Modular Platform Research Articles

A Modular Framework for Data Processing at the Edge: Design and Implementation.

There is a rapid increase in the number of edge devices in IoT solutions, generating vast amounts of data that need to be processed and analyzed efficiently. Traditional cloud-based architectures can face latency, bandwidth, and privacy challenges when dealing with this data flood. There is currently no unified approach to the creation of edge computing solutions. This work addresses this problem by exploring containerization for data processing solutions at the network's edge. The current approach involves creating a specialized application compatible with the device used. Another approach involves using containerization for deployment and monitoring. The heterogeneity of edge environments would greatly benefit from a universal modular platform. Our proposed edge computing-based framework implements a streaming extract, transform, and load pipeline for data processing and analysis using ZeroMQ as the communication backbone and containerization for scalable deployment. Results demonstrate the effectiveness of the proposed framework, making it suitable for time-sensitive IoT applications.

Vision-Based Virtual Simulation Platform for Planetary Rovers

In order to evaluate the feasibility of planetary exploration missions, it is imperative to construct planetary terrain environments on the ground. Nevertheless, the implementation of this method is characterized by time-consuming and challenging factors. By contrast, resorting to simulation approaches represents a cost-effective and high-efficiency alternative, which can facilitate the simulation validation of planetary rover exploration missions in an effective manner. In this paper, a modular planet rover simulation platform is proposed; by building and overlaying multiple feature layers corresponding to the surface of the planet, we realize the simulation of high-resolution fine terrain and through adjusting the terrain parameters to meet the needs of different simulated terrain. The experimental results show that we have built a scene to satisfy the requirements of visual effects and physically realistic characteristics of simulation. Using an improved PatchMatch stereomethod to recover images captured real time by a planetary rover navigation camera in a virtual environment provided more complete three-dimensional terrain data for subsequent simulation validation of local path planning. Finally, a simulation environment that combines high-fidelity visual effects and kinematic characteristics supports visualizing the simulation platform: we propose a path planning method using global planning combined with local obstacle avoidance, and we obtain the optimal path that satisfies the kinematic constraints.

778 New Intervention: Transanal Local Excision of Rectal Lesions with CMR Versius Robotic Surgical System

Abstract Introduction The Versius robotic surgical system (CMR) is a modular robotic platform. Since its launch in clinical practice in 2019 for General Surgical and Gynaecological procedures it has rapidly expanded into other clinical specialties. We describe its implementation and the world's first series of its use for trans-anal resection of significant rectal lesions. Method The optimum bedside unit set-up and port placement was determined in an exploratory study using dry and wet-lab models prior to clinical implementation. The early intervention panel at NHS Lothian were consulted prior to introducing the technique into clinical practice. The case series of patients undergoing robotic Trans-Anal Minimally Invasive Surgery (rTAMIS) were prospectively identified and data collected retrospectively. Results A total of 12 patients were included in this case series. Data was collected from cases over a 6-month period from December 2021 to June 2022. 8 patients underwent robotic TAMIS using the Versius platform. 2 cases were converted to laparoscopic TAMIS due to external arm clashes. The average length of stay in hospital was 1 day (range 0-3). There was only one Clavien-Dindo grade II morbidity. Conclusions The Versius surgical system is a safe and feasible alternative to TEMS and TAMIS. The technique allows access to the rectum with the advantages of enhanced optics and wristed instruments. We have produced a blueprint for optimised bedside unit positioning and port placement enabling resection of anterior, lateral, and posterior rectal lesions without further patient position changes. Further studies are needed for accurate outcome and cost comparisons to TEMS and TAMIS.

Visible Light‐Mediated Cobalt and Photoredox Dual‐Catalyzed Asymmetric Reductive Coupling for Axially Chiral Secondary Alcohols†

Comprehensive SummarySecondary alcohols bearing both axial and central chirality comprise attractive biological activity and exhibit excellent chiral induction in asymmetric reactions. However, only very limited asymmetric catalytic approaches were developed for their synthesis. We herein describe visible light‐mediated cobalt‐catalyzed asymmetric reductive Grignard‐type addition of aryl iodides with axially prochiral biaryl dialdehydes leading to the direct construction of axially chiral secondary alcohols. Preliminary mechanistic studies indicate that efficient kinetic recognition of diastereomers might occur for axially prochiral dialdehydes to improve the stereoselectivity, which might open a new avenue for the challenging cascade construction of multiple chiral elements. This protocol features excellent enantio‐ and diastereoselectivity, green and mild conditions, simple operation, and broad substrate scope, providing a modular platform for the synthesis of secondary axially chiral alcohols.

Cell type-specific delivery by modular envelope design

The delivery of genetic cargo remains one of the largest obstacles to the successful translation of experimental therapies, in large part due to the absence of targetable delivery vectors. Enveloped delivery modalities use viral envelope proteins, which determine tropism and induce membrane fusion. Here we develop DIRECTED (Delivery to Intended REcipient Cells Through Envelope Design), a modular platform that consists of separate fusion and targeting components. To achieve high modularity and programmable cell type specificity, we develop multiple strategies to recruit or immobilize antibodies on the viral envelope, including a chimeric antibody binding protein and a SNAP-tag enabling the use of antibodies or other proteins as targeting molecules. Moreover, we show that fusogens from multiple viral families are compatible with DIRECTED and that DIRECTED components can target multiple delivery chassis (e.g., lentivirus and MMLV gag) to specific cell types, including primary human T cells in PBMCs and whole blood.

A Modular Chemistry Platform for the Development of a Cereblon E3 Ligase-Based Partial PROTAC Library.

Proteolysis targeting chimeras (PROTACs) are a promising therapeutic strategy to selectively promote the degradation of protein targets by exploiting the ubiquitin-proteasome system. Among the limited number of E3 ligase ligands discovered for the PROTAC technology, ligands of cereblon (CRBN) E3 ligase, such as pomalidomide, thalidomide, or lenalidomide, are the most frequently used for the development of PROTACs. Our group previously reported that a phenyl group could be tolerated on the C4-position of lenalidomide as the ligand of CRBN to develop PROTACs. Herein, we report a modular chemistry platform for the efficient attachment of various ortho-, meta-, and para-substituted phenyls to the C4-position of the lenalidomide via Suzuki cross-coupling reaction, which allows the systematic investigation of the linker effect for the development of PROTACs against any target. We examined the substrate scope by preparing twelve lenalidomide-derived CRBN E3 ligase ligands with different linkers.

CD98hc is a target for brain delivery of biotherapeutics

Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report the engineering and characterization of a BBB transport vehicle targeting the CD98 heavy chain (CD98hc or SLC3A2) of heterodimeric amino acid transporters (TVCD98hc). The pharmacokinetic and biodistribution properties of a CD98hc antibody transport vehicle (ATVCD98hc) are assessed in humanized CD98hc knock-in mice and cynomolgus monkeys. Compared to most existing BBB platforms targeting the transferrin receptor, peripherally administered ATVCD98hc demonstrates differentiated brain delivery with markedly slower and more prolonged kinetic properties. Specific biodistribution profiles within the brain parenchyma can be modulated by introducing Fc mutations on ATVCD98hc that impact FcγR engagement, changing the valency of CD98hc binding, and by altering the extent of target engagement with Fabs. Our study establishes TVCD98hc as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms.

Disrupting Protein Expression with Double-Clicked sgRNA-Cas9 Complexes: A Modular Approach to CRISPR Gene Editing.

CRISPR-Cas9 is currently the most versatile technique to perform gene editing in living organisms. In this approach, the Cas9 endonuclease is guided toward its DNA target sequence by the guide RNA (gRNA). Chemical synthesis of a functional single gRNA (sgRNA) is nontrivial because of the length of the RNA strand. Recently we demonstrated that a sgRNA can be stitched together from three smaller fragments through a copper-catalyzed azide-alkyne cycloaddition, making the process highly modular. Here we further advance this approach by leveraging this modulator platform by incorporating chemically modified nucleotides at both ends of the modular sgRNA to increase resistance against ribonucleases. Modified nucleotides consisted of a 2'-O-Me group and a phosphorothioate backbone in varying number at both the 5'- and 3'-ends of the sgRNA. It was observed that three modified nucleotides at both ends of the sgRNA significantly increased the success of Cas9 in knocking out a gene of interest. Using these chemically stabilized sgRNAs facilitates multigene editing at the protein level, as demonstrated by successful knockout of both Siglec-3 and Siglec-7 using two fluorophores in conjunction with fluorescence-activated cell sorting. These results demonstrate the versatility of this modular platform for assembling sgRNAs from small, chemically modified strands to simultaneously disrupt the gene expression of two proteins.

FungalBraid 2.0: expanding the synthetic biology toolbox for the biotechnological exploitation of filamentous fungi.

Fungal synthetic biology is a rapidly expanding field that aims to optimize the biotechnological exploitation of fungi through the generation of standard, ready-to-use genetic elements, and universal syntax and rules for contributory use by the fungal research community. Recently, an increasing number of synthetic biology toolkits have been developed and applied to filamentous fungi, which highlights the relevance of these organisms in the biotechnology field. The FungalBraid (FB) modular cloning platform enables interchangeability of DNA parts with the GoldenBraid (GB) platform, which is designed for plants, and other systems that are compatible with the standard Golden Gate cloning and syntax, and uses binary pCAMBIA-derived vectors to allow Agrobacterium tumefaciens-mediated transformation of a wide range of fungal species. In this study, we have expanded the original FB catalog by adding 27 new DNA parts that were functionally validated in vivo. Among these are the resistance selection markers for the antibiotics phleomycin and terbinafine, as well as the uridine-auxotrophic marker pyr4. We also used a normalized luciferase reporter system to validate several promoters, such as PpkiA, P7760, Pef1α, and PafpB constitutive promoters, and PglaA, PamyB, and PxlnA inducible promoters. Additionally, the recently developed dCas9-regulated GB_SynP synthetic promoter collection for orthogonal CRISPR activation (CRISPRa) in plants has been adapted in fungi through the FB system. In general, the expansion of the FB catalog is of great interest to the scientific community since it increases the number of possible modular and interchangeable DNA assemblies, exponentially increasing the possibilities of studying, developing, and exploiting filamentous fungi.

ROBOMINER: Development of a Highly Configurable and Modular Scaled-Down Prototype of a Mining Robot

Historically, mining operations have faced numerous challenges, including safety hazards, inefficiencies, and environmental concerns. However, recent advances in robotics, automation, and artificial intelligence have presented opportunities for the mining industry. The ROBOMINERS project, a Horizon 2020 European Union initiative, aims to revolutionize the mining ecosystem by implementing disruptive robotic concepts. One such concept is resilience, which involves enabling mining robots to reconfigure morphologically during operation. This article presents the development of a modular robotic system that focuses on modularity and self-assembly to provide insight into developing a highly adaptable and compact solution for future mining robots. The robotic system is composed of a set of highly configurable modular robotic platforms that can be reconfigured with other robotic modules or submodules to form more complex systems to perform different tasks. Several module configurations are presented, and different locomotion experiments were carried out to test the ability of the modules to navigate unstructured environments. The modules exhibited great maneuverability in unstructured terrain and demonstrated self-assembly and reconfiguration capabilities during operation. This is a foundational step towards the long-term goal of developing compact autonomous agents capable of self-assembly and mining task execution.

Boron-Methylated Dipyrromethene as a Green Light Activated Type I Photoinitiator for Rapid Radical Polymerizations.

Unimolecular (Type I) radical photoinitiators (PIs) have transformed the chemical manufacturing industry by enabling (stereo)lithography for microelectronics and emergent 3D printing technologies. However, the reliance on high energy UV-violet light (≤420 nm) restricts the end-use applications. Herein, boron-methylated dipyrromethene (methylated-BODIPY) is shown to act as a highly efficient Type I radical PI upon irradiation with low energy green light. Using a low intensity (∼4 mW/cm2) light emitting diode centered at 530 nm and a low PI concentration (0.3 mol %), acrylic-based resins were polymerized to maximum conversion in ∼10 s. Under equivalent conditions (wavelength, intensity, and PI concentration), state-of-the-art visible light PIs Ivocerin and Irgacure 784 show no appreciable polymerization. Spectroscopic characterization suggests that homolytic β-scission at the boron-carbon bond results in radical formation, which is further facilitated by accessing long-lived triplet excited states through installment of bromine. Alkylated-BODIPYs represent a new modular visible light PI platform with exciting potential to enable next generation manufacturing and biomedical applications where a spectrally discrete, low energy, and thus benign light source is required.

Bioorthogonal Reaction-Mediated Tumor-Selective Delivery of CRISPR/Cas9 System for Dual-Targeted Cancer Immunotherapy.

CRISPR system-assisted immunotherapy is an attractive option in cancer therapy. However, its efficacy is still less than expected due to the limitations in delivering the CRISPR system to target cancer cells. Here, we report a new CRISPR/Cas9 tumor-targeting delivery strategy based on bioorthogonal reactions for dual-targeted cancer immunotherapy. First, selective in vivo metabolic labeling of cancer and activation of the cGAS-STING pathway was achieved simultaneously through tumor microenvironment (TME)-biodegradable hollow manganese dioxide (H-MnO2 ) nano-platform. Subsequently, CRISPR/Cas9 system-loaded liposome was accumulated within the modified tumor tissue through in vivo click chemistry, resulting in the loss of protein tyrosine phosphatase N2 (PTPN2) and further sensitizing tumors to immunotherapy. Overall, our strategy provides a modular platform for precise gene editing in vivo and exhibits potent antitumor response by boosting innate and adaptive antitumor immunity.

Bioorthogonal Reaction‐Mediated Tumor‐Selective Delivery of CRISPR/Cas9 System for Dual‐Targeted Cancer Immunotherapy

AbstractCRISPR system‐assisted immunotherapy is an attractive option in cancer therapy. However, its efficacy is still less than expected due to the limitations in delivering the CRISPR system to target cancer cells. Here, we report a new CRISPR/Cas9 tumor‐targeting delivery strategy based on bioorthogonal reactions for dual‐targeted cancer immunotherapy. First, selective in vivo metabolic labeling of cancer and activation of the cGAS‐STING pathway was achieved simultaneously through tumor microenvironment (TME)‐biodegradable hollow manganese dioxide (H‐MnO2) nano‐platform. Subsequently, CRISPR/Cas9 system‐loaded liposome was accumulated within the modified tumor tissue through in vivo click chemistry, resulting in the loss of protein tyrosine phosphatase N2 (PTPN2) and further sensitizing tumors to immunotherapy. Overall, our strategy provides a modular platform for precise gene editing in vivo and exhibits potent antitumor response by boosting innate and adaptive antitumor immunity.

HYbrid DegRAding Copolymer (HYDRAC): Heterobifunctional polymers for targeted degradation of undruggable proteins.

22 Background: Of the ~20,000 proteins encoded by the human genome, only a small subset can be modulated via traditional pharmacological approaches. Included in the list of “undruggable” proteins are ones with pivotal roles in cancer. We aim to expand the arsenal of compounds able to affect the activity of these therapeutically relevant targets by introducing a modular proteomimetic platform technology designed to carry side chains consisting of targeting warheads and recruiters of cellular protein degradation machinery. We term these compounds HYbrid DegRAding Copolymers (HYDRACs) in reference to the multiplexing of different protein binders and degradation inducing sequences. Peptides arranged as HYDRACs exhibit favorable emergent properties including resistance to proteolysis, high levels of cell uptake, and payload-specific activity. Initial studies were conducted focusing on a undruggable transcription factor MYC, which is widely dysregulated in human cancers. Methods: A library of HYDRACs and control polymers were synthesized and were cell-penetrating with antiproliferative effects at sub-micromolar IC50s in a formulation- and MYC-dependent manner across multiple cell lines. Results: HYDRAC treatment resulted in significant decreases in MYC protein levels, which was rescued by proteasome inhibitor MG132 and neddylation inhibitor MLN4924, without changes in mRNA levels. RNAseq showed selective overexpression of MYC pathway genes only in HYDRAC treated cells, confirming on-target effects. Circular dichroism showed strong HYDRAC-MYC interactions, which was supported by the presence of MYC following pull-down of biotin-terminated HYDRACs. Removal of the RRRG degron, scrambling the H1 sequence, and disassociation of the two domains on separate polymers all abrogated MYC-degradation. Mice bearing transplanted Myc-CaP tumors showed delayed tumor growth and reduced tumor cell proliferation following HYDRAC treatment. Mice bearing luminescent Luc-MV-411 tumors treated with Cy5.5-labeled HDRACs showed selective tumor accumulation with detectable fluorescent signal in the tumor up to 72 hours following a single IP administration. The versatility of the platform was demonstrated by substituting the degron for recruiters of three different E3 ligases (VHL, KEAP1, and CRBN), which all maintained ability to degrade MYC. HYDRACs were also able to selectively degrade other protein targets including alpha-syn and RAS. Conclusions: We present a platform technology that addresses challenges inherent to small molecule drug design. HYDRACs have the potential to dramatically alter the drug discovery landscape, allowing for development of modulators of "undruggable" targets. We envision the HYDRAC platform as a generalizable approach to designing degraders of proteins of interest, greatly expanding the therapeutic armamentarium for target protein degradation.

Modeling, Control and Implementation of Adaptive Reconfigurable ROtary Wings (ARROWs)

Inspired by the self-rotating motion of the descending maple seeds, we introduce a novel modular aerial robotic platform—ARROWs. With customized wing and control modules, ARROWs can be easily reassembled into different configurations. Unlike conventional multirotor aerial vehicles which rely on the direct thrust from propellers, ARROWs can generate more lift by their revolving wings. However, the complex dynamics causes difficulties in flight controller development. In this work, we first analyze the flight dynamics by considering a combination of effects from the propeller, aerodynamic force on the wing, as well as self-rotating motion. As a result, a cascaded flight controller with a unified framework is designed based on reduced flight dynamics and relaxed hovering conditions to achieve stable flights in all proposed configurations. In addition, a set of inertial measurement units is employed for each flight module to estimate the flight configuration to overcome the dynamic uncertainties caused by manual re-construction. Finally, our proposed platform and flight control strategy are validated using several flight experiments in 12 different configurations (include both centrosymmetric and centrally asymmetric cases). The results show an average position error of 8.9 cm with a deviation of 2.4 cm among all configurations in hovering tests.

Aerial Manipulation via Modular Quadrotors With Passively Foldable Airframes

The need for physical interactions and aerial manipulation has driven the demand for small multirotor vehicles with higher degrees of actuation and adaptability. This leads to the development of reconfigurable flying robots and modular flight platforms. In this work, we propose a modular vehicle comprising flight-capable quadrotors with passively deformable rotor arms as subunits. The foldable arms with preloaded elastic components are designed to be stable in both folded and unfolded states such that the reconfiguration can be achieved passively through the manipulation of the propelling thrust. A docking mechanism is devised to permit multiple modules to combine during a mission without human intervention. Through a series of experiments, we show that passive reconfigurability enables the platform to perform perching. With the added modularity, the integrated platform can be used to perform thrust vectoring or grip and transport heavier payloads. The ability to accomplish a wide range of tasks in a single platform is unique from existing aerial robots, thanks to the combination of reconfigurability and modularity.

DSCIM-Coastal v1.1: an open-source modeling platform for global impacts of sea level rise

Abstract. Sea level rise (SLR) may impose substantial economic costs to coastal communities worldwide, but characterizing its global impact remains challenging because SLR costs depend heavily on natural characteristics and human investments at each location – including topography, the spatial distribution of assets, and local adaptation decisions. To date, several impact models have been developed to estimate the global costs of SLR. Yet, the limited availability of open-source and modular platforms that easily ingest up-to-date socioeconomic and physical data sources restricts the ability of existing systems to incorporate new insights transparently. In this paper, we present a modular, open-source platform designed to address this need, providing end-to-end transparency from global input data to a scalable least-cost optimization framework that estimates adaptation and net SLR costs for nearly 10 000 global coastline segments and administrative regions. Our approach accounts both for uncertainty in the magnitude of global mean sea level (g.m.s.l.) rise and spatial variability in local relative sea level rise. Using this platform, we evaluate costs across 230 possible socioeconomic and SLR trajectories in the 21st century. According to the latest Intergovernmental Panel on Climate Change Assessment Report (AR6), g.m.s.l. is likely to rise during the 21st century by 0.40–0.69 m if late-century warming reaches 2 ∘C and by 0.58–0.91 m with 4 ∘C of warming (Fox-Kemper et al., 2021). With no forward-looking adaptation, we estimate that annual costs of sea level rise associated with a 2 ∘C scenario will likely fall between USD 1.2 and 4.0 trillion (0.1 % and 1.2 % of GDP, respectively) by 2100, depending on socioeconomic and sea level rise trajectories. Cost-effective, proactive adaptation would provide substantial benefits, lowering these values to between USD 110 and USD 530 billion (0.02 and 0.06 %) under an optimal adaptation scenario. For the likely SLR trajectories associated with 4 ∘C warming, these costs range from USD 3.1 to 6.9 trillion (0.3 % and 2.0 %) with no forward-looking adaptation and USD 200 billion to USD 750 billion (0.04 % to 0.09 %) under optimal adaptation. The Intergovernmental Panel on Climate Change (IPCC) notes that deeply uncertain physical processes like marine ice cliff instability could drive substantially higher global sea level rise, potentially approaching 2.0 m by 2100 in very high emission scenarios. Accordingly, we also model the impacts of 1.5 and 2.0 m g.m.s.l. rises by 2100; the associated annual cost estimates range from USD 11.2 to 30.6 trillion (1.2 % and 7.6 %) under no forward-looking adaptation and USD 420 billion to 1.5 trillion (0.08 % to 0.20 %) under optimal adaptation. Our modeling platform used to generate these estimates is publicly available in an effort to spur research collaboration and support decision-making, with segment-level physical and socioeconomic input characteristics provided at https://doi.org/10.5281/zenodo.7693868 (Bolliger et al., 2023a) and model results at https://doi.org/10.5281/zenodo.7693869 (Bolliger et al., 2023b).

Modular assembly of microswimmers with liquid compartments.

Artificial microswimmers, i.e. colloidal scale objects capable of self-propulsion, have garnered significant attention due to their central role as models for out of equilibrium systems. Moreover, their potential applications in diverse fields such as biomedicine, environmental remediation, and materials science have long been hypothesized, often in conjunction with their ability to deliver cargoes to overcome mass transport limitations. A very efficient way to load molecular cargoes is to disperse them in a liquid compartment, however, fabricating microswimmers with multiple liquid compartments remains a significant challenge. To address this challenge, we present a modular fabrication platform that combines microfluidic synthesis and sequential capillarity-assisted particle assembly (sCAPA) for microswimmers with various liquid compartments. We demonstrate the synthesis of monodisperse, small polymer-based microcapsules (Ø = 3-6μm) with different liquid cargoes using a flow-focusing microfluidic device. By employing the sCAPA technique, we assemble multiple microcapsules into microswimmers with high precision, resulting in versatile microswimmers with multiple liquid compartments and programmable functionalities. Our work provides a flexible approach for the fabrication of modular microswimmers, which could potentially actively transport cargoes and release them on demand in the future.

Cancer Bioenergetics and Tumor Microenvironments-Enhancing Chemotherapeutics and Targeting Resistant Niches through Nanosystems.

Cancer is an impending bottleneck in the advanced scientific workflow to achieve diagnostic, prognostic, and therapeutic success. Most cancers are refractory to conventional diagnostic and chemotherapeutics due to their limited targetability, specificity, solubility, and side effects. The inherent ability of each cancer to evolve through various genetic and epigenetic transformations and metabolic reprogramming underlies therapeutic limitations. Though tumor microenvironments (TMEs) are quite well understood in some cancers, each microenvironment differs from the other in internal perturbations and metabolic skew thereby impeding the development of appropriate diagnostics, drugs, vaccines, and therapies. Cancer associated bioenergetics modulations regulate TME, angiogenesis, immune evasion, generation of resistant niches and tumor progression, and a thorough understanding is crucial to the development of metabolic therapies. However, this remains a missing element in cancer theranostics, necessitating the development of modalities that can be adapted for targetability, diagnostics and therapeutics. In this challenging scenario, nanomaterials are modular platforms for understanding TME and achieving successful theranostics. Several nanoscale particles have been successfully researched in animal models, quite a few have reached clinical trials, and some have achieved clinical success. Nanoparticles exhibit an intrinsic capability to interact with diverse biomolecules and modulate their functions. Furthermore, nanoparticles can be functionalized with receptors, modulators, and drugs to facilitate specific targeting with reduced toxicity. This review discusses the current understanding of different theranostic nanosystems, their synthesis, functionalization, and targetability for therapeutic modulation of bioenergetics, and metabolic reprogramming of the cancer microenvironment. We highlight the potential of nanosystems for enhanced chemotherapeutic success emphasizing the questions that remain unanswered.

An expandable, modular de novo protein platform for precision redox engineering

The electron-conducting circuitry of life represents an as-yet untapped resource of exquisite, nanoscale biomolecular engineering. Here, we report the characterization and structure of a de novo diheme "maquette" protein, 4D2, which we subsequently use to create an expanded, modular platform for heme protein design. A well-folded monoheme variant was created by computational redesign, which was then utilized for the experimental validation of continuum electrostatic redox potential calculations. This demonstrates how fundamental biophysical properties can be predicted and fine-tuned. 4D2 was then extended into a tetraheme helical bundle, representing a 7 nm molecular wire. Despite a molecular weight of only 24 kDa, electron cryomicroscopy illustrated a remarkable level of detail, indicating the positioning of the secondary structure and the heme cofactors. This robust, expressible, highly thermostable and readily designable modular platform presents a valuable resource for redox protein design and the future construction of artificial electron-conducting circuitry.