Dual and opposing roles for the kinesin-2 motor, KIF17, in Hedgehog-dependent cerebellar development.

While the kinesin-2 motors KIF3A and KIF3B have essential roles in ciliogenesis and Hedgehog (HH) signal transduction, potential role(s) for another kinesin-2 motor, KIF17, in HH signaling have yet to be explored. Here, we investigated the contribution of KIF17 to HH-dependent cerebellar development, where Kif17 is expressed in both HH-producing Purkinje cells and HH-responding cerebellar granule neuron progenitors (CGNPs). Germline Kif17 deletion in mice results in cerebellar hypoplasia due to reduced CGNP proliferation, a consequence of decreased HH pathway activity mediated through decreased Sonic HH (SHH) protein. Notably, Purkinje cell-specific Kif17 deletion partially phenocopies Kif17 germline mutants. Unexpectedly, CGNP-specific Kif17 deletion results in the opposite phenotype-increased CGNP proliferation and HH target gene expression due to altered GLI transcription factor processing. Together, these data identify KIF17 as a key regulator of HH-dependent cerebellar development, with dual and opposing roles in HH-producing Purkinje cells and HH-responding CGNPs.

Nonlinear social evolution and the emergence of collective action.

Organisms from microbes to humans engage in a variety of social behaviors, which affect fitness in complex, often nonlinear ways. The question of how these behaviors evolve has consequences ranging from antibiotic resistance to human origins. However, evolution with nonlinear social interactions is challenging to model mathematically, especially in combination with spatial, group, and/or kin assortment. We derive a mathematical condition for natural selection with synergistic interactions among any number of individuals. This result applies to populations with arbitrary (but fixed) spatial or network structure, group subdivision, and/or mating patterns. In this condition, nonlinear fitness effects are ascribed to collectives, and weighted by a new measure of collective relatedness. For weak selection, this condition can be systematically evaluated by computing branch lengths of ancestral trees. We apply this condition to pairwise games between diploid relatives, and to dilemmas of collective help or harm among siblings and on spatial networks. Our work provides a rigorous basis for extending the notion of "actor", in the study of social evolution, from individuals to collectives.

A Pd-Catalyzed Annulation Strategy to Linearly Fused Functionalized N-Heterocycles.

Linearly fused polycyclic piperidines represent common substructures in natural products and biologically active small molecules. We have devised a Pd-catalyzed annulation strategy to these compounds that converts readily available 2-tetralones and indanones into these scaffolds with the potential for control of both enantio- and diastereoselectivity. Importantly, these compounds can be chemoselectively functionalized, providing an efficient and robust methodology to these important nitrogen-containing molecules.

Symmetry in models of natural selection.

Symmetry arguments are frequently used-often implicitly-in mathematical modelling of natural selection. Symmetry simplifies the analysis of models and reduces the number of distinct population states to be considered. Here, I introduce a formal definition of symmetry in mathematical models of natural selection. This definition applies to a broad class of models that satisfy a minimal set of assumptions, using a framework developed in previous works. In this framework, population structure is represented by a set of sites at which alleles can live, and transitions occur via replacement of some alleles by copies of others. A symmetry is defined as a permutation of sites that preserves probabilities of replacement and mutation. The symmetries of a given selection process form a group, which acts on population states in a way that preserves the Markov chain representing selection. Applying classical results on group actions, I formally characterize the use of symmetry to reduce the states of this Markov chain, and obtain bounds on the number of states in the reduced chain.

Trouble in paradise: When two species of conservation and cultural value clash, causing a management conundrum.

Threatened species throughout the world are in decline due to various causes. In some cases, predators of conservation or cultural value are causing the decline of threatened prey, presenting a conservation conundrum for managers. We surveyed marine turtle nests on K'gari (formally known as Fraser Island), Australia, to investigate dingo predation of green and loggerhead turtle nests, where each of these species is of conservation value. Our monitoring revealed that 84% of nests were predated by dingoes. Only 16% of nests were not consumed by dingoes, and only 5.7% of nests were confirmed to have successfully hatched. Up to 94% of nests were consumed in some areas, and predation rates were similar across different dingo packs. Information on the available numbers of nests and dingoes in the area indicated that turtle nests alone are sufficient to support extant dingoes over the summer. These results indicate that marine turtle eggs represent a previously unquantified but important food source for dingoes on K'gari, and that turtle nests at this rookery site are under serious threat from dingoes. This research should highlight the importance of prioritising the protection of turtle nests from dingoes or risk losing the entire rookery forever in the near future.

Attitudes towards the Potential Use of Aversive Geofencing Devices to Manage Wild Elephant Movement.

Aversive geofencing devices (AGDs) or animal-borne satellite-linked shock collars might become a useful tool to mitigate human-elephant conflict (HEC). AGDs have the potential to condition problem elephants to avoid human-dominated landscapes by associating mild electric shocks with preceding audio warnings given as they approach virtual boundaries. We assessed the opinions of different stakeholders (experts, farmers, and others who have and have not experienced HEC; n = 611) on the potential use of AGDs on Asian elephants. Most respondents expressed positive opinions on the potential effectiveness of AGDs in managing elephant movement (62.2%). About 62.8% respondents also provided positive responses for the acceptability of AGDs if pilot studies with captive elephants have been successful in managing their movements. Some respondents perceived AGDs to be unacceptable because they are unethical or harmful and would be unsuccessful given wild elephants may respond differently to AGDs than captive elephants. Respondents identified acceptability, support and awareness of stakeholders, safety and wellbeing of elephants, logistical difficulties, durability and reliable functionality of AGDs, and uncertainties in elephants' responses to AGDs as potential challenges for implementing AGDs. These issues need attention when developing AGDs to increase support from stakeholders and to effectively reduce HEC incidents in the future.

Why humans kill animals and why we cannot avoid it.

Killing animals has been a ubiquitous human behaviour throughout history, yet it is becoming increasingly controversial and criticised in some parts of contemporary human society. Here we review 10 primary reasons why humans kill animals, discuss the necessity (or not) of these forms of killing, and describe the global ecological context for human killing of animals. Humans historically and currently kill animals either directly or indirectly for the following reasons: (1) wild harvest or food acquisition, (2) human health and safety, (3) agriculture and aquaculture, (4) urbanisation and industrialisation, (5) invasive, overabundant or nuisance wildlife control, (6) threatened species conservation, (7) recreation, sport or entertainment, (8) mercy or compassion, (9) cultural and religious practice, and (10) research, education and testing. While the necessity of some forms of animal killing is debatable and further depends on individual values, we emphasise that several of these forms of animal killing are a necessary component of our inescapable involvement in a single, functioning, finite, global food web. We conclude that humans (and all other animals) cannot live in a way that does not require animal killing either directly or indirectly, but humans can modify some of these killing behaviours in ways that improve the welfare of animals while they are alive, or to reduce animal suffering whenever they must be killed. We encourage a constructive dialogue that (1) accepts and permits human participation in one enormous global food web dependent on animal killing and (2) focuses on animal welfare and environmental sustainability. Doing so will improve the lives of both wild and domestic animals to a greater extent than efforts to avoid, prohibit or vilify human animal-killing behaviour.

Impact of COVID-19 on 1-Year Survival Outcomes in Hepatocellular Carcinoma: A Multicenter Cohort Study.

INTRODUCTION: The COVID-19 pandemic has caused severe disruption of healthcare services worldwide and interrupted patients' access to essential services. During the first lockdown, many healthcare services were shut to all but emergencies. In this study, we aimed to determine the immediate and long-term indirect impact of COVID-19 health services utilisation on hepatocellular cancer (HCC) outcomes. METHODS: A prospective cohort study was conducted from 1 March 2020 until 30 June 2020, correlating to the first wave of the COVID-19 pandemic. Patients were enrolled from tertiary hospitals in the UK and Germany with dedicated HCC management services. All patients with current or past HCC who were discussed at a multidisciplinary meeting (MDM) were identified. Any delay to treatment (DTT) and the effect on survival at one year were reported. RESULTS: The median time to receipt of therapy following MDM discussion was 49 days. Patients with Barcelona Clinic Liver Cancer (BCLC) stages-A/B disease were more likely to experience DTT. Significant delays across all treatments for HCC were observed, but delay was most marked for those undergoing curative therapies. Even though severe delays were observed in curative HCC treatments, this did not translate into reduced survival in patients. CONCLUSION: Interruption of routine healthcare services because of the COVID-19 pandemic caused severe delays in HCC treatment. However, DTT did not translate to reduced survival. Longer follow is important given the delay in therapy in those receiving curative therapy.

Survey of Invasive Mosquito Surveillance and Control Capacity in Southeastern USA Reveals Training and Resource Needs.

Several invasive mosquito species that are nuisances or of medical and veterinary importance have been introduced into the Southeastern region of the USA, posing a threat to other species and the local ecosystems and/or increasing the risk of pathogen transmission to people, livestock, and domestic pets. Prompt and effective monitoring and control of invasive species is essential to prevent them from spreading and causing harmful effects. However, the capacity for invasive mosquito species surveillance is highly variable among mosquito control programs in the Southeast, depending on a combination of factors such as regional geography and climate, access to resources, and the ability to interact with other programs. To facilitate the development of invasive mosquito surveillance in the region, we, the Mosquito BEACONS (Biodiversity Enhancement and Control of Non-native Species) working group, conducted a survey on the capacities of various public health agencies and pest control agencies engaged in mosquito surveillance and control in seven Southeastern states (Alabama, Florida, Georgia, Louisiana, Mississippi, North Carolina, and South Carolina). Ninety control programs completed the survey, representing an overall response rate of 25.8%. We report key findings from our survey, emphasizing the training and resource needs, and discuss their implications for future invasive mosquito surveillance and control capacity building. By increasing communication and collaboration opportunities (e.g., real-time sharing of collection records, coordinated multistate programs), the establishment of Mosquito BEACONS and the implementation of this survey can accelerate knowledge transfer and improve decision support capacity in response to or in preparation for invasive mosquito surveillance and can establish infrastructure that can be used to inform programs around the world.

Developing Future Biologists: developmental biology for undergraduates from underserved communities.

Developing Future Biologists (DFB) is an inclusive, trainee-run organization that strives to excite and engage the next generation of biologists, regardless of race, gender or socioeconomic status, in the field of developmental biology. DFB offers a week-long course consisting of active lectures, hands-on laboratory sessions, and professional development opportunities through interactions with scientists from a variety of backgrounds and careers. A major goal of DFB is to propel undergraduate students from underserved communities to pursue biomedical research opportunities and advanced degrees in science. To achieve this goal, we provide DFB participants with continuing access to a diverse network of scientists that students can utilize to secure opportunities and foster success throughout multiple stages of their research careers. Here, we describe the flourishing DFB program at the University of Michigan to encourage other institutions to create their own DFB programs.

Viral transmission and infection prevalence in a cannibalistic host-pathogen system.

Cannibalism, while prevalent in the natural world, is often viewed as detrimental to a cannibal's health, especially when they consume pathogen-infected conspecifics. The argument stems from the idea that cannibalizing infected individuals increases the chance of coming into contact with a pathogen and subsequently becoming infected. Using an insect pest, the fall armyworm (Spodoptera frugiperda), that readily cannibalizes at the larval stage and its lethal pathogen, we experimentally examined how cannibalism affects viral transmission at both an individual and population level. Prior to death, the pathogen in the system stops the larval host from growing, resulting in infected individuals being smaller than healthy individuals. This leads to size-structured cannibalism of infected individuals with the larger healthy larvae consuming the smaller infected larvae, which is commonly observed. At the individual level, we show that the probability of cannibalism is relatively high for both infected and uninfected individuals especially when the cannibal is larger than the victim. However, the probability of the cannibal becoming infected given that a pathogen-infected individual has been cannibalized is relatively low. On a population level, when cannibalism is allowed to occur transmission rates decline. Additionally, by cannibalizing infected larvae, cannibals lower the infection risk for non-cannibals. Thus, cannibalism can decrease infection prevalence and, therefore, may not be as deleterious as once thought. Under certain circumstances, cannibalizing infected individuals, from the uninfected host's perspective, may even be advantageous, as one obtains a meal and decreases competition for resources with little chance of becoming infected.

Efficacy of Management Efforts to Reduce Food-Related Dingo-Human Interactions and Conflict on K'gari (Fraser Island), Australia.

Humans and dingoes (Canis familiaris (dingo)) share the environment of K'gari, and conflict inevitably occurs between the two species, particularly over food. Dingo attacks on humans have occurred, and some have been serious and even fatal in outcome. Wildlife feeding may cause animals to develop unnatural and potentially dangerous behaviours towards conspecifics and humans on a relatively frequent basis. Food-based attraction has been implicated in the development of human-directed aggression in the dingo population of K'gari. Supplemental feeding, whether intentional or accidental, alters wildlife foraging behaviours and may have consequences at the population and ecosystem levels. Management strategies such as education programs, prohibition of inappropriate human behaviours (compliance) and fencing of garbage dumps have each been implemented to stop the intentional or inadvertent feeding of dingoes by people. However, there has been no formal assessment of the effectiveness of these interventions at reducing food-related dingo-human incidents over time. We collated and analysed 7791 unique reports of dingo-human interactions on K'gari between 1990 and 2020, inclusive of 1307 food-related reports, including the severity of these interactions. These data showed clear seasonal peaks in the percentage of food-related dingo-human interactions, corresponding with biologically significant breeding periods in autumn and weaning and dispersing in spring. Trends in serious food-related incidents remained stable overtime. Less serious food-related incidents declined, suggesting that management efforts were successful. However, these efforts appear to have reached the limits of their effectiveness. Further innovations are required to reduce serious incidents involving the relatively few dingoes and people still experiencing conflict, and thereby provide protection to both species on K'gari.

CDON contributes to Hedgehog-dependent patterning and growth of the developing limb.

Hedgehog (HH) signaling is a major driver of tissue patterning during embryonic development through the regulation of a multitude of cell behaviors including cell fate specification, proliferation, migration, and survival. HH ligands signal through the canonical receptor PTCH1 and three co-receptors, GAS1, CDON and BOC. While previous studies demonstrated an overlapping and collective requirement for these co-receptors in early HH-dependent processes, the early embryonic lethality of Gas1;Cdon;Boc mutants precluded an assessment of their collective contribution to later HH-dependent signaling events. Specifically, a collective role for these co-receptors during limb development has yet to be explored. Here, we investigate the combined contribution of these co-receptors to digit specification, limb patterning and long bone growth through limb-specific conditional deletion of Cdon in a Gas1;Boc null background. Combined deletion of Gas1, Cdon and Boc in the limb results in digit loss as well as defects in limb outgrowth and long bone patterning. Taken together, these data demonstrate that GAS1, CDON and BOC are collectively required for HH-dependent patterning and growth of the developing limb.

Metagenome-assembled genome extraction and analysis from microbiomes using KBase.

Uncultivated Bacteria and Archaea account for the vast majority of species on Earth, but obtaining their genomes directly from the environment, using shotgun sequencing, has only become possible recently. To realize the hope of capturing Earth's microbial genetic complement and to facilitate the investigation of the functional roles of specific lineages in a given ecosystem, technologies that accelerate the recovery of high-quality genomes are necessary. We present a series of analysis steps and data products for the extraction of high-quality metagenome-assembled genomes (MAGs) from microbiomes using the U.S. Department of Energy Systems Biology Knowledgebase (KBase) platform ( http://www.kbase.us/ ). Overall, these steps take about a day to obtain extracted genomes when starting from smaller environmental shotgun read libraries, or up to about a week from larger libraries. In KBase, the process is end-to-end, allowing a user to go from the initial sequencing reads all the way through to MAGs, which can then be analyzed with other KBase capabilities such as phylogenetic placement, functional assignment, metabolic modeling, pangenome functional profiling, RNA-Seq and others. While portions of such capabilities are available individually from other resources, the combination of the intuitive usability, data interoperability and integration of tools in a freely available computational resource makes KBase a powerful platform for obtaining MAGs from microbiomes. While this workflow offers tools for each of the key steps in the genome extraction process, it also provides a scaffold that can be easily extended with additional MAG recovery and analysis tools, via the KBase software development kit (SDK).

Current and Future Approaches to Mitigate Conflict between Humans and Asian Elephants: The Potential Use of Aversive Geofencing Devices.

Asian elephants are a principal cause of human-wildlife conflict. This results in the death/injury of elephants and humans and large-scale crop and property damage. Most current human-elephant conflict (HEC) mitigation tools lack the flexibility to accommodate the ecological needs of elephants and are ineffective at reducing HEC in the long-term. Here we review common HEC mitigation tools used in Asia and the potential of Aversive Geofencing Devices (AGDs) to manage problem elephants. AGDs can be configured to monitor animal movements in real-time and deliver auditory warnings followed by electric stimuli whenever animals attempt to move across user-specified virtual boundaries. Thus, AGDs are expected to condition elephants to avoid receiving shocks and keep them away from virtually fenced areas, while providing alternative routes that can be modified if required. Studies conducted using AGDs with other species provide an overview of their potential in conditioning wild animals. We recommend that the efficacy and welfare impact of AGDs be evaluated using captive elephants along with public perception of using AGDs on elephants as a means of addressing the inherent deficiencies of common HEC mitigation tools. If elephants could be successfully conditioned to avoid virtual fences, then AGDs could resolve many HEC incidents throughout Asia.

Compassionate Conservation is indistinguishable from traditional forms of conservation in practice.

Animal welfare and ethics are important factors influencing wildlife conservation practice, and critics are increasingly challenging the underlying ethics and motivations supporting common conservation practices. "Compassionate Conservationists" argue that all conservationists should respect the rights of individual sentient animals and approach conservation problems from a position of compassion, and that doing so requires implementing practices that avoid direct harm to individual animals. In this way Compassionate Conservationists seek to contrast themselves with "Traditional Conservationists" who often express consequentialist decision-making processes that ostensibly aim to dispassionately minimize net animal harms, resulting in the common use of practices that directly harm or kill some animals. Conservationists and other observers might therefore conclude that the two sides of this debate are distinct and/or that their policy proscriptions produce different welfare outcomes for animals. To explore the validity of this conclusion we review the ethical philosophies underpinning two types of Compassionate Conservation-deontology and virtue ethics. Deontology focusses on animal rights or the moral duties or obligations of conservationists, whereas virtue ethics focusses on acting in ways that are virtuous or compassionate. We demonstrate that both types permit the intentional harm and killing of animals when faced with common conservation problems where animals will be harmed no matter what the conservationist does or does not do. We then describe the applied decision-making processes exhibited by Compassionate Conservationists (of both types) and Traditional Conservationists to show that they may each lead to the implementation of similar conservation practices (including lethal control) and produce similar outcomes for animals, despite the perceived differences in their ethical motivations. The widespread presence of wildlife conservation problems that cannot be resolved without causing at least some harm to some animals means that conservationists of all persuasions must routinely make trade-offs between the welfare of some animals over others. Compassionate Conservationists do this from an explicit position of animal rights and/or compassion, whereas Traditional Conservationists respect animal rights and exhibit this same compassion implicitly. These observations lead to the conclusion that Compassionate Conservation is indistinguishable from traditional forms of conservation in practice, and that the apparent disagreement among conservationists primarily concerns the effectiveness of various wildlife management practices at minimizing animal harm, and not the underlying ethics, motivations or morality of those practices.

Plexins promote Hedgehog signaling through their cytoplasmic GAP activity.

Hedgehog signaling controls tissue patterning during embryonic and postnatal development and continues to play important roles throughout life. Characterizing the full complement of Hedgehog pathway components is essential to understanding its wide-ranging functions. Previous work has identified neuropilins, established semaphorin receptors, as positive regulators of Hedgehog signaling. Neuropilins require plexin co-receptors to mediate semaphorin signaling, but the role of plexins in Hedgehog signaling has not yet been explored. Here, we provide evidence that multiple plexins promote Hedgehog signaling in NIH/3T3 mouse fibroblasts and that plexin loss of function in these cells results in significantly reduced Hedgehog pathway activity. Catalytic activity of the plexin GTPase-activating protein (GAP) domain is required for Hedgehog signal promotion, and constitutive activation of the GAP domain further amplifies Hedgehog signaling. Additionally, we demonstrate that plexins promote Hedgehog signaling at the level of GLI transcription factors and that this promotion requires intact primary cilia. Finally, we find that plexin loss of function significantly reduces the response to Hedgehog pathway activation in the mouse dentate gyrus. Together, these data identify plexins as novel components of the Hedgehog pathway and provide insight into their mechanism of action.

Combinatorial Gli activity directs immune infiltration and tumor growth in pancreatic cancer.

Proper Hedgehog (HH) signaling is essential for embryonic development, while aberrant HH signaling drives pediatric and adult cancers. HH signaling is frequently dysregulated in pancreatic cancer, yet its role remains controversial, with both tumor-promoting and tumor-restraining functions reported. Notably, the GLI family of HH transcription factors (GLI1, GLI2, GLI3), remain largely unexplored in pancreatic cancer. We therefore investigated the individual and combined contributions of GLI1-3 to pancreatic cancer progression. At pre-cancerous stages, fibroblast-specific Gli2/Gli3 deletion decreases immunosuppressive macrophage infiltration and promotes T cell infiltration. Strikingly, combined loss of Gli1/Gli2/Gli3 promotes macrophage infiltration, indicating that subtle changes in Gli expression differentially regulate immune infiltration. In invasive tumors, Gli2/Gli3 KO fibroblasts exclude immunosuppressive myeloid cells and suppress tumor growth by recruiting natural killer cells. Finally, we demonstrate that fibroblasts directly regulate macrophage and T cell migration through the expression of Gli-dependent cytokines. Thus, the coordinated activity of GLI1-3 directs the fibroinflammatory response throughout pancreatic cancer progression.