Modelling contact spread of infection in host-parasitoid systems: Vertical transmission of pathogens can cause chaos

All animals and plants are, to some extent, susceptible to disease caused by varying combinations of parasites, viruses and bacteria. In this paper, we develop a mathematical model of contact spread infection to investigate the effect of introducing a parasitoid-vectored infection into a one-host-two-parasitoid competition model. We use a system of ordinary differential equations to investigate the separate influences of horizontal and vertical pathogen transmission on a model system appropriate for a variety of competitive situations. Computational simulations and steady-state analysis show that the transient and long-term dynamics exhibited under contact spread infection are highly complex. Horizontal pathogen transmission has a stabilising effect on the system whilst vertical transmission can destabilise it to the point of chaotic fluctuations in population levels. This has implications when considering the introduction of host pathogens for the control of insect vectored diseases such as bovine tuberculosis or yellow fever.     

Modeling immune complex-mediated autoimmune inflammation

A number of autoimmune diseases are thought to feature a particular type of self-sustaining inflammation, caused by the deposition of immune complexes (IC) in the inflamed tissue and a consequent activation of local effector cells. The persistence of this inflammation is due to a positive feedback loop, where autoantigen particles released as part of the tissue damage caused by the inflammation stimulate autoreactive B cells, leading to the formation of further immune complexes and their subsequent deposition. We present a mathematical model for the exploration of IC-mediated autoimmune inflammation and its clinical implications. We characterize the possible differences between normal individuals and those susceptible to such inflammation, and show that both random perturbations and bifurcations can lead to disease onset. Our model explains how defects in the mechanisms responsible for cellular debris clearance contribute to the development of disease, in agreement with empirical evidence. Moreover, we show that parameters governing the dynamics of immune complexes, such as their clearance rate, have an even stronger effect in determining the behavior of the system. We demonstrate the existence of hysteresis, implying that once IC-mediated autoimmune inflammation is triggered, its long-term suppression may be difficult to achieve. Our results can serve to guide the development of novel therapies to autoimmune diseases involving this type of inflammation.     

实验猴主要细菌性感染疾病的病理特点分析

目的通过对实验猴细菌性感染疾病脏器病理改变的观察和分析,完善实验猴病理检测资料,为实验动物病理检测标准的制定提供依据。方法选取86例实验猴按5种必检细菌性感染疾病（沙门菌病;志贺菌病;结核杆菌病;小肠结肠炎耶尔森菌病;空肠弯曲菌病）病原种类分组,对脏器标本进行病理剖检,HE染色观察记录病变,建立实验猴必检细菌性疾病病理检测资料。结果病理检测结果显示：沙门菌病表现为伤寒肉芽肿,结核杆菌病表现为结核肉芽肿,小肠结肠炎耶尔森菌病表现为纵行溃疡、急性炎及化脓性肉芽肿;志贺菌病、空肠弯曲菌病表现为急性炎和表浅溃疡。结论感染5种必检细菌的实验猴分别表现出不同的病理变化,病理检测对疾病的分析诊断有重要价值,检测结果补充了实验猴细菌性疾病病理检测资料,为制定实验动物病理检测指南提供了相关依据。     

宠物重要人兽共患病毒病

随着人们生活水平的不断提高,城市家庭饲养宠物日益增多,宠物已经成为人们日常生活中接触最多的动物。然而,许多宠物是人兽共患疾病的重要传染源,随着人类与各种动物间＂零＂距离的接触,各种宠物携带的人兽共患病也悄然传入人类,给人们身体健康和公共卫生安全带来了严重的威胁。近年来,许多学者对犬、猫、鸟、鼠和其他宠物易感的人兽共患病毒病开展了许多研究工作,本文对狂犬病、戊型肝炎、禽流感、淋巴细胞脉络膜脑膜炎、流行性出血热、西尼罗热等一些严重危害的宠物人兽共患病毒病进行了概述。     

αB-Crystallin inhibits the cell toxicity associated with amyloid fibril formation by κ-casein and the amyloid-β peptide

Amyloid fibril formation is associated with diseases such as Alzheimer’s, Parkinson’s, and prion diseases. Inhibition of amyloid fibril formation by molecular chaperone proteins, such as the small heat-shock protein αB-crystallin, may play a protective role in preventing the toxicity associated with this form of protein misfolding. Reduced and carboxymethylated κ-casein (RCMκ-CN), a protein derived from milk, readily and reproducibly forms fibrils at physiological temperature and pH. We investigated the toxicity of fibril formation by RCMκ-CN using neuronal model PC12 cells and determined whether the inhibition of fibril formation altered its cell toxicity. To resolve ambiguities in the literature, we also investigated whether fibril formation by amyloid-β1–40 (Aβ_1–40), the peptide associated with Alzheimer’s disease, was inhibited by αB-crystallin and if this affected the toxicity of Aβ. To this end, either RCMκ-CN or Aβ_1–40 was incubated at neutral pH to induce fibril formation before treating PC12 cells and assessing cell viability. Incubated (fibrillar) RCMκ-CN was more toxic to PC12 cells than native RCMκ-CN with the highest level of toxicity being associated with mature fibrils and protofibrils. Furthermore, the toxicity of RCMκ-CN was attenuated when its fibril formation was inhibited, either through the chaperone action of αB-crystallin or when it interacted with its natural binding partners in milk, α_S- and β-casein. Likewise, incubating Aβ_1–40 with αB-crystallin inhibited both Aβ_1–40 fibril formation and the associated cell toxicity. Importantly, by inhibiting fibril formation, αB-crystallin prevents the cell toxicity associated with protein misfolding.     

β-Amyloid Precursor Protein Mutants Respond to γ-Secretase Modulators

Pathogenic generation of the 42-amino acid variant of the amyloid β-peptide (Aβ) by β- and γ-secretase cleavage of the β-amyloid precursor protein (APP) is believed to be causative for Alzheimer disease (AD). Lowering of Aβ₄₂ production by γ-secretase modulators (GSMs) is a hopeful approach toward AD treatment. The mechanism of GSM action is not fully understood. Moreover, whether GSMs target the Aβ domain is controversial. To further our understanding of the mode of action of GSMs and the cleavage mechanism of γ-secretase, we analyzed mutations located at different positions of the APP transmembrane domain around or within the Aβ domain regarding their response to GSMs. We found that Aβ₄₂-increasing familial AD mutations of the γ-secretase cleavage site domain responded robustly to Aβ₄₂-lowering GSMs, especially to the potent compound GSM-1, irrespective of the amount of Aβ₄₂ produced. We thus expect that familial AD patients carrying mutations at the γ-secretase cleavage sites of APP should respond to GSM-based therapeutic approaches. Systematic phenylalanine-scanning mutagenesis of this region revealed a high permissiveness to GSM-1 and demonstrated a complex mechanism of GSM action as other Aβ species (Aβ₄₁, Aβ₃₉) could also be lowered besides Aβ₄₂. Moreover, certain mutations simultaneously increased Aβ₄₂ and the shorter peptide Aβ₃₈, arguing that the proposed precursor-product relationship of these Aβ species is not general. Finally, mutations of residues in the proposed GSM-binding site implicated in Aβ₄₂ generation (Gly-29, Gly-33) and potentially in GSM-binding (Lys-28) were also responsive to GSMs, a finding that may question APP substrate targeting of GSMs.     

Galantamine-induced amyloid-{beta} clearance mediated via stimulation of microglial nicotinic acetylcholine receptors

Reduction of brain amyloid-β (Aβ) has been proposed as a therapeutic target for Alzheimer disease (AD), and microglial Aβ phagocytosis is noted as an Aβ clearance system in brains. Galantamine is an acetylcholinesterase inhibitor approved for symptomatic treatment of AD. Galantamine also acts as an allosterically potentiating ligand (APL) for nicotinic acetylcholine receptors (nAChRs). APL-binding site is located close to but distinct from that for acetylcholine on nAChRs, and FK1 antibody specifically binds to the APL-binding site without interfering with the acetylcholine-binding site. We found that in human AD brain, microglia accumulated on Aβ deposits and expressed α7 nAChRs including the APL-binding site recognized with FK1 antibody. Treatment of rat microglia with galantamine significantly enhanced microglial Aβ phagocytosis, and acetylcholine competitive antagonists as well as FK1 antibody inhibited the enhancement. Thus, the galantamine-enhanced microglial Aβ phagocytosis required the combined actions of an acetylcholine competitive agonist and the APL for nAChRs. Indeed, depletion of choline, an acetylcholine-competitive α7 nAChR agonist, from the culture medium impeded the enhancement. Similarly, Ca(2+) depletion or inhibition of the calmodulin-dependent pathways for the actin reorganization abolished the enhancement. These results suggest that galantamine sensitizes microglial α7 nAChRs to choline and induces Ca(2+) influx into microglia. The Ca(2+)-induced intracellular signaling cascades may then stimulate Aβ phagocytosis through the actin reorganization. We further demonstrated that galantamine treatment facilitated Aβ clearance in brains of rodent AD models. In conclusion, we propose a further advantage of galantamine in clinical AD treatment and microglial nAChRs as a new therapeutic target.     

��-Amyloid1�C42 Gene Transfer Model Exhibits Intraneuronal Amyloid, Gliosis, Tau Phosphorylation, and Neuronal Loss

Alzheimer disease is characterized by extracellular β-amyloid (Aβ) plaques and intracellular inclusions containing neurofibrillary tangles of phospho-Tau and intraneuronal Aβ associated with neuronal cell death. We generated a novel gene transfer animal model using lentiviral Aβ_1–42 that resulted in intracellular but not extracellular Aβ accumulations in the targeted rat primary motor cortex. Expression of intracellular Aβ_1–42 led to pathological changes seen in human Alzheimer disease brains, including cell death, inflammatory signs, activation of two Tau kinases, and Tau hyperphosphorylation. Promoting clearance of lentiviral Aβ_1–42 reversed these effects, demonstrating that intraneuronal Aβ_1–42 is a toxic peptide that lies upstream of Tau modification. These studies reveal the role of intracellular Aβ_1–42 in a novel gene transfer animal model, which is a useful tool to study intraneuronal Aβ_1–42-induced pathology in the absence of extracellular plaques. Targeted delivery of Aβ will allow speedy delineation of pathological mechanisms associated with specific neurodegenerative lesions.     

Native-unlike Long-lived Intermediates along the Folding Pathway of the Amyloidogenic Protein ��2-Microglobulin Revealed by Real-time Two-dimensional NMR

β2-microglobulin (β2m), the light chain of class I major histocompatibility complex, is responsible for the dialysis-related amyloidosis and, in patients undergoing long term dialysis, the full-length and chemically unmodified β2m converts into amyloid fibrils. The protein, belonging to the immunoglobulin superfamily, in common to other members of this family, experiences during its folding a long-lived intermediate associated to the trans-to-cis isomerization of Pro-32 that has been addressed as the precursor of the amyloid fibril formation. In this respect, previous studies on the W60G β2m mutant, showing that the lack of Trp-60 prevents fibril formation in mild aggregating condition, prompted us to reinvestigate the refolding kinetics of wild type and W60G β2m at atomic resolution by real-time NMR. The analysis, conducted at ambient temperature by the band selective flip angle short transient real-time two-dimensional NMR techniques and probing the β2m states every 15 s, revealed a more complex folding energy landscape than previously reported for wild type β2m, involving more than a single intermediate species, and shedding new light into the fibrillogenic pathway. Moreover, a significant difference in the kinetic scheme previously characterized by optical spectroscopic methods was discovered for the W60G β2m mutant.