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About the Authors: Eleonora Chinchio * E-mail: eleonora.chinchio@unimi.it Affiliation: Department of Veterinary Medicine, Università degli Studi di Milano, Milan, Italy ORCID logo http://orcid.org/0000-0002-8104-2063 Matteo Crotta Affiliation: Veterinary Epidemiology, Economics and Public Health Group, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire, United Kingdom ORCID logo http://orcid.org/0000-0002-5508-9028 Claudia Romeo Affiliation: Department of Veterinary Medicine, Università degli Studi di Milano, Milan, Italy Julian A. Drewe Affiliation: Veterinary Epidemiology, Economics and Public Health Group, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire, United Kingdom Javier Guitian Affiliation: Veterinary Epidemiology, Economics and Public Health Group, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire, United Kingdom Nicola Ferrari Affiliation: Department of Veterinary Medicine, Università degli Studi di Milano, Milan, Italy Citation: Chinchio E, Crotta M, Romeo C, Drewe JA, Guitian J, Ferrari N (2020) Invasive alien species and disease risk: Why we should care about invasive alien species from a health perspective The anthropogenic movement of pathogens into new geographic locations or host species, so-called “pathogen pollution” [1], is one of the main threats to human and animal health in a globalized world. Since the majority of zoonotic emerging diseases originate from wildlife [2], as recent outbreaks like Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Nipah, or Chikungunya point out, particular attention should be paid to wild animals’ translocations, which represent a potential driver of change in pathogen ecology and distribution [1]. Some well-known examples of IAS include the south-American coypu Myocastor coypus, invasive in North America, Europe, and Asia, where it causes both environmental and economic impacts consuming aquatic vegetation and undermining riverbanks [5], and the eastern-Asiatic brown marmorated stink bug Halyomorpha halys, a successful global invader causing severe economic damages to agricultural crops [6]. Besides affecting biodiversity conservation and economy, IAS, as translocated species, may promote pathogen pollution in the invaded area leading to the emergence of diseases [1,7–9]. To this aim, we provide here an overview of how animal IAS may affect local disease dynamics both directly and indirectly, i.e., acting as pathogen hosts or disrupting the recipient ecosystem structure, through real-case examples from the ecological literature, and, in the last paragraph, we propose future initiatives aimed at improving our capacity for targeted actions toward the IAS most likely to threaten human and animal health, calling for an increased involvement of people working in the fields of animal and public health in a new invasion epidemiology field.

Aggressive behaviours of solid tumours are highly influenced by the tumour microenvironment. Multiple signalling pathways can affect the normal function of stromal fibroblasts in tumours, but how these events are coordinated to generate tumour-promoting cancer-associated fibroblasts (CAFs) is not well understood. Here we show that stromal expression of Dickkopf-3 (DKK3) is associated with aggressive breast, colorectal and ovarian cancers. We demonstrate that DKK3 is a HSF1 effector that modulates the pro-tumorigenic behaviour of CAFs in vitro and in vivo. DKK3 orchestrates a concomitant activation of β-catenin and YAP/TAZ. Whereas β-catenin is dispensable for CAF-mediated ECM remodelling, cancer cell growth and invasion, DKK3-driven YAP/TAZ activation is required to induce tumour-promoting phenotypes. Mechanistically, DKK3 in CAFs acts via canonical Wnt signalling by interfering with the negative regulator Kremen and increasing cell-surface levels of LRP6. This work reveals an unpredicted link between HSF1, Wnt signalling and YAP/TAZ relevant for the generation of tumour-promoting CAFs. It is unclear how specific signalling pathways are coordinated to generate pathologically activated cancer associated fibroblasts (CAFs). Here, Ferrari et al show that stromal expression of Dickkopf-3 (DKK3) associates with aggressive tumours. DKK3 is a HSF-1 effector that activates β-catenin and YAP/TAZ, and DKK3-driven YAP/TAZ activation regulates the pro-tumorigenic behaviour of CAFs.

Analysis of publicly available genomic and gene expression data demonstrates that MCL1 expression is frequently elevated in breast cancer. Distinct from other pro-survival Bcl-2 family members, the short half-life of MCL-1 protein led us to investigate MCL-1 protein expression in a breast cancer tissue microarray and correlate this with clinical data. Here, we report associations between high MCL-1 and poor prognosis in specific subtypes of breast cancer including triple-negative breast cancer, an aggressive form that lacks targeted treatment options. Deletion of MCL-1 in the mammary epithelium of genetically engineered mice revealed an absolute requirement for MCL-1 in breast tumorigenesis. The clinical applicability of these findings was tested through a combination of approaches including knock-down or inhibition of MCL-1 to show triple-negative breast cancer cell line dependence on MCL-1 in vitro and in vivo . Our data demonstrate that high MCL-1 protein expression is associated with poor outcome in breast cancer and support the therapeutic targeting of MCL-1 in this disease.

The tumor microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumor progression. The contribution of stromal cells to the reprogramming of the TME is not well understood. Here, we provide evidence of the role of the cytokine oncostatin M (OSM) as central node for multicellular interactions between immune and nonimmune stromal cells and the epithelial cancer cell compartment. OSM receptor (OSMR) deletion in a multistage breast cancer model halted tumor progression. We ascribed causality to the stromal function of the OSM axis by demonstrating reduced tumor burden of syngeneic tumors implanted in mice lacking OSMR. Single-cell and bioinformatic analysis of murine and human breast tumors revealed that OSM expression was restricted to myeloid cells, whereas OSMR was detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprogrammed fibroblasts to a more contractile and tumorigenic phenotype and elicited the secretion of VEGF and proinflammatory chemokines CXCL1 and CXCL16, leading to increased myeloid cell recruitment. Collectively, our data support the notion that the stromal OSM/OSMR axis reprograms the immune and nonimmune microenvironment and plays a key role in breast cancer progression.

West Nile disease is a vector-borne disease caused by West Nile virus (WNV), involving mosquitoes as vectors and birds as maintenance hosts. Humans and other mammals can be infected via mosquito bites, developing symptoms ranging from mild fever to severe neurological infection. Due to the worldwide spread of WNV, human infection risk is high in several countries. Nevertheless, there are still several knowledge gaps regarding WNV dynamics. Several aspects of transmission taking place between birds and mosquitoes, such as the length of the infectious period in birds or mosquito biting rates, are still not fully understood, and precise quantitative estimates are still lacking for the European species involved. This lack of knowledge affects the precision of parameter values when modelling the infection, consequently resulting in a potential impairment of the reliability of model simulations and predictions and in a lack of the overall understanding of WNV spread. Further investigations are thus needed to better understand these aspects, but field studies, especially those involving several wild species, such as in the case of WNV, can be challenging. Thus, it becomes crucial to identify which transmission processes most influence the dynamics of WNV. In the present work, we propose a sensitivity analysis to investigate which of the selected epidemiological parameters of WNV have the largest impact on the spread of the infection. Based on a mathematical model simulating WNV spread into the Lombardy region (northern Italy), the basic reproduction number of the infection was estimated and used to quantify infection spread into mosquitoes and birds. Then, we quantified how variations in four epidemiological parameters representing the duration of the infectious period in birds, the mosquito biting rate on birds, and the competence and susceptibility to infection of different bird species might affect WNV transmission. Our study highlights that knowledge gaps in WNV epidemiology affect the precision in several parameters. Although all investigated parameters affected the spread of WNV and the modelling precision, the duration of the infectious period in birds and mosquito biting rate are the most impactful, pointing out the need of focusing future studies on a better estimate of these parameters at first. In addition, our study suggests that a WNV outbreak is very likely to occur in all areas with suitable temperatures, highlighting the wide area where WNV represents a serious risk for public health.

Background The use of serological tests based on antibody detection plays a pivotal role in the definition of past exposure to pathogens and therefore monitor infection presence, guide treatment decisions, and support disease control efforts through detection and surveillance. Nevertheless, the information obtained from serological antibody tests may be incomplete, as acute infections can go unnoticed due to the delay between infection and the development of detectable antibodies. This is particularly relevant for those pathogens for which acute cases drive pathogen transmission and are associated with the onset of clinical symptoms. We therefore developed a computational framework based on mathematical models to estimate the prevalence of acute infections from serological testing to be broadly applicable to different pathogens. Results and conclusions We showed the effectiveness of our framework and highlighted that, in addition to seroprevalence, prevalence of acute cases also depends on the recovery rate and the mean life expectancy of the population. We applied our framework to Toxoplasma gondii , a model pathogen for infections that are largely asymptomatic, highly prevalent in herds, and exhibit clinical signs (e.g., abortions) associated with the acute phase of a primary infection (following the acute phase, in the case of T. gondii ). Despite the sanitary importance of diagnosing acute infections, in livestock T. gondii infection is usually investigated by identifying specific antibodies through serological testing, which limits our ability to predict the infection risk and the expected number of abortions. Through this worked example, we showed that our model allows for the estimation of the number of individuals in acute infection phase and prediction of the infection dynamics, providing valuable insights into disease spread and informing management strategies for the control of pathogens. Also, given the generalizability of the model proposed, it can be easily applied to different pathogens whose diagnosis relies on serological testing. Finally, to enhance accessibility, we have developed an interactive Shiny application to support the implementation and use of the framework.

Background West Nile virus (WNV) is an emerging vector-borne pathogen that is becoming increasingly prevalent in temperate regions. The development of effective intervention strategies is crucial for limiting its spread; however, the adaptability and ubiquity of mosquitoes, combined with the complexity of the WNV transmission cycle, continue to hinder its eradication. Methods This study employs a deterministic compartmental model to evaluate the effectiveness of ten intervention strategies targeting either the mosquito (vector) or avian (host) population in the Lombardy region of Italy. Results Vector-targeted interventions were more effective than host-targeted measures, with breeding site reduction and larvicide treatments demonstrating the greatest efficacy. In contrast, interventions targeting adult mosquitoes, including adulticide treatments and elimination of overwintering mosquitoes, showed moderate efficacy. Furthermore, the impact of eliminating overwintering mosquitoes gradually diminished over time. Host-targeted strategies, such as bird population reduction, were ineffective and, in some cases, led to increased WNV transmission. The efficacy of all interventions varied temporally, peaking in mid-summer. Conclusions These findings highlight the importance of prioritising mosquito control, particularly targeting immature stages, to mitigate WNV outbreaks. Our study highlights the critical role of mathematical modelling in designing effective intervention strategies. By providing a structured framework to evaluate and predict the outcomes of various approaches, modelling can aid disease control while optimising resource allocation and minimising environmental impact. Mathematical models, therefore, prove to be powerful tools for balancing public health goals with sustainable practices. Graphical Abstract

During the last century, emerging diseases have increased in number, posing a severe threat for human health. Zoonoses, in particular, represent the 60% of emerging diseases, and are a big challenge for public health due to the complexity of their dynamics. Mathematical models, by allowing an a priori analysis of dynamic systems and the simulation of different scenarios at once, may represent an efficient tool for the determination of factors and phenomena involved in zoonotic infection cycles, but are often underexploited in public health. In this context, we developed a deterministic mathematical model to compare the efficacy of different intervention strategies aimed at reducing environmental contamination by macroparasites, using raccoons (Procyon lotor) and their zoonotic parasite Bayilsascaris procyonis as a model system. The three intervention strategies simulated are raccoon depopulation, anthelmintic treatment of raccoons and faeces removal. Our results show that all these strategies are able to eliminate the parasite egg population from the environment, but they are effective only above specific threshold coverages. Host removal and anthelmintic treatment showed the fastest results in eliminating the egg population, but anthelmintic treatment requires a higher effort to reach an effective result compared to host removal. Our simulations show that mathematical models can help to shed light on the dynamics of communicable infectious diseases, and give specific guidelines to contain B. procyonis environmental contamination in native, as well as in new, areas of parasite emergence. In particular, the present study highlights that identifying in advance the appropriate treatment coverage is fundamental to achieve the desired results, allowing for the implementation of cost- and time-effective intervention strategies.

The influence of the physical, rheological, and process parameters on the cellulose nanocrystal (CNC) drops before and after external gelation in a CaCl2 solution was investigated. The dominant role of the CNC’s colloidal suspension properties, such as the viscous force, inertial, and surface tension forces in the fluid dynamics was quantitatively evaluated in the formation of drops and jellified beads. The similarity and difference between the behavior of carbohydrate polymers and rod-like crystallites such as CNC were enlightened. Pump-driven and centrifugally-driven external gelation approaches were followed to obtain CNC hydrogel beads with tunable size and regular shape. A superior morphological control—that is, a more regular shape and smaller dimension of the beads—were obtained by centrifugal force-driven gelation. These results suggest that even by using a simple set-up and a low-speed centrifuge device, the extrusion of a colloidal solution through a small nozzle under a centrifugal field is an efficient approach for the production of CNC hydrogel beads with good reproducibility, control over the bead morphology and size monodispersion.

In contrast to the depth of knowledge on the pathological effects of parasitism in domestic animals, the impact of the vast majority of parasites on wildlife hosts is poorly understood and, besides, information from domestics is rarely usable to disclose the parasites' impact on free-ranging populations' dynamics. Here we use Toxoplasmosis as a study model since, until now, the infection process and the protozoan's effects in natural conditions has received little attention. We analysed 81 sera from red deer (Cervus elaphus) sampled in Italian Alps and through generalized linear models we evaluated (1) the epidemiological factors influencing T. gondii infection dynamics; (2) its impact on female fertility [corrected]. High seroprevalence of T. gondii infection was recorded in yearling (1 year-old; prevalence = 52.4%) and adult (>2 year-old; prevalence = 51.3%) red deer, while calves (<1 year-old) did not contract the infection suggesting horizontal transmission as the main route of infection. The stable prevalence between yearlings and adults and the higher serological titres of younger individuals lead to two alternative infection processes suggesting a difference between age classes or in acquiring the infection or in responding to the pathogen. No associations between T. gondii serological titres and pregnancy status was observed indicating no direct effect on the probability of being pregnant; nevertheless a relation between females' higher serological titres and lower foetal development emerged, suggesting potential effects of the parasite infection on deer reproduction. The results demonstrate high seroprevalence of T. gondii infection in free-ranging red deer and, furthermore, the effect on foetal development suggests the potential impact of the parasite on red deer fertility and thus on its population dynamics.