eLife

The lateral line system enables all fishes and aquatic-stage amphibians to detect local water movement via mechanosensory hair cells in neuromasts, and many species to detect weak electric fields via electroreceptors (modified hair cells) in ampullary organs. Both neuromasts and ampullary organs develop from lateral line placodes. However, the molecular mechanisms underpinning ampullary organ formation are understudied relative to neuromasts, as the ancestral lineages of zebrafish (teleosts) and Xenopus (frogs) independently lost electroreception. We identified Bmp5 as a promising candidate via differential RNA-seq in an electroreceptive ray-finned fish, the Mississippi paddlefish (Polyodon spathula; Modrell et al., 2017, eLife 6: e24197). In an experimentally tractable relative, the sterlet sturgeon (Acipenser ruthenus), we found that Bmp5 and four other Bmp pathway genes are expressed in the developing lateral line, and that Bmp signalling is active. Furthermore, CRISPR/Cas9-mediated mutagenesis targeting Bmp5 in G0-injected sterlet embryos resulted in fewer ampullary organs. Conversely, when Bmp signalling was inhibited by DMH1 treatment shortly before the formation of ampullary organ primordia, supernumerary ampullary organs developed. These data suggest that Bmp5 promotes ampullary organ development, whereas Bmp signalling via another ligand(s) prevents their overproduction. Taken together, this demonstrates two opposing roles for Bmp signalling during ampullary organ formation.

Sharks (Selachimorpha) are iconic marine predators that have survived multiple mass extinctions over geologic time. Their fossil record is represented by an abundance of teeth, which traditionally formed the basis for reconstructing large-scale diversity changes among different selachimorph clades. By contrast, corresponding patterns in shark ecology, as measured through morphological disparity, have received comparatively limited analytical attention. Here, we use a geometric morphometric approach to comprehensively examine the dental morphology of multiple shark lineages traversing the catastrophic end-Cretaceous mass extinction -- this event terminated the Mesozoic Era 66 million years ago. Our results show that selachimorphs maintained virtually static levels of dental disparity in most of their constituent clades during the Cretaceous/Paleogene transition. Nevertheless, selective extinctions did impact on apex predator lineages characterized by triangular blade-like teeth, and in particular, lamniforms including the dominant Cretaceous anacoracids. Other groups, such as, triakid carcharhiniforms, squalids, and hexanchids, were seemingly unaffected. Finally, while some lamniform lineages experienced morphological depletion, others underwent a post-extinction disparity increase, especially odontaspidids, which are typified by narrow-cusped teeth adapted for feeding on fishes. This disparity shift coincides with the early Paleogene radiation of teleosts, a possible prey source, as well as the geographic relocation of shark disparity hotspots, perhaps indicating a regionally disjunct pattern of extinction recovery. Ultimately, our study reveals a complex morphological response to the end-Cretaceous mass extinction event, the dynamics of which we are only just beginning to understand.

Mice are increasingly used to study the neural circuit-level basis of behavior, often with the ultimate goal of extrapolating these insights to humans. To generalize insights about neural functioning across species, it is crucial to ensure correspondence in behavioral and cognitive strategy. We previously showed that human observers evidence accumulation is biased by previous choices (Urai et al., 2019). To replicate these findings across species, we fit Diffusion Decision Models (Fengler et al., 2025) to behavioral data from 62 mice performing a standardized perceptual decision-making task (The International Brain Laboratory et al., 2021). We identified the same cognitive strategy of history-dependent evidence accumulation: individual differences in choice repetition were explained by a history-dependent bias in the rate of evidence accumulation rather than its starting point. We argue that history-biased evidence integration reflects a fundamental aspect of perceptual decision-making, that may transcend the specific species.

Like in many voltage-gated K+ channels (Kv), inactivation of the cardiac Kv7.1 channel is voltage-dependent but does not exhibit the hallmarks of N-type or C-type mechanisms. This peculiar inactivation is observed in wild-type channels and is exacerbated in many Kv7.1 mutations triggering cardiac arrhythmias. Previously, we showed that Kv7.1 inactivation could strikingly be prevented by Ca2+-calmodulin (Ca2+-CaM). Thus, how can Ca2+-CaM, localized at the channel inner boundaries, prevent inactivation that occurs distantly at the outer pore region and converges to the selectivity filter? Here, using network analysis, molecular dynamics simulations, and electrophysiology, we identify the inactivation paths coupling the voltage sensor domain to the selectivity filter, involving helices S1 and S6, and the P-Helix, which represents the underlying mechanism of Kv7.1 inactivation. Moreover, our data reveal the allosteric coupling mechanisms by which Ca2+-CaM signals interfere with the inactivation paths and prevent channel inactivation.

Studies of climate variation commonly rely on chemical and isotopic changes recorded in sequentially-produced growth layers, such as in corals, shells and tree rings, as well as in accretionary deposits--ice and sediment cores, and speleothems. Oxygen isotopic compositions ({delta}18O) of tooth enamel are a direct method of reconstructing environmental variation experienced by an individual animal. Here we utilize long-forming orangutan dentitions (Pongo spp.) to probe recent and ancient rainfall trends on a weekly basis over [~] 3-11 years per individual. We first demonstrate the lack of any consistent isotopic enrichment effect during exclusive nursing, supporting the use of primate first molar teeth as environmental proxies. Comparisons of {delta}18O values (n = 2016) in twelve molars from six modern Bornean and Sumatran orangutans reveal a high degree of overlap, with more consistent annual and bimodal rainfall patterns in the Sumatran individuals. Comparisons with fossil orangutan {delta}18O values (n = 955 measurements from six molars) reveal similarities between modern and late Pleistocene fossil Sumatran individuals, but differences between modern and late Pleistocene/early Holocene Bornean orangutans. These suggest drier and more open environments with reduced monsoon intensity during this earlier period in northern Borneo, consistent with other Niah Caves studies and long-term speleothem {delta}18O records in the broader region. This approach can be extended to test hypotheses about the paleoenvironments that early humans encountered in southeast Asia.

Any assessment of whether or not Saccharum species are native or introduced in New Guinea require an evolutionary (in a geological sense), geophysical and climatological assessment of the island. Like many of the land masses circling the Pacific (in the volcanically active region known as the ring of fire) New Guinea is geologically young, with the island in its modern form not pre-dating 2 Ma. Novel modelling of the 74 ka youngest Toba supereruption indicates a potential extinction level tsunami and loss of habitat. The late Pleistocene megafaunal mass extinction and the last glacial maximum (33-16 ka) are two global effects that would have significantly altered the flora on New Guinea; though the implications of these events on New Guinea have not previously been studied. Even if the genus Saccharum was established on the island during pre-historic times the consequences of Toba and other global climate change events means that it would have been eliminated from New Guinea and would have had to be re-introduced during the period of human colonization. Indeed, given the evolution of Saccharums immediate ancestors in Africa and Indochina it is most parsimonious to conclude that it was never native to New Guinea, but was introduced by humans relatively recently. Little work has been done on palaeotsunami evidence and ancient tsunami modelling in New Guinea. However, the recent recognition that the Aitape skull (dating to about 6 ka) may have been the victim of a tsunami (Goff et al. 2017) show that, in the past, tsunami have pen etrated significantly (about 10 km in this case) into the interior of the island to have a profound effect on biodiversity. This tsunami would have left the north coast of the island impoverished of plant life for several decades after.

The paradigm postulating that tissue stable isotopic ratios ({delta}tissue) equal those of the diet ({delta}diet) plus a small, quasi-constant isotope discrimination factor {Delta} emerged in the late 1970s, establishing stable isotope analysis as a dietary proxy. Today, this framework is still widely used across multiple branches of science, despite growing contradicting evidence. Here, we reanalysed several well-controlled laboratory experiments and universally found that {Delta} not only varies strongly with{delta} diet, but also changes sign at a certain{delta} eq ={delta} diet ={delta} tissue value, which we term the {Delta}-equilibrium. The {Delta}-equilibrium phenomenon results from the sub-unity slope of the linear regression between{delta} diet and{delta} tissue and leads to converging of{delta} tissue values. The most frequently observed position of the {Delta}-equilibrium on the ({delta}13C,{delta} 15N) plane is (-21{+/-}1{per thousand}, 12{+/-}1{per thousand}). These findings firmly establish that stable isotopes are not neutral spectators but active participants in biochemical processes. If presented evidence holds in a much broader study, the paradigm{delta} tissue ={delta} food + {Delta} can finally be retired after half a century of service, being replaced by{delta} tissue = ax{delta}food + Const, where a is the newly defined isotope assimilation factor. The {Delta}-equilibrium position is then found as{delta} eq = Const/(1 - a). The reason for isotope convergence remains a subject for future research, but likely hypotheses include evolutionary adaptation and isotopic resonance.

The authors have withdrawn their manuscript after issues with the cell viability validation (Fig. 8) were found. In the interest of furthering science and ensuring that clinical decisions are based on best practices and evidence, the issue is described in more detail in the peer-reviewed, published paper: https://www.frontiersin.org/articles/10.3389/fphys.2021.647603/full Knothe Tate ML, Srikantha A, Wojek C, Zeidler D (2021) Connectomics of Bone to Brain-- Probing Physical Renderings of Cellular Experience, Frontiers in Physiology 12: 1018, doi: 10.3389/fphys.2021.647603 As noted in that published work: "Osteocyte coordinates can be extracted from the YOLO classified image set, enabling high throughput analyses of massive datasets, which in the future could include other cellular inhabitants of tissues including blood cells, immune cells, chondrocytes, etc. While the method shows great promise for automated detection of cells, the greatest limitation of the method is the definition of appropriate and unbiased classifiers. The definition of osteocytes as pyknotic and viable based on the number of cell processes was shown to be flawed in a parallel study testing the assumption using biochemical based viability measures (Anastopolous and Knothe Tate, 2021)." Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

A lack of temporal context for paleoecological data from molluscan death assemblages (DAs) makes integrating them with monitoring data from living communities to inform habitat management difficult. Here we illustrate this challenge by documenting the spatial and stratigraphic variability in age and time-averaging of oyster reef death assemblages. We radiocarbon dated a total of 573 oyster shells from samples of two burial depths on 28 oyster reefs around Florida and found 1) that spatial and stratigraphic variability in DA sample ages and time-averaging are of similar magnitude, and 2) that the shallow oyster reef DAs are among the youngest and highest-resolution molluscan DAs documented to-date, with most having time-averaging estimates of decades or less. This information increases the potential usefulness of the DAs for habitat management because measured indicators can be placed in temporal context relative to monitoring data. More broadly, the results highlight the potential to obtain decadal-scale resolution from oyster bioherms in the fossil record.

ABSTRACTImage-forming compound eyes are such a valuable adaptation that similar visual systems have evolved independently across crustaceans. But if different compound eye types have evolved independently multiple times, how useful are eye structures and ommatidia morphology for resolving phylogenetic relationships? Crabs are ideal study organisms to explore these questions because they have a good fossil record extending back into the Jurassic, they possess a great variety of optical designs, and details of eye form can be compared between extant and fossil groups. True crabs, or Brachyura, have been traditionally divided into two groups based on the position of the sexual openings in males and females: the so-called ‘Podotremata’ (females bearing their sexual openings on the legs), and the Eubrachyura, or ‘higher’ true crabs (females bearing their sexual openings on the thorax). Although Eubrachyura appears to be monophyletic, the monophyly of podotreme crabs remains controversial and therefore requires exploration of new character systems. The earliest podotremous lineages share the plesiomorphic condition of ‘mirror’ reflecting superposition eyes with most shrimp, lobsters, and anomurans (false crabs and allies). The optical mechanisms of fossil and extant podotreme groups more closely related to Eubrachyura, however, are still poorly investigated. To better judge the phylogenetic utility of compound eye form, we investigated the distribution of eye types in fossil and extant podotreme crabs. Our findings suggest the plesiomorphic ‘mirror’ eyes—seen in most decapod crustaceans including the earliest true crabs—has been lost in several ‘higher’ podotremes and in eubrachyurans. We conclude that the secondary retention of larval apposition eyes has existed in eubrachyurans and some podotremes since at least the Early Cretaceous, and that the distribution of eye types among true crabs supports a paraphyletic podotreme grade, as suggested by recent molecular and morphological phylogenetic studies. We also review photoreceptor structure and visual pigment evolution, currently known in crabs exclusively from eubrachyuran representatives. These topics are critical for future expansion of research on podotremes to deeply investigate the homology of eye types across crabs.View Full Text

The development of multicellular organisms requires proper interplays between cell-autonomous genetic programs controlled by combinations of transcription factors that regulate the differentiation of distinct cell populations and non-cell autonomous processes that coordinate the proliferation, the fate, the survival, the respective location, and the proper interactions of these populations. During the development of the nervous system, non-cell autonomous mechanisms determine neuronal fate, survival, distribution, axon guidance, and connectivity. Although similar processes are suggested to be at work in the formation of spinal motor circuits, the molecular mechanisms involved remain mostly elusive. Here, we provide evidence that the Onecut transcription factors regulate a non-cell autonomous mechanism that modulate pre-motor interneuron development. We show that conditional inactivation of the Onecut factors in spinal motor neurons affects the differentiation and the positioning of pre-motor interneuron populations. We identify that Neurotrophin-3 produced by motor neurons under the control of the Onecut factors non-cell autonomously regulate the production and the distribution of pre-motor interneuron populations. Thus, we elucidated one of the non-cell autonomous mechanisms that coordinate the formation of the spinal motor circuits.

Repetition of a specific movement biases subsequent actions towards the recently practiced movement, a phenomenon referred to as use-dependent learning (UDL). UDL has been attributed to shifts in the tuning of neurons in the motor cortex. However, recent studies employing a forced reaction time task, including the eLife article by Marinovic et al (2017), indicate that these biases may also arise from a contaminated motor plan, one that is biased towards the practiced direction. We advanced this line of inquiry, seeking to establish the relative contribution of execution and planning processes to UDL in a center-out reaching task in which participants were able to initiate movements of their own volition. On most trials, the target appeared at a designated "frequent" location; on other trials, the target appeared at one of six "rare" locations. In Experiment 1, participants exhibited a robust movement bias towards the frequent target when movements were self-initiated quickly, but a small movement bias when movements were self-initiated slowly - the signature of a contaminated motor plan. Strikingly, the heading angles were bimodally distributed, with one peak at the frequent target location and the other at the rare target location - a finding reinforced by a re-analysis of two widely cited studies on UDL. Notably, the latter peak was shifted in the frequently practiced direction, a signature of a motor execution bias. To eliminate the contribution of planning-related UDL, we imposed a delay between target onset and movement initiation in Experiment 2. As predicted, the heading angles became unimodally distributed around the rare target. The peak of this distribution was again shifted towards the location of the frequent target, indicative of a persistent bias in motor execution. Taken together, these results highlight two distinct components of UDL even when movements are self-initiated: First, the temporal dynamics underlying movement planning, in which a default plan is progressively overridden by a new plan, produces a pronounced motor planning bias. Second, there is a small, temporally stable bias that may reflect shifts in motor unit tuning.

Loss-of-function mutations in Kv7.1 often lead to long QT syndrome (LQTS), a cardiac repolarization disorder associated with increased risk of arrhythmia and subsequent sudden cardiac death. The discovery of agonistic IKs modulators may offer a new potential strategy in pharmacological treatment of this disorder. The benzodiazepine (R)-L3 potently activates Kv7.1 channels and shortens action potential duration, thus may represent a starting point for drug development. However, the molecular mechanisms underlying modulation by (R)-L3 are still unknown. By combining alanine scanning mutagenesis, non-canonical amino acid incorporation, voltage-clamp electrophysiology and fluorometry, and in silico protein modelling, we showed that (R)-L3 not only stimulates currents by allosteric modulation of the pore domain but also alters the kinetics independently from the pore domain effects. We identified novel (R)-L3-interacting key residues in the lower S4-segment of Kv7.1 and observed an uncoupling of the outer S4 segment with the inner S5, S6 and selectivity filter segments. Summarizing, we provide structural and functional evidence for two independent Kv7.1 activating mechanisms by a single modulator.

Ontogenetic change is a major source of phenotypic variation among members of a species and is often of greater magnitude than the anatomical differences that distinguish closely related species. Ontogeny has therefore become a problematic confounding variable in vertebrate paleontology, especially in study systems distant from extant crown clades, rendering taxonomic hypothesis testing (a fundamental process in evolutionary biology) rife with difficulty. Paleontologists have adopted quantitative methods to compensate for the perception that juvenile specimens lack diagnostic apomorphies seen in their adult conspecifics. Here, I critically evaluate these methods and the assumptions that guide their interpretation using a {micro}CT dataset comprising growth series of American and Chinese alligator. I find that several widespread assumptions are scientifically unjustifiable, and that two popular methods - geometric morphometrics and cladistic analysis of ontogeny - have unacceptably high rates of type II error and present numerous procedural difficulties. However, I also identify a suite of ontogenetically invariant characters that differentiate the living species of Alligator throughout ontogeny. These characters overwhelmingly correspond to anatomical systems that develop prior to (and play a signaling role in) the development of the cranial skeleton itself, suggesting that their ontogenetic invariance is a consequence of the widely conserved vertebrate developmental program. These observations suggest that the architecture of the cranium is fixed early in embryonic development, and that ontogenetic remodeling does not alter the topological relationships of the cranial bones or the soft tissue structures they house. I propose a general model for future taxonomic hypothesis tests in the fossil record, in which the hypothesis that two specimens different ontogenetic stages of a single species can be falsified by the discovery of character differences that cannot be attributed plausibly to ontogenetic variation.

Chloroquine and hydroxychloroquine (H)CQ are well known anti-malarial drugs, while their use against COVID-19 is more controversial. (H)CQ activity was examined in tissue culture cells to determine if their anti-viral benefits or adverse effects might be due to altering host cell pathways. Metabolic analysis revealed (H)CQ inhibit oxidative phosphorylation in mitochondria, likely by sequestering protons needed to drive ATP synthase. This activity could cause cardiotoxicity because heart muscle relies on beta oxidation of fatty acids. However, it might also explain their therapeutic benefit against COVID-19. A new model of SARS-CoV-2 infection postulates virus enters host cell mitochondria and uses its protons for genome release. Oxidative phosphorylation is eventually compromised, so glycolysis is upregulated to maintain ATP levels. (H)CQ could prevent viral infection and/or slow its replication by sequestering these protons. In support of this model other potential COVID-19 therapeutics also targeted mitochondria, as did tobacco smoke, which may underlie smokers protection. The mitochondria of young people are naturally more adaptable and resilient, providing a rationale for their resistance to disease progression. Conversely, obesity and diabetes could exacerbate disease severity by providing extra glucose to infected cells dependent on glycolysis. The description of (H)CQ function presented here, together with its implications for understanding SARS-CO-V2 infection, makes testable predictions about disease progression and identifies new approaches for treating COVID-19.

Fertilization of an egg by more than one sperm presents one of the earliest and most prevalent obstacles to successful reproduction. As such, eggs employ multiple mechanisms to prevent sperm entry into the nascent zygote. The fast block to polyspermy is a depolarization of the egg membrane initiated by sperm entry and is employed by diverse external fertilizers including frogs and sea urchins. For some external fertilizers, sperm entry is associated with actin polymerization during the initiation of the fast block. We therefore sought to determine whether the fast block to polyspermy in the African clawed frog, Xenopus laevis, requires actin polymerization. Although actin polymerization is required for sperm entry into eggs from diverse external fertilizers, including sea urchins and zebrafish, here we demonstrate that actin polymerization is not required for the fast block to polyspermy in X. laevis.Competing Interest StatementThe authors have declared no competing interest.View Full Text

CaMKII plays a critical role in long-term potentiation (LTP), a well-established model for learning and memory through the enhancement of synaptic transmission. Biochemical studies indicate that CaMKII catalyzes a phosphotransferase (kinase) reaction of both itself (autophosphorylation) and of multiple downstream target proteins. However, whether either type of phosphorylation plays any role in the synaptic enhancing action of CaMKII remains hotly contested. We have designed a series of experiments to define the minimal requirements for the synaptic enhancement by CaMKII. We find that autophosphorylation of T286 and further binding of CaMKII to the GluN2B subunit are required both for initiating LTP and for its maintenance (synaptic memory). Once bound to the NMDA receptor, the synaptic action of CaMKII occurs in the absence of kinase activity. Thus, autophosphorylation, together with binding to the GluN2B subunit, are the only two requirements for CaMKII in synaptic memory.

The COVID-19 pandemic is a national tragedy, one that has focused our attention on both the need to improve science education and the need to confront systemic racism in our country. We know that active learning strategies, in particular research experiences, can engage and empower STEM undergraduates, effectively closing the achievement gap for historically excluded persons. The apprenticeship model for STEM training - supervised research under a dedicated mentor - is highly effective, but out of reach for most students. Recent efforts have demonstrated that Course-based Undergraduate Research Experiences (CUREs) can be an effective approach for making STEM research accessible for all. Our meta-analysis of CUREs finds that published examples now cover the breadth of the typical undergraduate biology curriculum. A thoughtfully designed CURE can go beyond foundational knowledge and analytical thinking to include career-related skills, e.g., teamwork and communication. Similarly, it can be designed with equity as a foundational principle, taking into account the unique contributions of all students and their varying needs. We provide here an example framework (The "Do Science Framework") for making STEM training more effective and inclusive using CUREs. While CUREs do not inherently address equity, there can be no equity in STEM education without equal access to research participation, and progress toward this goal can be achieved using CUREs. However, implementing new CUREs is not a trivial undertaking, particularly at schools with high teaching loads and little or no research infrastructure, including many community colleges. We therefore propose a National Center for Science Engagement to support this transition, building on experiences of current nationally established CUREs as well as the work of many individual faculty. In the aftermath of the COVID-19 pandemic, academia has a renewed responsibility to dismantle structural inequities in education; engaging all STEM students in research can be a key step.

Pavlovian influences notoriously interfere with operant behaviour; various such may be associated with the release of the neuromodulator dopamine in the nucleus accumbens. One role for cognitive control is suppressing these influences. Here, using the examples of active avoidance and omission behaviour, we examine the possibility that one instrument of control is direct manipulation of the dopamine signal itself.

A central principle of synaptic transmission is that action potential-induced presynaptic neurotransmitter release occurs exclusively via Ca2+-dependent secretion (CDS). The discovery and mechanistic investigations of Ca2+-independent but voltage-dependent secretion (CiVDS) have demonstrated that the action potential per se is sufficient to trigger neurotransmission in the somata of primary sensory and sympathetic neurons in mammals. One key question remains, however, whether CiVDS contributes to central synaptic transmission. Here we report, in the central transmission from presynaptic (dorsal root ganglion) to postsynaptic (spinal dorsal horn) neurons, (1) excitatory postsynaptic currents (EPSCs) are mediated by glutamate transmission through both CiVDS (up to 87%) and CDS; (2) CiVDS-EPSCs are independent of extracellular and intracellular Ca2+; (3) CiVDS is >100 times faster than CDS in vesicle recycling with much less short-term depression; (4) the fusion machinery of CiVDS includes Cav2.2 (voltage sensor) and SNARE (fusion pore). Together, an essential component of activity-induced EPSCs is mediated by CiVDS in a central synapse.