Dopamine was first described by George Barger, James Ewens, and Henry Dale in 1910 as an epinephrine-like monoamine compound. Initially believed to be a mere precursor of norepinephrine, it was mostly ignored for the next four decades (Figure 1A). However, in the 1950s Kathleen Montagu showed that dopamine occurred in the brain by itself, and a series of studies by Arvid Carlsson and collaborators demonstrated that dopamine is a bona fide neurotransmitter, a finding that would earn Carlsson the 2000 Nobel Prize in Physiology and Medicine. In a landmark experiment, he pharmacologically blocked all dopamine neurotransmission in rabbits, which rendered them completely paralyzed, and then fully recovered their behavior with an injection of the dopamine precursor L-DOPA, demonstrating that dopamine was essential for self-initiated movement (Figure 1B). A similar effect was quickly reproduced by Oleg Hornykiewicz and collaborators in human Parkinsonian patients. Within a few years, dopamine jumped from relative obscurity to being critical for life as we know it.

Ivens and Kronauer provide an overview of the farming mutualism between ants and aphids, in which ants protect aphids in exchange for food.

Interview with Ralf Reski, who works on fundamental and applied issues using moss plants.

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Because the expression of pain in babies' cries is based on universal acoustic features, it is assumed that adult listeners should be able to detect when a crying baby is experiencing pain1-3. We report that detecting that a baby's cry expresses pain actually requires learning through experience. Our psychoacoustic experiments reveal that adults with no experience of caring for babies are unable to identify whether a baby's cry is a pain cry induced by vaccination or a mild discomfort cry recorded during a bath, even when they are familiar with the discomfort cries from this particular baby. In contrast, people with prior experience of babies - parents or professional caregivers - identify a familiar baby's pain cries without having heard these cries before. Parents of very young children are even able to identify the pain cries of a baby who is completely unfamiliar to them. Exposure through caregiving and/or parenting thus shapes the auditory and cognitive abilities involved in decoding the information conveyed by the baby's communication signals.

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A foundational pressure in the evolution of all animals is the ability to travel through the world, inherently coupling the sensory and motor systems. While this relationship has been explored in several species,1-4 it has been largely overlooked in primates, which have typically relied on paradigms in which head-restrained subjects view stimuli on screens.5 Natural visual behaviors, by contrast, are typified by locomotion through the environment guided by active sensing as animals explore and interact with the world,4,6 a relationship well illustrated by prey capture.7-12 Here, we characterized prey capture in wild marmoset monkeys as they negotiated their dynamic, arboreal habitat to illustrate the inherent role of vision as an active process in natural nonhuman primate behavior. Not only do marmosets share the core properties of vision that typify the primate Order,13-18 but they are prolific hunters that prey on a diverse set of prey animals.19-22 Marmosets pursued prey using vision in several different contexts, but executed precise visually guided motor control that predominantly involved grasping with hands for successful capture of prey. Applying markerless tracking for the first time in wild primates yielded novel findings that precisely quantified how marmosets track insects prior to initiating an attack and the rapid visually guided corrections of the hands during capture. These findings offer the first detailed insight into the active nature of vision to guide multiple facets of a natural goal-directed behavior in wild primates and can inform future laboratory studies of natural primate visual behaviors and the supporting neural processes.

Symbiotic systems vary in the degree to which the partners are bound to each other1. At one extreme, there are intracellular endosymbionts in mutually obligate relationships with their host, often interpreted as mutualistic. The symbiosis between the betaproteobacterium Polynucleobacter and the ciliate Euplotes (clade B) challenges this view2: although freshwater Euplotes species long ago became dependent on endosymbionts, the many extant Polynucleobacter lineages they harbour arose recently and in parallel from different free-living ancestors2. The host requires the endosymbionts for reproduction and survival3, but each newly established symbiont is ultimately driven to extinction in a cycle of establishment, degeneration, and replacement. Similar replacement events have been observed in sap-feeding insects4-6, a model for bacteria-eukaryote symbioses7, but usually only affect a small subset of the host populations. Most insects retain an ancient coevolving symbiont, suggesting that long-term mutualism and permanent integration remain the rule and symbiont turnovers are mere evolutionary side-stories. Here we show that this is not the case for Euplotes. We examined all known essential Euplotes symbionts and found that none are ancient or coevolving; rather, all are recently established and continuously replaced over relatively short evolutionary time spans, making the symbiosis ancient for the host but not for any bacterial lineage.

Iron is critical in host-microbe interactions, and its availability is tightly regulated in the mammalian gut. Antibiotics and inflammation can perturb iron availability in the gut, which could alter host-microbe interactions. Here, we show that an adaptive allele of iscR, a major regulator of iron homeostasis of Escherichia coli, is under fluctuating selection in the mouse gut. In vivo competitions in immune-competent, immune-compromised, and germ-free mice reveal that the selective pressure on an iscR mutant E. coli is modulated by the presence of antibiotics, the microbiota, and the immune system. In vitro assays show that iron availability is an important mediator of the iscR allele fitness benefits or costs. We identify Lipocalin-2, a host's immune protein that prevents bacterial iron acquisition, as a major host mechanism underlying fluctuating selection of iscR. Our results provide a remarkable example of strong fluctuating selection acting on bacterial iron regulation in the mammalian gut.

Comment in Curr Biol. 2022 Aug 8;32(15):R839-R841.

Supervolcanoes are volcanoes capable of mega-colossal eruptions that emit more than 1,000 km3 of ash and other particles.1 The earth's most recent mega-colossal eruption was the Oruanui eruption of the Taupo supervolcano 25,580 years before present (YBP) on the central North Island of New Zealand.2 This eruption blanketed major swaths of the North Island in thick layers of ash and igneous rock,2,3 devastating habitats and likely causing widespread population extinctions.4-7 An additional devastating super-colossal eruption (>100 km3) of the Taupo supervolcano occurred approximately 1,690 YBP.8 The impacts of such massive but ephemeral natural disasters on contemporary population genetic structure remain underexplored. Here, we combined data for 4,951 SNPs with spatially explicit demographic and coalescent models within an approximate Bayesian computation framework to test the drivers of genetic structure in brown kiwi (Apteryx mantelli). Our results strongly support the importance of eruptions of the Taupo supervolcano in restructuring pre-existing geographic patterns of population differentiation and genetic diversity. Range shifts due to climatic oscillations-a frequent explanation for genetic structure9-are insufficient to fully explain the empirical data. Meanwhile, recent range contraction and fragmentation due to historically documented anthropogenic habitat alteration adds no explanatory power to our models. Our results support a major role for cycles of destruction and post-volcanic recolonization in restructuring the population genomic landscape of brown kiwi and highlight how ancient and ephemeral mega-disasters may leave a lasting legacy on patterns of intraspecific genetic variation.

Animals often display prosocial behaviors, performing actions that benefit others. Although prosociality is essential for social bonding and cooperation, we still know little about how animals integrate behavioral cues from those in need to make decisions that increase their well-being. To address this question, we used a two-choice task where rats can provide rewards to a conspecific in the absence of self-benefit and investigated which conditions promote prosociality by manipulating the social context of the interacting animals. Although sex or degree of familiarity did not affect prosocial choices in rats, social hierarchy revealed to be a potent modulator, with dominant decision-makers showing faster emergence and higher levels of prosocial choices toward their submissive cage mates. Leveraging quantitative analysis of multimodal social dynamics prior to choice, we identified that pairs with dominant decision-makers exhibited more proximal interactions. Interestingly, these closer interactions were driven by submissive animals that modulated their position and movement following their dominants and whose 50-kHz vocalization rate correlated with dominants' prosociality. Moreover, Granger causality revealed stronger bidirectional influences in pairs with dominant focals and submissive recipients, indicating increased behavioral coordination. Finally, multivariate analysis highlighted body language as the main information dominants use on a trial-by-trial basis to learn that their actions have effects on others. Our results provide a refined understanding of the behavioral dynamics that rats use for action-selection upon perception of socially relevant cues and navigate social decision-making.

Woody plant material represents a vast renewable resource that has the potential to produce biofuels and other bio-based products with favorable net CO2 emissions.1,2 Its potential has been demonstrated in a recent study that generated novel structural materials from flexible moldable wood.3 Apple rubbery wood (ARW) disease is the result of a viral infection that causes woody stems to exhibit increased flexibility.4 Although ARW disease is associated with the presence of an RNA virus5 known as apple rubbery wood virus (ARWV), how the unique symptoms develop is unknown. We demonstrate that the symptoms of ARWV infections arise from reduced lignification within the secondary cell wall of xylem fibers and result in increased wood digestibility. In contrast, the mid-lamellae region and xylem ray cells are largely unaffected by the infection. Gene expression and proteomic data from symptomatic xylem clearly show the downregulation of phenylalanine ammonia lyase (PAL), the enzyme catalyzing the first committed step in the phenylpropanoid pathway leading to lignin biosynthesis. A large increase in soluble phenolics in symptomatic xylem, including the lignin precursor phenylalanine, is also consistent with PAL downregulation. ARWV infection results in the accumulation of many host-derived virus-activated small interfering RNAs (vasiRNAs). PAL-derived vasiRNAs are among the most abundant vasiRNAs in symptomatic xylem and are likely the cause of reduced PAL activity. Apparently, the mechanism used by the virus to alter lignin exhibits similarities to the RNAi strategy used to alter lignin in genetically modified trees to generate comparable improvements in wood properties.6-8.

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Comment in Curr Biol. 2022 Aug 8;32(15):R833-R836.

Color pattern polymorphism occurs when more than one form is found within the same population. It is widespread in a variety of taxa, leading us to ask what maintains this variation. One stabilizing mechanism is negative frequency-dependent selection, also known as apostatic selection, in which the fitness of a phenotype decreases with its frequency.1-6 Negative frequency-dependent selection has been proposed as one of the most powerful selective forces in maintaining phenotypic and genetic diversity in both plant and animal populations.1,5 Despite its importance and experimental evidence,1,2,6 no study has documented that natural selection due to predation may result in negative frequency-dependent selection in a wild undisturbed vertebrate population. Here, we report the results of a long-term study, spanning 37 years from 1984 to 2020, of two distinct color morphs, zigzag and melanistic, within a population of adult adders (Vipera berus) on the island of Hallands Väderö in southern Sweden (Figure 1). Our results strongly suggest that the color pattern polymorphism is maintained by negative frequency-dependent natural selection in both males and females.

Light is a crucial exogenous signal sensed by cryptochrome (CRY) blue light receptors to modulate growth and the circadian clock in plants and animals. However, how CRYs interpret light quantity to regulate growth in plants remains poorly understood. Furthermore, CRY2 protein levels and activity are tightly regulated in light to fine-tune hypocotyl growth; however, details of the mechanisms that explain precise control of CRY2 levels are not fully understood. We show that in Arabidopsis, UBP12 and UBP13 deubiquitinases physically interact with CRY2 in light. UBP12/13 negatively regulates CRY2 by promoting its ubiquitination and turnover to modulate hypocotyl growth. Growth and development were explicitly affected in blue light when UBP12/13 were disrupted or overexpressed, indicating their role alongside CRY2. UBP12/13 also interacted with and stabilized COP1, which is partially required for CRY2 turnover. Our combined genetic and molecular data support a mechanistic model in which UBP12/13 interact with CRY2 and COP1, leading to the stabilization of COP1. Stabilized COP1 then promotes the ubiquitination and degradation of CRY2 under blue light. Despite decades of studies on deubiquitinases, the knowledge of how their activity is regulated is limited. Our study provides insight into how exogenous signals and ligands, along with their receptors, regulate deubiquitinase activity by protein-protein interaction. Collectively, our results provide a framework of cryptochromes and deubiquitinases to detect and interpret light signals to control plant growth at the most appropriate time.

Secreted neuromodulators, like biogenic amines and neuropeptides, can reconfigure circuit functions both locally and at a distance and establish global brain states that alter circuit outputs over prolonged timescales.1-3 Despite their diversity and ubiquitous presence, many studies on neuromodulation tend to focus on dissecting the function and site of action of individual neuropeptides. Here, we take a different approach by conducting a systems-level investigation of neuropeptide receptor signaling function and cell-type-specific distribution in the context of the Caenorhabditis elegans diapause entry developmental decision. C. elegans diapause entry is controlled by sensory perception of external factors and is regulated by neuropeptide signaling.4-8 We performed a comprehensive functional screen of neuropeptide receptor mutants for pheromone-induced diapause entry phenotypes and integrated these results with published C. elegans single-cell RNA-seq data to reveal that almost all neuron classes expressed at least one receptor with a role in diapause entry.9 Our receptor expression analysis also identified four highly modulated neural hubs with no previously reported roles in diapause entry that are distributed throughout the animal's body, possibly as a means of synchronizing the whole-organism transition into the appropriate larval morph. Furthermore, most neuron classes expressed unique neuropeptide receptor repertoires that have opposing effects on the diapause entry decision. We propose that brain-wide antagonistic neuropeptide modulation of individual neuron classes by distinct neuropeptide receptor subsets could serve as a strategy against overmodulation and that this motif might generalize to other decision-making paradigms in other organisms.

The ability to inhibit or adapt unwanted actions or movements is a critical feature of almost all forms of behavior. Many have attributed this ability to frontal brain areas such as the anterior cingulate cortex (ACC) and the medial prefrontal cortex (mPFC), but the exact contribution of each brain region is often debated because their functions are not examined in animals performing the same task. Recently, we have shown that ACC signals a need for cognitive control and is crucial for the adaptation of action selection signals in dorsomedial striatum (DMS) in rats performing a stop-change task. Here, we show that unlike ACC, the prelimbic region of mPFC does not disrupt the inhibition or adaption of an action plan at either the level of behavior or downstream firing in DMS. Instead, lesions to mPFC correlate with changes in DMS signals involved in action initiation and disrupt performance on GO trials while improving performance on STOP trials.

Associative memory formation and recall in the fruit fly Drosophila melanogaster is subserved by the mushroom body (MB). Upon arrival in the MB, sensory information undergoes a profound transformation from broadly tuned and stereotyped odorant responses in the olfactory projection neuron (PN) layer to narrowly tuned and nonstereotyped responses in the Kenyon cells (KCs). Theory and experiment suggest that this transformation is implemented by random connectivity between KCs and PNs. However, this hypothesis has been challenging to test, given the difficulty of mapping synaptic connections between large numbers of brain-spanning neurons. Here, we used a recent whole-brain electron microscopy volume of the adult fruit fly to map PN-to-KC connectivity at synaptic resolution. The PN-KC connectome revealed unexpected structure, with preponderantly food-responsive PN types converging at above-chance levels on downstream KCs. Axons of the overconvergent PN types tended to arborize near one another in the MB main calyx, making local KC dendrites more likely to receive input from those types. Overconvergent PN types preferentially co-arborize and connect with dendrites of αβ and α'β' KC subtypes. Computational simulation of the observed network showed degraded discrimination performance compared with a random network, except when all signal flowed through the overconvergent, primarily food-responsive PN types. Additional theory and experiment will be needed to fully characterize the impact of the observed non-random network structure on associative memory formation and recall.

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Microbial eukaryotes display a stunning diversity of feeding strategies, ranging from generalist predators to highly specialized parasites. The unicellular "protoplast feeders" represent a fascinating mechanistic intermediate, as they penetrate other eukaryotic cells (algae and fungi) like some parasites but then devour their cell contents by phagocytosis.1 Besides prey recognition and attachment, this complex behavior involves the local, pre-phagocytotic dissolution of the prey cell wall, which results in well-defined perforations of species-specific size and structure.2 Yet the molecular processes that enable protoplast feeders to overcome cell walls of diverse biochemical composition remain unknown. We used the flagellate Orciraptor agilis (Viridiraptoridae, Rhizaria) as a model protoplast feeder and applied differential gene expression analysis to examine its penetration of green algal cell walls. Besides distinct expression changes that reflect major cellular processes (e.g., locomotion and cell division), we found lytic carbohydrate-active enzymes that are highly expressed and upregulated during the attack on the alga. A putative endocellulase (family GH5_5) with a secretion signal is most prominent, and a potential key factor for cell wall dissolution. Other candidate enzymes (e.g., lytic polysaccharide monooxygenases) belong to families that are largely uncharacterized, emphasizing the potential of non-fungal microeukaryotes for enzyme exploration. Unexpectedly, we discovered various chitin-related factors that point to an unknown chitin metabolism in Orciraptor agilis, potentially also involved in the feeding process. Our findings provide first molecular insights into an important microbial feeding behavior and new directions for cell biology research on non-model eukaryotes.

Biologists have forever sought to understand how species arise and persist. Historically, species that rarely interbreed, or are reproductively isolated, were considered the norm, while those with incomplete reproductive isolation were considered less common. Over the last few decades, advances in genomics have transformed our understanding of the frequency of gene flow between species and with it our ideas about reproductive isolation in nature. These advances have uncovered a rich and often complicated history of genetic exchange between species - demonstrating that such genetic introgression is an important evolutionary process widespread across the tree of life (Figure 1).

Interview with Rod Peakall, who studies the evolution of specialised pollinator interactions at the Australian National University.

Gustv Hellström and colleagues introduce acoustic telemetry used to track movements and behaviors of aquatic animals.

Comment in Curr Biol. 2022 Aug 22;32(16):R876-R879.

Comparative whole-genome analyses hold great power to illuminate commonalities and differences in the evolution of related species that share similar ecologies. The mustelid subfamily Lutrinae includes 13 currently recognized extant species of otters,1-5 a semiaquatic group whose evolutionary history is incompletely understood. We assembled a dataset comprising 24 genomes from all living otter species, 14 of which were newly sequenced. We used this dataset to infer phylogenetic relationships and divergence times, to characterize patterns of genome-wide genealogical discordance, and to investigate demographic history and current genomic diversity. We found that genera Lutra, Aonyx, Amblonyx, and Lutrogale form a coherent clade that should be synonymized under Lutra, simplifying the taxonomic structure of the subfamily. The poorly known tropical African Aonyx congicus and the more widespread Aonyx capensis were found to be reciprocally monophyletic (having diverged 440,000 years ago), supporting the validity of the former as a distinct species. We observed variable changes in effective population sizes over time among otters within and among continents, although several species showed similar trends of expansions and declines during the last 100,000 years. This has led to different levels of genomic diversity assessed by overall heterozygosity, genome-wide SNV density, and run of homozygosity burden. Interestingly, there were cases in which diversity metrics were consistent with the current threat status (mostly based on census size), highlighting the potential of genomic data for conservation assessment. Overall, our results shed light on otter evolutionary history and provide a framework for further in-depth comparative genomic studies targeting this group.

In the internet era, the digital architecture that keeps us connected and informed may also amplify the spread of misinformation. This problem is gaining global attention, as evidence accumulates that misinformation may interfere with democratic processes and undermine collective responses to environmental and health crises1,2. In an increasingly polluted information ecosystem, understanding the factors underlying the generation and spread of misinformation is becoming a pressing scientific and societal challenge3. Here, we studied the global spread of (mis-)information on spiders using a high-resolution global database of online newspaper articles on spider-human interactions, covering stories of spider-human encounters and biting events published from 2010-20204. We found that 47% of articles contained errors and 43% were sensationalist. Moreover, we show that the flow of spider-related news occurs within a highly interconnected global network and provide evidence that sensationalism is a key factor underlying the spread of misinformation.

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Venomous animals utilize venom glands to secrete and store powerful toxins for intraspecific and/or interspecific antagonistic interactions, implying that tissue-specific resistance is essential for venom glands to anatomically separate toxins from other tissues. Here, we show the mechanism of tissue-specific resistance in centipedes (Scolopendra subspinipes mutilans), where the splice variant of the receptor repels its own toxin. Unlike the well-known resistance mechanism by mutation in a given exon, we found that the KCNQ1 channel is highly expressed in the venom gland as a unique splice variant in which the pore domain and transmembrane domain six, partially encoded by exon 6 (rather than 7 as found in other tissues), contain eleven mutated residues. Such a splice variant is sufficient to gain resistance to SsTx (a lethal toxin for giant prey capture) in the venom gland due to a partially buried binding site. Therefore, the tissue-specific KCNQ1 modification confers resistance to the toxins, establishing a safe zone in the venom-storing/secreting environment.

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In humans, tear volume increases during emotional arousal. To our knowledge, no previous studies have investigated the relationship between emotional arousal and tear volume in animals. We performed the Schirmer tear test (STT) and measured tear volume in dogs before and after reunions with owners and familiar non-owners. Tear volume increased significantly during reunion with the owner, but not with a familiar non-owner. When an oxytocin solution was applied to dogs' eyes, the tear volume also increased, suggesting that oxytocin might mediate tear secretion during owner-dog reunions. Finally, human participants rated their impressions on photos of dogs with or without artificial tears and they assigned more positive scores to the photos with artificial tears. These results suggest that emotion-elicited tears can facilitate human-dog emotional connections. VIDEO ABSTRACT.

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During development, all animals undergo major adaptations to accommodate behavioral flexibility and diversity. How these adaptations are reflected in the changes in the motor circuits controlling our behaviors remains poorly understood. Here, we show, using a combination of techniques applied at larval and adult zebrafish stages, that the pattern-generating V0d inhibitory interneurons within the locomotor circuit undergo a developmental switch in their role. In larvae, we show that V0d interneurons have a primary function in high-speed motor behavior yet are redundant for explorative swimming. By contrast, adult V0d interneurons have diversified into speed-dependent subclasses, with an overrepresentation of those active at the slowest speeds. The ablation of V0d interneurons in adults disrupts slow explorative swimming, which is associated with a loss of mid-cycle inhibition onto target motoneurons. Thus, we reveal a developmental switch in V0d interneuron function from a role in high-speed motor behavior to a function in timing and thus coordinating slow explorative locomotion. Our study suggests that early motor circuit composition is not predictive of the adult system but instead undergoes major functional transformations during development.

The duplication of genes and their associated cis-regulatory elements, or enhancers, is a key contributor to genome evolution and biological complexity. Moreover, many paralogs, particularly tandem duplicates, are fixed for long periods of time under the control of shared enhancers. However, in most cases, the mechanism by which gene expression and function diverge following duplication is not known. Here, we dissect the regulation and function of the paralogous nubbin/pdm2 genes during wing development in Drosophila melanogaster. We show that these paralogs play a redundant role in the wing and that their expression relies on a single shared wing enhancer. However, the two genes differ in their ability to respond to this enhancer, with nub responding in all wing progenitor cells and pdm2 only in a small subset. This divergence is a result of a pdm2-specific silencer element at the pdm2 promoter that receives repressive input from the transcription factor Rotund. Repression through this silencer also depends on nub, allowing pdm2 to fully respond to the wing enhancer when nub expression is perturbed and functional compensation to occur. Thus, expression divergence downstream of a shared enhancer arises as a consequence of silencing the promoter of one paralog.

The hippocampus occupies a central role in mammalian navigation and memory. Yet an understanding of the rules that govern the statistics and granularity of the spatial code, as well as its interactions with perceptual stimuli, is lacking. We analyzed CA1 place cell activity recorded while rats foraged in different large-scale environments. We found that place cell activity was subject to an unexpected but precise homeostasis-the distribution of activity in the population as a whole being constant at all locations within and between environments. Using a virtual reconstruction of the largest environment, we showed that the rate of transition through this statistically stable population matches the rate of change in the animals' visual scene. Thus, place fields near boundaries were small but numerous, while in the environment's interior, they were larger but more dispersed. These results indicate that hippocampal spatial activity is governed by a small number of simple laws and, in particular, suggest the presence of an information-theoretic bound imposed by perception on the fidelity of the spatial memory system.

Comment in Curr Biol. 2022 Aug 22;32(16):R884-R886.

The wiring architecture of neuronal networks is assumed to be a strong determinant of their dynamical computations. An ongoing effort in neuroscience is therefore to generate comprehensive synapse-resolution connectomes alongside brain-wide activity maps. However, the structure-function relationship, i.e., how the anatomical connectome and neuronal dynamics relate to each other on a global scale, remains unsolved. Systematically, comparing graph features in the C. elegans connectome with correlations in nervous system-wide neuronal dynamics, we found that few local connectivity motifs and mostly other non-local features such as triplet motifs and input similarities can predict functional relationships between neurons. Surprisingly, quantities such as connection strength and amount of common inputs do not improve these predictions, suggesting that the network's topology is sufficient. We demonstrate that hub neurons in the connectome are key to these relevant graph features. Consistently, inhibition of multiple hub neurons specifically disrupts brain-wide correlations. Thus, we propose that a set of hub neurons and non-local connectivity features provide an anatomical substrate for global brain dynamics.

Comment in Curr Biol. 2022 Aug 22;32(16):R884-R886.

Abnormal/cancerous cells within healthy epithelial tissues undergo apical extrusion to protect against carcinogenesis, although they acquire invasive capacity once carcinogenesis progresses. However, the molecular mechanisms by which cancer cells escape from apical extrusion and invade surrounding tissues remain elusive. In this study, we demonstrate a molecular mechanism for cell fate switching during epithelial cell competition. We found that during competition within epithelial cell layers, Src transformation promotes maturation of focal adhesions and degradation of extracellular matrix. Src-transformed cells underwent basal delamination by Src activation within sphingolipid/cholesterol-enriched membrane microdomains/lipid rafts, whereas they were apically extruded when Src was outside of lipid rafts. A comparative analysis of contrasting phenotypes revealed that activation of the Src-STAT3-MMP axis through lipid rafts was required for basal delamination. CUB-domain-containing protein 1 (CDCP1) was identified as an Src-activating scaffold and as a Met regulator in lipid rafts, and its overexpression induced basal delamination. In renal cancer models, CDCP1 promoted epithelial-mesenchymal transition-mediated invasive behavior by activating the Src-STAT3-MMP axis through Met activation. Overall, these results suggest that spatial activation of Src signaling in lipid rafts confers resistance to apical extrusion and invasive potential on epithelial cells to promote carcinogenesis.

Comment in Curr Biol. 2022 Aug 22;32(16):R886-R889.

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Wound healing entails a fine balance between re-epithelialization and inflammation1,2 so that the risk of infection is minimized, tissue architecture is restored without scarring, and the epithelium regains its ability to withstand mechanical forces. How the two events are orchestrated in vivo remains poorly understood, largely due to the experimental challenges of simultaneously addressing mechanical and molecular aspects of the damage response. Here, exploiting Drosophila's genetic tractability and live imaging potential, we uncover a dual role for Piezo-a mechanosensitive channel involved in calcium influx3-during re-epithelialization and inflammation following injury in vivo. We show that loss of Piezo leads to faster wound closure due to increased wound edge intercalation and exacerbated myosin cable heterogeneity. Moreover, we show that loss of Piezo leads to impaired inflammation due to lower epidermal calcium levels and, subsequently, insufficient damage-induced ROS production. Despite initially appearing beneficial, loss of Piezo is severely detrimental to the long-term effectiveness of repair. In fact, wounds inflicted on Piezo knockout embryos become a permanent point of weakness within the epithelium, leading to impaired barrier function and reduced ability of wounded embryos to survive. In summary, our study uncovers a role for Piezo in regulating epithelial cell dynamics and immune cell responsiveness during damage repair in vivo. We propose a model whereby Piezo acts as molecular brake during wound healing, slowing down closure to ensure activation of sustained inflammation and re-establishment of a fully functional epithelial barrier.

Phylogenomic analyses have boosted our understanding of the evolutionary trajectories of all living forms by providing continuous improvements to the tree of life.1-5 Within this tree, fungi represent an ancient eukaryote group,6 having diverged from the animals ∼1.35 billion years ago.7 Estimates of the number of extant species range between 1.5 and 3.8 million.8,9 Recent reclassifications and the discovery of the deep-branching Sanchytriomycota lineage10 have brought the number of proposed phyla to 20,11 21 if the Microsporidia are included.12-14 Uncovering how the diverse and globally distributed fungi are related to each other is fundamental for understanding how their lifestyles, morphologies, and metabolic capacities evolved. To date, many of the proposed relationships among the phyla remain controversial and no phylogenomic study has examined the entire fungal tree using a taxonomically comprehensive dataset and suitable models of evolution. We assembled and curated a 299-protein dataset with a taxon sampling broad enough to encompass all recognized fungal diversity with available data, but selective enough to run computationally intensive analyses using best-fitting models. Using a range of reconstruction methods, we were able to resolve many contested nodes, such as a sister relationship of Chytridiomyceta to all other non-Opisthosporidia fungi (with Chytridiomycota being sister to Monoblepharomycota + Neocallimastigomycota), a branching of Blastocladiomycota + Sanchytriomycota after the Chytridiomyceta but before other non-Opisthosporidia fungi, and a branching of Glomeromycota as sister to the Dikarya. Our up-to-date fungal tree of life will serve as a springboard for future investigations on the early evolution of fungi.

Comment in Curr Biol. 2022 Aug 22;32(16):R889-R891.

Adaptive behavior requires flexible control over learning and exploitation of potentially viable options. Within a particular task, careful learning of strategies that differ from the initially learned rule is especially important as it sets an individual's strategy repertoire. However, whether and how such strategy updating is mediated by specific brain networks has remained unclear. Retrosplenial cortex (RSC), a cortical area exhibiting extensive connectivity to dorso-medial striatum (DMS) and the hippocampal formation, has been broadly implicated in flexible learning and might be involved in strategy updating. Here, we investigate the specific role of mouse RSC in flexible learning, map relevant RSC-anchored cortico-thalamo-basal ganglia circuits, and dissect their role in strategy updating. Activity in RSC was neither required for initial rule learning nor to switch between previously learned rules but was specifically required to explore and learn new alternative options when previous ones were available but no longer appropriate. Such strategy updating depended on activity in RSC c-Fos+ ensembles associated with the original rule and on their connections to DMS and thalamic parafascicular nucleus (PF) neurons. At the circuit level, rule-related RSC projection neurons branched to innervate both DMS and PF neurons and mediated strategy updating through a RSC-DMS-substantia nigra reticulata (SNr)-PF network, coupling alternative exploration to outcome. In addition, a separate RSC-PF-RSC looped network promoted alternative exploration. Our results uncover cortico-basal ganglia-thalamo and cortico-thalamo networks involving subpopulations of neurons in RSC and PF that specifically control and implement strategy updating.

Shock waves are supersonic high-amplitude pressure waves that cause barotrauma when they transfer kinetic energy to the tissues of animals.1-4 Snapping shrimp (Alpheidae) produce shock waves and are exposed to them frequently, so we asked if these animals have evolved mechanisms of physical protection against them. Snapping shrimp generate shock waves by closing their snapping claws rapidly enough to form cavitation bubbles that release energy as an audible "snap" and a shock wave when they collapse.5-8 We tested if snapping shrimp are protected from shock waves by a helmet-like extension of their exoskeleton termed the orbital hood. Using behavioral trials, we found shock wave exposure slowed shelter-seeking and caused a loss of motor control in Alpheus heterochaelis from which we had removed orbital hoods but did not significantly affect behavior in shrimp with unaltered orbital hoods. Shock waves thus have the potential to harm snapping shrimp but may not do so under natural conditions because of protection provided to shrimp by their orbital hoods. Using pressure recordings, we discovered the orbital hoods of A. heterochaelis dampen shock waves. Sealing the anterior openings of orbital hoods diminished how much they altered the magnitudes of shock waves, which suggests these helmet-like structures dampen shock waves by trapping and expelling water so that kinetic energy is redirected and released away from the heads of shrimp. Our results indicate orbital hoods mitigate blast-induced neurotrauma in snapping shrimp by dampening shock waves, making them the first biological armor system known to have such a function. VIDEO ABSTRACT.