Endogenous Opioid Antagonism in Physiological Experimental Pain Models: A Systematic Review

Opioid antagonists are pharmacological tools applied as an indirect measure to detect activation of the endogenous opioid system (EOS) in experimental pain models. The objective of this systematic review was to examine the effect of mu-opioid-receptor (MOR) antagonists in placebo-controlled, double-blind studies using ʻinhibitoryʼ or ʻsensitizingʼ, physiological test paradigms in healthy human subjects. The databases PubMed and Embase were searched according to predefined criteria. Out of a total of 2,142 records, 63 studies (1,477 subjects [male/female ratio = 1.5]) were considered relevant. Twenty-five studies utilized ʻinhibitoryʼ test paradigms (ITP) and 38 studies utilized ʻsensitizingʼ test paradigms (STP). The ITP-studies were characterized as conditioning modulation models (22 studies) and repetitive transcranial magnetic stimulation models (rTMS; 3 studies), and, the STP-studies as secondary hyperalgesia models (6 studies), ʻpainʼ models (25 studies), summation models (2 studies), nociceptive reflex models (3 studies) and miscellaneous models (2 studies). A consistent reversal of analgesia by a MOR-antagonist was demonstrated in 10 of the 25 ITP-studies, including stress-induced analgesia and rTMS. In the remaining 14 conditioning modulation studies either absence of effects or ambiguous effects by MOR-antagonists, were observed. In the STP-studies, no effect of the opioid-blockade could be demonstrated in 5 out of 6 secondary hyperalgesia studies. The direction of MOR-antagonist dependent effects upon pain ratings, threshold assessments and somatosensory evoked potentials (SSEP), did not appear consistent in 28 out of 32 ʻpainʼ model studies. In conclusion, only in 2 experimental human pain models, i.e., stress-induced analgesia and rTMS, administration of MOR-antagonist demonstrated a consistent effect, presumably mediated by an EOS-dependent mechanisms of analgesia and hyperalgesia.     

Physical Models for Exploring DNA Topology

Abstract

Two types of physical models have been developed for treating DNA molecules whose topology is of interest The two model motifs combine jacks-and-straws molecular representations with flexible tubing in different proportions. Both motifs present a low-resolution construct of DNA that retains helix axes, strand individuality and the distinguishabiity of the major and minor grooves. Molecules whose double helix axes are branched are modelled by stiff double helices and flexible branch sites. Supercoiled and knotted DNA molecules are modelled on a smaller scale, in a system in which a flexible backbone is supported by a series of stiff helical struts; removal of this scaffolding immediately reveals the linking of the strands. The models are light and easy to construct. They may be used either for demonstrations or as a research tool that assists the interpretation data.     

Exploring Migration Data Using Interval-Censored Time-to-Event Models

Abstract: Ecologists and wildlife biologists rely on periodic observation of radiocollared animals to study habitat use, survival, movement, and migration, resulting in response times (e.g., mortality and migration) known only to occur within an interval of time. We illustrate methods for analyzing interval-censored data using data on the timing of fall migration (from spring-summer-fall to winter ranges) for white-tailed deer (Odocoileus virginianus) in northern Minnesota, USA, during years 1991–1992 to 2005–2006. We compare both nonparametric and parametric methods for estimating the cumulative distribution function of migration times, and we suggest a parametric (cure rate) model that accounts for conditional (facultative) migrators as a potential alternative to traditional parametric models. Lastly, we illustrate methods for exploring the effect of environmental covariates on migration timing. Models with time-dependent covariates (snow depth, temp) were sensitive to the treatment of the data (as interval-censored or known event times), suggesting the need to account for interval-censoring when modeling the effect of these covariates.     

Score Tests for Exploring Complex Models: Application to HIV Dynamics Models

In biostatistics, more and more complex models are being developed. This is particularly the case in system biology. Fitting complex models can be very time‐consuming, since many models often have to be explored. Among the possibilities are the introduction of explanatory variables and the determination of random effects. The particularity of this use of the score test is that the null hypothesis is not itself very simple; typically, some random effects may be present under the null hypothesis. Moreover, the information matrix cannot be computed, but only an approximation based on the score. This article examines this situation with the specific example of HIV dynamics models. We examine the score test statistics for testing the effect of explanatory variables and the variance of random effect in this complex situation. We study type I errors and the statistical powers of this score test statistics and we apply the score test approach to a real data set of HIV‐infected patients.     

Mathematical Models of Cell Motility

Cell motility is an essential biological action in the creation, operation and maintenance of our bodies. Developing mathematical models elucidating cell motility will greatly advance our understanding of this fundamental biological process. With accurate models it is possible to explore many permutations of the same event and concisely investigate their outcome. While great advancements have been made in experimental studies of cell motility, it now has somewhat fallen on mathematical models to taking a leading role in future developments. The obvious reason for this is the complexity of cell motility. Employing the processing power of today’s computers will give researches the ability to run complex biophysical and biochemical scenarios, without the inherent difficulty and time associated with in vitro investigations. Before any great advancement can be made, the basics of cell motility will have to be well-defined. Without this, complicated mathematical models will be hindered by their inherent conjecture. This review will look at current mathematical investigations of cell motility, explore the reasoning behind such work and conclude with how best to advance this interesting and challenging research area.     

Models of Cell Number Increase in Developing Leaves

Negative logistic and negative exponential models to accountfor cell number changes in primary leaves of Phaseolus are considered.The negative exponential model gives a close fit to observeddata for cell number when the average division time is 12 h.From this model it is considered that about 20 per cent of thecells in the leaf are capable of continued division at the timewhen divisions actually cease.     

Leptin对陕北白绒山羊体细胞核移植的影响

Leptin的功能较为复杂,主要调控机体能量代谢。有研究表明Leptin在卵母细胞成熟及胚胎发育过程中也具有重要作用。本研究在卵母细胞体外成熟基础培养液中添加了不同浓度的Leptin,其中未添加Leptin的设为Ⅰ组,添加10ng/mL和50ng/mL Leptin的分别设为Ⅱ组和Ⅲ组。以陕北白绒山羊皮肤成纤维细胞为供体细胞,三组体外培养成熟的卵母细胞作为受体,利用显微操作方法对成熟卵母细胞进行去核操作,然后将供体细胞注射到卵周隙内,经电融合后形成体细胞克隆胚。根据卵母细胞体外成熟率、核移植效率以及克隆胚囊胚发育率分析Leptin在山羊核移植中的作用。结果表明Ⅰ组山羊卵母细胞体外成熟率和核移植效率显著高于其他两组(P<0.05),三组克隆囊胚发育率无显著差异(P>0.05)。Leptin降低了山羊卵母细胞体外成熟和核移植效率,对克隆胚发育能力无影响。     

Mathematical Models for Cell Migration with Real-Time Cell Cycle Dynamics

The fluorescent ubiquitination-based cell cycle indicator, also known as FUCCI, allows the visualization of the G1 and S/G2/M cell cycle phases of individual cells. FUCCI consists of two fluorescent probes, so that cells in the G1 phase fluoresce red and cells in the S/G2/M phase fluoresce green. FUCCI reveals real-time information about cell cycle dynamics of individual cells, and can be used to explore how the cell cycle relates to the location of individual cells, local cell density, and different cellular microenvironments. In particular, FUCCI is used in experimental studies examining cell migration, such as malignant invasion and wound healing. Here we present, to our knowledge, new mathematical models that can describe cell migration and cell cycle dynamics as indicated by FUCCI. The fundamental model describes the two cell cycle phases, G1 and S/G2/M, which FUCCI directly labels. The extended model includes a third phase, early S, which FUCCI indirectly labels. We present experimental data from scratch assays using FUCCI-transduced melanoma cells, and show that the predictions of spatial and temporal patterns of cell density in the experiments can be described by the fundamental model. We obtain numerical solutions of both the fundamental and extended models, which can take the form of traveling waves. These solutions are mathematically interesting because they are a combination of moving wavefronts and moving pulses. We derive and confirm a simple analytical expression for the minimum wave speed, as well as exploring how the wave speed depends on the spatial decay rate of the initial condition.     

Non-local Parabolic and Hyperbolic Models for Cell Polarisation in Heterogeneous Cancer Cell Populations

Tumours consist of heterogeneous populations of cells. The sub-populations can have different features, including cell motility, proliferation and metastatic potential. The interactions between clonal sub-populations are complex, from stable coexistence to dominant behaviours. The cell–cell interactions, i.e. attraction, repulsion and alignment, processes critical in cancer invasion and metastasis, can be influenced by the mutation of cancer cells. In this study, we develop a mathematical model describing cancer cell invasion and movement for two polarised cancer cell populations with different levels of mutation. We consider a system of non-local hyperbolic equations that incorporate cell–cell interactions in the speed and the turning behaviour of cancer cells, and take a formal parabolic limit to transform this model into a non-local parabolic model. We then investigate the possibility of aggregations to form, and perform numerical simulations for both hyperbolic and parabolic models, comparing the patterns obtained for these models.     

Synergistic Interaction between Selective Drugs in Cell Populations Models

The design of selective drugs and combinatorial drug treatments are two of the main focuses in modern pharmacology. In this study we use a mathematical model of chimeric ligand-receptor interaction to show that the combination of selective drugs is synergistic in nature, providing a way to gain optimal selective potential at reduced doses compared to the same drugs when applied individually. We use a cell population model of proliferating cells expressing two different amounts of a target protein to show that both selectivity and synergism are robust against variability and heritability in the cell population. The reduction in the total drug administered due to the synergistic performance of the selective drugs can potentially result in reduced toxicity and off-target interactions, providing a mechanism to improve the treatment of cell-based diseases caused by aberrant gene overexpression, such as cancer and diabetes.     

慢性阻塞性肺疾病大鼠模型中痩素及白介素-8 的表达分析

目的:观察COPD大鼠模型中瘦素(leptin)、白细胞介素8(IL-8)的表达情况,分析其相关性,探讨leptin在COPD发生发展中的作用及意义.方法:36只雄性SD大鼠随机分为①健康对照组;②COPD模型1组:分别于第(1、14)d经气管内注入内毒素200ug,熏5％香烟(第1、14d除外),2h/d,共4周;③COPD模型2组:单纯熏5％香烟2h/d,共12周.观察肺组织病理变化,免疫组化法测定leptin、IL-8在支气管肺组织的表达情况,放免法测定血清leptin及IL-8浓度.结果:细胞因子leptin及炎性因子IL-8在支气管肺组织阳性表达.LPS联合熏烟诱导COPD1组支气管肺组织中leptin(52.67±04.72)和IL-8(59.56± 3.94)表达较单纯熏烟诱导COPD2组leptin(38.89± 2.57)和IL-8(55.22± 3.42)表达明显升高,P＜0.05,两组COPD大鼠模型支气管肺组织中leptin及IL-8表达较正常对照组leptin( 1690± 1.52)和IL-8 (28.00± 4.24)表达均明显增高,P＜0.05,COPD1组血清中leptin(3.26± 0.95)ng/mL和IL-8( 107.51±13.38 )pg/mL-较COPD2组中leptin(2.42± 0.69 )ng/mL和IL-8((94.07± 11.20)pg/mL明显增高,P＜0.05,两组COPD大鼠模型血清中leptin及IL-8浓度较正常对照组leptin(0.95±0.56)ng/mL和IL-8( 39.48± 6.35 )pg/mL浓度显著升高,P＜0.05.血清中Leptin与IL-8表达水平呈显著正相关(r值分别为0.72 0.67 0.84均P＜0.05).经过q检验,两两之间比较均有统计学意义.结论:leptin和IL-8均参与COPD炎症反应过程,并且具有相关性,LPS促进二者的表达.     

慢性阻塞性肺疾病大鼠模型中瘦素及白介素-8的表达分析

目的：观察COPD大鼠模型中瘦素（1eptin）、白细胞介素8（IL-8）的表达情况,分析其相关性,探讨leptin在COPD发生发展中的作用及意义。方法：36只雄性SD大鼠随机分为①健康对照组;②COPD模型1组：分别于第（1、14）d经气管内注入内毒素200ug,熏5％香烟（第1、14d除外）,2h／d,共4周;⑧COPD模型2组：单纯熏5％香烟2h／d,共12周。观察肺组织病理变化,免疫组化法测定leptin、IL-8在支气管肺组织的表达情况,放免法测定血清leptin及IL-8浓度。结果：细胞因子leptin及炎性因子IL-8在支气管肺组织阳性表达。LPS联合熏烟诱导COPDl组支气管肺组织中leptin（52．67±04．72）和IL-8（59．56±3．94）表达较单纯熏烟诱导COPD2组leptin（38．89±2．57）和IL-8（55．22±3．42）表达明显升高,P〈0．05,两组COPD大鼠模型支气管肺组织中leptin及IL-8表达较正常对照组leptin（16．90＋1．52）和IL-8（28．00±4．24）表达均明显增高,P〈0．05,COPD1组血清中leptin（3．26±0．95）ng／mL和IL-8（107．51±13.38）pg／mL较COPD2组中leptin（2．42±0．69）ng／mL和IL-8（（94．07±11．20）pg／mL明显增高,P〈0．05,两组COPD大鼠模型血清中leptin及IL培浓度较正常对照组leptin（0．95±0．56）ng／mL和IL-8（39．48±6．35）pg／mL浓度显著升高,P〈0．05。血清中Leptin与IL-8表达水平呈显著~-ffn关（r值分别为0．720．670．84均P〈0．05）。经过q检验,两两之间比较均有统计学意义。结论：leptin和IL-8均参与cOPD炎症反应过程,并且具有相关性,LPS促进二者的表达。