Arginine-178 is an essential residue for ITPA function

The inosine triphosphate pyrophosphatase (ITPA) enzyme plays a critical cellular role by removing noncanonical nucleoside triphosphates from nucleotide pools. One of the first pathological ITPA mutants identified is R178C (rs746930990), which causes a fatal infantile encephalopathy, termed developmental and epileptic encephalopathy 35 (DEE 35). The accumulation of noncanonical nucleotides such as inosine triphosphate (ITP), is suspected to affect RNA and/or interfere with normal nucleotide function, leading to development of DEE 35. Molecular dynamics simulations have shown that the very rare R178C mutation does not significantly perturb the overall structure of the protein, but results in a high level of structural flexibility and disrupts active-site hydrogen bond networks, while preliminary biochemical data indicate that ITP hydrolyzing activity is significantly reduced for the R178C mutant. Here we report Michaelis-Menten enzyme kinetics data for the R178C ITPA mutant and three other position 178 ITPA mutants. These data confirm that position 178 is essential for ITPA activity and even conservative mutation at this site (R178K) results in significantly reduced enzyme activity. Our data support that disruption of the active-site hydrogen bond network is a major cause of diminished ITP hydrolyzing activity for the R178C mutation. These results suggest an avenue for developing therapies to address DEE 35

Haemosporidian parasite diversity in an under-surveyed Australian avifauna

Haemosporidian parasites of birds are geographically widespread, have been detected in a phylogenetically diverse array of hosts, and have been the focus of extensive research due to both their impacts on birds and their similarity to vector-borne diseases of humans. Advances in molecular diagnostic tools have created a greater awareness of the genetic diversity of haemosporidian infections. Yet in spite of their more or less global distribution, comparatively little is known about the haemosporidians affecting birds in Australia. We screened blood from 889 birds (23 species) for haemosporidian blood parasite infections during the 2019 breeding season at Brookfield Conservation Park, South Australia. We examined the genetic (lineage) diversity of haemosporidian infections in this behaviorally and ecologically diverse host assemblage and examined the congruence between parasite and host phylogenies. We identified seven Haemoproteus mitochondrial cytochrome b lineages, five of which were novel. Four birds had simultaneous co-infections by two Haemoproteus lineages each. The Haemoproteus lineages clustered at the host family level. Two Plasmodium lineages were also identified, each of which had been previously detected in different avian host species in Australasia. We did not detect any Leucocytozoon infections in our sample. This study supplies critical baseline data on host–parasite associations in a poorly-surveyed geographic region

Coastal development and precipitation drive pathogen flow from land to sea: evidence from a Toxoplasma gondii and felid host system

Rapidly developing coastal regions face consequences of land use and climate change including flooding and increased sediment, nutrient, and chemical runoff, but these forces may also enhance pathogen runoff, which threatens human, animal, and ecosystem health. Using the zoonotic parasite Toxoplasma gondii in California, USA as a model for coastal pathogen pollution, we examine the spatial distribution of parasite runoff and the impacts of precipitation and development on projected pathogen delivery to the ocean. Oocysts, the extremely hardy free-living environmental stage of T. gondii shed in faeces of domestic and wild felids, are carried to the ocean by freshwater runoff. Linking spatial pathogen loading and transport models, we show that watersheds with the highest levels of oocyst runoff align closely with regions of increased sentinel marine mammal T. gondii infection. These watersheds are characterized by higher levels of coastal development and larger domestic cat populations. Increases in coastal development and precipitation independently raised oocyst delivery to the ocean (average increases of 44% and 79%, respectively), but dramatically increased parasite runoff when combined (175% average increase). Anthropogenic changes in landscapes and climate can accelerate runoff of diverse pathogens from terrestrial to aquatic environments, influencing transmission to people, domestic animals, and wildlife

Toxoplasma gondii, source to sea: higher contribution of domestic felids to terrestrial parasite loading despite lower infection prevalence

Abstract: Environmental transmission of Toxoplasma gondii, a global zoonotic parasite, adversely impacts human and animal health. Toxoplasma is a significant cause of mortality in threatened Southern sea otters, which serve as sentinels for disease threats to people and animals in coastal environments. As wild and domestic felids are the only recognized hosts capable of shedding Toxoplasma oocysts into the environment, otter infection suggests land-to-sea pathogen transmission. To assess relative contributions to terrestrial parasite loading, we evaluated infection and shedding among managed and unmanaged feral domestic cats, mountain lions, and bobcats in coastal California, USA. Infection prevalence differed among sympatric felids, with a significantly lower prevalence for managed feral cats (17%) than mountain lions, bobcats, or unmanaged feral cats subsisting on wild prey (73-81%). A geographic hotspot of infection in felids was identified near Monterey Bay, bordering a high-risk site for otter infection. Increased odds of oocyst shedding were detected in bobcats and unmanaged feral cats. Due to their large populations, pet and feral domestic cats likely contribute more oocysts to lands bordering the sea otter range than native wild felids. Continued coastal development may influence felid numbers and distribution, increase terrestrial pathogens in freshwater runoff, and alter disease dynamics at the human-animal-environment interface

The One Health Approach to Toxoplasmosis: Epidemiology, Control, and Prevention Strategies

One Health is a collaborative, interdisciplinary effort that seeks optimal health for people, animals, plants, and the environment. Toxoplasmosis, caused by Toxoplasma gondii, is an intracellular protozoan infection distributed worldwide, with a heteroxenous life cycle that practically affects all homeotherms and in which felines act as definitive reservoirs. Herein, we review the natural history of T. gondii, its transmission and impacts in humans, domestic animals, wildlife both terrestrial and aquatic, and ecosystems. The epidemiology, prevention, and control strategies are reviewed, with the objective of facilitating awareness of this disease and promoting transdisciplinary collaborations, integrative research, and capacity building among universities, government agencies, NGOs, policy makers, practicing physicians, veterinarians, and the general public

Trends in Incidence of Hospitalized Acute Myocardial Infarction in the Cardiovascular Research Network (CVRN)

Monitoring trends in cardiovascular events can provide key insights into the effectiveness of prevention efforts. Leveraging data from electronic health records provides a unique opportunity to examine contemporary, community-based trends in acute myocardial infarction hospitalizations

Fluctuation of the dynamic load nature in the power transmission train

U ovom se radu analizira utjecaj parametara: režima rada, konstrukcijskih parametara i parametara stanja prijenosnika snage na dinamičko opterećenje pojedinih njegovih elemenata. Pored analitičkog razmatranja, dani su i rezultati eksperimentalnog ispitivanja utjecaja parametara režima rada i stanja prijenosnika na vrijednost momenta poluvratila jednog putničkog vozila. Na osnovu teorijskih i eksperimentalnih ispitivanja doneseni su zaključci o utjecaju parametara na opterećenje elemenata prijenosnika snage. U radu su također prikazane i usporedbe između korištenih modela i metoda ispitivanja.This paper analyses the impact of the selected parameters: operating mode, design parameters and condition of power transmission system onto the dynamic load of some on its components. Apart from analytical considerations, we also offer the experimental results related to the influence of the operating mode parameters and the condition of power transmission train system onto the torque of a passenger’s car axle-shaft. On the basis of the theoretical and experimental research, we drew some conclusions related to the impact of some parameters on the power transmission load. Furthermore, we have given the comparative study of the used models and researching methods