Mycorrhizal-mediated uptake of 33P by plants was maintained regardless of aphid presence or elevated [CO2], meaning insect herbivory drove asymmetry in carbon for nutrient exchange between symbionts. Here, we provide direct evidence that external biotic C sinks can limit plant C allocation to an AM fungus without hindering mycorrhizal-acquired nutrient uptake. Our findings highlight the context dependency of resource exchange between plants and AM fungi and suggest biotic factors-individually and in combination with abiotic factors-should be considered as powerful regulators of symbiotic function. Crown All rights reserved.Evolutionary theory expects social, communicative species to eavesdrop most on other species' alarm calls [e.g., 1, 2] but also that solitary-living species benefit most from eavesdropping [3, 4]. Examples of solitary species responding to the alarm calls of other species, however, are limited and unconvincing [3-5]. The Swahili name for the red-billed oxpecker (Buphagus erythrorynchus) is Askari wa kifaru, the rhinos' guard [6]. Black rhino (Diceros bicornis) are a solitary-living, non-vocal species and are critically endangered through hunting. We searched Hluhluwe-iMfolozi Park, South Africa, for rhinoceros for 27 months with and without the aid of radio telemetry and conducted 86 experimental, unconcealed approaches to 11 rhino, without or with varying numbers of resident oxpecker. Oxpeckers enabled rhinos to evade detection by us in 40% to 50% of encounters. Alarm-calling by oxpeckers significantly improved the rate and distance that rhinos detected our approach from 23% to 100% and 27 ± 6 m to 61 ± 4 m, respectively. Every additional oxpecker improved detection distance by 9 m. Rhinos alerted by oxpeckers' alarm calls never re-oriented in our direction but moved to face downwind. Thus, oxpeckers' calls communicate only threat proximity, not direction, and rhinos assume the hunter is stalking from downwind. We confirm that oxpeckers guard rhinos and the importance of depredation, not sociality, in the evolution of eavesdropping [4, 7]. Conservationists should consider reintroducing oxpeckers to rhino populations, reinstating their anti-human sentinel [8]. VIDEO ABSTRACT. Disease progression in many tumor types involves the interaction of genetically abnormal cancer cells with normal stromal cells. Neoplastic transformation in a Drosophila genetic model of epidermal growth factor receptor (EGFR)-driven tumorigenesis similarly relies on the interaction between epithelial and mesenchymal cells, providing a simple system to investigate mechanisms used for the cross-talk. Using the Drosophila model, we show that the transformed epithelium hijacks the mesenchymal cells through Notch signaling, which prevents their differentiation and promotes proliferation. A key downstream target in the mesenchyme is Zfh1/ZEB. When Notch or zfh1 are depleted in the mesenchymal cells, tumor growth is compromised. The ligand Delta is highly upregulated in the epithelial cells where it is found on long cellular processes. By using a live transcription assay in cultured cells and by depleting actin-rich processes in the tumor epithelium, we provide evidence that signaling can be mediated by cytonemes from Delta-expressing cells. We, thus, propose that high Notch activity in the unmodified mesenchymal cells is driven by ligands produced by the cancerous epithelial. This long-range Notch signaling integrates the two tissues to promote tumorigenesis, by co-opting a normal regulatory mechanism that prevents the mesenchymal cells from differentiating. The ability of bees and ants to learn long visually guided routes in complex environments is perhaps one of the most spectacular pieces of evidence for the impressive power of their small brains. Whereas flying bees can visit flowers in an optimized sequence over kilometers, walking solitary foraging ants can precisely recapitulate routes of up to 100 m in complex environments [1]. It is clear that route following depends largely on learned visual information and we have a good idea of how visual memories can guide individuals along them [2-6], as well as how this is implemented in the insect brain [7, 8]. However, little is known about the mechanisms that control route learning and development. Here we show that ants (Melophorus bagoti and Cataglyphis fortis) navigating in their natural environments can actively learn a route detour to avoid a pit trap. This adaptive flexibility depends on a mechanism of aversive learning based on memory traces of recently encountered stimuli, reflecting the laboratory paradigm of trace conditioning. The views experienced before falling into the trap become associated with the ensuing negative outcome and thus trigger salutary turns on the subsequent trip. This drives the ants to orient away from the goal direction and avoid the trap. If the pit trap is avoided, the novel views experienced during the detour become positively reinforced and the new route crystallizes. We discuss how such an interplay between appetitive and aversive memories might be implemented in insect neural circuitry. While recombination is widely recognized to be a key modulator of numerous evolutionary phenomena, we have a poor understanding of how recombination rate itself varies and evolves within a species. Here, we performed a comprehensive study of recombination rate (rate of meiotic crossing over) in two natural populations of Drosophila pseudoobscura from Utah and Arizona, USA. We used an amplicon sequencing approach to obtain high-quality genotypes in approximately 8,000 individual backcrossed offspring (17 mapping populations with roughly 530 individuals each), for which we then quantified crossovers. Interestingly, variation in recombination rate within and between populations largely manifested as differences in genome-wide recombination rate rather than remodeling of the local recombination landscape. Comparing populations, we discovered individuals from the Utah population displayed on average 8% higher crossover rates than the Arizona population, a statistically significant difference. Using a QST-FST analysis, we found that this difference in crossover rate was dramatically higher than expected under neutrality, indicating that this difference may have been driven by natural selection. Finally, using a combination of short- and long-read whole-genome sequencing, we found no significant association between crossover rate and structural variation at the 200-400 kb scale. Our results demonstrate that (1) there is abundant variation in genome-wide crossover rate in natural populations, (2) at the 200-400 kb scale, recombination rate appears to vary largely genome-wide, rather than in specific intervals, and (3) interpopulation differences in recombination rate may be the result of local adaptation. BACKGROUND (+)-SJ000557733 (SJ733) is a novel, orally bioavailable inhibitor of Plasmodium falciparum ATP4. In this first-in-human and induced blood-stage malaria phase 1a/b trial, we investigated the safety, tolerability, pharmacokinetics, and antimalarial activity of SJ733 in humans. METHODS The phase 1a was a single-centre, dose-escalation, first-in-human study of SJ733 allowing modifications to dose increments and dose-cohort size on the basis of safety and pharmacokinetic results. The phase 1a took place at St Jude Children's Research Hospital and at the University of Tennessee Clinical Research Center (Memphis, TN, USA). Enrolment in more than one non-consecutive dose cohort was allowed with at least 14 days required between doses. Participants were fasted in seven dose cohorts and fed in one 600 mg dose cohort. Single ascending doses of SJ733 (75, 150, 300, 600, 900, or 1200 mg) were administered to participants, who were followed up for 14 days after SJ733 dosing. Phase 1a primary endpoints were safett common adverse events were related to malaria. Based on parasite clearance half-life, the derived log10PRR48 and corresponding parasite clearance half-lives were 2·2 (95% CI 2·0-2·5) and 6·47 h (95% CI 5·88-7·18) for 150 mg, and 4·1 (3·7-4·4) and 3·56 h (3·29-3·88) for 600 mg. https://www.selleckchem.com/products/Rapamycin.html INTERPRETATION The favourable pharmacokinetic, tolerability, and safety profile of SJ733, and rapid antiparasitic effect support its development as a fast-acting component of combination antimalarial therapy. FUNDING Global Health Innovative Technology Fund, Medicines for Malaria Venture, and the American Lebanese Syrian Associated Charities. The trace elements iron and selenium play decisive roles in a distinct form of necrotic cell death, known as ferroptosis. While iron promotes ferroptosis by contributing to Fenton-type reactions and uncontrolled lipid autoxidation, the hallmark of ferroptosis, selenium in the form of glutathione peroxidase 4 (GPX4), subdues phospholipid peroxidation and associated cell death. Beyond the canonical cystine/glutamate antiporter system xc-/glutathione/GPX4 nexus, recent studies unveiled the second mainstay in ferroptosis entailing extra-mitochondrial ubiquinone, ferroptosis suppressor protein 1, and NAD(P)H as electron donor. Unlike GPX4, this selenium- and thiol-independent system acts on the level of peroxyl radicals in membranes, thereby restraining lipid peroxidation. Therefore, ferroptosis is a multifaceted cell-death paradigm characterized by several metabolic networks, whereby metabolic dyshomeostasis may cause ferroptotic cell death and organ failure. Here, we discuss the basic features of ferroptosis with a focus on selenium, offering exciting opportunities to control diseases linked to ferroptosis, including transient ischemia/reperfusion and neurodegeneration. Redox balance is essential for normal brain, hence dis-coordinated oxidative reactions leading to neuronal death, including programs of regulated death, are commonly viewed as an inevitable pathogenic penalty for acute neuro-injury and neurodegenerative diseases. Ferroptosis is one of these programs triggered by dyshomeostasis of three metabolic pillars iron, thiols, and polyunsaturated phospholipids. This review focuses on (1) lipid peroxidation (LPO) as the major instrument of cell demise, (2) iron as its catalytic mechanism, and (3) thiols as regulators of pro-ferroptotic signals, hydroperoxy lipids. Given the central role of LPO, we discuss the engagement of selective and specific enzymatic pathways versus random free radical chemical reactions in the context of the phospholipid substrates, their biosynthesis, intracellular location, and related oxygenating machinery as participants in ferroptotic cascades. link2 These concepts are discussed in the light of emerging neuro-therapeutic approaches controlling intracellular production of pro-ferroptotic phospholipid signals and their non-cell-autonomous spreading, leading to ferroptosis-associated necroinflammation. Ferroptosis is a non-apoptotic mode of regulated cell death that is iron and lipid peroxidation dependent. As new mechanistic insight into ferroptotic effectors and how they are regulated in different disease contexts is uncovered, our understanding of the physiological and pathological relevance of this mode of cell death continues to grow. Along these lines, a host of pharmacological modulators of this pathway have been identified, targeting proteins involved in iron homeostasis; the generation and reduction of lipid peroxides; or cystine import and glutathione metabolism. Also, of note, many components of the ferroptosis cascade are target genes of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), indicating its critical role in mediating the ferroptotic response. link3 In this review, we discuss the in vitro, in vivo, and clinical evidence of ferroptosis in disease, including a brief discussion of targeting upstream mediators of this cascade, including NRF2, to treat ferroptosis-driven diseases.