A cAMP signalosome in primary cilia drives gene expression and kidney cyst formation.

The primary cilium constitutes an organelle that orchestrates signal transduction independently from the cell body. Dysregulation of this intricate molecular architecture leads to severe human diseases, commonly referred to as ciliopathies. However, the molecular underpinnings how ciliary signaling orchestrates a specific cellular output remain elusive. By combining spatially resolved optogenetics with RNA sequencing and imaging, we reveal a novel cAMP signalosome that is functionally distinct from the cytoplasm. We identify the genes and pathways targeted by the ciliary cAMP signalosome and shed light on the underlying mechanisms and downstream signaling. We reveal that chronic stimulation of the ciliary cAMP signalosome transforms kidney epithelia from tubules into cysts. Counteracting this chronic cAMP elevation in the cilium by small molecules targeting activation of phosphodiesterase-4 long isoforms inhibits cyst growth. Thereby, we identify a novel concept of how the primary cilium controls cellular functions and maintains tissue integrity in a specific and spatially distinct manner and reveal novel molecular components that might be involved in the development of one of the most common genetic diseases, polycystic kidney disease.

The rostral micro-tooth morphology of blue marlin, Makaira nigricans.

Billfish rostra potentially have several functions; however, their role in feeding is unequivocal in some species. Recent work linked morphological variation in rostral micro-teeth to differences in feeding behavior in two billfish species, the striped marlin (Kajikia audax) and the sailfish (Istiophorus platypterus). Here, we present the rostral micro-tooth morphology for a third billfish species, the blue marlin (Makaira nigricans), for which the use of the rostrum in feeding behavior is still undocumented from systematic observations in the wild. We measured the micro-teeth on rostrum tips of blue marlin, striped marlin, and sailfish using a micro-computed tomography approach and compared the tooth morphology among the three species. This was done after an analysis of video-recorded hunting behavior of striped marlin and sailfish revealed that both species strike prey predominantly with the first third of the rostrum, which provided the justification to focus our analysis on the rostrum tips. In blue marlin, intact micro-teeth were longer compared to striped marlin but not to sailfish. Blue marlin had a higher fraction of broken teeth than both striped marlin and sailfish, and broken teeth were distributed more evenly on the rostrum. Micro-tooth regrowth was equally low in both marlin species but higher in sailfish. Based on the differences and similarities in the micro-tooth morphology between the billfish species, we discuss potential feeding-related rostrum use in blue marlin. We put forward the hypothesis that blue marlin might use their rostra in high-speed dashes as observed in striped marlin, rather than in the high-precision rostral strikes described for sailfish, possibly focusing on larger prey organisms.

Leveraging big data to uncover the eco-evolutionary factors shaping behavioural development.

Mapping the eco-evolutionary factors shaping the development of animals' behavioural phenotypes remains a great challenge. Recent advances in 'big behavioural data' research-the high-resolution tracking of individuals and the harnessing of that data with powerful analytical tools-have vastly improved our ability to measure and model developing behavioural phenotypes. Applied to the study of behavioural ontogeny, the unfolding of whole behavioural repertoires can be mapped in unprecedented detail with relative ease. This overcomes long-standing experimental bottlenecks and heralds a surge of studies that more finely define and explore behavioural-experiential trajectories across development. In this review, we first provide a brief guide to state-of-the-art approaches that allow the collection and analysis of high-resolution behavioural data across development. We then outline how such approaches can be used to address key issues regarding the ecological and evolutionary factors shaping behavioural development: developmental feedbacks between behaviour and underlying states, early life effects and behavioural transitions, and information integration across development.

Self-organization and information transfer in Antarctic krill swarms.

Antarctic krill swarms are one of the largest known animal aggregations, and yet, despite being the keystone species of the Southern Ocean, little is known about how swarms are formed and maintained. Understanding the local interactions between individuals that provide the basis for these swarms is fundamental to knowing how swarms arise in nature, and what potential factors might lead to their breakdown. Here, we analysed the trajectories of captive, wild-caught krill in 3D to determine individual-level interaction rules and quantify patterns of information flow. Our results demonstrate that krill align with near neighbours and that they regulate both their direction and speed relative to the positions of groupmates. These results suggest that social factors are vital to the formation and maintenance of swarms. Furthermore, krill operate a novel form of collective organization, with measures of information flow and individual movement adjustments expressed most strongly in the vertical dimension, a finding not seen in other swarming species. This research represents a vital step in understanding the fundamentally important swarming behaviour of krill.

The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88.

BAFF and APRIL are innate immune mediators that trigger immunoglobulin G (IgG) and IgA class-switch recombination (CSR) in B cells by engaging the receptor TACI. The mechanism that underlies CSR signaling by TACI remains unknown. Here we found that the cytoplasmic domain of TACI encompasses a conserved motif that bound MyD88, an adaptor that activates transcription factor NF-kappaB signaling pathways via a Toll-interleukin 1 (IL-1) receptor (TIR) domain. TACI lacks a TIR domain, yet triggered CSR via the DNA-editing enzyme AID by activating NF-kappaB through a Toll-like receptor (TLR)-like MyD88-IRAK1-IRAK4-TRAF6-TAK1 pathway. TACI-induced CSR was impaired in mice and humans lacking MyD88 or the kinase IRAK4, which indicates that MyD88 controls a B cell-intrinsic, TIR-independent, TACI-dependent pathway for immunoglobulin diversification.

Lacunae rostralis: A new structure on the rostrum of sailfish Istiophorus platypterus.

Recent comparative studies of billfishes (Istiophoridae and Xiphiidae) have provided evidence of differences in the form and function of the rostra (bill) among species. Here, we report the discovery of a new structure, lacuna rostralis, on the rostra of sailfish Istiophorus platypterus, which is absent on the rostra of swordfish Xiphias gladius, striped marlin Kajikia audax and blue marlin Makaira nigricans. The lacunae rostralis are small cavities that contain teeth. They were found on the ventral rostrum surface of all I. platypterus specimens examined and dorsally in half of them. Ventrally, the lacunae rostralis were most prominent in the mid-section of the rostrum. Dorsally, they occurred closer to the tip. The density of lacunae rostralis increased towards the rostrum tip but, because they are smaller in size, the percentage of rostrum coverage decreased. The teeth located within the lacunae rostralis were found to be different in size, location and orientation from the previously identified micro-teeth of billfish. We propose two potential functions of the lacunae rostralis that both relate to the use of the bill in feeding: mechanoreception of prey before tapping it with the bill and more efficient prey handling via the creation of suction, or physical grip.

Personality-driven life history trade-offs differ in two subpopulations of free-ranging predators.

Consistent individual differences in behaviour (i.e. personality) can be explained in an evolutionary context if they are favoured by life history trade-offs as conceptualized in the pace-of-life syndrome (POLS) hypothesis. Theory predicts that faster-growing individuals suffer higher mortality and that this trade-off is mediated through exploration/risk-taking personality, but empirical support for this remains limited and ambiguous. Equivocal support to the POLS hypothesis suggests that the link between life history and personality may only emerge under certain circumstances. Understanding personality-driven trade-offs would be facilitated by long-term studies in wild populations experiencing different ecological conditions. Here, we tested whether personality measured in semi-captivity was associated with a growth-mortality trade-off via risk-taking in the wild in two subpopulations of juvenile lemon sharks Negaprion brevirostris known to differ in their predator abundance. We expected stronger personality-driven trade-offs in the predator-rich environment as compared to the predator-poor environment. Sharks were captured yearly from 1995 onwards allowing us to obtain long-term data on growth and apparent survival in each subpopulation. We then used a novel open-field assay to test sharks for exploration personality yearly from 2012 to 2017. A subset of the tested sharks was monitored in the field using telemetry to document risk-taking behaviours. We tested (a) if fast explorers in captivity took more risks and grew faster in the wild and (b) if natural selection acted against more explorative, faster-growing sharks. In the subpopulation with fewer predators, more explorative sharks in captivity took more risks in the wild and grew faster. In turn, larger, fast-growing sharks had lower apparent survival. In the predator-rich subpopulation, despite finding selection on fast growth, we found no link between exploration personality and the growth-mortality trade-off. Our study demonstrates that the association between personality and life history is favoured in some ecological contexts but not in others. We identify predator and resource abundance as two main potential drivers of the personality-mediated trade-off and emphasize that future work on the POLS hypothesis would benefit from an approach integrating behaviour and life history across ecological conditions.

Parasite infection disrupts escape behaviours in fish shoals.

Many prey species have evolved collective responses to avoid predation. They rapidly transfer information about potential predators to trigger and coordinate escape waves. Predation avoidance behaviour is often manipulated by trophically transmitted parasites, to facilitate their transmission to the next host. We hypothesized that the presence of infected, behaviourally altered individuals might disturb the spread of escape waves. We used the tapeworm Schistocephalus solidus, which increases risk-taking behaviour and decreases social responsiveness of its host, the three-spined stickleback, to test this hypothesis. Three subgroups of sticklebacks were placed next to one another in separate compartments with shelter. The middle subgroup contained either uninfected or infected sticklebacks. We confronted an outer subgroup with an artificial bird strike and studied how the escape response spread through the subgroups. With uninfected sticklebacks in the middle, escape waves spread rapidly through the entire shoal and fish remained in shelter thereafter. With infected sticklebacks in the middle, the escape wave was disrupted and uninfected fish rarely used the shelter. Infected individuals can disrupt the transmission of flight responses, thereby not only increasing their own predation risk but also that of their uninfected shoal members. Our study uncovers a potentially far-reaching fitness consequence of grouping with infected individuals.

Group-level patterns emerge from individual speed as revealed by an extremely social robotic fish.

Understanding the emergence of collective behaviour has long been a key research focus in the natural sciences. Besides the fundamental role of social interaction rules, a combination of theoretical and empirical work indicates individual speed may be a key process that drives the collective behaviour of animal groups. Socially induced changes in speed by interacting animals make it difficult to isolate the effects of individual speed on group-level behaviours. Here, we tackled this issue by pairing guppies with a biomimetic robot. We used a closed-loop tracking and feedback system to let a robotic fish naturally interact with a live partner in real time, and programmed it to strongly copy and follow its partner's movements while lacking any preferred movement speed or directionality of its own. We show that individual differences in guppies' movement speed were highly repeatable and in turn shaped key collective patterns: a higher individual speed resulted in stronger leadership, lower cohesion, higher alignment and better temporal coordination of the pairs. By combining the strengths of individual-based models and observational work with state-of-the-art robotics, we provide novel evidence that individual speed is a key, fundamental process in the emergence of collective behaviour.

Females facilitate male food patch discovery in a wild fish population.

Responding to the information provided by others is an important foraging strategy in many species. Through social foraging, individuals can more efficiently find unpredictable resources and thereby increase their foraging success. When individuals are more socially responsive to particular phenotypes than others, however, the advantage they obtain from foraging socially is likely to depend on the phenotype composition of the social environment. We tested this hypothesis by performing experimental manipulations of guppy, Poecilia reticulata, sex compositions in the wild. Males found fewer novel food patches in the absence of females than in mixed-sex compositions, while female patch discovery did not differ regardless of the presence or absence of males. We argue that these results were driven by sex-dependent mechanisms of social association: Markov chain-based fission-fusion modelling revealed that less social individuals found fewer patches and that males reduced sociality when females were absent. In contrast, females were similarly social with or without males. Our findings highlight the relevance of considering how individual- and population-level traits interact in shaping the advantages of social foraging in the wild.

Boosting medical diagnostics by pooling independent judgments.

Collective intelligence refers to the ability of groups to outperform individual decision makers when solving complex cognitive problems. Despite its potential to revolutionize decision making in a wide range of domains, including medical, economic, and political decision making, at present, little is known about the conditions underlying collective intelligence in real-world contexts. We here focus on two key areas of medical diagnostics, breast and skin cancer detection. Using a simulation study that draws on large real-world datasets, involving more than 140 doctors making more than 20,000 diagnoses, we investigate when combining the independent judgments of multiple doctors outperforms the best doctor in a group. We find that similarity in diagnostic accuracy is a key condition for collective intelligence: Aggregating the independent judgments of doctors outperforms the best doctor in a group whenever the diagnostic accuracy of doctors is relatively similar, but not when doctors' diagnostic accuracy differs too much. This intriguingly simple result is highly robust and holds across different group sizes, performance levels of the best doctor, and collective intelligence rules. The enabling role of similarity, in turn, is explained by its systematic effects on the number of correct and incorrect decisions of the best doctor that are overruled by the collective. By identifying a key factor underlying collective intelligence in two important real-world contexts, our findings pave the way for innovative and more effective approaches to complex real-world decision making, and to the scientific analyses of those approaches.

Parasite-infected sticklebacks increase the risk-taking behaviour of uninfected group members.

Trophically transmitted parasites frequently increase their hosts' risk-taking behaviour, to facilitate transmission to the next host. Whether such elevated risk-taking can spill over to uninfected group members is, however, unknown. To investigate this, we confronted groups of 6 three-spined sticklebacks, Gasterosteus aculeatus, containing 0, 2, 4 or 6 experimentally infected individuals with a simulated bird attack and studied their risk-taking behaviour. As a parasite, we used the tapeworm Schistocephalus solidus, which increases the risk-taking of infected sticklebacks, to facilitate transmission to its final host, most often piscivorous birds. Before the attack, infected and uninfected individuals did not differ in their risk-taking. However, after the attack, individuals in groups with only infected members showed lower escape responses and higher risk-taking than individuals from groups with only uninfected members. Importantly, uninfected individuals adjusted their risk-taking behaviour to the number of infected group members, taking more risk with an increasing number of infected group members. Infected individuals, however, did not adjust their risk-taking to the number of uninfected group members. Our results show that behavioural manipulation by parasites does not only affect the infected host, but also uninfected group members, shedding new light on the social dynamics involved in host-parasite interactions.

How predation shapes the social interaction rules of shoaling fish.

Predation is thought to shape the macroscopic properties of animal groups, making moving groups more cohesive and coordinated. Precisely how predation has shaped individuals' fine-scale social interactions in natural populations, however, is unknown. Using high-resolution tracking data of shoaling fish (Poecilia reticulata) from populations differing in natural predation pressure, we show how predation adapts individuals' social interaction rules. Fish originating from high predation environments formed larger, more cohesive, but not more polarized groups than fish from low predation environments. Using a new approach to detect the discrete points in time when individuals decide to update their movements based on the available social cues, we determine how these collective properties emerge from individuals' microscopic social interactions. We first confirm predictions that predation shapes the attraction-repulsion dynamic of these fish, reducing the critical distance at which neighbours move apart, or come back together. While we find strong evidence that fish align with their near neighbours, we do not find that predation shapes the strength or likelihood of these alignment tendencies. We also find that predation sharpens individuals' acceleration and deceleration responses, implying key perceptual and energetic differences associated with how individuals move in different predation regimes. Our results reveal how predation can shape the social interactions of individuals in groups, ultimately driving differences in groups' collective behaviour.

Proto-cooperation: group hunting sailfish improve hunting success by alternating attacks on grouping prey.

We present evidence of a novel form of group hunting. Individual sailfish (Istiophorus platypterus) alternate attacks with other group members on their schooling prey (Sardinella aurita). While only 24% of attacks result in prey capture, multiple prey are injured in 95% of attacks, resulting in an increase of injured fish in the school with the number of attacks. How quickly prey are captured is positively correlated with the level of injury of the school, suggesting that hunters can benefit from other conspecifics' attacks on the prey. To explore this, we built a mathematical model capturing the dynamics of the hunt. We show that group hunting provides major efficiency gains (prey caught per unit time) for individuals in groups of up to 70 members. We also demonstrate that a free riding strategy, where some individuals wait until the prey are sufficiently injured before attacking, is only beneficial if the cost of attacking is high, and only then when waiting times are short. Our findings provide evidence that cooperative benefits can be realized through the facilitative effects of individuals' hunting actions without spatial coordination of attacks. Such 'proto-cooperation' may be the pre-cursor to more complex group-hunting strategies.

Laser Therapy for Bladder Outlet Obstruction: A Prospective Analysis of All Patients Receiving Treatment with the GreenLight XPS 180-Watt Laser System after Introduction at a Single Center.

OBJECTIVE: The objective was to assess and publish our first experiences with the GreenLight XPS™ 180-watt laser in men suffering from bladder outlet obstruction. PATIENTS AND METHODS: From January 2013 to February 2014, the results of 142 patients were analyzed prospectively at a single center. Indications for disobstruction were in line with current EAU guidelines, but independent of the underlying causes of obstruction. Assessments were made of the prostate size, International Prostate Symptom Score (IPSS), postvoid residual (PVR) and maximum urinary flow (Qmax). Intraoperative data such as lasing time, surgery time, applied energy and blood transfusions were recorded. Reinterventions and complications were evaluated. RESULTS: The average prostate volume was 29.6 ml (2-82). The average surgery time was 50 min (13-157). Qmax increased by an average of 20.2 ml/s (p < 0.05). On average, PVR was reduced by 162 ml (p < 0.05). CONCLUSION: The GreenLight XPS™ 180-watt laser is an effective treatment option for bladder outlet obstruction with a low perioperative complications rate, and it shows results comparable with transurethral resection of the prostate. Even multimorbid patients and patients with long-term catheter requirements may be treated due to its high safety profile and reliable results.

Hemagglutinin stalk antibodies elicited by the 2009 pandemic influenza virus as a mechanism for the extinction of seasonal H1N1 viruses.

After the emergence of pandemic influenza viruses in 1957, 1968, and 2009, existing seasonal viruses were observed to be replaced in the human population by the novel pandemic strains. We have previously hypothesized that the replacement of seasonal strains was mediated, in part, by a population-scale boost in antibodies specific for conserved regions of the hemagglutinin stalk and the viral neuraminidase. Numerous recent studies have shown the role of stalk-specific antibodies in neutralization of influenza viruses; the finding that stalk antibodies can effectively neutralize virus alters the existing dogma that influenza virus neutralization is mediated solely by antibodies that react with the globular head of the viral hemagglutinin. The present study explores the possibility that stalk-specific antibodies were boosted by infection with the 2009 H1N1 pandemic virus and that those antibodies could have contributed to the disappearance of existing seasonal H1N1 influenza virus strains. To study stalk-specific antibodies, we have developed chimeric hemagglutinin constructs that enable the measurement of antibodies that bind the hemagglutinin protein and neutralize virus but do not have hemagglutination inhibition activity. Using these chimeric hemagglutinin reagents, we show that infection with the 2009 pandemic H1N1 virus elicited a boost in titer of virus-neutralizing antibodies directed against the hemagglutinin stalk. In addition, we describe assays that can be used to measure influenza virus-neutralizing antibodies that are not detected in the traditional hemagglutination inhibition assay.

Antibody recognition of the pandemic H1N1 Influenza virus hemagglutinin receptor binding site.

Influenza virus is a global health concern due to its unpredictable pandemic potential. This potential threat was realized in 2009 when an H1N1 virus emerged that resembled the 1918 virus in antigenicity but fortunately was not nearly as deadly. 5J8 is a human antibody that potently neutralizes a broad spectrum of H1N1 viruses, including the 1918 and 2009 pandemic viruses. Here, we present the crystal structure of 5J8 Fab in complex with a bacterially expressed and refolded globular head domain from the hemagglutinin (HA) of the A/California/07/2009 (H1N1) pandemic virus. 5J8 recognizes a conserved epitope in and around the receptor binding site (RBS), and its HCDR3 closely mimics interactions of the sialic acid receptor. Electron microscopy (EM) reconstructions of 5J8 Fab in complex with an HA trimer from a 1986 H1 strain and with an engineered stabilized HA trimer from the 2009 H1 pandemic virus showed a similar mode of binding. As for other characterized RBS-targeted antibodies, 5J8 uses avidity to extend its breadth and affinity against divergent H1 strains. 5J8 selectively interacts with HA insertion residue 133a, which is conserved in pandemic H1 strains and has precluded binding of other RBS-targeted antibodies. Thus, the RBS of divergent HAs is targeted by 5J8 and adds to the growing arsenal of common recognition motifs for design of therapeutics and vaccines. Moreover, consistent with previous studies, the bacterially expressed H1 HA properly refolds, retaining its antigenic structure, and presents a low-cost and rapid alternative for engineering and manufacturing candidate flu vaccines.

Recombinant IgA is sufficient to prevent influenza virus transmission in guinea pigs.

A serum hemagglutination inhibition (HAI) titer of 40 or greater is thought to be associated with reduced influenza virus pathogenesis in humans and is often used as a correlate of protection in influenza vaccine studies. We have previously demonstrated that intramuscular vaccination of guinea pigs with inactivated influenza virus generates HAI titers greater than 300 but does not protect vaccinated animals from becoming infected with influenza virus by transmission from an infected cage mate. Only guinea pigs intranasally inoculated with a live influenza virus or a live attenuated virus vaccine, prior to challenge, were protected from transmission (A. C. Lowen et al., J. Virol. 83:2803-2818, 2009.). Because the serum HAI titer is mostly determined by IgG content, these results led us to speculate that prevention of viral transmission may require IgA antibodies or cellular immune responses. To evaluate this hypothesis, guinea pigs and ferrets were administered a potent, neutralizing mouse IgG monoclonal antibody, 30D1 (Ms 30D1 IgG), against the A/California/04/2009 (H1N1) virus hemagglutinin and exposed to respiratory droplets from animals infected with this virus. Even though HAI titers were greater than 160 1 day postadministration, Ms 30D1 IgG did not prevent airborne transmission to passively immunized recipient animals. In contrast, intramuscular administration of recombinant 30D1 IgA (Ms 30D1 IgA) prevented transmission to 88% of recipient guinea pigs, and Ms 30D1 IgA was detected in animal nasal washes. Ms 30D1 IgG administered intranasally also prevented transmission, suggesting the importance of mucosal immunity in preventing influenza virus transmission. Collectively, our data indicate that IgG antibodies may prevent pathogenesis associated with influenza virus infection but do not protect from virus infection by airborne transmission, while IgA antibodies are more important for preventing transmission of influenza viruses.

Influenza human monoclonal antibody 1F1 interacts with three major antigenic sites and residues mediating human receptor specificity in H1N1 viruses.

Most monoclonal antibodies (mAbs) to the influenza A virus hemagglutinin (HA) head domain exhibit very limited breadth of inhibitory activity due to antigenic drift in field strains. However, mAb 1F1, isolated from a 1918 influenza pandemic survivor, inhibits select human H1 viruses (1918, 1943, 1947, and 1977 isolates). The crystal structure of 1F1 in complex with the 1918 HA shows that 1F1 contacts residues that are classically defined as belonging to three distinct antigenic sites, Sa, Sb and Ca(2). The 1F1 heavy chain also reaches into the receptor binding site (RBS) and interacts with residues that contact sialoglycan receptors and determine HA receptor specificity. The 1F1 epitope is remarkably similar to the previously described murine HC63 H3 epitope, despite significant sequence differences between H1 and H3 HAs. Both antibodies potently inhibit receptor binding, but only HC63 can block the pH-induced conformational changes in HA that drive membrane fusion. Contacts within the RBS suggested that 1F1 may be sensitive to changes that alter HA receptor binding activity. Affinity assays confirmed that sequence changes that switch the HA to avian receptor specificity affect binding of 1F1 and a mAb possessing a closely related heavy chain, 1I20. To characterize 1F1 cross-reactivity, additional escape mutant selection and site-directed mutagenesis were performed. Residues 190 and 227 in the 1F1 epitope were found to be critical for 1F1 reactivity towards 1918, 1943 and 1977 HAs, as well as for 1I20 reactivity towards the 1918 HA. Therefore, 1F1 heavy-chain interactions with conserved RBS residues likely contribute to its ability to inhibit divergent HAs.

Fast and accurate decisions through collective vigilance in fish shoals.

Although it has been suggested that large animal groups should make better decisions than smaller groups, there are few empirical demonstrations of this phenomenon and still fewer explanations of the how these improvements may be made. Here we show that both speed and accuracy of decision making increase with group size in fish shoals under predation threat. We examined two plausible mechanisms for this improvement: first, that groups are guided by a small proportion of high-quality decision makers and, second, that group members use self-organized division of vigilance. Repeated testing of individuals showed no evidence of different decision-making abilities between individual fish. Instead, we suggest that shoals achieve greater decision-making efficiencies through division of labor combined with social information transfer. Our results should prompt reconsideration of how we view cooperation in animal groups with fluid membership.