Integrative models of bat rabies immunology, epizootiology and disease demography

Bats are natural reservoirs of rabies. We address the maintenance of the disease in bat colonies by developing individual and population models that generate indicators of risk of rabies to bats, that provide dynamic estimates of effects of rabies on population densities, and that suggest consequences of viral exposures and infections in bats relative to physiological and ecological characteristics of bats in different habitats. We present individual models (within host) for the immune responses to a rabies virus challenge, an immunotypic disease model that describes the evolution of the disease and a disease demographics model, which is structured by immunotypic response governed by immune system efficiency. Model simulations are consistent with available data, characterized by relatively low prevalence of the virus in colonies and much higher prevalence of rabies virus-neutralizing antibodies. Under model conditions, there is a robust non-clinical state that can be attained by the exposed individual that allows persistence of the disease in the population.     

Persistence of viral infections on the population level explained by an immunoepidemiological model

We consider a mathematical model of viral spread in a population based on an immune response model embedded in an epidemic network model. The immune response model includes virus load and effector and memory T cells with two possible outcomes depending on parameters: (a) virus clearance and establishment of immune memory and (b) establishment of a non-zero viral presence characterized with increased T-cell concentrations. Isolated individuals can have different immune system parameters and, after a primary infection, can either return to the infection-free state or develop persistent or chronic infection. When individuals are connected in the network, they can reinfect each other. We show that the virus can persist in the epidemic network for indefinite time even if the whole population consists of individuals that are able to clear the virus when isolated from the network. In this case a few individuals with a relatively weak immune response can maintain the infection in the whole population. These results are in contrast to implications of classical epidemiological models that a viral epidemic will end if there is no influx of new susceptibles and if individuals can become immune after infection.     

Mathematical modeling of viral kinetics under immune control during primary HIV-1 infection

Primary human immunodeficiency virus (HIV) infection is characterized by an initial exponential increase of viral load in peripheral blood reaching a peak, followed by a rapid decline to the viral setpoint. Although the target-cell-limited model can account for part of the viral kinetics observed early in infection [Phillips, 1996. Reduction of HIV concentration during acute infection: independence from a specific immune response. Science 271 (5248), 497-499], it frequently predicts highly oscillatory kinetics after peak viremia, which is not typically observed in clinical data. Furthermore, the target-cell-limited model is unable to predict long-term viral kinetics, unless a delayed immune effect is assumed [Stafford et al., 2000. Modeling plasma virus concentration during primary HIV infection. J. Theor. Biol. 203 (3), 285-301]. We show here that extending the target-cell-limited model, by implementing a saturation term for HIV-infected cell loss dependent upon infected cell levels, is able to reproduce the diverse observed viral kinetic patterns without the assumption of a delayed immune response. Our results suggest that the immune response may have significant effect on the control of the virus during primary infection and may support experimental observations that an anti-HIV immune response is already functional during peak viremia.     

狂犬病毒鼠脑复壮后的典型形态恢复及感染细胞内的形态发生学

[目的]观察比较鼠脑复壮前后狂犬病毒的形态变化,并观察病毒感染BHK-21细胞后不同时间的形态发生情况.[方法]以保存时间较长的SRV9毒株为原始材料,经乳鼠脑传代复壮后接种BHK-21细胞,浓缩、纯化后观察.[结果](1)未经复壮的病毒中DI粒子占较高比例,典型粒子只占少数,而复壮后典型粒子所占比例升高到病毒粒子总数的90%.(2)感染24h后在细胞浆内可以观察到典型病毒粒子,其数量随着培养时间的延长而增加.带毒传代之后的培养过程中细胞内病毒数量增加不明显.(3)病毒可以在细胞内的空泡膜表面以多种方式成堆出芽.[结论](1)鼠脑复壮可恢复狂犬病毒中典型粒子所占比例.(2)带毒传代1～2次时为狂犬病毒收获的最佳时机.(3)本研究为狂犬病毒的装配机制补充了数据.     

Probing the effects of the well-mixed assumption on viral infection dynamics

Viral kinetics have been extensively studied in the past through the use of spatially well-mixed ordinary differential equations describing the time evolution of the diseased state. However, emerging spatial structures such as localized populations of dead cells might adversely affect the spread of infection, similar to the manner in which a counter-fire can stop a forest fire from spreading. In a previous publication [Beauchemin, C., Samuel, J., Tuszynski, J., 2005. A simple cellular automaton model for influenza A viral infections. J. Theor. Biol. 232(2), 223-234], a simple two-dimensional cellular automaton model was introduced and shown to be accurate enough to model an uncomplicated infection with influenza A. Here, this model is used to investigate the effects of relaxing the well-mixed assumption. Particularly, the effects of the initial distribution of infected cells, the regeneration rule for dead epithelial cells, and the proliferation rule for immune cells are explored and shown to have an important impact on the development and outcome of the viral infection in our model.     

The influence of viral infection on a plankton ecosystem undergoing nutrient enrichment

It is increasingly recognised that viruses are a significant active component of oceanic plankton ecosystems. They play an important role in biogeochemical cycles as well as being implicated in observed patterns of species abundance and diversity. The influence of viral infection in plankton ecosystems is not fully understood. Here we use a number of well-founded mathematical models to investigate the interplay of the ecological and epidemiological interactions of plankton and viruses in the sea. Of particular interest is the role of nutrient on the population dynamics. Nutrient forcing has been suggested as a means of absorbing excess anthropogenic atmospheric carbon dioxide by stimulating increased phytoplankton primary productivity. Here we show that enriching nutrient levels in the sea may decrease the amount of infected phytoplankton species thereby additionally enhancing the efficiency of the biological pump, a means by which carbon is transferred from the atmosphere to the deep ocean.     

树鼩模型在人类病毒性疾病研究中的应用进展

由于树鼩在进化上接近于灵长类动物,在生理、生化及解剖学等生物学特性方面与人类有着相似之处,树鼩得到越来越多的关注,研究人员运用与其他动物相比具有多种优势的树鼩建立了一系列的疾病模型,如病毒类疾病、神经系统、肿瘤等,本文着重就树鼩在人类病毒疾病方面的研究进展进行概述。     

Compensatory up-regulation of behavioral disease avoidance in immuno-compromised people with rheumatoid arthritis

Disgust and disease-related cues can activate the immune system. Here, we test whether immuno-suppression is associated with an up-regulation of cognitions and behaviors that assist in disease avoidance. People with rheumatoid arthritis (RA), who have a heightened risk of infection-related morbidity and mortality, were compared to age, gender and demographically matched healthy controls on a range of disease avoidance tasks. People with RA scored higher on reports of behavior likely to control infection, were more accurate in spotting individuals who were sick, and showed disease-specific ethnocentrism, ascribing a greater risk of contracting disease to non-Caucasians, although having no overall propensity for greater racism on the Modern Racism Scale. Contrary to predictions, disgust sensitivity (DS) did not differ between groups, however among people with RA, DS was found to be lower in those taking drugs that can increase infection risk. While more explicit disease avoidance behaviors are clearly up-regulated in people with RA, changes in DS may have a different and perhaps more biological casual basis.     

2009～2010年上海地区急性呼吸道感染病毒病原谱分析

调查2009~2010年上海地区人群急性呼吸道感染(ARTI)的病毒性病原,探讨2009甲型H1N1流感暴发背景下呼吸道感染病毒病原谱的构成。采用套式多重反转录-聚合酶链反应(RT-PCR)和实时荧光定量RT-PCR方法,对来自2 044例患者的2 044份标本(包括2 005份鼻咽拭子和39份肺泡灌洗液),同时检测腺病毒(ADV)、副流感病毒(PIV)、甲型流感病毒(FluA)、乙型流感病毒(FluB)、微小核糖核酸病毒、呼吸道合胞病毒(RSV)、人偏肺病毒(hMPV)、冠状病毒(CoV)和人博卡病毒(HBoV)。其中,656(32.09%)份标本经呼吸道病毒检测为阳性,52份标本为双重感染。FluA检出率最高(13.36%),其后依次为微小核糖核酸病毒(10.23%)、FluB(4.84%)、ADV(1.96%)、PIV(1.76%)、RSV(1.32%)、CoV(0.59%)、hMPV(0.39%)和HBoV(0.20%)。但各月病毒检出率分布不均,2009和2010年呼吸道病毒检出率高峰出现在当年11月(53.07%和65.59%),低谷都出现在当年5月,且2009年5~9月的病毒检出率高于2010年同期(32.02%vs15.38%,P<0.05)。其中,2009甲型H1N1流感暴发导致2009年10月~2010年1月2009甲型H1N1流感病毒占当月检出FluA的100%,2009年6~9月也占当月检出FluA的较高比率,依次为90.91%(20/22)、75.00%(15/20)、48.00%(12/25)和56.25%(18/32)。比较甲型H3N2流感病毒和2009甲型H1N1流感病毒分别在上呼吸道感染(URTI)和下呼吸道感染(LRTI)中的检出率,无统计学差异(URTI,85.29%vs76.61%;LRTI,14.71%vs23.39%;P>0.05)。呼吸道病毒检出率还与年龄相关,0~4岁组和5~14岁组病毒检出率高于其他年龄组。在0~4岁及≥65岁组中,微小核糖核酸病毒检出率最高,FluA次之;其余年龄组中FluA检出率最高。混合感染中15岁以下儿童占50%(26/52),微小核糖核酸病毒与其他病毒混合感染占84.62%(44/52)。本研究表明,上海地区2009~2010年FluA是最常见的急性呼吸道感染病原,2009甲型H1N1流感病毒成为2009年FluA的优势亚型。微小核糖核酸病毒是混合感染中最常见的病原。结果提示,应长期监测主要呼吸道病毒的活动水平,并加强对微小核糖核酸病毒流行病学和致病性的研究。     

Pathophysiological responses to a schistosome infection in a wild population of mourning doves (Zenaida macroura)

The blood trematode Gigantobilharzia huronensis typically infects passerine birds and has not been reported in other orders of wild birds. However, in the summer of 2011 in Tempe, Arizona, USA, mourning doves (Zenaida macroura; order: Columbiformes) were collected with infections of G. huronensis. This is the first report of a natural schistosome infection found in wild populations of doves. We sought to determine if G. huronensis infections alter the general body condition and physiology of doves, a seemingly unlikely host for this parasite. Specifically, we hypothesized that birds infected with schistosomes would exhibit reduced weight as well as increased markers of stress and immune system activation. Adult male mourning doves (n = 14) were captured using walk-in style funnel traps. After weighing the birds, blood and mesenteric tissue samples were collected. We measured biomarkers of stress including circulating heat shock proteins (HSPs) 60 and 70, as well as oxidized lipoproteins in schistosome-infected and non-infected birds. Indices of immune system reactivity were assessed using agglutination and lysis assays in addition to determining the leukocyte to erythrocyte ratios and prevalence of hemoparasite infections from blood smears. Schistosome-infected mourning doves had significantly increased oxidative stress and evidence of HSP70 mobilization. There was no evidence for weight loss in schistosome-infected birds nor evidence of significant immune system activation associated with schistosome infection. This may be a reflection of the small sample size available for the study. These findings suggest that schistosome infections have pathological effects in doves, but the lack of mature worms suggests that infected birds in this sampling may not have been suitable hosts for parasite maturation.     

1H, 13C and 15N resonance assignments of the PDZ of microtubule-associated serine/threonine kinase 205 (MAST205) in complex with the C-terminal motif from the rabies virus glycoprotein

Most of microbes hijack the cellular machinery to their advantage by interacting with specific target of the host cell. Glycoprotein of rabies virus is a key factor controlling the homeostasis of infected neuronal cells and proteins belonging to the human microtubule associated serine threonine kinase family have been identified as potential cellular partners. As a first step towards its structural study, we have assigned the backbone and side chain nuclei resonances of the PDZ domain (PSD-95, Discs Large, ZO-1) of MAST205 in complex with the C-terminal residues of the glycoprotein of rabies virus. The BMRB accession code is 155972.     

A comparison study of models and fitting procedures for biphasic viral dynamics in HIV-1 infected patients treated with antiviral therapies

The study of HIV dynamics is one of the most important developments in recent AIDS research. It has led to a new understanding of the pathogenesis of HIV infection. But, although important findings in HIV dynamics have been published in prestigious scientific journals in the last 5 years, the model-fitting procedures used in these publications have not been studied in any detail. In this paper, we evaluate the performance of four model-fitting procedures proposed and used in biphasic HIV dynamic data analysis via extensive Monte Carlo simulations. We propose some guidelines for practitioners to select an appropriate method for their own data analysis. Real data examples from an AIDS clinical trial are provided as illustrations.     

手足口病并发病毒性脑炎患儿的临床观察及护理

回顾性分析了52例手足口病并发病毒性脑炎的患儿的护理。总结护理经验：通过仔细的病情观察及早发现神经系统受累症状,采取早期干预,给予对症、饮食、口腔、皮肤、心理等护理措施,以阻止疾病发展,促进患儿早日康复。本组52例患儿均治愈出院,平均住院时间11.5天,无明显后遗症发生。     

不同中枢神经系统感染患儿血清和脑脊液炎症标记物及MMP-9水平及临床意义

摘要 目的：探讨不同中枢神经系统感染患儿血清和脑脊液中炎症标记物及基质金属蛋白酶9（Matrix metallo protein 9,MMP-9）的水平及临床意义。方法：选取本院2017年8月至2018年6月收治的198例脑膜炎儿童患者分为感染组,根据不同患病原因分成化脓性脑膜炎（Purulent Meningitis, PM=107例）和病毒性脑膜炎（Viral Meningitis, VM=91例）,另选取同期58例体检健康儿童作为对照组（Normal Control, NC=58例）。采用双抗夹心免疫荧光发光法检测患者血清和脑脊液（Cerebrospinal fluid,CF）中降钙素原（Prcoalcitonin,PCT）水平;采用免疫荧光分析仪检测患者血清和脑脊液内C反应蛋白（C-reactionprotein,CRP）水平;酶联免疫吸附实验（ELISA）检测三组患儿治疗前后血清和脑脊肿瘤坏死因子-α(Tumor necrosis factor-α, TNF-α)及MMP-9表达水平;电化学发光全自动免疫分析仪分析血清白蛋白和脑脊液白蛋白含量,并计算白蛋白指数。结果：与对照组相比,化脑组和病脑组患儿血清和脑脊液中CRP、PCT、TNF-α及MMP-9水平均明显增高（P<0.05）,化脑组患儿血清和脑脊液中CRP、PCT、TNF-α及MMP-9水平显著高于病脑组（P<0.05）。与对照组相比,化脑组患儿治疗前、治疗72小时和治疗1周后血清和脑脊液PCT水平降低（P<0.05）,与对照组相比,病脑组患儿治疗前后血清和脑脊液PCT水平表达差异无统计学意义（P>0.05）;化脑组和病脑组患儿脑脊液中CRP、PCT、TNF-α及MMP-9水平与患儿白蛋白指数均呈正相关。结论：血清和脑脊液炎症标记物及MMP-9变化可对化脓性脑膜炎和病毒性脑膜炎进行初步的鉴别。     

具免疫时滞的HIV感染模型动力学性质分析

讨论了一类具免疫时滞的HIV感染模型.分析了未感染平衡点的全局渐近稳定性,给出了感染无免疫平衡点及感染免疫平衡点局部渐近稳定的充分条件.数值模拟结果表明,当易感细胞生成率的取值使得基本再生数满足平衡存在的条件且低于某一临界值时,时滞对平衡点的稳定性没有影响;若大于该临界值,随着时滞增大,稳定性开关发生,平衡点不稳定,出现一系列Hopf分支,最终表现为周期波动模式.     

SARS-CoV-2 pathophysiology and assessment of coronaviruses in CNS diseases with a focus on therapeutic targets

The novel Coronavirus disease of 2019 (nCOV-19) is a viral outbreak noted first in Wuhan, China. This disease is caused by Severe Acute Respiratory Syndrome (SARS) Coronavirus (CoV)-2. In the past, other members of the coronavirus family, such as SARS and Middle East Respiratory Syndrome (MERS), have made an impact in China and the Arabian peninsula respectively. Both SARS and COVID-19 share similar symptoms such as fever, cough, and difficulty in breathing that can become fatal in later stages. However, SARS and MERS infections were epidemic diseases constrained to limited regions. By March 2020 the SARS-CoV-2 had spread across the globe and on March 11th, 2020 the World Health Organization (WHO) declared COVID-19 as pandemic disease. In severe SARS-CoV-2 infection, many patients succumbed to pneumonia. Higher rates of deaths were seen in older patients who had co-morbidities such as diabetes mellitus, hypertension, cardiovascular disease (CVD), and dementia. In this review paper, we discuss the effect of SARS-CoV-2 on CNS diseases, such as Alzheimer's-like dementia, and diabetes mellitus. We also focus on the virus genome, pathophysiology, theranostics, and autophagy mechanisms. We will assess the multiorgan failure reported in advanced stages of SARS-CoV-2 infection. Our paper will provide mechanistic clues and therapeutic targets for physicians and investigators to combat COVID-19.     

Effects of decreased resource availability, protozoan grazing and viral impact on a structure of bacterioplankton assemblage in a canyon-shaped reservoir

We conducted a transplant experiment to elucidate the effects of different levels of grazing pressure, nutrient availability, especially phosphorus, and the impact of viruses on the changes in the structure of bacterioplankton assemblage in a meso-eutrophic reservoir. A sample taken from the nutrient-rich inflow part of the reservoir was size-fractionated and incubated in dialysis bags in both inflow and dam area. The structure of bacterial assemblage was examined by fluorescence in situ hybridization using oligonucleotide probes with different levels of specificity. In terms of the relative proportions of different bacterial groups, we found very few significant changes in the bacterioplankton composition after transplanting the treatments to the nutrient-poor dam area. However, we observed marked shifts in morphology and biomass towards the development of filaments, flocs and "vibrio-like" morphotypes of selected probe-defined groups of bacteria induced by increased grazing pressure. Despite the very high abundances of viruses in all the treatments, their effects on bacterioplankton were rather negligible.     

脓毒症患儿高营养风险的影响因素及其对免疫功能、微量元素和疾病转归的影响

摘要 目的：研究脓毒症患儿高营养风险的影响因素及其对免疫功能、微量元素和疾病转归的影响。方法：选取2019年1月-2021年12月我院收治的168例脓毒症患儿,采用营养状况和生长风险筛查工具（STRONGkids）筛查其营养风险,根据评分结果将营养风险患儿分为中低营养风险组与高营养风险组。比较两组临床资料,采用Logistic回归模型分析高营养风险的影响因素;比较中低营养风险组与高营养风险组免疫功能指标（CD4⁺、CD8⁺、CD4⁺/CD8⁺）,微量元素[铜（Cu）、铁（Fe）、锌（Zn）]含量及疾病转归情况。结果：经STRONGkids营养风险筛查结果显示,151例脓毒症患儿存在营养风险,营养风险发生率为89.88%,其中存在中低营养风险110例（中低营养风险组）和高营养风险41例（高营养风险组）。高营养风险组急性生理与慢性健康状况评分系统Ⅱ（APACHE Ⅱ）评分、乳酸、降钙素原水平及严重脓毒症占比高于中低营养风险组,白蛋白水平低于中低营养风险组（P＜0.05）。多因素Logistic回归分析显示,APACHE Ⅱ评分升高、严重脓毒症是脓毒症患儿发生高营养风险的危险因素（P＜0.05）,白蛋白升高是脓毒症患儿发生高营养风险的保护因素（P＜0.05）。高营养风险组CD4⁺、CD4⁺/CD8⁺低于中低营养风险组,CD8⁺高于中低营养风险组（P＜0.05）。两组Cu含量差异无统计学意义（P＞0.05）,高营养风险组Fe、Zn含量低于中低营养风险组（P＜0.05）。中低营养风险组好转74例、未愈32例、死亡4例,高营养风险组好转19例、未愈15例、死亡7例,高营养风险组疾病转归良好率低于中低营养风险组（P＜0.05）。结论：脓毒症患儿高营养风险发生率较高,严重脓毒症、APACHE Ⅱ评分、白蛋白水平为高营养风险的影响因素,且高营养风险导致患儿免疫功能下降,体内Fe、Zn含量降低,疾病转归情况较差,建议早期实施营养干预,改善患儿的预后。     

Combined effects of resource heterogeneity and simulated herbivory on plasticity of clonal integration in a rhizomatous perennial herb

Previous lines of investigation assuming potential advantage of clonal integration generally have neglected its plasticity in complex heterogeneous environments. Clonal plants adaptively respond to abiotic heterogeneity (patchy resource distribution) and herbivory‐induced heterogeneity (within‐clone heterogeneity in ramet performance), but to date little is known about how resource heterogeneity and simulated herbivory jointly affect the overall performance of clones. Partial damage within a clone caused by herbivory might create herbivory‐induced heterogeneity in a resource‐homogeneous environment, and might also decrease or increase the extent of heterogeneity under resource‐heterogeneous conditions. We conducted a greenhouse experiment in which target‐ramets of Leymus chinensis segments within homogeneous or heterogeneous nutrient treatments were subject to clipping (0% or 75% shoot removal). In homogeneous environments with high (9:9) nutrient availability, ramet biomass of L. chinensis with intact or severed rhizomes is 0.70 or 0.69 g. Conversely, target‐ramet biomass with intact rhizomes is obviously lower than that of the severed target‐ramets in the homogeneous environments with medium (5:5) and low (1:1) nutrient availability. High resource availability and the presence of herbivory can alleviate negative effects of rhizome connection under homogeneous conditions, by providing copious resource or creating herbivory‐induced heterogeneity respectively. Herbivory tolerance of clonal fragments with connected rhizomes was higher than that of fragments with severed rhizomes under heterogeneous conditions. These findings confirmed the unconditional advantage of clonal integration on reproduction under the combined influence of resource heterogeneity and simulated herbivory. Moreover, our results made clear the synergistically interactive effects of resource heterogeneity and simulated herbivory on costs and benefits of clonal integration. This will undoubtedly advance our understanding on the plasticity of clonal integration under complex environmental conditions.