Influence of tree cover on carcass detection and consumption by facultative vertebrate scavengers.

Scavenging mammals and vultures can exploit and deplete carcasses much faster than other birds and invertebrates. Vultures are strongly influenced by habitat type, e.g. tree cover, since they rely on their eyesight to detect carcasses. It remains unclear whether and how facultative scavengers - both other birds and mammals - are influenced by tree cover and how that affect carcass decomposition time, which in turn affects biodiversity and ecological processes, including the cycle of energy and nutrients. We studied whether the carcass detection and consumption, hence carcass decomposition speed, by facultative avian and mammalian scavengers varies with tree cover in areas without vultures. Fresh mammal carcasses were placed in different landscapes across the Netherlands at locations that widely varied in tree cover. Camera traps were used to record carcass exploitation by facultative avian and mammalian scavengers and to estimate carcass decomposition time. We found that carcass detection and consumption by birds, wild boar, and other mammals varied between locations. Carcass decomposition speed indeed increased with carcass detection and exploitation by mammals, especially by wild boar. However, this variation was not related to tree cover. We conclude that tree cover is not a major determinant of carcass exploitation by facultative scavengers in areas without obligate scavengers and large carnivores.

Ionomic Variation Among Tissues in Fallow Deer (Dama dama) by Sex and Age.

(1) In mammals, the mineral nutrient and trace elemental composition of the body - the ionome - differs among individuals. It has been hypothesized that these differences may be related to age and sex, both for ecotoxic and essential elements. (2) We investigated whether and how intraspecific ionomic variation is related to age and sex in Fallow deer (Dama dama). We tested the predictions that concentrations of ecotoxic elements increase with age, that ionomic variation is lower among young individuals than among older individuals, and that reproductive females (does) have the lowest concentrations of essential elements. (3) Culled animals of different sex and age were obtained from a single protected area. The animals were dissected to collect 13 tissues, and concentrations of 22 different elements were measured in a sample of each tissue. (4) We described substantial ionomic variation between individuals. Some of this variation was related to age and sex, as predicted. Based on the limited existing knowledge on chemical element allocation and metabolism in the body, sex-related differences were more difficult to interpret than age-related differences. Since reference values are absent, we could not judge about the consequences of the elemental values that we found. (5) More extensive ionomic surveys, based on a wide range of elements and tissues, are needed to enlarge the understanding of within-species ionomic variation and potential biological, ecological, and metabolic consequences.

Combining camera trap surveys and IUCN range maps to improve knowledge of species distributions.

Reliable maps of species distributions are fundamental for biodiversity research and conservation. The International Union for Conservation of Nature (IUCN) range maps are widely recognized as authoritative representations of species' geographic limits, yet they might not always align with actual occurrence data. In recent area of habitat (AOH) maps, areas that are not habitat have been removed from IUCN ranges to reduce commission errors, but their concordance with actual species occurrence also remains untested. We tested concordance between occurrences recorded in camera trap surveys and predicted occurrences from the IUCN and AOH maps for 510 medium- to large-bodied mammalian species in 80 camera trap sampling areas. Across all areas, cameras detected only 39% of species expected to occur based on IUCN ranges and AOH maps; 85% of the IUCN only mismatches occurred within 200 km of range edges. Only 4% of species occurrences were detected by cameras outside IUCN ranges. The probability of mismatches between cameras and the IUCN range was significantly higher for smaller-bodied mammals and habitat specialists in the Neotropics and Indomalaya and in areas with shorter canopy forests. Our findings suggest that range and AOH maps rarely underrepresent areas where species occur, but they may more often overrepresent ranges by including areas where a species may be absent, particularly at range edges. We suggest that combining range maps with data from ground-based biodiversity sensors, such as camera traps, provides a richer knowledge base for conservation mapping and planning.

Combinación de censos con fototrampas y mapas de extensión de la UICN para incrementar el conocimiento sobre la distribución de las especies Resumen Los mapas confiables de la distribución de las especies son fundamentales para la investigación y conservación de la biodiversidad. Los mapas de distribución de la Unión Internacional para la Conservación de la Naturaleza (UICN) están reconocidos como representaciones de autoridad de los límites geográficos de las especies, aunque no siempre se alinean con los datos actuales de su presencia. En los mapas recientes de área de hábitat (ADH), las áreas que no son hábitat han sido eliminadas de la distribución de la UICN para reducir los errores de comisión, pero su concordancia con la presencia actual de las especies tampoco ha sido analizada. Analizamos la concordancia entre la presencia registrada por los censos de fototrampas y pronosticamos la presencia a partir de los mapas de la UICN y de ADH de 510 especies de mamíferos de talla mediana a grande en 80 áreas de muestreo de fototrampas. Las cámaras detectaron sólo el 39% de las especies esperadas con base en la distribución de la UICN y los mapas de ADH en todas las áreas; el 85% de las disparidades con la UICN ocurrieron dentro de los 200 km a partir del borde de la distribución. Sólo el 4% de la presencia de las especies fue detectada por las cámaras ubicadas fuera de la distribución de la UICN. La probabilidad de disparidad entre las cámaras y la UICN fue significativamente mayor para los mamíferos de talla pequeña y para los especialistas de hábitat en las regiones Neotropical e Indomalaya y en áreas con doseles forestales más bajos. Nuestros hallazgos sugieren que los mapas de distribución y ADH pocas veces subrepresentan las áreas con presencia de las especies, pero con frecuencia pueden sobrerrepresentar la distribución al incluir áreas en donde las especies pueden estar ausentes, en particular los bordes de la distribución. Sugerimos que la combinación de los mapas de distribución con los sensores de biodiversidad en tierra, como las fototrampas, proporciona una base más rica de conocimiento para el mapeo y la planeación de la conservación.

Novel methodologies for host-microbe interactions and microbiome-targeted therapeutics in 3D organotypic skin models.

BACKGROUND: Following descriptive studies on skin microbiota in health and disease, mechanistic studies on the interplay between skin and microbes are on the rise, for which experimental models are in great demand. Here, we present a novel methodology for microbial colonization of organotypic skin and analysis thereof. RESULTS: An inoculation device ensured a standardized application area on the stratum corneum and a homogenous distribution of bacteria, while preventing infection of the basolateral culture medium even during prolonged culture periods for up to 2 weeks at a specific culture temperature and humidity. Hereby, host-microbe interactions and antibiotic interventions could be studied, revealing diverse host responses to various skin-related bacteria and pathogens. CONCLUSIONS: Our methodology is easily transferable to a wide variety of organotypic skin or mucosal models and different microbes at every cell culture facility at low costs. We envision that this study will kick-start skin microbiome studies using human organotypic skin cultures, providing a powerful alternative to experimental animal models in pre-clinical research. Video Abstract.

Mycorrhizal feedbacks influence global forest structure and diversity.

One mechanism proposed to explain high species diversity in tropical systems is strong negative conspecific density dependence (CDD), which reduces recruitment of juveniles in proximity to conspecific adult plants. Although evidence shows that plant-specific soil pathogens can drive negative CDD, trees also form key mutualisms with mycorrhizal fungi, which may counteract these effects. Across 43 large-scale forest plots worldwide, we tested whether ectomycorrhizal tree species exhibit weaker negative CDD than arbuscular mycorrhizal tree species. We further tested for conmycorrhizal density dependence (CMDD) to test for benefit from shared mutualists. We found that the strength of CDD varies systematically with mycorrhizal type, with ectomycorrhizal tree species exhibiting higher sapling densities with increasing adult densities than arbuscular mycorrhizal tree species. Moreover, we found evidence of positive CMDD for tree species of both mycorrhizal types. Collectively, these findings indicate that mycorrhizal interactions likely play a foundational role in global forest diversity patterns and structure.

Variability of the Ionome of Wild Boar (Sus scrofa) and Red Deer (Cervus elaphus) in a Dutch National Park, with Implications for Biomonitoring.

The ionome-an important expression of the physiological state of organisms-is poorly known for mammals. The focus on particular tissues-such as liver, kidney, and bones-in biomonitoring of environmental pollution and potential deficiencies is based on widely held assumptions rather than solid knowledge of full mammalian ionomes. We examined the full ionome of Red deer (Cervus elaphus) and Wild boar (Sus scrofa), two commonly used mammals for biomonitoring, in a Dutch protected nature reserve (Veluwezoom). We used four individuals per species. We dissected 13 tissues and organs from each individuals (eight in total) of each species and measured 22 elemental concentrations in each. We assessed, for each element, how concentrations varied across tissues within and between individuals. Based on existing literature, we put our findings in the context of their function in the mammalian body. We found that the ionome was highly variable between as well as within the two species. For most elements, tissues containing the highest and lowest concentration differed between individuals. No single tissue accurately represented the accumulation of toxic elements or potential deficiencies in the bodies. Our assessment of the element's biological roles revealed a serious lack of reference values. Our findings imply that analyses of commonly used tissues in biomonitoring do not necessarily capture bioaccumulation of toxins or potential deficiencies. We recommend establishing a centralized database of mammalian ionomes to derive reference values in future. To our knowledge, our study is one of the most complete assessments of mammalian ionomes to date.

Occurrence dynamics of mammals in protected tropical forests respond to human presence and activities.

Protected areas (PAs) play a vital role in wildlife conservation. Nonetheless there is concern and uncertainty regarding how and at what spatial scales anthropogenic stressors influence the occurrence dynamics of wildlife populations inside PAs. Here we assessed how anthropogenic stressors influence occurrence dynamics of 159 mammal species in 16 tropical PAs from three biogeographic regions. We quantified these relationships for species groups (habitat specialists and generalists) and individual species. We used long-term camera-trap data (1,002 sites) and fitted Bayesian dynamic multispecies occupancy models to estimate local colonization (the probability that a previously empty site is colonized) and local survival (the probability that an occupied site remains occupied). Multiple covariates at both the local scale and landscape scale influenced mammal occurrence dynamics, although responses differed among species groups. Colonization by specialists increased with local-scale forest cover when landscape-scale fragmentation was low. Survival probability of generalists was higher near the edge than in the core of the PA when landscape-scale human population density was low but the opposite occurred when population density was high. We conclude that mammal occurrence dynamics are impacted by anthropogenic stressors acting at multiple scales including outside the PA itself.

The rise of hyperabundant native generalists threatens both humans and nature.

In many disturbed terrestrial landscapes, a subset of native generalist vertebrates thrives. The population trends of these disturbance-tolerant species may be driven by multiple factors, including habitat preferences, foraging opportunities (including crop raiding or human refuse), lower mortality when their predators are persecuted (the 'human shield' effect) and reduced competition due to declines of disturbance-sensitive species. A pronounced elevation in the abundance of disturbance-tolerant wildlife can drive numerous cascading impacts on food webs, biodiversity, vegetation structure and people in coupled human-natural systems. There is also concern for increased risk of zoonotic disease transfer to humans and domestic animals from wildlife species with high pathogen loads as their abundance and proximity to humans increases. Here we use field data from 58 landscapes to document a supra-regional phenomenon of the hyperabundance and community dominance of Southeast Asian wild pigs and macaques. These two groups were chosen as prime candidates capable of reaching hyperabundance as they are edge adapted, with gregarious social structure, omnivorous diets, rapid reproduction and high tolerance to human proximity. Compared to intact interior forests, population densities in degraded forests were 148% and 87% higher for wild boar and macaques, respectively. In landscapes with >60% oil palm coverage, wild boar and pig-tailed macaque estimated abundances were 337% and 447% higher than landscapes with <1% oil palm coverage, respectively, suggesting marked demographic benefits accrued by crop raiding on calorie-rich food subsidies. There was extreme community dominance in forest landscapes with >20% oil palm cover where two pig and two macaque species accounted for >80% of independent camera trap detections, leaving <20% for the other 85 mammal species >1 kg considered. Establishing the population trends of pigs and macaques is imperative since they are linked to cascading impacts on the fauna and flora of local forest ecosystems, disease and human health, and economics (i.e., crop losses). The severity of potential negative cascading effects may motivate control efforts to achieve ecosystem integrity, human health and conservation objectives. Our review concludes that the rise of native generalists can be mediated by specific types of degradation, which influences the ecology and conservation of natural areas, creating both positive and detrimental impacts on intact ecosystems and human society.

Gram-positive anaerobic cocci guard skin homeostasis by regulating host-defense mechanisms.

In atopic dermatitis (AD), chronic skin inflammation is associated with skin barrier defects and skin microbiome dysbiosis including a lower abundance of Gram-positive anaerobic cocci (GPACs). We here report that, through secreted soluble factors, GPAC rapidly and directly induced epidermal host-defense molecules in cultured human keratinocytes and indirectly via immune-cell activation and cytokines derived thereof. Host-derived antimicrobial peptides known to limit the growth of Staphylococcus aureus-a skin pathogen involved in AD pathology-were strongly upregulated by GPAC-induced signaling through aryl hydrocarbon receptor (AHR)-independent mechanisms, with a concomitant AHR-dependent induction of epidermal differentiation genes and control of pro-inflammatory gene expression in organotypic human epidermis. By these modes of operandi, GPAC may act as an "alarm signal" and protect the skin from pathogenic colonization and infection in the event of skin barrier disruption. Fostering growth or survival of GPAC may be starting point for microbiome-targeted therapeutics in AD.

Prey tracking and predator avoidance in a Neotropical moist forest: a camera-trapping approach.

Whether prey species avoid predators and predator species track prey is a poorly understood aspect of predator-prey interactions, given measuring prey tracking by predators and predator avoidance by prey is challenging. A common approach to study these interactions among mammals in field situations is to monitor the spatial proximity of animals at fixed times, using GPS tags fitted to individuals. However, this method is invasive and only allows tracking of a subset of individuals. Here, we use an alternative, noninvasive camera-trapping approach to monitor temporal proximity of predator and prey animals. We deployed camera traps at fixed locations on Barro Colorado Island, Panama, where the ocelot (Leopardus pardalis) is the principal mammalian predator, and tested two hypotheses: (1) prey animals avoid ocelots; and (2) ocelots track prey. We quantified temporal proximity of predators and prey by fitting parametric survival models to the time intervals between subsequent prey and predator captures by camera traps, and then compared the observed intervals to random permutations that retained the spatiotemporal distribution of animal activity. We found that time until a prey animal appeared at a location was significantly longer than expected by chance if an ocelot had passed, and that the time until an ocelot appeared at a location was significantly shorter than expected by chance after prey passage. These findings are indirect evidence for both predator avoidance and prey tracking in this system. Our results show that predator avoidance and prey tracking influence predator and prey distribution over time in a field setting. Moreover, this study demonstrates that camera trapping is a viable and noninvasive alternative to GPS tracking for studying certain predator-prey interactions.

Debido a las dificultades en evaluar como los depredadores rastrean su presa, y como las presas eluden a depredadores, un aspecto todavía poco conocido en la interacción entre depredadores y presas es si estas evitan a depredadores o si estos rastrean las presas. Una enfoque común para estudiar estas interacciones entre mamíferos bajo condiciones de campo es de seguir la proximidad espacial de animales a intervalos fijos, usando marbetes de GPS ajustados a los individuos. Sin embargo, este método es invasivo y solo permite obtener información de un número limitado de individuos. En este estudio, usamos cámaras trampas como método alternativo y no invasivo, para monitorear el proximidad temporal entre depredadores y presas en sitios fijos en Isla Barro Colorado, Panamá, donde los ocelotes (Leopardus pardalis) son el principal mamífero depredador. Evaluamos dos hipótesis: (1) las presas evitan a los ocelotes, y (2) los ocelotes rastrean a las presas. Cuantificamos la proximidad temporal de depredadores y presas ajustando modelos paramétricos de supervivencia a los intervalos de tiempo ocurridos entre observaciones subsecuentes en las cámaras trampas, y luego comparamos los intervalos observados con permutaciones aleatorias que retuvieron la distribución espacio-temporal de la actividad de los animales. Encontramos que, si un ocelote había pasado por dicha área, el tiempo en el cual una presa aparece en una ubicación fue significativamente mayor que lo esperado aleatoriamente. También encontramos que, después de pasar una presa por un área, el tiempo en que un ocelote tarda en aparecer fue significativamente menor que lo esperado al azar. Estos resultados constituyen evidencia indirecta que las presas evitan a los depredadores y que estos rastrean a las presas. Nuestros resultados muestran que la evitación de los depredadores y el rastreo de las presas influyen en la distribución de presas y depredadores a lo largo del tiempo en un escenario natural. Este estudio también demuestra que las cámaras trampas son una alternativa viable y no invasiva, con respecto a marbetes de GPS, para estudiar ciertas interacciones entre presas y depredadores.

Biodiversity in the Lyme-light: ecological restoration and tick-borne diseases in Europe.

Biodiversity loss and the emergence of zoonotic diseases are two major global challenges. An urgent question is how ecosystems and wildlife communities can be restored whilst minimizing the risk of zoonotic diseases carried by wildlife. Here, we evaluate how current ambitions to restore Europe's natural ecosystems may affect the hazard of diseases vectored by the tick Ixodes ricinus at different scales. We find that effects of restoration efforts on tick abundance are relatively straightforward but that the interacting effects of vertebrate diversity and abundance on pathogen transmission are insufficiently known. Long-term integrated surveillance of wildlife communities, ticks, and their pathogens is needed to understand their interactions and to prevent nature restoration from increasing tick-borne disease (TBD) hazard.

Investigations into the FLG Null Phenotype: Showcasing the Methodology for CRISPR/Cas9 Editing of Human Keratinocytes.

Ever since the association between FLG loss-of-function variants and ichthyosis vulgaris and atopic dermatitis disease onset was identified, FLGs function has been under investigation. Intraindividual genomic predisposition, immunological confounders, and environmental interactions complicate the comparison between FLG genotypes and related causal effects. Using CRISPR/Cas9, we generated human FLG-knockout (ΔFLG) N/TERT-2G keratinocytes. FLG deficiency was shown by immunohistochemistry of human epidermal equivalent cultures. Next to (partial) loss of structural proteins (involucrin, hornerin, keratin 2, and transglutaminase 1), the stratum corneum was denser and lacked the typical basket weave appearance. In addition, electrical impedance spectroscopy and transepidermal water loss analyses highlighted a compromised epidermal barrier in ΔFLG human epidermal equivalents. Correction of FLG reinstated the presence of keratohyalin granules in the stratum granulosum, FLG protein expression, and expression of the proteins mentioned earlier. The beneficial effects on stratum corneum formation were reflected by the normalization of electrical impedance spectroscopy and transepidermal water loss. This study shows the causal phenotypical and functional consequences of FLG deficiency, indicating that FLG is not only central in epidermal barrier function but also vital for epidermal differentiation by orchestrating the expression of other important epidermal proteins. These observations pave the way to fundamental investigations into the exact role of FLG in skin biology and disease.

CYSRT1: An Antimicrobial Epidermal Protein that Can Interact with Late Cornified Envelope Proteins.

Late cornified envelope (LCE) proteins are small cationic epidermal proteins with antimicrobial properties, and the combined deletion of LCE3B and LCE3C genes is a risk factor for psoriasis that affects skin microbiome composition. In a yeast two-hybrid screen, we identified CYSRT1 as an interacting partner of members of all LCE groups except LCE6. These interactions were confirmed in a mammalian cell system by coimmunoprecipitation. CYSRT1 is a protein of unknown function that is specifically expressed in cutaneous and oral epithelia and spatially colocalizes with LCE proteins in the upper layers of the suprabasal epidermis. Constitutive CYSRT1 expression is present in fully differentiated epidermis and can be further induced in vivo by disruption of the skin barrier upon stratum corneum removal. Transcriptional regulation correlates to keratinocyte terminal differentiation but not to skin bacteria exposure. Similar to LCEs, CYSRT1 was found to have antibacterial activity against Pseudomonas aeruginosa. Comparative gene sequence analysis and protein amino acid alignment indicate that CYSRT1 is highly conserved among vertebrates and has putative antimicrobial activity. To summarize, we identified CYSRT1 in the outer skin layer, where it colocalizes with LCE proteins and contributes to the constitutive epidermal antimicrobial host defense repertoire.

Top-down and bottom-up forces explain patch utilization by two deer species and forest recruitment.

Ungulates play an important role in temperate systems. Through their feeding behaviour, they can respond to vegetation by selecting patches or modify vegetation composition by herbivory. The degree in which they interact with vegetation can either reinforce landscape heterogeneity by creating disturbance or reduce heterogeneity in case of overbrowsing. This study evaluates how bottom-up (patch quality, structure), top-down forces (hunting, distance to village, forest edge) and deer features (feeding type, abundance) mediate patch utilization in a temperate forest and assess the implications of patch utilization and light on forest recruitment. Theory predicts that animals seek to maximize their energetic gains by food intake while minimizing the costs associated to foraging, such as the energy required for avoiding predators and exploiting resources. We focused on two deer species with contrasting feeding type: a browser (C. capreolus) and a mixed feeder (C. elaphus). We paired camera traps to vegetation sub-plots in ten forest sites in the Netherlands that widely ranged in deer abundance and landscape heterogeneity. Results showed that patch utilization is simultaneously explained by bottom-up, top-down forces and by deer abundance, as predicted by the safety-in-numbers hypothesis. Yet, forces best explaining patch utilization differed between deer species. Overall, higher patch utilization came with higher browsing, lower tree diversity and a large difference in forest composition: from a mix of broadleaves and conifers towards only conifers. We conclude that these two deer species, although living in the same area and belonging to the same guild, differentially perceive, interact with and shape their surrounding landscape.

Defaunation changes leaf trait composition of recruit communities in tropical forests in French Guiana.

Hunting impacts tropical vertebrate populations, causing declines of species that function as seed dispersers and predators, or that browse seedlings and saplings. Whether and how the resulting reductions in seed dispersal, seed predation, and browsing translate to changes in the tree composition is poorly understood. Here, we assess the effect of defaunation on the functional composition of communities of tree recruits in tropical rainforests in French Guiana. We selected eight sites along a gradient of defaunation, caused by differences in hunting pressure, in otherwise intact old-growth forests in French Guiana. We measured shifts in functional composition by comparing leaf and fruit traits and wood density between tree recruits (up to 5 cm diameter at breast height) and adults, and tested whether and how these compositional shifts related to defaunation. We found a positive relationship with defaunation for shifts in specific leaf area, a negative relationship for shifts of leaf toughness and wood density, and a weak relationship for shifts in fruit traits. Our results suggest that the loss of vertebrates affects ecological processes such as seed dispersal and browsing, of which browsing remains understudied. Even though these changes sometimes seem minor, together they result in major shifts in forest composition. These changes have long-term ramifications that may alter forest dynamics for generations.

Consistent diel activity patterns of forest mammals among tropical regions.

An animal's daily use of time (their "diel activity") reflects their adaptations, requirements, and interactions, yet we know little about the underlying processes governing diel activity within and among communities. Here we examine whether community-level activity patterns differ among biogeographic regions, and explore the roles of top-down versus bottom-up processes and thermoregulatory constraints. Using data from systematic camera-trap networks in 16 protected forests across the tropics, we examine the relationships of mammals' diel activity to body mass and trophic guild. Also, we assess the activity relationships within and among guilds. Apart from Neotropical insectivores, guilds exhibited consistent cross-regional activity in relation to body mass. Results indicate that thermoregulation constrains herbivore and insectivore activity (e.g., larger Afrotropical herbivores are ~7 times more likely to be nocturnal than smaller herbivores), while bottom-up processes constrain the activity of carnivores in relation to herbivores, and top-down processes constrain the activity of small omnivores and insectivores in relation to large carnivores' activity. Overall, diel activity of tropical mammal communities appears shaped by similar processes and constraints among regions reflecting body mass and trophic guilds.

Occupancy winners in tropical protected forests: a pantropical analysis.

The structure of forest mammal communities appears surprisingly consistent across the continental tropics, presumably due to convergent evolution in similar environments. Whether such consistency extends to mammal occupancy, despite variation in species characteristics and context, remains unclear. Here we ask whether we can predict occupancy patterns and, if so, whether these relationships are consistent across biogeographic regions. Specifically, we assessed how mammal feeding guild, body mass and ecological specialization relate to occupancy in protected forests across the tropics. We used standardized camera-trap data (1002 camera-trap locations and 2-10 years of data) and a hierarchical Bayesian occupancy model. We found that occupancy varied by regions, and certain species characteristics explained much of this variation. Herbivores consistently had the highest occupancy. However, only in the Neotropics did we detect a significant effect of body mass on occupancy: large mammals had lowest occupancy. Importantly, habitat specialists generally had higher occupancy than generalists, though this was reversed in the Indo-Malayan sites. We conclude that habitat specialization is key for understanding variation in mammal occupancy across regions, and that habitat specialists often benefit more from protected areas, than do generalists. The contrasting examples seen in the Indo-Malayan region probably reflect distinct anthropogenic pressures.

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183.

Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a > 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission.

Mutual cheating strengthens a tropical seed dispersal mutualism.

While cheating can cause the degradation or collapse of mutualisms, mutualisms may theoretically stabilize or strengthen if the cheating is mutual. Here, we present an asymmetric two-player game model to explore the evolutionary dynamics of mutual cheating in a mutualistic interaction. We found that the interaction evolved toward mutual cheating if cheating can help both partners obtain higher benefits or if counter-cheating yields more benefits to victims than simply tolerating exploitation by partners. Then, we present empirical evidence for such mutual cheating strengthening a seed dispersal mutualism in which rodents disperse seeds by scatter hoarding, rodents sabotage seed germination by pruning radicles, and seeds escape rodents by resprouting. By tracking >8,000 Pittosporopsis kerrii seeds throughout the dispersal process in a tropical forest in southwest China, we found that rodents provided better dispersal to seeds that they pruned, i.e., pruned seeds were dispersed farther and were more likely to establish seedlings than unpruned seeds. Compared with unpruned seeds, pruned seeds retained more of their nutrients, i.e., dry mass of pruned seeds was greater than that of unpruned seeds, and were stored for longer by rodents. These findings indicate that mutual cheating benefited both partners. Payoffs estimated from the field experiments indicated that mutual cheating was indeed favored in rodents and plants P. kerrii, and that neither partner was enslaved by the other under mutual cheating. Rather, the mutualism remained stable because the partners were able to exploit each other, and each partner attempted to gain the maximum benefits from the interaction. Our findings indicate that mutual cheating between two mutualists can enhance and stabilize mutualisms.

Antimicrobial Late Cornified Envelope Proteins: The Psoriasis Risk Factor Deletion of LCE3B/C Genes Affects Microbiota Composition.

Late cornified envelope proteins are predominantly expressed in the skin and other cornified epithelia. On the basis of sequence similarity, this 18-member homologous gene family has been subdivided into six groups. The LCE3 proteins have been the focus of dermatological research because the combined deletion of LCE3B and LCE3C genes (LCE3B/C-del) is a risk factor for psoriasis. We previously reported that LCE3B/C-del increases the expression of the LCE3A gene and that LCE3 proteins exert antibacterial activity. In this study, we analyzed the antimicrobial properties of other family members and the role of LCE3B/C-del in the modulation of microbiota composition of the skin and oral cavity. Differences in killing efficiency and specificity between the late cornified envelope proteins and their target microbes were found, and the amino acid content rather than the order of the well-conserved central domain of the LCE3A protein was found responsible for its antibacterial activity. In vivo, LCE3B/C-del correlated with a higher beta-diversity in the skin and oral microbiota. From these results, we conclude that all late cornified envelope proteins possess antimicrobial activity. Tissue-specific and genotype-dependent antimicrobial protein profiles impact skin and oral microbiota composition, which could direct toward LCE3B/C-del‒associated dysbiosis and a possible role for microbiota in the pathophysiology of psoriasis.