of a novel strain of influenza, where we assume that two types of intervention may be available during the epidemic: (1) vaccines and antiviral drugs, and (2) transmission reducing measures, such as social distancing or mask use, that may be turned "on" or "off" repeatedly during the course of epidemic. In this example, the optimal dynamic health policy maximizes the overall population's health during the epidemic by specifying at any point of time, based on observable conditions, (1) the number of individuals to vaccinate if vaccines are available, and (2) whether the transmission-reducing intervention should be either employed or removed.     

Aggression and welfare in a common aquarium fish, the Midas cichlid

Many species of fishes are aggressive when placed in small aquaria. Aggression can negatively affect the welfare of those individuals toward whom it is directed. Animals may behave aggressively in order to defend resources such as food, shelter, mates, and offspring. The decision to defend depends on the distribution of resources and on ecological factors such as number of competitors, amount of available space, and amount of habitat complexity. This study tested the effects of these factors on aggression in a common aquarium fish, the Midas cichlid (Amphilophus citrinellus). The study found that time spent behaving aggressively was not associated with small-scale differences in group size or available space. Aggression was significantly lower in a large aquarium with a complex habitat. Aquaria of sizes typically used in the companion animal (pet) hobby did not provide optimal welfare for cichlids housed with aggressive conspecifics. The public should be aware that this and similar species require larger aquaria with complex habitat, which elicit more natural behavior.     

Optimum spacing of genetic markers for determining linkage between marker loci and quantitative trait loci

The cost of experiments aimed at determining linkage between marker loci and quantitative trait loci (QTL) was investigated as a function of marker spacing and number of individuals scored. It was found that for a variety of experimental designs, fairly wide marker spacings (ca. 50 cM) are optimum or close to optimum for initial studies of marker-QTL linkage, in the sense of minimizing overall cost of the experiment. Thus, even when large numbers of more or less evenly spaced markers are available, it will not always be cost effective to make full utilization of this capacity. This is particularly true when costs of rearing and trait evaluation per individual scored are low, as when marker data are obtained on individuals raised and evaluated for quantitative traits as part of existing programs. When costs of rearing and trait evaluation per individual scored are high, however, as in human family data collection carried out primarily for subsequent marker — QTL analyses, or when plants or animals are raised specifically for purposes of marker — QTL linkage experiments, optimum spacing may be rather narrow. It is noteworthy that when marginal costs of additional markers or individuals are constant, total resources allocated to a given experiment will determine total number of individuals sampled, but not the optimal marker spacing.     

Harvesting in a resource dependent age structured Leslie type population model

We analyse the effect of harvesting in a resource dependent age structured population model, deriving the conditions for the existence of a stable steady state as a function of fertility coefficients, harvesting mortality and carrying capacity of the resources. Under the effect of proportional harvest, we give a sufficient condition for a population to extinguish, and we show that the magnitude of proportional harvest depends on the resources available to the population. We show that the harvesting yield can be periodic, quasi-periodic or chaotic, depending on the dynamics of the harvested population. For populations with large fertility numbers, small harvesting mortality leads to abrupt extinction, but larger harvesting mortality leads to controlled population numbers by avoiding over consumption of resources. Harvesting can be a strategy in order to stabilise periodic or quasi-periodic oscillations in the number of individuals of a population.     

Species–energy relationships and habitat complexity in bird communities

Species–energy theory is a commonly invoked theory predicting a positive relationship between species richness and available energy. The More Individuals Hypothesis (MIH) attempts to explain this pattern, and assumes that areas with greater food resources support more individuals, and that communities with more individuals include more species. Using a large dataset for North American birds, I tested these predictions of the MIH, and also examined the effect of habitat complexity on community structure. I found qualitative support for the relationships predicted by the MIH, however, the MIH alone was inadequate for fully explaining richness patterns. Communities in more productive sites had more individuals, but they also had more even relative abundance distributions such that a given number of individuals yielded a greater number of species. Richness and evenness were also higher in structurally complex forests compared to structurally more simple grasslands when controlling for available energy.     

Biotic stress resistance in agriculture through antimicrobial peptides

Antimicrobial peptides (AMPs) are the hosts' defense molecules against microbial pathogens and gaining extensive research attention worldwide. These have been reported to play vital role of host innate immunity in response to microbial challenges. AMPs can be used as a natural antibiotic as an alternative of their chemical counterpart for protection of plants/animals against diseases. There are a number of sources of AMPs including prokaryotic and eukaryotic organisms and are present, both in vertebrates and invertebrates. AMPs can be classified as cationic or anionic, based on net charges. Large number of databases and tools are available in the public domain which can be used for development of new genetically modified disease resistant varieties/breeds for agricultural production. The results of the biotechnological research as well as genetic engineering related to AMPs have shown high potential for reduction of economic losses of agricultural produce due to pathogens. In this article, an attempt has been made to introduce the role of AMPs in relation to plants and animals. Their functional and structural characteristics have been described in terms of its role in agriculture. Different sources of AMPs and importance of these sources has been reviewed in terms of its availability. This article also reviews the bioinformatics resources including different database tools and algorithms available in public domain. References of promising biotechnology research in relation to AMPs, prospects of AMPs for further development of genetically modified varieties/breeds are highlighted. AMPs are valuable resource for students, researchers, educators and medical and industrial personnel.     

Autozygome Sequencing Expands the Horizon of Human Knockout Research and Provides Novel Insights into Human Phenotypic Variation

The use of autozygosity as a mapping tool in the search for autosomal recessive disease genes is well established. We hypothesized that autozygosity not only unmasks the recessiveness of disease causing variants, but can also reveal natural knockouts of genes with less obvious phenotypic consequences. To test this hypothesis, we exome sequenced 77 well phenotyped individuals born to first cousin parents in search of genes that are biallelically inactivated. Using a very conservative estimate, we show that each of these individuals carries biallelic inactivation of 22.8 genes on average. For many of the 169 genes that appear to be biallelically inactivated, available data support involvement in modulating metabolism, immunity, perception, external appearance and other phenotypic aspects, and appear therefore to contribute to human phenotypic variation. Other genes with biallelic inactivation may contribute in yet unknown mechanisms or may be on their way to conversion into pseudogenes due to true recent dispensability. We conclude that sequencing the autozygome is an efficient way to map the contribution of genes to human phenotypic variation that goes beyond the classical definition of disease.     

Immunotherapy as a therapeutic treatment for neurodegenerative disorders

Human neurodegenerative illnesses such as Alzheimer's disease and Creutzfeldt-Jakob disease exact an enormous cost on individuals, families and society. For these and related disorders, current treatment is largely symptomatic without influencing the underlying disease process. Until recently, the development of immunotherapeutic approaches to neurodegenerative disorders had been almost completely ignored despite growing successes against other non-infectious diseases such as cancer. However, since Schenk and colleagues described the antibody-mediated clearance of amyloid plaques in a transgenic mouse model of Alzheimer's disease, a number of studies have confirmed the feasibility of this strategy for several neurodegenerative disorders including Huntington's disease and prion diseases. These reports offer the exciting prospect that either the immune system or its derivative components can be harnessed to fight the misfolded and/or aggregated proteins that accumulate in many neurodegenerative illnesses. If the remarkable power of clonal expansion, specificity and efficiency of the immune system can successfully inactivate these abnormal proteins, real hope exists that effective immunotherapeutic treatments for neurodegenerative illnesses may be available in the near future.     

Status signalling and the ability to recognize dominants: an experiment with siskins (Carduelis spinus)

Because dominants usually exploit others and take a disproportionate share of the available resources, we should expect foragers to be choosy as to which individuals they join. Here we show that siskins (Carduelis spinus) discriminate between dominant and subordinate individuals on the first encounter without requiring cues such as overt aggression, and prefer to join subordinate individuals. Experimental enlargement or removal of the siskin black bib, which has been shown previously to be a reliable predictor of dominance, strongly suggests that dominance discrimination is based on the use of badges of status.     

Modelling dominance hierarchy formation as a multi-player game

Animals who live in groups need to divide available resources amongst themselves. This is often achieved by means of a dominance hierarchy, where dominant individuals obtain a larger share of the resources than subordinate individuals. This paper introduces a model of dominance hierarchy formation using a multi-player extension of the classical Hawk-Dove game. Animals play non-independent pairwise games in a Swiss tournament which pairs opponents against those which have performed equally well in the conflict so far, for a fixed number of rounds. Resources are divided according to the number of contests won. The model, and its emergent properties, are discussed in the context of experimental observations.     

Saturation recovery leads to multiple endemic equilibria and backward bifurcation

The number of patients need to be treated may exceed the carry capacity of local hospitals during the spreading of a severe infectious disease. We propose an epidemic model with saturation recovery from infective individuals to understand the effect of limited resources for treatment of infectives on the emergency disease control. It is shown that saturation recovery from infective individuals leads to vital dynamics, such as bistability and periodicity, when the basic reproduction number R₀ is less than unity. An interesting dynamical behavior of the model is a backward bifurcation which raises many new challenges to effective infection control.     

Frequency-dependent conspecific attraction to food patches

In many ecological situations, resources are difficult to find but become more apparent to nearby searchers after one of their numbers discovers and begins to exploit them. If the discoverer cannot monopolize the resources, then others may benefit from joining the discoverer and sharing their discovery. Existing theories for this type of conspecific attraction have often used very simple rules for how the decision to join a discovered resource patch should be influenced by the number of individuals already exploiting that patch. We use a mechanistic, spatially explicit model to demonstrate that individuals should not necessarily simply join patches more often as the number of individuals exploiting the patch increases, because those patches are likely to be exhausted soon or joining them will intensify future local competition. Furthermore, we show that this decision should be sensitive to the nature of the resource patches, with individuals being more responsive to discoveries in general and more tolerant of larger numbers of existing exploiters on a patch when patches are resource-rich and challenging to locate alone. As such, we argue that this greater focus on underlying joining mechanisms suggests that conspecific attraction is a more sophisticated and flexible tactic than currently appreciated.     

Bayesian biomarker identification based on marker-expression proteomics data

We are studying variable selection in multiple regression models in which molecular markers and/or gene-expression measurements as well as intensity measurements from protein spectra serve as predictors for the outcome variable (i.e., trait or disease state). Finding genetic biomarkers and searching genetic–epidemiological factors can be formulated as a statistical problem of variable selection, in which, from a large set of candidates, a small number of trait-associated predictors are identified. We illustrate our approach by analyzing the data available for chronic fatigue syndrome (CFS). CFS is a complex disease from several aspects, e.g., it is difficult to diagnose and difficult to quantify. To identify biomarkers we used microarray data and SELDI-TOF-based proteomics data. We also analyzed genetic marker information for a large number of SNPs for an overlapping set of individuals. The objectives of the analyses were to identify markers specific to fatigue that are also possibly exclusive to CFS. The use of such models can be motivated, for example, by the search for new biomarkers for the diagnosis and prognosis of cancer and measures of response to therapy. Generally, for this we use Bayesian hierarchical modeling and Markov Chain Monte Carlo computation.     

Aggregations from using inadvertent social information: a form of ideal habitat selection

Social information in breeding site selection has received extensive study; however, few attempts have been made to link this process to pre‐existing models. We examine the importance of social information to three pertinent models of habitat selection that describe breeding aggregations and spatial patterns: 1) the ideal despotic distribution (IDD) which considers conspecific competition and habitat availability, 2) the perceptual constraints model which accounts for patch selection when animals experience a threshold of undetectable difference in quality, and 3) the “neighbourhood model” which predicts concordance between resources and settlers can be disrupted by conspecific attraction when resources are patchy. These models all predict initial settlers will select a high quality patch first. However, their predictions of subsequent settlement behaviour in remaining patches differ: the IDD predicts subsequent settlers will be distributed regularly, the perceptual constraints model predicts a random distribution, and the neighbourhood model predicts clustering from conspecific attraction. We examined which model best described settlement patterns of bobolink Dolichonyx oryzivorus and savannah sparrow Passerculus sandwichensis, in the context of social information. We observed settlement timing, quantified available resources, and determined where they occurred in the highest (local population “core”) and lowest densities (local population “periphery”). We then assessed whether individuals in the periphery settled in greater concordance with resources or conspecific presence. Core territories were clustered strongly on relevant resources, and these territory holders were older than in the periphery. Peripheral territories were likewise clustered but did not always co‐occur with the best available resources, matching the neighbourhood model prediction that social information may not always direct them to the best sites available. This suggests older individuals used their own experience to locate ideal habitat, whereas younger individuals attempted to aggregate on seemingly ideal habitat by using conspecific location; such information asymmetry due to age can be viewed as an “ideal aggregative distribution”.