Modelling seasonality of Lassa fever incidences and vector dynamics in Nigeria.

Lassa fever (Lf) is a viral haemorrhagic disease endemic to West Africa and is caused by the Lassa mammarenavirus. The rodent Mastomys natalensis serves as the primary reservoir and its ecology and behaviour have been linked to the distinct spatial and temporal patterns in the incidence of Lf. Nigeria has experienced an unprecedented epidemic that lasted from January until April of 2018, which has been followed by subsequent epidemics of Lf in the same period every year since. While previous research has modelled the case seasonality within Nigeria, this did not capture the seasonal variation in the reproduction of the zoonotic reservoir and its effect on case numbers. To this end, we introduce an approximate Bayesian computation scheme to fit our model to the case data from 2018-2020 supplied by the NCDC. In this study we used a periodically forced seasonal nonautonomous system of ordinary differential equations as a vector model to demonstrate that the population dynamics of the rodent reservoir may be responsible for the spikes in the number of observed cases in humans. The results show that in December through to March, spillover from the zoonotic reservoir drastically increases and spreads the virus to the people of Nigeria. Therefore to effectively combat Lf, attention and efforts should be concentrated during this period.

Modelling African horse sickness emergence and transmission in the South African control area using a deterministic metapopulation approach.

African horse sickness is an equine orbivirus transmitted by Culicoides Latreille biting midges. In the last 80 years, it has caused several devastating outbreaks in the equine population in Europe, the Far and Middle East, North Africa, South-East Asia, and sub-Saharan Africa. The disease is endemic in South Africa; however, a unique control area has been set up in the Western Cape where increased surveillance and control measures have been put in place. A deterministic metapopulation model was developed to explore if an outbreak might occur, and how it might develop, if a latently infected horse was to be imported into the control area, by varying the geographical location and months of import. To do this, a previously published ordinary differential equation model was developed with a metapopulation approach and included a vaccinated horse population. Outbreak length, time to peak infection, number of infected horses at the peak, number of horses overall affected (recovered or dead), re-emergence, and Rv (the basic reproduction number in the presence of vaccination) were recorded and displayed using GIS mapping. The model predictions were compared to previous outbreak data to ensure validity. The warmer months (November to March) had longer outbreaks than the colder months (May to September), took more time to reach the peak, and had a greater total outbreak size with more horses infected at the peak. Rv appeared to be a poor predictor of outbreak dynamics for this simulation. A sensitivity analysis indicated that control measures such as vaccination and vector control are potentially effective to manage the spread of an outbreak, and shortening the vaccination window to July to September may reduce the risk of vaccine-associated outbreaks.

Modelling the persistence and control of Rift Valley fever virus in a spatially heterogeneous landscape.

The persistence mechanisms of Rift Valley fever (RVF), a zoonotic arboviral haemorrhagic fever, at both local and broader geographical scales have yet to be fully understood and rigorously quantified. We developed a mathematical metapopulation model describing RVF virus transmission in livestock across the four islands of the Comoros archipelago, accounting for island-specific environments and inter-island animal movements. By fitting our model in a Bayesian framework to 2004-2015 surveillance data, we estimated the importance of environmental drivers and animal movements on disease persistence, and tested the impact of different control scenarios on reducing disease burden throughout the archipelago. Here we report that (i) the archipelago network was able to sustain viral transmission in the absence of explicit disease introduction events after early 2007, (ii) repeated outbreaks during 2004-2020 may have gone under-detected by local surveillance, and (iii) co-ordinated within-island control measures are more effective than between-island animal movement restrictions.

Climate drivers of plague epidemiology in British India, 1898-1949.

Plague, caused by Yersinia pestis infection, continues to threaten low- and middle-income countries throughout the world. The complex interactions between rodents and fleas with their respective environments challenge our understanding of human plague epidemiology. Historical long-term datasets of reported plague cases offer a unique opportunity to elucidate the effects of climate on plague outbreaks in detail. Here, we analyse monthly plague deaths and climate data from 25 provinces in British India from 1898 to 1949 to generate insights into the influence of temperature, rainfall and humidity on the occurrence, severity and timing of plague outbreaks. We find that moderate relative humidity levels of between 60% and 80% were strongly associated with outbreaks. Using wavelet analysis, we determine that the nationwide spread of plague was driven by changes in humidity, where, on average, a one-month delay in the onset of rising humidity translated into a one-month delay in the timing of plague outbreaks. This work can inform modern spatio-temporal predictive models for the disease and aid in the development of early-warning strategies for the deployment of prophylactic treatments and other control measures.

Identification of efficient pentapeptide substrates for the tyrosine kinase pp60c-src.

The development of inhibitors of protein tyrosine kinases (PTKs) is a promising approach to obtaining new therapeutic agents for a variety of diseases, particularly cancer. However, the discovery of peptide-based inhibitors has been hindered by the lack of small peptide substrate sequences (i.e. five residues or less) with which a variety of inhibitor designs could be readily evaluated by replacing the Tyr with natural and unnatural amino acids. These prototypical small peptide inhibitors could then form the basis for designing analogous conformationally constrained, peptide-mimetic or non-peptide inhibitors with improved therapeutic potential. In this study we have identified the best known small peptide substrate for the PTK pp60c-src, which is the parent of the src family of nonreceptor PTKs. This pentapeptide substrate, Ac-Ile-Tyr-Gly-Glu-Phe-NH2, has a Km of 368 microM and Vmax of 1.02 mumol/min/mg when tested utilizing the assay methodology of Budde et al. (Anal. Biochem. 1992, 200, 347-351) after a series of modifications were made to more closely simulate the conditions inside a typical mammalian cell. This substrate was designed from information obtained by Songyang et al. (Nature 1995, 373, 536-539) with a 2.5 billion member combinatorial library of peptide substrates for pp60c-src. A second pentapeptide substrate, Ac-Glu-Asp-Ala-Ile-Tyr-NH2, with a weaker binding affinity (Km = 880 microM) but improved Vmax (1.86 mumol/min/mg), was also identified. This peptide was designed from the pp60c-src autophosphorylation sequence and information obtained by Songyang et al. (Ibid.) and Till et al. (J. Biol. Chem. 1994, 269, 7423-7428) with combinatorial libraries of peptide substrates. These new substrates provide sufficient binding affinities and rates of phosphorylation to be utilized for evaluating the relative effectiveness of various reversible and mechanism-based irreversible inhibitor designs for pp60c-src while appended to easily prepared small peptides.

Cicatricial pemphigoid.

This case of CP is of interest because of its "not-so-benign" course in this patient, its unusual immunofluorescence patterns, and the need for a complex therapeutic regimen to achieve control. This patient had severe ocular; laryngeal, and oropharyngeal involvement leading to visual problems, hoarseness, and marked weight loss and dehydration. He also had anemia thought to be partially related to dapsone use. We believe the side effects of dapsone, combined with fluid retention due to prednisone therapy, contributed to cardiac failure. The diagnosis of CP is usually established by correlation of clinical findings with immunofluorescence studies. However, indirect immunofluorescence may show strong intercellular antibody binding in the epidermis (ie, pemphigus-like antibodies). Treatment alternatives for patients with CP who have adverse reactions to, or no significant benefit from, conventional agents such as dapsone or prednisone may include immunosuppressive agents such as azathioprine or cyclophosphamide. As this case demonstrates, care of patients having CP involves a cooperative effort from a number of different specialties, including dermatology, primary care, ophthalmology, and otolaryngology.

Improving the tumor retention of radioiodinated antibody: aryl carbohydrate adducts.

Improved methods for attaching radioiodine to monoclonal antibodies have been developed. Ten aryl carbohydrate adducts were synthesized by the reductive amination of a carbohydrate with an aryl amine, using sodium cyanoborohydride as a reducing agent. After purification by chromatography and characterization by nuclear magnetic resonance they were iodinated using the chloramine-T method. Iodinated adducts were activated with cyanuric chloride and incubated with protein at room temperature. The immunoreactivity and avidity of radioiodinated tyramine cellobiose (TCB) labeled antibody were fully preserved when compared to electrophilically radioiodinated antibody. Radioiodinated TCB-and tyramine glucose-labeled monoclonal antibodies showed much greater intracellular retention of radioiodine when compared to electrophilically radioiodinated monoclonal antibodies. Neither radioiodinated tyramine nor radioiodinated TCB had any specific tissue uptake or retention. In mice the retention of radioiodinated TCB labeled anti-Thy-1.1 antibody (1A14) by Thy-1.1-bearing lymphoma cells was 2 times greater than that of chloramine-T labeled 1A14 antibody, whereas the plasma clearance curve and uptake in normal tissues was not changed. This method of radioiodinating monoclonal antibodies increases the retention time of radioiodine in tumor and thus may obviate the problem of intracellular deiodination, a perceived disadvantage of electrophilically iodinated antibodies, with respect to tumor retention of radioactivity.

Synthesis and radioiodination of tyramine cellobiose for labeling monoclonal antibodies.

A tyramine cellobiose (TCB) adduct was synthesized by the reductive amination of cellobiose by tyramine with a product yield of 78%. The TCB adduct was purified by chromatography and then iodinated using the chloramine-T method. After iodination, the adduct was activated with cyanuric chloride and linked to protein by incubation at room temperature for 2 h. Immunoreactivity and avidity were well maintained compared to electrophilically radioiodinated 1A14 whole antibody. The tumor uptake and retention were strikingly greater with iodinated TCB-antibody compared to that of the conventionally iodinated antibody; whereas, the plasma clearance curve and uptake in other organs were not changed. This method of labeling increases the retention time of radioiodine in tumors and thus extends to iodinated antibodies one of the advantages of indium labels, namely that the isotope is not readily washed out of the tumor after it becomes localized.