Analysis of sir model for predicting the spread of measles

The main task of the health care system in any country is to control the spread of infectious diseases. The social consequences, as well as the material losses, strongly demonstrate the need to predict the occurrence of epidemics. Measles is one of the most contagious diseases. In Ukraine, according to the Public Health Center of the Ministry of Health of Ukraine, more than 115,000 people have contracted measles since summer 2017, 41 of whom have died [1]. Simulation of the measles spreading allows to predict new outbreaks of measles and evaluate the strategy to prevent them

Epizootic pertussis focus of hamadryad baboons

The absence of an adequate experimental animal model makes difficult study of immunity against whooping cough and its pathogenesis. Experimental whooping cough reported by us earlier in pubescent non-human primates of the Old World was accompanied by specific clinical and laboratory marks in the absence of cough. The possibility of pertussis modelling while experimental whooping cough in impuberal hamadryad baboons was investigated. In the process of selection of monkeys for the further studies for perfecting of experimental model for pertussis research unexpectedly were detected specific pertussis antibodies in impuberal hamadryad baboons.The aim of the study: revealing of source of infection and transmission of pertussis to hamadryad baboons and investigation of response of antibody-positive impuberal hamadryad baboons to secondary contagion by B. pertussis bacteria while experimental infection.Results. 18 veterinary checked, somatically healthy hamadryad baboons of various gender managed in two neighboring cages. Specific pertussis IgM and IgG antibodies were found in blood serum of all the animals and one of the monkey keepers. By real-time PCR in nasopharyngeal swabs of the monkey keeper and three 7- and 9-month-old hamadryad baboons were registered single B. pertussis genom equivalents. Seropositive impuberal hamadryad baboons were experimentally challenged by virulent B. pertussis 475 strain. Quantity of B. pertussis genom equivalents and percentage of IgM and IgG antibodies in impuberal hamadryad baboons after experimental infection were detected. These results were comparable with such received after secondary experimental challenge of monkeys by B. pertussis. Humoral immuneresponse was characterized by booster effect and rapid B. pertussis elimination.Conclusion. The case of transmission of B.pertussis bacteria to hamadryad baboons by natural contagion and epizootic focus of pertussis in apery conditions were registered. In dynamics of immune response and level of bacterial load in experimentally infected impuberal and pubescent hamadryad baboons were not revealed significant differences. The possibility of asymptomatic B.pertussis transmission from man to monkey and from monkey to man without definitive spasmodic cough was reviewed. Pertussis research perspectives using experimental model of non-human primates of the Old World were marked

Aggregation of αSynuclein promotes progressive in vivo neurotoxicity in adult rat dopaminergic neurons

Fibrillar αSynuclein is the major constituent of Lewy bodies and Lewy neurites, the protein deposits characteristic for Parkinson’s disease (PD). Multiplications of the αSynuclein gene, as well as point mutations cause familial PD. However, the exact role of αSynuclein in neurodegeneration remains uncertain. Recent research in invertebrates has suggested that oligomeric rather than fibrillizing αSynuclein mediates neurotoxicity. To investigate the impact of αSynuclein aggregation on the progression of neurodegeneration, we expressed variants with different fibrillation propensities in the rat substantia nigra (SN) by means of recombinant adeno-associated viral (AAV) vectors. The formation of proteinase K-resistant αSynuclein aggregates was correlated to the loss of nigral dopaminergic (DA) neurons and striatal fibers. Expression of two prefibrillar, structure-based design mutants of αSynuclein (i.e., A56P and A30P/A56P/A76P) resulted in less aggregate formation in nigral DA neurons as compared to human wild-type (WT) or the inherited A30P mutation. However, only the αSynuclein variants capable of forming fibrils (WT/A30P), but not the oligomeric αSynuclein species induced a sustained progressive loss of adult nigral DA neurons. These results demonstrate that divergent modes of αSynuclein neurotoxicity exist in invertebrate and mammalian DA neurons in vivo and suggest that fibrillation of αSynuclein promotes the progressive degeneration of nigral DA neurons as found in PD patients

CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.

Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA-processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases

Эпизоотический очаг коклюша у обезьян вида Papio gamadryas

The absence of an adequate experimental animal model makes difficult study of immunity against whooping cough and its pathogenesis. Experimental whooping cough reported by us earlier in pubescent non-human primates of the Old World was accompanied by specific clinical and laboratory marks in the absence of cough. The possibility of pertussis modelling while experimental whooping cough in impuberal hamadryad baboons was investigated. In the process of selection of monkeys for the further studies for perfecting of experimental model for pertussis research unexpectedly were detected specific pertussis antibodies in impuberal hamadryad baboons.The aim of the study: revealing of source of infection and transmission of pertussis to hamadryad baboons and investigation of response of antibody-positive impuberal hamadryad baboons to secondary contagion by B. pertussis bacteria while experimental infection.Results. 18 veterinary checked, somatically healthy hamadryad baboons of various gender managed in two neighboring cages. Specific pertussis IgM and IgG antibodies were found in blood serum of all the animals and one of the monkey keepers. By real-time PCR in nasopharyngeal swabs of the monkey keeper and three 7- and 9-month-old hamadryad baboons were registered single B. pertussis genom equivalents. Seropositive impuberal hamadryad baboons were experimentally challenged by virulent B. pertussis 475 strain. Quantity of B. pertussis genom equivalents and percentage of IgM and IgG antibodies in impuberal hamadryad baboons after experimental infection were detected. These results were comparable with such received after secondary experimental challenge of monkeys by B. pertussis. Humoral immuneresponse was characterized by booster effect and rapid B. pertussis elimination.Conclusion. The case of transmission of B.pertussis bacteria to hamadryad baboons by natural contagion and epizootic focus of pertussis in apery conditions were registered. In dynamics of immune response and level of bacterial load in experimentally infected impuberal and pubescent hamadryad baboons were not revealed significant differences. The possibility of asymptomatic B.pertussis transmission from man to monkey and from monkey to man without definitive spasmodic cough was reviewed. Pertussis research perspectives using experimental model of non-human primates of the Old World were marked.Введение. Изучение патогенеза и иммунитета при коклюше затруднено в связи с отсутствием адекватной экспериментальной модели. Описанный нами ранее экспериментальный коклюш у половозрелых обезьян Старого Света сопровождался развитием характерных клинико-лабораторных признаков коклюша при отсутствии кашля. В процессе отбора обезьян для дальнейшей работы по совершенствованию экспериментальной модели для изучения коклюша у неполовозрелых павианов гамадрилов неожиданно были обнаруженыспецифические противококлюшные антитела.Цель. Выявление источника бактерий В. рertussis и пути их передачи павианам гамадрилам, а также изучение реакции организма серопозитивных неполовозрелых павианов на вторичный контакт с возбудителем коклюша при экспериментальном заражении. Результаты. 18 обследованных павианов гамадрилов разного пола, размещённые в двух соседних вольерных клетках, находились в состоянии соматического здоровья. В сыворотке крови всех животных и одного из сотрудников по уходу за животными были выявлены специфические антитела класса IgG и IgМ к возбудителю коклюша. Методом ПЦР в режиме реального времени из материала назофарингеальных мазков зарегистрированы единичные геном-эквиваленты B. pertussis у рабочего по уходу за животными и трёх павианов гамадрилов в возрасте 7–9 месяцев. Серопозитивные неполовозрелые павианы гамадрилы были экспериментально заражены вирулентными бактериями B. pertussis 475. Результаты определения количества геном-эквивалентов B. pertussis и относительного количества специфических IgG и IgМ у неполовозрелых павианов гамадрилов после экспериментального заражения были сопоставимы с таковыми у взрослых, дважды инфицированных обезьян. Гуморальный иммунный ответ характеризовался бустерным эффектом с быстрой элиминацией возбудителя. Заключение. Зарегистрирован случай передачи бактерий B. pertussis павианам гамадрилам естественным путем и эпизоотический очаг коклюша в условиях питомника. Не выявлено значимых различий в динамике развития иммунного ответа и бактериальной нагрузки у экспериментально инфицированных неполовозрелых и половозрелых павианов гамадрилов. Показана возможность передачи бактерий B. pertussis без характерного коклюшного кашля от человека к обезьяне и от обезьяны к обезьяне. Описаны перспективы изучения коклюша на экспериментальной модели обезьян Старого Света

Silencing and Un-silencing of Tetracycline-Controlled Genes in Neurons

To identify the underlying reason for the controversial performance of tetracycline (Tet)-controlled regulated gene expression in mammalian neurons, we investigated each of the three components that comprise the Tet inducible systems, namely tetracyclines as inducers, tetracycline-transactivator (tTA) and reverse tTA (rtTA), and tTA-responsive promoters (Ptets). We have discovered that stably integrated Ptet becomes functionally silenced in the majority of neurons when it is inactive during development. Ptet silencing can be avoided when it is either not integrated in the genome or stably-integrated with basal activity. Moreover, long-term, high transactivator levels in neurons can often overcome integration-induced Ptet gene silencing, possibly by inducing promoter accessibility

An Efficient and Versatile System for Visualization and Genetic Modification of Dopaminergic Neurons in Transgenic Mice.

BACKGROUND & AIMS: The brain dopaminergic (DA) system is involved in fine tuning many behaviors and several human diseases are associated with pathological alterations of the DA system such as Parkinson's disease (PD) and drug addiction. Because of its complex network integration, detailed analyses of physiological and pathophysiological conditions are only possible in a whole organism with a sophisticated tool box for visualization and functional modification. METHODS & RESULTS: Here, we have generated transgenic mice expressing the tetracycline-regulated transactivator (tTA) or the reverse tetracycline-regulated transactivator (rtTA) under control of the tyrosine hydroxylase (TH) promoter, TH-tTA (tet-OFF) and TH-rtTA (tet-ON) mice, to visualize and genetically modify DA neurons. We show their tight regulation and efficient use to overexpress proteins under the control of tet-responsive elements or to delete genes of interest with tet-responsive Cre. In combination with mice encoding tet-responsive luciferase, we visualized the DA system in living mice progressively over time. CONCLUSION: These experiments establish TH-tTA and TH-rtTA mice as a powerful tool to generate and monitor mouse models for DA system diseases

Using viral vectors as gene transfer tools (Cell Biology and Toxicology Special Issue: ETCS-UK 1 day meeting on genetic manipulation of cells)

In recent years, the development of powerful viral gene transfer techniques has greatly facilitated the study of gene function. This review summarises some of the viral delivery systems routinely used to mediate gene transfer into cell lines, primary cell cultures and in whole animal models. The systems described were originally discussed at a 1-day European Tissue Culture Society (ETCS-UK) workshop that was held at University College London on 1st April 2009. Recombinant-deficient viral vectors (viruses that are no longer able to replicate) are used to transduce dividing and post-mitotic cells, and they have been optimised to mediate regulatable, powerful, long-term and cell-specific expression. Hence, viral systems have become very widely used, especially in the field of neurobiology. This review introduces the main categories of viral vectors, focusing on their initial development and highlighting modifications and improvements made since their introduction. In particular, the use of specific promoters to restrict expression, translational enhancers and regulatory elements to boost expression from a single virion and the development of regulatable systems is described