两种复吸动物模型的神经生物学机制

复吸是指撤药一段时间后,觅药和用药行为的恢复。它是药物成瘾的主要特征之一,也是药物成瘾治疗亟待解决的头号难题。本文介绍两种复吸动物模型——自身给药消退恢复模型、条件性位置偏爱消退复燃模型建立的方法,对模型的效标效度进行评价,探讨复吸的神经生物学机制,为药物成瘾的治疗提供研究思路。     

Some Physiological Mechanisms Functioning in Models of Pain-Related Processes

Neurophysiology - Psychophysiological sensing of pain is formed due to the activity of a number of neuronal mechanisms. Among the pain-related processes, nociception per se, peripheral...     

Penicillin Fermentation: Mechanisms and Models for Industrial-Scale Bioreactors

ABSTRACT:?

Even after many years of research and industrial practice, the production of penicillin G in fed-batch fermentation by Penicillium crysogenum continues to attract research interest. There are many reasons: the commercial and therapeutic importance of penicillin and its derivatives, the complexity of cell growth, and the impact of engineering variables, the last of which are significant in large bioreactors but are not yet fully understood. Extensive research has generated new information on the mechanisms of cellular reactions and morphological features of the mycelia and their role in the synthesis of the product. Given a choice of mechanisms, models of different degrees of complexity, for both cellular differentiation and bioreactor performance, have been proposed. The more complex models require and provide more information. They are also more difficult to evaluate and apply in automatic control systems for production-scale bioreactors. The present review considers the evolution of recent knowledge and models from this perspective.     

Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease

Lipoxygenase (LOX) activity has been implicated in neurodegenerative disorders such as Alzheimer''s disease, but its effects in Parkinson''s disease (PD) pathogenesis are less understood. Gene-environment interaction models have utility in unmasking the impact of specific cellular pathways in toxicity that may not be observed using a solely genetic or toxicant disease model alone. To evaluate if distinct LOX isozymes selectively contribute to PD-related neurodegeneration, transgenic (i.e. 5-LOX and 12/15-LOX deficient) mice can be challenged with a toxin that mimics cell injury and death in the disorder. Here we describe the use of a neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces a nigrostriatal lesion to elucidate the distinct contributions of LOX isozymes to neurodegeneration related to PD. The use of MPTP in mouse, and nonhuman primate, is well-established to recapitulate the nigrostriatal damage in PD. The extent of MPTP-induced lesioning is measured by HPLC analysis of dopamine and its metabolites and semi-quantitative Western blot analysis of striatum for tyrosine hydroxylase (TH), the rate-limiting enzyme for the synthesis of dopamine. To assess inflammatory markers, which may demonstrate LOX isozyme-selective sensitivity, glial fibrillary acidic protein (GFAP) and Iba-1 immunohistochemistry are performed on brain sections containing substantia nigra, and GFAP Western blot analysis is performed on striatal homogenates. This experimental approach can provide novel insights into gene-environment interactions underlying nigrostriatal degeneration and PD.     

Mechanisms of Granulin Deficiency: Lessons from Cellular and Animal Models

The identification of causative mutations in the (pro)granulin gene (GRN) has been a major breakthrough in the research on frontotemporal dementia (FTD). So far, all FTD-associated GRN mutations are leading to neurodegeneration through a “loss-of-function” mechanism, encouraging researchers to develop a growing number of cellular and animal models for GRN deficiency. GRN is a multifunctional secreted growth factor, and loss of its function can affect different cellular processes. Besides loss-of-function (i.e., mostly premature termination codons) mutations, which cause GRN haploinsufficiency through reduction of GRN expression, FTD-associated GRN missense mutations have also been identified. Several of these missense mutations are predicted to increase the risk of developing neurodegenerative diseases through altering various key biological properties of GRN-like protein secretion, proteolytic processing, and neurite outgrowth. With the use of cellular and animal models for GRN deficiency, the portfolio of GRN functions has recently been extended to include functions in important biological processes like energy and protein homeostasis, inflammation as well as neuronal survival, neurite outgrowth, and branching. Furthermore, GRN-deficient animal models have been established and they are believed to be promising disease models as they show accelerated aging and recapitulate at least some neuropathological features of FTD. In this review, we summarize the current knowledge on the molecular mechanisms leading to GRN deficiency and the lessons we learned from the established cellular and animal models. Furthermore, we discuss how these insights might help in developing therapeutic strategies for GRN-associated FTD.     

Syringeal anatomy and allometry in murres (Alcidae: Uria)

Species and sexual differences in vocalizations and the vocal tract are widespread. We studied the vocal tract of Common (Uria aalge) and Thick-billed (U. lomvia) Murres. We predicted anatomical or allometric differences in adults between species and sexes due to vocal differences related to social behavior (Common Murres nest at higher densities; males are the more aggressive sex, etc.). The vocal tract was anatomically simple and similar between species and sexes. The trachea was mainly cartilage, but the posteriormost 4–6 tracheal rings were calcified and fused as the tympanum, as part of the syrinx. The syrinx included the (unfused) first bronchial semirings, which were enlarged and calcified beneath the insertion of M. tracheolateralis. Weak bilateral asymmetry (right side larger) occurred in widths of M. tracheolateralis and M. sternotrachealis. The trachea was ∼10% longer in Common Murres; the tympanum and M. sternotrachealis width were relatively larger in Thick-billed Murres. Vocal-tract morphology and size did not differ between the sexes in either species. In allometric analyses on adults, isometry characterized (1) tympanum size in relation to head + bill length, and to humerus length (respectively), in Thick-billed Murres, and (2) M. sternotrachealis width in relation to tarsometatarsal length in both species. Comparative field studies on species and sexes are needed to clarify the functional significance of our findings in relation to vocalization.     

Distinguishing Antimicrobial Models with Different Resistance Mechanisms via Population Pharmacodynamic Modeling

Semi-mechanistic pharmacokinetic-pharmacodynamic (PK-PD) modeling is increasingly used for antimicrobial drug development and optimization of dosage regimens, but systematic simulation-estimation studies to distinguish between competing PD models are lacking. This study compared the ability of static and dynamic in vitro infection models to distinguish between models with different resistance mechanisms and support accurate and precise parameter estimation. Monte Carlo simulations (MCS) were performed for models with one susceptible bacterial population without (M1) or with a resting stage (M2), a one population model with adaptive resistance (M5), models with pre-existing susceptible and resistant populations without (M3) or with (M4) inter-conversion, and a model with two pre-existing populations with adaptive resistance (M6). For each model, 200 datasets of the total bacterial population were simulated over 24h using static antibiotic concentrations (256-fold concentration range) or over 48h under dynamic conditions (dosing every 12h; elimination half-life: 1h). Twelve-hundred random datasets (each containing 20 curves for static or four curves for dynamic conditions) were generated by bootstrapping. Each dataset was estimated by all six models via population PD modeling to compare bias and precision. For M1 and M3, most parameter estimates were unbiased (<10%) and had good imprecision (<30%). However, parameters for adaptive resistance and inter-conversion for M2, M4, M5 and M6 had poor bias and large imprecision under static and dynamic conditions. For datasets that only contained viable counts of the total population, common statistical criteria and diagnostic plots did not support sound identification of the true resistance mechanism. Therefore, it seems advisable to quantify resistant bacteria and characterize their MICs and resistance mechanisms to support extended simulations and translate from in vitro experiments to animal infection models and ultimately patients.     

The Mechanisms of Coexistence and Competitive Exclusion in Complex Plankton Ecosystem Models

The biodiversity of plankton ecosystems may no longer be a paradox, but the mechanisms that determine coexistence of explicit competitors in ecosystems remain a mystery. This is particularly so in ecosystem models, where competitive exclusion remains the dominant process. Climate and fisheries models require plankton ecosystem sub-models that maintain competing plankton functional types extant, but coexistence can be reproduced in only a few ‘just so’ theoretical models. This limits our ability to predict the impacts of climate change and fisheries on ocean biota. We consider ecosystems of Kolmogorov form that conserve mass (CK systems). These systems describe a general class of ecosystem models that includes many theoretical and applied models. We develop heuristics that illuminate the key mechanisms that allow the coexistence of explicit competitors in these systems. These heuristics facilitate the identification of a large class of models with the structural property that all species coexist for all time. Our approach unifies many theoretical and applied models in a common biogeochemical framework, providing a powerful tool with the potential to generate new insights into the properties of complex ecosystems.     

TLR4在鼠感染疾病模型的作用机理

TLRs是宿主识别各种病原体相关分子模式、并激活和调节天然免疫-适应性免疫反应的一类模式识别受体。在哺乳动物发现13种TLRs成员;已利用近交系小鼠对其作用机理进行了深入研究,本文简要综述TLR4在抗细菌、病毒、寄生虫感染中的作用机理。     

Syringeal specialization of frequency control during song production in the Bengalese finch (Lonchura striata domestica)

Background

Singing in songbirds is a complex, learned behavior which shares many parallels with human speech. The avian vocal organ (syrinx) has two potential sound sources, and each sound generator is under unilateral, ipsilateral neural control. Different songbird species vary in their use of bilateral or unilateral phonation (lateralized sound production) and rapid switching between left and right sound generation (interhemispheric switching of motor control). Bengalese finches (Lonchura striata domestica) have received considerable attention, because they rapidly modify their song in response to manipulations of auditory feedback. However, how the left and right sides of the syrinx contribute to acoustic control of song has not been studied.

Methodology

Three manipulations of lateralized syringeal control of sound production were conducted. First, unilateral syringeal muscular control was eliminated by resection of the left or right tracheosyringeal portion of the hypoglossal nerve, which provides neuromuscular innervation of the syrinx. Spectral and temporal features of song were compared before and after lateralized nerve injury. In a second experiment, either the left or right sound source was devoiced to confirm the role of each sound generator in the control of acoustic phonology. Third, air pressure was recorded before and after unilateral denervation to enable quantification of acoustic change within individual syllables following lateralized nerve resection.

Significance

These experiments demonstrate that the left sound source produces louder, higher frequency, lower entropy sounds, and the right sound generator produces lower amplitude, lower frequency, higher entropy sounds. The bilateral division of labor is complex and the frequency specialization is the opposite pattern observed in most songbirds. Further, there is evidence for rapid interhemispheric switching during song production. Lateralized control of song production in Bengalese finches may enhance acoustic complexity of song and facilitate the rapid modification of sound production following manipulations of auditory feedback.     

Two-Dimensional Aerodynamic Models of Insect Flight for Robotic Flapping Wing Mechanisms of Maximum Efficiency

In the ＂modified quasi-steady＂ approach, two-dimensional （2D） aerodynamic models of flapping wing motions are analyzed with focus on different types of wing rotation and different positions of rotation axis to explain the force peak at the end of each half stroke. In this model, an additional velocity of the mid chord position due to rotation is superimposed on the translational relative velocity of air with respect to the wing. This modification produces augmented forces around the end of each stroke. For each case of the flapping wing motions with various combination of controlled translational and rotational velocities of the wing along inclined stroke planes with thin figure-of-eight trajectory, discussions focus on lift-drag evolution during one stroke cycle and efficiency of types of wing rotation. This ＂modified quasi-steady＂ approach provides a systematic analysis of various parameters and their effects on efficiency of flapping wing mechanism. Flapping mechanism with delayed rotation around quarter-chord axis is an efficient one and can be made simple by a passive rotation mechanism so that it can be useful for robotic application.