Re-assessing thermal response of schistosomiasis transmission risk: Evidence for a higher thermal optimum than previously predicted.

The geographical range of schistosomiasis is affected by the ecology of schistosome parasites and their obligate host snails, including their response to temperature. Previous models predicted schistosomiasis' thermal optimum at 21.7°C, which is not compatible with the temperature in sub-Saharan Africa (SSA) regions where schistosomiasis is hyperendemic. We performed an extensive literature search for empirical data on the effect of temperature on physiological and epidemiological parameters regulating the free-living stages of S. mansoni and S. haematobium and their obligate host snails, i.e., Biomphalaria spp. and Bulinus spp., respectively. We derived nonlinear thermal responses fitted on these data to parameterize a mechanistic, process-based model of schistosomiasis. We then re-cast the basic reproduction number and the prevalence of schistosome infection as functions of temperature. We found that the thermal optima for transmission of S. mansoni and S. haematobium range between 23.1-27.3°C and 23.6-27.9°C (95% CI) respectively. We also found that the thermal optimum shifts toward higher temperatures as the human water contact rate increases with temperature. Our findings align with an extensive dataset of schistosomiasis prevalence in SSA. The refined nonlinear thermal-response model developed here suggests a more suitable current climate and a greater risk of increased transmission with future warming for more than half of the schistosomiasis suitable regions with mean annual temperature below the thermal optimum.

Re-assessing thermal response of schistosomiasis transmission risk: evidence for a higher thermal optimum than previously predicted.

The geographical range of schistosomiasis is affected by the ecology of schistosome parasites and their obligate host snails, including their response to temperature. Previous models predicted schistosomiasis' thermal optimum at 21.7 °C, which is not compatible with the temperature in sub-Saharan Africa (SSA) regions where schistosomiasis is hyperendemic. We performed an extensive literature search for empirical data on the effect of temperature on physiological and epidemiological parameters regulating the free-living stages of S. mansoni and S. haematobium and their obligate host snails, i.e., Biomphalaria spp. and Bulinus spp., respectively. We derived nonlinear thermal responses fitted on these data to parameterize a mechanistic, process-based model of schistosomiasis. We then re-cast the basic reproduction number and the prevalence of schistosome infection as functions of temperature. We found that the thermal optima for transmission of S. mansoni and S. haematobium range between 23.1-27.3 °C and 23.6-27.9 °C (95 % CI) respectively. We also found that the thermal optimum shifts toward higher temperatures as the human water contact rate increases with temperature. Our findings align with an extensive dataset of schistosomiasis prevalence in SSA. The refined nonlinear thermal-response model developed here suggests a more suitable current climate and a greater risk of increased transmission with future warming for more than half of the schistosomiasis suitable regions with mean annual temperature below the thermal optimum.

Analysis of Adeno-Associated Virus Serotype 8 (AAV8)-antibody complexes using epitope mapping by molecular imprinting leads to the identification of Fab peptides that potentially evade AAV8 neutralisation.

Gene therapy is a promising approach for treating genetic disorders by delivering therapeutic genes to replace or correct malfunctioning genes. However, the introduced gene therapy vector can trigger an immune response, leading to reduced efficacy and potential harm to the patient. To improve the efficiency and safety of gene therapy, preventing the immune response to the vector is crucial. This can be achieved through the use of immunosuppressive drugs, vector engineering to evade the immune system, or delivery methods that bypass the immune system altogether. By reducing the immune response, gene therapy can deliver therapeutic genes more effectively and potentially cure genetic diseases. In this study, a novel molecular imprinting technique, combined with mass-spectrometry and bioinformatics, was used to identify four antigen-binding fragments (Fab) sequences of Adeno-Associated Virus (AAV) - neutralising antibodies capable of binding to AAV. The identified Fab peptides were shown to prevent AAV8's binding to antibodies, demonstrating their potential to improve gene therapy efficiency by preventing the immune response.

Positive feedback loops exacerbate the influence of superspreaders in disease transmission.

Superspreaders are recognized as being important drivers of disease spread. However, models to date have assumed random occurrence of superspreaders, irrespective of whom they were infected by. Evidence suggests though that those individuals infected by superspreaders may be more likely to become superspreaders themselves. Here, we begin to explore, theoretically, the effects of such a positive feedback loop on (1) the final epidemic size, (2) the herd immunity threshold, (3) the basic reproduction number, R0, and (4) the peak prevalence of superspreaders, using a generic model for a hypothetical acute viral infection and illustrative parameter values. We show that positive feedback loops can have a profound effect on our chosen epidemic outcomes, even when the transmission advantage of superspreaders is moderate, and despite peak prevalence of superspreaders remaining low. We argue that positive superspreader feedback loops in different infectious diseases, including SARS-CoV-2, should be investigated further, both theoretically and empirically.

Snapshot imprinting as a tool for surface mapping and identification of novel biomarkers of senescent cells.

Cellular senescence has proved to be a strong contributor to ageing and age-related diseases, such as cancer and atherosclerosis. Therefore, the protein content of senescent cells is highly relevant to drug discovery, diagnostics and therapeutic applications. However, current technologies for the analysis of proteins are based on a combination of separation techniques and mass spectrometry, which require handling large sample sizes and a large volume of data and are time-consuming. This limits their application in personalised medicine. An easy, quick and inexpensive procedure is needed for qualitative and quantitative analysis of proteins expressed by a cell or tissue. Here, we describe the use of the "snapshot imprinting" approach for the identification of proteins differentially expressed by senescent cells. Molecularly imprinted polymer nanoparticles (MIPs) were formed in the presence of whole cells. Following trypsinolysis, protein epitopes protected by complex with MIPs were eluted from the nanoparticles and analysed by LC-MS/MS. In this work, "snapshot imprinting" was performed parallel to a standard proteomic "shaving approach", showing similar results. The analysis by "snapshot imprinting" identified three senescent-specific proteins: cell division cycle 7-related protein kinase, partitioning defective three homolog B and putative ATP-dependent RNA helicase DHX57, the abundance of which could potentially make them specific markers of senescence. Identifying biomarkers for the future elimination of senescent cells grants the potential for developing therapeutics for age-related diseases.

Molecular imprinting as a tool for determining molecular markers: a lung cancer case.

Determining which cancer patients will be sensitive to a given therapy is essential for personalised medicine. Thus, it is important to develop new tools that will allow us to stratify patients according to their predicted response to treatment. The aim of work presented here was to use molecular imprinting for determining the sensitivity of lung cancer cell lines to ionising radiation based on cell surface proteomic differences. Molecularly imprinted polymer nanoparticles (nanoMIPs) were formed in the presence of whole cells. Following trypsinolysis, protein epitopes protected by complexing with MIPs were eluted from the nanoparticles and analysed by LC-MS/MS. The analysis identified two membrane proteins, neutral amino acid transporter B (0) and 4F2 cell-surface antigen heavy chain, the abundance of which in the lung cancer cells could indicate resistance of these cells to radiotherapy. This proof-of-principle experiments shows that this technology can be used in the discovery of new biomarkers and in development of novel diagnostic and therapeutic tools for a personalised medicine approach to treating cancer.

Modulation of acetylcholinesterase activity using molecularly imprinted polymer nanoparticles.

Modulation of enzyme activity allows for control over many biological pathways and while strategies for the pharmaceutical design of inhibitors are well established; methods for promoting activation, that is an increase in enzymatic activity, are not. Here we demonstrate an innovative epitope mapping technique using molecular imprinting to identify four surface epitopes of acetylcholinesterase (AChE). These identified epitopes were then used as targets for the synthesis of molecularly imprinted nanoparticles (nanoMIPs). The enzymatic activity of AChE was increased upon exposure to these nanoMIPs, with one particular identified epitope nanoMIP leading to an increase in activity of 47× compared to enzyme only. The impact of nanoMIPs on the inhibited enzyme is also explored, with AChE activity recovering from 11% (following exposure to an organophosphate) to 73% (following the addition of nanoMIPs). By stabilizing the conformation of the protein rather than targeting the active site, the allosteric nature of MIP-induced reactivation suggests a new way to promote enzyme activity, even under the presence of an inhibitor. This method of enzyme activation shows promise to treat enzyme deficiency diseases or in medical emergencies where an external agent affects protein function.

Mass spectrometric detection of KRAS protein mutations using molecular imprinting.

Cancer is a disease of cellular evolution where single base changes in the genetic code can have significant impact on the translation of proteins and their activity. Thus, in cancer research there is significant interest in methods that can determine mutations and identify the significant binding sites (epitopes) of antibodies to proteins in order to develop novel therapies. Nano molecularly imprinted polymers (nanoMIPs) provide an alternative to antibodies as reagents capable of specifically capturing target molecules depending on their structure. In this study, we used nanoMIPs to capture KRAS, a critical oncogene, to identify mutations which when present are indicative of oncological progress. Herein, coupling nanoMIPs (capture) and liquid chromatography-mass spectrometry (detection), LC-MS has allowed us to investigate mutational assignment and epitope discovery. Specifically, we have shown epitope discovery by generating nanoMIPs to a recombinant KRAS protein and identifying three regions of the protein which have been previously assigned as epitopes using much more time-consuming protocols. The mutation status of the released tryptic peptide was identified by LC-MS following capture of the conserved region of KRAS using nanoMIPS, which were tryptically digested, thus releasing the sequence of a non-conserved (mutated) region. This approach was tested in cell lines where we showed the effective genotyping of a KRAS cell line and in the plasma of cancer patients, thus demonstrating its ability to diagnose precisely the mutational status of a patient. This work provides a clear line-of-sight for the use of nanoMIPs to its translation from research into diagnostic and clinical utility.

The measurement of KRAS G12 mutants using multiplexed selected reaction monitoring and ion mobility mass spectrometry.

RATIONALE: There is a considerable clinical demand to determine key mutations in genes involved with cancer which necessitates the deployment of highly specific and robust analytical methods. Multiplex liquid chromatography with selected reaction monitoring (LC/SRM) assays offer the ability to achieve quantitation down to levels expected to be present in clinical samples. Ion mobility mass spectrometry (IMS/MS) assays can provide increased peak capacity and hence separation in an extremely short time frame, and in addition provide physicochemical data regarding the collision cross-section of an analyte which can be used in conjunction with the m/z value of an ion to increase detection specificity. METHODS: For LC/SRM, unlabelled peptides and corresponding stable-isotope-labelled standards were spiked into digested human plasma and analysed using ultrahigh-performance liquid chromatography (UHPLC) coupled to a triple quadrupole mass spectrometer to enable the generation of analyte-specific calibration lines. Synthetic unlabelled peptides were infused into a Synapt G2 mass spectrometer for travelling wave ion mobility separation and TW CCSN2 values were derived from comparison with previously generated TW CCSN2 calibration values. RESULTS: Linear calibration lines (0.125 to 25 fmol/µL) were established for each of the KRAS peptides. UHPLC separated the peptides and hence enabled them to be split into different retention time functions/windows. This separation enabled detection of three or four transitions for each light and heavy peptide with at least 10 points per peak for accurate quantitation. All six KRAS G12 peptides were separated using IMS/MS, enabling precise TW CCSN2 values to be determined. Although some of the G12 peptides chromatographically co-eluted, all the peptides were distinguished by m/z, retention time and/or drift time. CONCLUSIONS: This study advocates that LC/SRM and IMS/MS could both be used to identify single amino acid substitutions in KRAS as an alternative to commonly used methods such as circulating tumour DNA analysis.

What is a vector?

Many important and rapidly emerging pathogens of humans, livestock and wildlife are 'vector-borne'. However, the term 'vector' has been applied to diverse agents in a broad range of epidemiological systems. In this perspective, we briefly review some common definitions, identify the strengths and weaknesses of each and consider the functional differences between vectors and other hosts from a range of ecological, evolutionary and public health perspectives. We then consider how the use of designations can afford insights into our understanding of epidemiological and evolutionary processes that are not otherwise apparent. We conclude that from a medical and veterinary perspective, a combination of the 'haematophagous arthropod' and 'mobility' definitions is most useful because it offers important insights into contact structure and control and emphasizes the opportunities for pathogen shifts among taxonomically similar species with similar feeding modes and internal environments. From a population dynamics and evolutionary perspective, we suggest that a combination of the 'micropredator' and 'sequential' definition is most appropriate because it captures the key aspects of transmission biology and fitness consequences for the pathogen and vector itself. However, we explicitly recognize that the value of a definition always depends on the research question under study.This article is part of the themed issue 'Opening the black box: re-examining the ecology and evolution of parasite transmission'.

Breaking beta: deconstructing the parasite transmission function.

Transmission is a fundamental step in the life cycle of every parasite but it is also one of the most challenging processes to model and quantify. In most host-parasite models, the transmission process is encapsulated by a single parameter ß Many different biological processes and interactions, acting on both hosts and infectious organisms, are subsumed in this single term. There are, however, at least two undesirable consequences of this high level of abstraction. First, nonlinearities and heterogeneities that can be critical to the dynamic behaviour of infections are poorly represented; second, estimating the transmission coefficient ß from field data is often very difficult. In this paper, we present a conceptual model, which breaks the transmission process into its component parts. This deconstruction enables us to identify circumstances that generate nonlinearities in transmission, with potential implications for emergent transmission behaviour at individual and population scales. Such behaviour cannot be explained by the traditional linear transmission frameworks. The deconstruction also provides a clearer link to the empirical estimation of key components of transmission and enables the construction of flexible models that produce a unified understanding of the spread of both micro- and macro-parasite infectious disease agents.This article is part of the themed issue 'Opening the black box: re-examining the ecology and evolution of parasite transmission'.

Correction: Predicting the Potential for Natural Recovery of Atlantic Salmon (Salmo salar L.) Populations following the Introduction of Gyrodactylus salaris Malmberg, 1957 (Monogenea).

[This corrects the article DOI: 10.1371/journal.pone.0169168.].

Preliminary evidence that testosterone's association with aggression depends on self-construal.

A contribution to a special issue on Hormones and Human Competition. Previous research and theory suggest testosterone is an important hormone for modulating aggression and self-regulation. We propose that self-construal, a culturally-relevant difference in how individuals define the self in relation to others, may be an important moderator of the relationship between testosterone and behaviors linked to aggression. Within two studies (Study 1 N=80; Study 2 N=237) and an integrated data analysis, we find evidence suggesting that acute testosterone changes in men are positively associated with aggressive behavior for those with more independent self-construals, whereas basal testosterone is negatively associated with aggression when individuals have more interdependent self-construals. Although preliminary, these findings suggest that self-construal moderates the association between testosterone and aggression, thereby paving the way toward future work examining the potential cultural moderation of the behavioral effects of testosterone.

Predicting the Potential for Natural Recovery of Atlantic Salmon (Salmo salar L.) Populations following the Introduction of Gyrodactylus salaris Malmberg, 1957 (Monogenea).

Gyrodactylus salaris (Monogenea, Platyhelminthes) is a notifiable freshwater pathogen responsible for causing catastrophic damage to wild Atlantic salmon stocks, most notably in Norway. In some strains of Baltic salmon (e.g., from the river Neva) however, the impact is greatly reduced due to some form of innate resistance that regulates parasite numbers, resulting in fewer host mortalities. Gyrodactylus salaris is known from 17 European states; its status in a further 35 states remains unknown; the UK, the Republic of Ireland and certain watersheds in Finland are free of the parasite. Thus, the parasite poses a serious threat if it emerges in Atlantic salmon rearing regions throughout Europe. At present, infections are generally controlled via extreme measures such as the treatment of entire river catchments with the biocide rotenone, in order to remove all hosts, before restocking with the original genetic stock. The use of rotenone in this way in EU countries is unlikely as it would be in contravention of the Water Framework Directive. Not only are such treatments economically and environmentally costly, they also eradicate the potential for any host/parasite evolutionary process to occur. Based on previous studies, UK salmon stocks have been shown to be highly susceptible to infection, analogous to Norwegian stocks. The present study investigates the impact of a G. salaris outbreak within a naïve salmon population in order to determine long-term consequences of infection and the likelihood of coexistence. Simulation of the salmon/ G. salaris system was carried out via a deterministic mathematical modelling approach to examine the dynamics of host-pathogen interactions. Results indicated that in order for highly susceptible Atlantic strains to evolve a resistance, both a moderate-strong deceleratingly costly trade-off on birth rate and a lower overall cost of the immune response are required. The present study provides insights into the potential long term impact of G. salaris if introduced into G. salaris-free territories and suggests that in the absence of external controls salmon populations are likely to recover to high densities nearing 90% of that observed pre-infection.

Anterior cingulate cortex gray matter volume mediates an association between 2D:4D ratio and trait aggression in women but not men.

Previous research demonstrates that prenatal testosterone exposure increases aggression, possibly through its effects on the structure and function of neural circuits supporting threat detection and emotion regulation. Here we examined associations between regional gray matter volume, trait aggression, and the ratio of the second and fourth digit of the hand (2D:4D ratio) as a putative index of prenatal testosterone exposure in 464 healthy young adult volunteers. Our analyses revealed a significant positive correlation between 2D:4D ratio and gray matter volume of the dorsal anterior cingulate cortex (dACC), a brain region supporting emotion regulation, conflict monitoring, and behavioral inhibition. Subsequent analyses demonstrated that reduced (i.e., masculinized) gray matter volume in the dACC mediated the relationship between 2D:4D ratio and aggression in women, but not men. Expanding on this gender-specific mediation, additional analyses demonstrated that the shared variance between 2D:4D ratio, dACC gray matter volume, and aggression in women reflected the tendency to engage in cognitive reappraisal of emotionally provocative stimuli. Our results provide novel evidence that 2D:4D ratio is associated with masculinization of dACC gray matter volume, and that this neural phenotype mediates, in part, the expression of trait aggression in women.

Reproductive trade-offs may moderate the impact of Gyrodactylus salaris in warmer climates.

Gyrodactylus salaris is a notifiable freshwater ectoparasite of salmonids. Its primary host is Atlantic salmon (Salmo salar), upon which infections can cause death, and have led to massive declines in salmon numbers in Norway, where the parasite is widespread. Different strains of S. salar vary in their susceptibility, with Atlantic strains (such as those found in Norway) exhibiting no resistance to the parasite, and Baltic strains demonstrating an innate resistance sufficient to regulate parasite numbers on the host causing it to either die out or persist at a low level. In this study, Leslie matrix and compartmental models were used to generate data that demonstrated the population growth of G. salaris on an individual host is dependent on the total number of offspring per parasite, its longevity and the timing of its births. The data demonstrated that the key factor determining the rate of G. salaris population growth is the time at which the parasite first gives birth, with rapid birth rate giving rise to large population size. Furthermore, it was shown that though the parasite can give birth up to four times, only two births are required for the population to persist as long as the first birth occurs before a parasite is three days old. As temperature is known to influence the timing of the parasite's first birth, greater impact may be predicted if introduced to countries with warmer climates than Norway, such as the UK and Ireland which are currently recognised to be free of G. salaris. However, the outputs from the models developed in this study suggest that temperature induced trade-offs between the total number of offspring the parasite gives birth to and the first birth timing may prevent increased population growth rates over those observed in Norway.

Using process algebra to develop predator-prey models of within-host parasite dynamics.

As a first approximation of immune-mediated within-host parasite dynamics we can consider the immune response as a predator, with the parasite as its prey. In the ecological literature of predator-prey interactions there are a number of different functional responses used to describe how a predator reproduces in response to consuming prey. Until recently most of the models of the immune system that have taken a predator-prey approach have used simple mass action dynamics to capture the interaction between the immune response and the parasite. More recently Fenton and Perkins (2010) employed three of the most commonly used prey-dependent functional response terms from the ecological literature. In this paper we make use of a technique from computing science, process algebra, to develop mathematical models. The novelty of the process algebra approach is to allow stochastic models of the population (parasite and immune cells) to be developed from rules of individual cell behaviour. By using this approach in which individual cellular behaviour is captured we have derived a ratio-dependent response similar to that seen in the previous models of immune-mediated parasite dynamics, confirming that, whilst this type of term is controversial in ecological predator-prey models, it is appropriate for models of the immune system.

A rigorous approach to investigating common assumptions about disease transmission: Process algebra as an emerging modelling methodology for epidemiology.

Changing scale, for example, the ability to move seamlessly from an individual-based model to a population-based model, is an important problem in many fields. In this paper, we introduce process algebra as a novel solution to this problem in the context of models of infectious disease spread. Process algebra allows us to describe a system in terms of the stochastic behaviour of individuals, and is a technique from computer science. We review the use of process algebra in biological systems, and the variety of quantitative and qualitative analysis techniques available. The analysis illustrated here solves the changing scale problem: from the individual behaviour we can rigorously derive equations to describe the mean behaviour of the system at the level of the population. The biological problem investigated is the transmission of infection, and how this relates to individual interactions.