Honey bees and social wasps reach convergent architectural solutions to nest-building problems.

The hexagonal cells built by honey bees and social wasps are an example of adaptive architecture; hexagons minimize material use, while maximizing storage space and structural stability. Hexagon building evolved independently in the bees and wasps, but in some species of both groups, the hexagonal cells are size dimorphic-small worker cells and large reproductive cells-which forces the builders to join differently sized hexagons together. This inherent tiling problem creates a unique opportunity to investigate how similar architectural challenges are solved across independent evolutionary origins. We investigated how 5 honey bee and 5 wasp species solved this problem by extracting per-cell metrics from 22,745 cells. Here, we show that all species used the same building techniques: intermediate-sized cells and pairs of non-hexagonal cells, which increase in frequency with increasing size dimorphism. We then derive a simple geometric model that explains and predicts the observed pairing of non-hexagonal cells and their rate of occurrence. Our results show that despite different building materials, comb configurations, and 179 million years of independent evolution, honey bees and social wasps have converged on the same solutions for the same architectural problems, thereby revealing fundamental building properties and evolutionary convergence in construction behavior.

Programmable self-organization of heterogeneous microrobot collectives.

At the microscale, coupled physical interactions between collectives of agents can be exploited to enable self-organization. Past systems typically consist of identical agents; however, heterogeneous agents can exhibit asymmetric pairwise interactions which can be used to generate more diverse patterns of self-organization. Here, we study the effect of size heterogeneity in microrobot collectives composed of circular, magnetic microdisks on a fluid-air interface. Each microrobot spins or oscillates about its center axis in response to an external oscillating magnetic field, in turn producing local magnetic, hydrodynamic, and capillary forces that enable diverse collective behaviors. We demonstrate through physical experiments and simulations that the heterogeneous collective can exploit the differences in microrobot size to enable programmable self-organization, density, morphology, and interaction with external passive objects. Specifically, we can control the level of self-organization by microrobot size, enable organized aggregation, dispersion, and locomotion, change the overall shape of the collective from circular to ellipse, and cage or expel objects. We characterize the fundamental self-organization behavior across a parameter space of magnetic field frequency, relative disk size, and relative populations; we replicate the behavior through a physical model and a swarming coupled oscillator model to show that the dominant effect stems from asymmetric interactions between the different-sized disks. Our work furthers insights into self-organization in heterogeneous microrobot collectives and moves us closer to the goal of applying such collectives to programmable self-assembly and active matter.

Imperfect comb construction reveals the architectural abilities of honeybees.

Honeybees are renowned for their perfectly hexagonal honeycomb, hailed as the pinnacle of biological architecture for its ability to maximize storage area while minimizing building material. However, in natural nests, workers must regularly transition between different cell sizes, merge inconsistent combs, and optimize construction in constrained geometries. These spatial obstacles pose challenges to workers building perfect hexagons, but it is unknown to what extent workers act as architects versus simple automatons during these irregular building scenarios. Using automated image analysis to extract the irregularities in natural comb building, we show that some building configurations are more difficult for the bees than others, and that workers overcome these challenges using a combination of building techniques, such as: intermediate-sized cells, regular motifs of irregular shapes, and gradual modifications of cell tilt. Remarkably, by anticipating these building challenges, workers achieve high-quality merges using limited local sensing, on par with analytical models that require global optimization. Unlike automatons building perfectly replicated hexagons, these building irregularities showcase the active role that workers take in shaping their nest and the true architectural abilities of honeybees.

Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction.

Since the late 1980s, mutations in the RAS genes have been recognized as major oncogenes with a high occurrence rate in human cancers. Such mutations reduce the ability of the small GTPase RAS to hydrolyze GTP, keeping this molecular switch in a constitutively active GTP-bound form that drives, unchecked, oncogenic downstream signaling. One strategy to reduce the levels of active RAS is to target guanine nucleotide exchange factors, which allow RAS to cycle from the inactive GDP-bound state to the active GTP-bound form. Here, we describe the identification of potent and cell-active small-molecule inhibitors which efficiently disrupt the interaction between KRAS and its exchange factor SOS1, a mode of action confirmed by a series of biophysical techniques. The binding sites, mode of action, and selectivity were elucidated using crystal structures of KRASG12C-SOS1, SOS1, and SOS2. By preventing formation of the KRAS-SOS1 complex, these inhibitors block reloading of KRAS with GTP, leading to antiproliferative activity. The final compound 23 (BAY-293) selectively inhibits the KRAS-SOS1 interaction with an IC50 of 21 nM and is a valuable chemical probe for future investigations.

Functional and Structural Characterization of Bub3·BubR1 Interactions Required for Spindle Assembly Checkpoint Signaling in Human Cells.

The spindle assembly checkpoint (SAC) is an essential safeguarding mechanism devised to ensure equal chromosome distribution in daughter cells upon mitosis. The proteins Bub3 and BubR1 are key components of the mitotic checkpoint complex, an essential part of the molecular machinery on which the SAC relies. In the present work we have performed a detailed functional and biochemical characterization of the interaction between human Bub3 and BubR1 in cells and in vitro Our results demonstrate that genetic knockdown of Bub3 abrogates the SAC, promotes apoptosis, and inhibits the proliferation of human cancer cells. We also show that the integrity of the human mitotic checkpoint complex depends on the specific recognition between BubR1 and Bub3, for which the BubR1 Gle2 binding sequence motif is essential. This 1:1 binding event is high affinity, enthalpy-driven and with slow dissociation kinetics. The affinity, kinetics, and thermodynamic parameters of the interaction are differentially modulated by small regions in the N and C termini of the Gle2 binding domain sequence, suggesting the existence of "hotspots" for this protein-protein interaction. Furthermore, we show that specific disruption of endogenous BubR1·Bub3 complexes in human cancer cells phenocopies the effects observed in gene targeting experiments. Our work enhances the current understanding of key members of the SAC and paves the road for the pursuit of novel targeted cancer therapies based on SAC inhibition.

Optimization of allosteric MEK inhibitors. Part 1: Venturing into underexplored SAR territories.

Using PD325901 as a starting point for identifying novel allosteric MEK inhibitors with high cell potency and long-lasting target inhibition in vivo, truncation of its hydroxamic ester headgroup was combined with incorporation of alkyl and aryl ethers at the neighboring ring position. Whereas alkoxy side chains did not yield sufficient levels of cell potency, specifically substituted aryloxy groups allowed for high enzymatic and cellular potencies. Sulfamide 28 was identified as a highly potent MEK inhibitor with nanomolar cell potency against B-RAF (V600E) as well as Ras-mutated cell lines, high metabolic stability and resulting long half-lives. It was efficacious against B-RAF as well as K-Ras driven xenograft models and showed-despite being orally bioavailable and not a P-glycoprotein substrate-much lower brain/plasma exposure ratios than PD325901.

Diverse behaviors in non-uniform chiral and non-chiral swarmalators.

We study the emergent behaviors of a population of swarming coupled oscillators, dubbed swarmalators. Previous work considered the simplest, idealized case: identical swarmalators with global coupling. Here we expand this work by adding more realistic features: local coupling, non-identical natural frequencies, and chirality. This more realistic model generates a variety of new behaviors including lattices of vortices, beating clusters, and interacting phase waves. Similar behaviors are found across natural and artificial micro-scale collective systems, including social slime mold, spermatozoa vortex arrays, and Quincke rollers. Our results indicate a wide range of future use cases, both to aid characterization and understanding of natural swarms, and to design complex interactions in collective systems from soft and active matter to micro-robotics.

Discovery and Characterization of BAY-805, a Potent and Selective Inhibitor of Ubiquitin-Specific Protease USP21.

USP21 belongs to the ubiquitin-specific protease (USP) subfamily of deubiquitinating enzymes (DUBs). Due to its relevance in tumor development and growth, USP21 has been reported as a promising novel therapeutic target for cancer treatment. Herein, we present the discovery of the first highly potent and selective USP21 inhibitor. Following high-throughput screening and subsequent structure-based optimization, we identified BAY-805 to be a non-covalent inhibitor with low nanomolar affinity for USP21 and high selectivity over other DUB targets as well as kinases, proteases, and other common off-targets. Furthermore, surface plasmon resonance (SPR) and cellular thermal shift assays (CETSA) demonstrated high-affinity target engagement of BAY-805, resulting in strong NF-κB activation in a cell-based reporter assay. To the best of our knowledge, BAY-805 is the first potent and selective USP21 inhibitor and represents a valuable high-quality in vitro chemical probe to further explore the complex biology of USP21.

Bay846, a new irreversible small molecule inhibitor of EGFR and Her2, is highly effective against malignant brain tumor models.

The epidermal growth factor receptor (EGFR) pathway is aberrantly activated in tumors and plays a key role in promoting tumor growth. Small molecule inhibitors which bind reversibly to EGFR have demonstrated limited clinical activity. Thus, there is a continued need to develop novel EGFR inhibitors with improved anti-tumor activity. Bay846 is a newly developed small molecule inhibitor that binds irreversibly to the tyrosine kinase domains of EGFR and Her2. The in vitro and in vivo efficacy of Bay846 was tested using a panel of nine human malignant brain tumor (glioma) models. Lapatinib, a reversible inhibitor of EGFR and Her2, was included for comparison. Six glioma cell lines were sensitive to Bay846 treatment. Bay846 strongly suppressed tumor cell growth in vitro by inducing cell lysis/death rather than cell cycle arrest. Consistent with this, Bay846 had potent anti-tumor activity which led to regressions in tumor size. The active, phosphorylated form of EGFR was reduced by Bay846 treatment in vitro and in tumors. Importantly, the efficacy of Bay846 was significantly greater than lapatinib in all assays. Bay846-sensitivity was associated with expression of a wild-type PTEN in conjunction with high levels of an oncogenic EGFR variant (A289V or EGFRvIII). These studies demonstrate that targeting the EGFR pathway with the irreversible inhibitor Bay846 has great potential to increase the efficacy of this cancer therapy.

Local osteogenic expression of cyclooxygenase-2 and systemic response in porcine models of osteomyelitis.

It is suggested that cyclooxygenase 2 (COX-2) derived prostaglandins contributes to the progressive bone loss seen in osteomyelitis lesions. In the present study we examined the expression of COX-2 in bones from 23 pigs with experimental osteomyelitis. Osteomyelitis was induced with Staphylococcus aureus and groups of animals were euthanized following 6 h, 12 h, 24 h, 2 days, 5 days, 11 days and 15 days, respectively. Expression of COX-2 was evaluated immunohistochemically and combined with characterization of morphological changes in bone tissue. Furthermore, the serum concentrations of alkaline phosphatase and haptoglobin were measured. Extensive COX-2 expression by osteoblasts was present 2 days after inoculation together with many activated osteoclasts. Simultaneously, the serum concentration of alkaline phosphatase decreased whereas the haptoglobin concentration increased. This is the first in vivo study showing an early wave of COX-2 mediated bone resorption during osteomyelitis. Therefore, treatment aiming to reduce the break down of bone tissue directed by the COX-2 pathway might be suggested early in the course of the disease.

Best practices for instrumenting honey bees.

Honey bees are vital pollinators and can be used to monitor the landscape. Consequently, interest in mounting technologies onto bees to track foraging behaviors is increasing. The barrier to entry is steep, in part because the methodology for fastening tags to bees, and the success rates, are often missing from publications. We tested six factors suspected to influence the presence and tag retention rates of nurse honey bees after their introduction to hives, and followed bees until foraging age. We also compared reintroducing foragers to their maternal colony using the best method for nurse bees to releasing them in front of their maternal hive and allowing them to fly back unaided. Nurses were most likely to be present in the hive with their tag still attached when introduced using an introduction cage at night. Glue type was important, but may further be influenced by tag material. Foragers were most likely to be present with a tag attached if released in front of their colony. Preparation and introduction techniques influence the likelihood of tagged honey bee survival and of the tags remaining attached, which should be considered when executing honey bee tagging and tracking experiments.

Collective behavior of swarmalators on a ring.

We study the collective behavior of swarmalators, generalizations of phase oscillators that both sync and swarm, confined to move on a one-dimensional (1D) ring. This simple model captures the essence of movement in two or three dimensions, but has the benefit of being solvable: most of the collective states and their bifurcations can be specified exactly. The model also captures the behavior of real-world swarmalators which swarm in quasi-1D rings such as bordertaxic vinegar eels and sperm.

Microrobot collectives with reconfigurable morphologies, behaviors, and functions.

Mobile microrobots, which can navigate, sense, and interact with their environment, could potentially revolutionize biomedicine and environmental remediation. Many self-organizing microrobotic collectives have been developed to overcome inherent limits in actuation, sensing, and manipulation of individual microrobots; however, reconfigurable collectives with robust transitions between behaviors are rare. Such systems that perform multiple functions are advantageous to operate in complex environments. Here, we present a versatile microrobotic collective system capable of on-demand reconfiguration to adapt to and utilize their environments to perform various functions at the air-water interface. Our system exhibits diverse modes ranging from isotropic to anisotrpic behaviors and transitions between a globally driven and a novel self-propelling behavior. We show the transition between different modes in experiments and simulations, and demonstrate various functions, using the reconfigurability of our system to navigate, explore, and interact with the environment. Such versatile microrobot collectives with globally driven and self-propelled behaviors have great potential in future medical and environmental applications.

System design for inferring colony-level pollination activity through miniature bee-mounted sensors.

In digital agriculture, large-scale data acquisition and analysis can improve farm management by allowing growers to constantly monitor the state of a field. Deploying large autonomous robot teams to navigate and monitor cluttered environments, however, is difficult and costly. Here, we present methods that would allow us to leverage managed colonies of honey bees equipped with miniature flight recorders to monitor orchard pollination activity. Tracking honey bee flights can inform estimates of crop pollination, allowing growers to improve yield and resource allocation. Honey bees are adept at maneuvering complex environments and collectively pool information about nectar and pollen sources through thousands of daily flights. Additionally, colonies are present in orchards before and during bloom for many crops, as growers often rent hives to ensure successful pollination. We characterize existing Angle-Sensitive Pixels (ASPs) for use in flight recorders and calculate memory and resolution trade-offs. We further integrate ASP data into a colony foraging simulator and show how large numbers of flights refine system accuracy, using methods from robotic mapping literature. Our results indicate promising potential for such agricultural monitoring, where we leverage the superiority of social insects to sense the physical world, while providing data acquisition on par with explicitly engineered systems.

Scalable and Robust Fabrication, Operation, and Control of Compliant Modular Robots.

A major goal of autonomous robot collectives is to robustly perform complex tasks in unstructured environments by leveraging hardware redundancy and the emergent ability to adapt to perturbations. In such collectives, large numbers is a major contributor to system-level robustness. Designing robot collectives, however, requires more than isolated development of hardware and software that supports large scales. Rather, to support scalability, we must also incorporate robust constituents and weigh interrelated design choices that span fabrication, operation, and control with an explicit focus on achieving system-level robustness. Following this philosophy, we present the first iteration of a new framework toward a scalable and robust, planar, modular robot collective capable of gradient tracking in cluttered environments. To support co-design, our framework consists of hardware, low-level motion primitives, and control algorithms validated through a kinematic simulation environment. We discuss how modules made primarily of flexible printed circuit boards enable inexpensive, rapid, low-precision manufacturing; safe interactions between modules and their environment; and large-scale lattice structures beyond what manufacturing tolerances allow using rigid parts. To support redundancy, our proposed modules have on-board processing, sensing, and communication. To lower wear and consequently maintenance, modules have no internally moving parts, and instead move collaboratively via switchable magnets on their perimeter. These magnets can be in any of three states enabling a large range of module configurations and motion primitives, in turn supporting higher system adaptability. We introduce and compare several controllers that can plan in the collective's configuration space without restricting motion to a discrete occupancy grid as has been done in many past planners. We show how we can incentively redundant connections to prevent single-module failures from causing collective-wide failure, explore bad configurations which impede progress as a result of the motion constraints, and discuss an alternative "naive" planner with improved performance in both clutter-free and cluttered environments. This dedicated focus on system-level robustness over all parts of a complete design cycle, advances the state-of-the-art robots capable of long-term exploration.

Artificial shaking signals in honey bee colonies elicit natural responses.

Honey bee signals are primarily studied through natural observation combined with manipulations of the colony or environment, not direct manipulation of the signal stimulus or receivers. Consequently, we know little about which signal aspects are necessary to reproduce behavioral responses. Here, we focus on the shaking signal, wherein a worker grabs onto another bee and vibrates. All castes receive shaking signals, but individual responses depend on context, and the signal may be multi-modal (mechanical, odor, sound, etc.). We designed a tool to mimic the shaking signal. We tested whether a purely mechanical stimulus elicited the same behavioral response as a natural shaking signal, teasing apart the effects of signal and receiver characteristics. We found that both workers and drones increased their movement after being artificially shaken, and that shaken drones were more likely to engage in feeding and grooming than a sham control. These behavioral changes support the idea that the shaking signal serves to generally increase worker activity, but also serves to activate male reproductives (drones). With this tool, we show that vibration itself is responsible for eliciting much of the shaking signal's behavioral response, in one of the few examples of direct playback in social insects.

A review of collective robotic construction.

The increasing need for safe, inexpensive, and sustainable construction, combined with novel technological enablers, has made large-scale construction by robot teams an active research area. Collective robotic construction (CRC) specifically concerns embodied, autonomous, multirobot systems that modify a shared environment according to high-level user-specified goals. CRC tightly integrates architectural design, the construction process, mechanisms, and control to achieve scalability and adaptability. This review gives a comprehensive overview of research trends, open questions, and performance metrics.

Soft Actuators for Small-Scale Robotics.

This review comprises a detailed survey of ongoing methodologies for soft actuators, highlighting approaches suitable for nanometer- to centimeter-scale robotic applications. Soft robots present a special design challenge in that their actuation and sensing mechanisms are often highly integrated with the robot body and overall functionality. When less than a centimeter, they belong to an even more special subcategory of robots or devices, in that they often lack on-board power, sensing, computation, and control. Soft, active materials are particularly well suited for this task, with a wide range of stimulants and a number of impressive examples, demonstrating large deformations, high motion complexities, and varied multifunctionality. Recent research includes both the development of new materials and composites, as well as novel implementations leveraging the unique properties of soft materials.

BAY 1143269, a novel MNK1 inhibitor, targets oncogenic protein expression and shows potent anti-tumor activity.

The initiation of mRNA translation has received increasing attention as an attractive target for cancer treatment in the recent years. The oncogenic eukaryotic translation initiation factor 4E (eIF4E) is the major substrate of MAP kinase-interacting kinase 1 (MNK1), and it is located at the junction of the cancer-associated PI3K and MAPK pathways. The fact that MNK1 is linked to cell transformation and tumorigenesis renders the kinase a promising target for cancer therapy. We identified a novel small molecule MNK1 inhibitor, BAY 1143269, by high-throughput screening and lead optimization. In kinase assays, BAY 1143269 showed potent and selective inhibition of MNK1. By targeting MNK1 activity, BAY 1143269 strongly regulated downstream factors involved in cell cycle regulation, apoptosis, immune response and epithelial-mesenchymal transition in vitro or in vivo. In addition, BAY 1143269 demonstrated strong efficacy in monotherapy in cell line and patient-derived non-small cell lung cancer xenograft models as well as delayed tumor regrowth in combination treatment with standard of care chemotherapeutics. In summary, the inhibition of MNK1 activity with a highly potent and selective inhibitor BAY 1143269 may provide an innovative approach for anti-cancer therapy.

Inflated Soft Actuators with Reversible Stable Deformations.

Most soft robotic systems are currently dependent on bulky compressors or pumps. A soft actuation method is presented combining hyperelastic membranes and dielectric elastomer actuators to switch between stable deformations of sealed chambers. This method is capable of large repeatable deformations, and has a number of stable states proportional to the number of actuatable membranes in the chamber.