The Use of SCID Mice in Biotechnology and as a Model for Human Disease

Abstract

The use of SCID (severe combined immunodeficient) mice in medical research and biotechnology has increased tremendously in recent years. This review outlines the major characteristics of these animals and the impediments that they pose to the engraftment of human cells and tissues. The development of our SCID mice pretreatment protocol (anti-asialo GM1 antisera and radiation) is described, and the results of xenotransplantation studies of human cells and tissues in these pretreated animals are outlined. Wherever possible, data from transplantation studies (of human tissues and cells) in pretreated and nonpretreated animals are compared. The potential of our pretreated SCID mice for medical research and biotechnology is discussed.     

我国疾病动物模型的研究现状和展望

由于医学科学研究的需要,各类疾病动物模型被广泛用来研究人类疾病的发生发展机制、药物筛选以及治疗评价等.本文全面梳理了我国疾病动物模型的研究和发展现状,分析了我国在这方面的特色优势以及与国际上的差距,内容涵盖了肿瘤、神经及精神疾病、感染及免疫性疾病、心血管与代谢性疾病、药物筛选等不同领域.简要介绍了国家自然科学基金对疾病动物模型项目的资助情况,同时指出了我国疾病模型今后的主要发展方向.     

The idea of environment in a historical perspective of human population

The history of environment in human terms is the history of knowing... and of not knowing... about the nature and extent of human interactions with that environment. In recent human history, those interactions (with the environment and among people) have accelerated dramatically. Human-environment relationships are complicated by that acceleration and by the resulting increases in levels of complexity. The acceleration requires a re-definition, in global terms, of what environment means and a greatly increased awareness on the part of individual people of the changes in the interaction patterns and of the resulting changes in environment, both in perception and in reality. A transcendent awareness could radically change the forms of human institutions, especially those of law and ethics. Such changes might then allow humans to temper their exchanges with and impacts on the environment.     

Evaluation of TorsinA as a Target for Parkinson Disease Therapy in Mouse Models

Parkinson disease (PD) is a common and disabling disorder. No current therapy can slow or reverse disease progression. An important aspect of research in this field is target validation, a systematic approach to evaluating the likelihood that modification of a certain molecule, mechanism or biological pathway may be useful for the development of pharmacological or molecular treatments for the disease. TorsinA, a member of the AAA+ family of chaperone proteins, has been proposed as a potential target of neuroprotective therapy. TorsinA is found in Lewy bodies in human PD, and can suppress toxicity in cellular and invertebrate models of PD. Here, we evaluated the neuroprotective properties of torsinA in mouse models of PD based on intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as well as recombinant adeno associated virus (rAAV) induced overexpression of alpha-synuclein (α-syn). Using either transgenic mice with overexpression of human torsinA (hWT mice) or mice in which torsinA expression was induced using an rAAV vector, we found no evidence for protection against acute MPTP intoxication. Similarly, genetic deletion of the endogenous mouse gene for torsinA (Dyt1) using an rAAV delivered Cre recombinase did not enhance the vulnerability of dopaminergic neurons to MPTP. Overexpression of α-syn using rAAV in the mouse substantia nigra lead to a loss of TH positive neurons six months after administration, and no difference in the degree of loss was observed between transgenic animals expressing forms of torsinA and wild type controls. Collectively, we did not observe evidence for a protective effect of torsinA in the mouse models we examined. Each of these models has limitations, and there is no single model with established predictive value with respect to the human disease. Nevertheless, these data do seem to support the view that torsinA is unlikely to be successfully translated as a target of therapy for human PD.     

An Interactive Model of Human and Companion Animal Dynamics: The Ecology and Economics of Dog Overpopulation and the Human Costs of Addressing the Problem

Companion animal overpopulation is a problem of human creation with significant human costs that can only be addressed through human action. A model was constructed to understand the dynamics of canine overpopulation and the effectiveness of various policy options for reducing euthanasia. The model includes economic and ecological factors in human and dog populations. According to the model, a no-kill society is an achievable goal at an acceptable human cost. Spay/neuter programs were generally found to be the most effective, with increasing adoptions also being an effective option. However, spay/neuter policies need to be evaluated over a very long time horizon since full impact may not be achieved for 30 years or more. Spay/neuter efforts can have a large impact even if they only effect a small portion of the human population. Adoption and spay/neuter programs were found to work well in combination, and to continue being effective as society approaches no-kill dynamics.     

Landscape as a model: the importance of geometry

In all models, but especially in those used to predict uncertain processes (e.g., climate change and nonnative species establishment), it is important to identify and remove any sources of bias that may confound results. This is critical in models designed to help support decisionmaking. The geometry used to represent virtual landscapes in spatially explicit models is a potential source of bias. The majority of spatial models use regular square geometry, although regular hexagonal landscapes have also been used. However, there are other ways in which space can be represented in spatially explicit models. For the first time, we explicitly compare the range of alternative geometries available to the modeller, and present a mechanism by which uncertainty in the representation of landscapes can be incorporated. We test how geometry can affect cell-to-cell movement across homogeneous virtual landscapes and compare regular geometries with a suite of irregular mosaics. We show that regular geometries have the potential to systematically bias the direction and distance of movement, whereas even individual instances of landscapes with irregular geometry do not. We also examine how geometry can affect the gross representation of real-world landscapes, and again show that individual instances of regular geometries will always create qualitative and quantitative errors. These can be reduced by the use of multiple randomized instances, though this still creates scale-dependent biases. In contrast, virtual landscapes formed using irregular geometries can represent complex real-world landscapes without error. We found that the potential for bias caused by regular geometries can be effectively eliminated by subdividing virtual landscapes using irregular geometry. The use of irregular geometry appears to offer spatial modellers other potential advantages, which are as yet underdeveloped. We recommend their use in all spatially explicit models, but especially for predictive models that are used in decisionmaking.     

Fish as Bioreactors: Transgene Expression of Human Coagulation Factor VII in Fish Embryos

A plasmid containing human coagulation factor VII (hFVII) complementary DNA regulated by a cytomegalovirus promoter was microinjected into fertilized eggs of zebrafish, African catfish, and tilapia. The active form of hFVll was detected in the fish embryos by various assays. This positive expression of human therapeutic protein in fish embryos demonstrates the possibility of exploitation of transgenic fish as bioreactors.     

The sandfly fauna,anthropophily and the seasonal activities of Pintomyia spinicrassa (Diptera: Psychodidae: Phlebotominae) in a focus of cutaneous leishmaniasis in northeastern Colombia

This study was conducted to identify the sandfly fauna and the anthropophilic species in a coffee-growing area of Villanueva, Norte de Santander, Colombia, a focus of American cutaneous leishmaniasis, and to analyse the relationship between the most frequent species and rainfall, relative humidity and temperature, with the aim of contributing to epidemiological surveillance in the area. Sandfly collections were performed fortnightly between February 2006-September 2007 using automatic light traps, Shannon traps, protected human bait and aspiration in resting places. A total of 7,051 sandflies belonging to 12 species were captured. Pintomyia spinicrassa (95.7%) predominated. Pintomyia oresbia and Lutzomyia sp. of Pichinde were found in the state of Norte de Santander for the first time. Pi. spinicrassa, Pintomyia nuneztovari, Micropygomyia venezuelensis, Lutzomyia (Helcocyrtomyia) scorzai and Lu. (Helcocyrtomyia) sp. were captured on the protected human bait. A significant association between Pi. spinicrassa abundance and the total rainfall and the average temperature and humidity 10 days before the collection was observed. The dominance of Pi. spinicrassa, a recognised vector of Leishmania braziliensis, especially during the dry periods, indicates that the risk of parasite transmission may increase.     

The Projection of a Test Genome onto a Reference Population and Applications to Humans and Archaic Hominins

We introduce a method for comparing a test genome with numerous genomes from a reference population. Sites in the test genome are given a weight, w, that depends on the allele frequency, x, in the reference population. The projection of the test genome onto the reference population is the average weight for each x, w¯(x). The weight is assigned in such a way that, if the test genome is a random sample from the reference population, then w¯(x)=1. Using analytic theory, numerical analysis, and simulations, we show how the projection depends on the time of population splitting, the history of admixture, and changes in past population size. The projection is sensitive to small amounts of past admixture, the direction of admixture, and admixture from a population not sampled (a ghost population). We compute the projections of several human and two archaic genomes onto three reference populations from the 1000 Genomes project—Europeans, Han Chinese, and Yoruba—and discuss the consistency of our analysis with previously published results for European and Yoruba demographic history. Including higher amounts of admixture between Europeans and Yoruba soon after their separation and low amounts of admixture more recently can resolve discrepancies between the projections and demographic inferences from some previous studies.     

Log-linear Models in a Study of Gall Bladder Disease

Biliary drainage and X-rays have been used singly and together in the diagnosis of gall bladder disease. Data from two sets of patients were statistically analyzed using log-linear analysis of contingency tables. The results of the study show that “biliary drainage” is dependent of “X-ray” and “Pathology”; abnormal X-ray is associated with abnormal pathology. Thus, biliary drainage is not of such value as to base surgery on it alone. However, X-rays are of significant value in the diagnosis of the gall bladder disease and to decide whether a surgery is needed or not.     

Floristic heterogeneity between forested sites in Kibale National Park, Uganda: insights into the fine-scale determinants of density in a large-bodied frugivorous primate

1.  Despite a long history of research on the influence of fruit availability on the population density of large-bodied vertebrate frugivores, operational understanding of the factors regulating density in these taxa remains elusive. We propose that fruit resources can be distinguished from one another on the basis of their functional role for the animals in question, and that such a classification system can aid in identifying the most influential determinants of frugivore density.
2.  We compared the availability of several resource classes between two sites in Kibale National Park, Uganda separated by only 12 km yet differing threefold in density of chimpanzees ( Pan troglodytes ).
3.  We categorized plant species used for fruit by chimpanzees according to their availability relative to habitat-wide fruit productivity, and by their tendency towards inter-individual fruiting synchrony. We predicted that the site of high chimpanzee density would support a higher density of food plant species tending to produce crops during periods of high habitat-wide productivity [high fruit abundance (HFA foods)] and of those tending to fruit synchronously among individuals during times of low habitat-wide availability (sLFA foods). The first food class should provide chimpanzees with a high nutrient density (and thus promote population growth), whereas the second should provide stable subsistence during lean periods and thus a temporally consistent resource base.
4.  Counter to our prediction, only sLFA resources were more abundant at the site of high chimpanzee density than at the site of low density. We suggest that sLFA resources are most important in influencing density of large-bodied frugivores.     

Syntactic Computation in the Human Brain: The Degree of Merger as a Key Factor

Our goal of this study is to characterize the functions of language areas in most precise terms. Previous neuroimaging studies have reported that more complex sentences elicit larger activations in the left inferior frontal gyrus (L. F3op/F3t), although the most critical factor still remains to be identified. We hypothesize that pseudowords with grammatical particles and morphosyntactic information alone impose a construction of syntactic structures, just like normal sentences, and that “the Degree of Merger” (DoM) in recursively merged sentences parametrically modulates neural activations. Using jabberwocky sentences with distinct constructions, we fitted various parametric models of syntactic, other linguistic, and nonlinguistic factors to activations measured with functional magnetic resonance imaging. We demonstrated that the models of DoM and “DoM+number of Search (searching syntactic features)” were the best to explain activations in the L. F3op/F3t and supramarginal gyrus (L. SMG), respectively. We further introduced letter strings, which had neither lexical associations nor grammatical particles, but retained both matching orders and symbol orders of sentences. By directly contrasting jabberwocky sentences with letter strings, localized activations in L. F3op/F3t and L. SMG were indeed independent of matching orders and symbol orders. Moreover, by using dynamic causal modeling, we found that the model with a inhibitory modulatory effect for the bottom-up connectivity from L. SMG to L. F3op/F3t was the best one. For this best model, the top-down connection from L. F3op/F3t to L. SMG was significantly positive. By using diffusion-tensor imaging, we confirmed that the left dorsal pathway of the superior longitudinal and arcuate fasciculi consistently connected these regions. Lastly, we established that nonlinguistic order-related and error-related factors significantly activated the right (R.) lateral premotor cortex and R. F3op/F3t, respectively. These results indicate that the identified network of L. F3op/F3t and L. SMG subserves the calculation of DoM in recursively merged sentences.     

Inference of Super-exponential Human Population Growth via Efficient Computation of the Site Frequency Spectrum for Generalized Models

The site frequency spectrum (SFS) and other genetic summary statistics are at the heart of many population genetic studies. Previous studies have shown that human populations have undergone a recent epoch of fast growth in effective population size. These studies assumed that growth is exponential, and the ensuing models leave an excess amount of extremely rare variants. This suggests that human populations might have experienced a recent growth with speed faster than exponential. Recent studies have introduced a generalized growth model where the growth speed can be faster or slower than exponential. However, only simulation approaches were available for obtaining summary statistics under such generalized models. In this study, we provide expressions to accurately and efficiently evaluate the SFS and other summary statistics under generalized models, which we further implement in a publicly available software. Investigating the power to infer deviation of growth from being exponential, we observed that adequate sample sizes facilitate accurate inference; e.g., a sample of 3000 individuals with the amount of data expected from exome sequencing allows observing and accurately estimating growth with speed deviating by ≥10% from that of exponential. Applying our inference framework to data from the NHLBI Exome Sequencing Project, we found that a model with a generalized growth epoch fits the observed SFS significantly better than the equivalent model with exponential growth (P-value = 3.85 × 10^?6). The estimated growth speed significantly deviates from exponential (P-value  ? 10^?12), with the best-fit estimate being of growth speed 12% faster than exponential.