Modular Strategy Research Articles

A Library of Nanocrystal‐Inserted Ordered Mesoporous Frameworks with Ultrahigh Density and Spatial Dispersity

AbstractIt is a great challenge to integrate incompatible subunits into ordered macroscopic materials with tailored functionalities. Herein, a facile modular assembly strategy is demonstrated to link incompatible colloidal nanocrystals and polymer micelles by using the phenolic resol as the “molecule glue” for the synthesis of nanocrystal‐inserted mesoporous frameworks with diverse functionalities. It is found that the uniform nanocrystals can be inserted into the mesoporous frameworks with outstanding spatial dispersity, even in the case of high incorporation density. This modular assembly route is versatile, a library of nanocrystals with diverse diameters, shapes, and compositions can be integrated into various kinds of mesoporous frameworks (carbon, carbon‐SiO2, and carbon‐TiO2 composites). Unprecedently, this strategy also allows the controllable assembly of two, even three types of nanocrystals within the mesoporous frameworks to achieve multiple functionalities. The as‐prepared nanocomposites can simultaneously exhibit catalytic, magnetic, and adsorption properties independently, and show synergistic effects for tandem catalytic applications.

Construction of logic circuit with modular molecular switching strategy based on DNA strand displacement

SummaryAt present, many DNA logic circuits have been successfully constructed. However, advanced complex DNA computing tasks with simple structure, fast response, and modularization still remain a huge challenge. In this paper, molecular switch circuits (MSCs) are constructed based on DNA strand displacement to improve above problems. At first, molecular switch is constructed, which is the basic element for building logic circuits. Next, the functions of AND, OR, Fan‐in, and Fan‐out are realized through switches cascading in series or parallel. Furthermore, switch canvas strategy is explored to obtain the shortest reaction path and highest output concentration for circuits. Finally, a novel strategy of integrating computing module using molecular switches is proposed. Here, we construct a half‐adder, half‐subtractor, and a 9‐bit parity checking circuits to verify its feasibility. Compared with the classical monorail and dual‐track logic circuits, the structure scale is reduced by more than two times, and the DNA strands are decreased by more than four times, which effectively reduces the circuit complexity and raises the reaction speed. The above results show that MSC strategy has a great potential to construct large‐scale DNA circuits and provides a development model for the scalability and modularity of biological computing.

Supramolecular Modular Assembly of Imaging‐Trackable Enzymatic Nanomotors

AbstractSelf‐propelled micro/nanomotors (MNMs) have shown great application potential in biomedicine, sensing, environmental remediation, etc. In the past decade, various strategies or technologies have been used to prepare and functionalize MNMs. However, the current preparation strategies of the MNMs were mainly following the pre‐designed methods based on specific tasks to introduce expected functional parts on the various micro/nanocarriers, which lacks a universal platform and common features, making it difficult to apply to different application scenarios. Here, we have developed a modular assembly strategy based on host–guest chemistry, which enables the on‐demand construction of imaging‐trackable nanomotors mounted with suitable driving and imaging modules using a universal assembly platform, according to different application scenarios. These assembled nanomotors exhibited enhanced diffusion behavior driven by enzymatic reactions. The loaded imaging functions were used to dynamically trace the swarm motion behavior of assembled nanomotors with corresponding fuel conditions both in vitro and in vivo. The modular assembly strategy endowed with host–guest interaction provides a universal approach to producing multifunctional MNMs in a facile and controllable manner, which paves the way for the future development of MNMs systems with programmable functions.

Modular Synthesis of Improbable Rotaxanes with All‐Benzene Scaffolds

Abstract“Improbable” rotaxanes consisting of interlocked conjugated components represent non‐trivial synthetic targets, not to mention those with all‐benzene scaffolds. Herein, a modular synthetic strategy has been established using an isolable azo‐linked pre‐rotaxane as the core module, in which the azo group functions as a tracelessly removable template to direct mechanical bond formations. Through versatile connections of the pre‐rotaxane and other customizable modules, [2]‐ and [3]rotaxanes derived from all‐benzene scaffolds have been accomplished, demonstrating the utility and potential of the synthetic design for all‐benzene interlocked supramolecules.

Neuromorphic Event Signal-Driven Network for Video De-raining

Convolutional neural networks-based video de-raining methods commonly rely on dense intensity frames captured by CMOS sensors. However, the limited temporal resolution of these sensors hinders the capture of dynamic rainfall information, limiting further improvement in de-raining performance. This study aims to overcome this issue by incorporating the neuromorphic event signal into the video de-raining to enhance the dynamic information perception. Specifically, we first utilize the dynamic information from the event signal as prior knowledge, and integrate it into existing de-raining objectives to better constrain the solution space. We then design an optimization algorithm to solve the objective, and construct a de-raining network with CNNs as the backbone architecture using a modular strategy to mimic the optimization process. To further explore the temporal correlation of the event signal, we incorporate a spiking self-attention module into our network. By leveraging the low latency and high temporal resolution of the event signal, along with the spatial and temporal representation capabilities of convolutional and spiking neural networks, our model captures more accurate dynamic information and significantly improves de-raining performance. For example, our network achieves a 1.24dB improvement on the SynHeavy25 dataset compared to the previous state-of-the-art method, while utilizing only 39% of the parameters.

Analysing the Modular Design Strategies to Enhance the Adaptive Capacity of Buildings

In recent years all industries have faced a growing demand for customizable and flexible products that are adaptable to human needs. Buildings being an integral part of our daily lives provide a space to live, work, learn, and socialize and are thus driven to be adaptable according to the dynamic needs of the individuals. New design strategies and technologies are required to make it adaptable without consequences on the economy, ecology, waste generation, and energy consumption. This paper explores the potential application of modular design strategies to address the changing needs and ensure the buildings have enhanced adaptive capacity. To comprehend the nature of these changes and building capacity for adaptation, a thorough analysis of a few chosen case studies based on the type of modular design strategy employed was done. In the cases analyzed, strategies were identified and assessed based on adaptability's key determinants and dimensions. The results of the case studies helped in identifying different modular design strategies that can be employed for different building systems for different purposes to enhance the adaptive capacity of a building. Thus, helping in designing future-proof adaptable structures with a modular approach for a sustainable future. KEYWORDS: adaptability; adaptable building; adaptive capacity; adaptability determinants; modular design; modules

Research on the Modular Design Strategy of Old Community Facilities for the Elderly based on "Gerontology"

With the intensification of the aging of the population, the adaptation of community space to the elderly has become an important issue that needs urgent attention in the renewal of community space. In view of the contradiction between the current public space facilities in old communities that are difficult to meet the growing needs of the elderly, this paper takes the old communities in Beijing as the research object, studies the modular design of the facilities suitable for the elderly in the old communities based on the behavioral needs of the elderly, analyzes the existing space problems and the needs of the elderly through site research and questionnaires, and finally puts forward design strategies and design schemes to provide ideas for the renewal of old community spaces.

Design a reducing CO2 emission system using nonfermentable substrates for carbon-economic biosynthesis of poly-2-hydrobutanedioic acid

Reducing carbon dioxide (CO2) emissions in the aerobic biorefinery system is becoming a crucial effort for achieving carbon-economic biosynthesis of biomaterials and chemicals. Poly-2-hydrobutanedioic acid (P2HBD), a long-carbon chain polyester produced by the fungus Aureobasidium pullulans, has garnered significant attention in the biomaterials and chemical industries. In this study, we designed a CO2 emission reduction system using nonfermentable substrates to enable efficient biosynthesis of P2HBD. Based on the genome-scale model iZX637 of A. pullulans, glycerol and ethanol were stimulated to show the potential advantages over glucose in terms of reduced CO2 emission. Additionally, we employed an NADH/NAD+ fluorescent probe called SoNar to dynamically monitor the reductive power ratio during CO2 emission. Subsequently, glycerol metabolism and rTCA carbon fixation pathway were engineered, while implementing a modular assembly strategy to achieve balanced integration between these two modules through precise promoter engineering regulation. The optimal strain ZX-LM03 showed the advantages of less carbon emission with glycerol and ethanol as the co-substrates, and achieved the higher P2HBD titer and yield of 15.07 ± 0.18 g/L and 0.54 ± 0.01 g/g, with the lower carbon emission of 31.08 % compared to glucose in the 5 L fermenter. In conclusion, this study provides novel insights into achieving carbon neutrality using renewable substrates for reducing carbon emission in aerobic fermentation systems.

A modular and multi-functional purification strategy that enables a common framework for manufacturing scale integrated and continuous biomanufacturing.

Biopharmaceutical manufacture is transitioning from batch to integrated and continuous biomanufacturing (ICB). The common framework for most ICB, potentially enables a global biomanufacturing ecosystem utilizing modular and multi-function manufacturing equipment. Integrating unit operation hardware and software from multiple suppliers, complex supply chains enabled by multiple customized single-use flow paths, and large volume buffer production/storage make this ICB vision difficult to achieve with commercially available manufacturing equipment. Thus, we developed SymphonX™, a downstream processing skid with advanced buffer management capabilities, a single disposable generic flow path design that provides plug-and-play flexibility across all downstream unit operations and a single interface to reduce operational risk. Designed for multi-product and multi-process cGMP facilities, SymphonX™ can perform stand-alone batch processing or ICB. This study utilized an Apollo™ X CHO-DG44 mAb-expressing cell line in a steady-state perfusion bioreactor, harvesting product continuously with a cell retention device and connected SymphonX™ purification skids. The downstream process used the same chemistry (resins, buffer composition, membrane composition) as our historical batch processing platform, with SymphonX™ in-line conditioning and buffer concentrates. We used surge vessels between unit operations, single-column chromatography (protein A, cation and anion exchange) and two-tank batch virus inactivation. After the first polishing step (cation exchange), we continuously pooled product for 6 days. These 6 day pools were processed in batch-mode from anion exchange to bulk drug substance. This manufacturing scale proof-of-concept ICB produced 0.54 kg/day of drug substance with consistent product quality attributes and demonstrated successful bioburden control for unit-operations undergoing continuous operation.

An Antibiotic Nanobomb Constructed from pH-Responsive Chemical Bonds in Metal-Phenolic Network Nanoparticles for Biofilm Eradication and Corneal Ulcer Healing.

In the treatment of refractory corneal ulcers caused by Pseudomonas aeruginosa, antibacterial drugs delivery faces the drawbacks of low permeability and short ocular surface retention time. Hence, novel positively-charged modular nanoparticles (NPs) are developed to load tobramycin (TOB) through a one-step self-assembly method based on metal-phenolic network and Schiff base reaction using 3,4,5-trihydroxybenzaldehyde (THBA), ε-poly-ʟ-lysine (EPL), and Cu2+ as matrix components. In vitro antibacterial test demonstrates that THBA-Cu-TOB NPs exhibit efficient instantaneous sterilization owing to the rapid pH responsiveness to bacterial infections. Notably, only 2.6µgmL-1 TOP is needed to eradicate P. aeruginosa biofilm in the nano-formed THBA-Cu-TOB owing to the greatly enhanced penetration, which is only 1.6% the concentration of free TOB (160µgmL-1). In animal experiments, THBA-Cu-TOB NPs show significant advantages in ocular surface retention, corneal permeability, rapid sterilization, and inflammation elimination. Based on molecular biology analysis, the toll-like receptor 4 and nuclear factor kappa B signaling pathways are greatly downregulated as well as the reduction of inflammatory cytokines secretions. Such a simple and modular strategy in constructing nano-drug delivery platform offers a new idea for toxicity reduction, physiological barrier penetration, and intelligent drug delivery.

Supramolecular Modular Assembly of Imaging-Trackable Enzymatic Nanomotors.

Self-propelled micro/nanomotors (MNMs) have shown great application potential in biomedicine, sensing, environmental remediation, etc. In the past decade, various strategies or technologies have been used to prepare and functionalize MNMs. However, the current preparation strategies of the MNMs were mainly following the pre-designed methods based on specific tasks to introduce expected functional parts on the various micro/nanocarriers, which lacks a universal platform and common features, making it difficult to apply to different application scenarios. Here, we have developed a modular assembly strategy based on host-guest chemistry, which enables the on-demand construction of imaging-trackable nanomotors mounted with suitable driving and imaging modules using a universal assembly platform, according to different application scenarios. These assembled nanomotors exhibited enhanced diffusion behavior driven by enzymatic reactions. The loaded imaging functions were used to dynamically trace the swarm motion behavior of assembled nanomotors with corresponding fuel conditions both in vitro and in vivo. The modular assembly strategy endowed with host-guest interaction provides a universal approach to producing multifunctional MNMs in a facile and controllable manner, which paves the way for the future development of MNMs systems with programmable functions.

Modular Synthesis of Improbable Rotaxanes with All-Benzene Scaffolds.

"Improbable" rotaxanes consisting of interlocked conjugated components represent non-trivial synthetic targets, not to mention those with all-benzene scaffolds. Herein, a modular synthetic strategy has been established using an isolable azo-linked pre-rotaxane as the core module, in which the azo group functions as a tracelessly removable template to direct mechanical bond formations. Through versatile connections of the pre-rotaxane and other customizable modules, [2]- and [3]rotaxanes derived from all-benzene scaffolds have been accomplished, demonstrating the utility and potential of the synthetic design for all-benzene interlocked supramolecules.

Modular Strategy for Constructing para-Cage[n]arenes, meta-Cage[n]arenes, and meta-Bimacrocyclic-Arenes.

Here, we present a versatile modular strategy for crafting novel covalent organic cages (para-cage[n]arenes and meta-cage[n]arenes, n = 3,4) and bimacrocycles (meta-bimacrocyclic-arenes) with stable backbones and modifiable rims. These structures can be synthesized from commercially available aromatic multialdehydes in a three-step process: quantitative bromination, Suzuki-Miyaura reaction (yielding over 60%), and a rapid one-pot Friedel-Crafts reaction with paraformaldehyde. Notably, the cage[n]arenes exhibit a well-defined prismatic shape, and the bimacrocyclic-arenes display both dimeric and monomeric configurations.

Data-Efficient Generation of Protein Conformational Ensembles with Backbone-to-Side-Chain Transformers.

Excitement at the prospect of using data-driven generative models to sample configurational ensembles of biomolecular systems stems from the extraordinary success of these models on a diverse set of high-dimensional sampling tasks. Unlike image generation or even the closely related problem of protein structure prediction, there are currently no data sources with sufficient breadth to parametrize generative models for conformational ensembles. To enable discovery, a fundamentally different approach to building generative models is required: models should be able to propose rare, albeit physical, conformations that may not arise in even the largest data sets. Here we introduce a modular strategy to generate conformations based on "backmapping" from a fixed protein backbone that (1) maintains conformational diversity of the side chains and (2) couples the side-chain fluctuations using global information about the protein conformation. Our model combines simple statistical models of side-chain conformations based on rotamer libraries with the now ubiquitous transformer architecture to sample with atomistic accuracy. Together, these ingredients provide a strategy for rapid data acquisition and hence a crucial ingredient for scalable physical simulation with generative neural networks.

A Modular Turn-On Strategy to Profile E2-Specific Ubiquitination Events in Living Cells.

A cascade of three enzymes, E1-E2-E3, is responsible for transferring ubiquitin to target proteins, which controls many different aspects of cellular signaling. The role of the E2 has been largely overlooked, despite influencing substrate identity, chain multiplicity, and topology. Here we report a method-targeted charging of ubiquitin to E2 (tCUbE)-that can track a tagged ubiquitin through its entire enzymatic cascade in living mammalian cells. We use this approach to reveal new targets whose ubiquitination depends on UbcH5a E2 activity. We demonstrate that tCUbE can be broadly applied to multiple E2s and in different human cell lines. tCUbE is uniquely suited to examine E2-E3-substrate cascades of interest and/or piece together previously unidentified cascades, thereby illuminating entire branches of the UPS and providing critical insight that will be useful for identifying new therapeutic targets in the UPS.

Exploiting Orthogonal C-C Cross-Coupling Reactions for Chemistry-on-the-Complex: Modular Assembly of 2,6-Di(quinolin-8-yl)pyridine Ruthenium(II) Photosensitizer Triads.

In this work, we present a concise modular assembly strategy using one universal heteroleptic 2,6-di(quinolin-8-yl)pyridine-based ruthenium(II) complex as a starting building block. Extending the concept from established ligand modifications and subsequent complexation (classical route), the later appearing chemistry-on-the-complex methodology was used for late-stage syntheses, i.e., assembling discrete building blocks to molecular architectures (here: dyad and triads). We focused on Suzuki-Miyaura and Sonogashira cross-couplings as two of the best-known C-C bond forming reactions. Both were performed on one building block complex bearing a bromine and TIPS-protected alkyne for functional group interconversion (bromine to TMS-protected alkyne, a benzyl azide, or a boronic acid pinacol ester moiety with ≥95% isolated yield and simple purification) as well as building block assemblies using both a triarylamine-based donor and a naphthalene diimide-based acceptor in up to 86% isolated yield. Additionally, the developed purification via automated flash chromatography is simple compared to tedious manual chromatography for ruthenium(II)-based substrates in the classical route. Based on the preliminary characterization by steady-state spectroscopy, the observed emission quenching in the triad (55%) serves as an entry to rationally optimize the modular units via chemistry-on-the-complex to elucidate energy and electron transfer.

A Modular Strategy for the Synthesis of Macrocycles and Medium-Sized Rings via Cyclization/Ring Expansion Cascade Reactions.

Macrocycles and medium-sized rings are important in many scientific fields and technologies but are hard to make using current methods, especially on a large scale. Outlined herein is a strategy by which functionalized macrocycles and medium-sized rings can be prepared using cyclization/ring expansion (CRE) cascade reactions, without resorting to high dilution conditions. CRE cascade reactions are designed to operate exclusively via kinetically favorable 5-7-membered ring cyclization steps; this means that the problems typically associated with classical end-to-end macrocyclization reactions are avoided. A modular synthetic approach has been developed to facilitate the simple assembly of the requisite linear precursors, which can then be converted into an extremely broad range of functionalized macrocycles and medium-sized rings using one of nine CRE protocols.

1D Covalent Organic Frameworks Triggering Highly Efficient Photosynthesis of H2 O2 via Controllable Modular Design.

The topological diversity of covalent organic frameworks (COFs) enables considerable space for exploring their structure-performance relationships. In this study, we report a sequence of novel 1D COFs (EO, ES, and ESe-COF) with typical 4-c sql topology that can be interconnected with VIA group elements (O, S, and Se) via a modular design strategy. It is found that the electronic structures, charge delivery property, light harvesting ability, and hydrophilicity of these 1D COFs can be profoundly influenced by the bridge-linked atom ordinal. Finally, EO-COF, possessing the highest quantity of active sites, the longest lifetime of the active electron, the strongest interaction with O2 , and the lowest energy barrier of O2 reduction, exhibits exceptional photocatalytic O2 -to-H2 O2 activity under visible light, with a production rate of 2675 μmol g-1 h-1 and a high apparent quantum yield of 6.57 % at 450 nm. This is the first systematic report on 1D COFs for H2 O2 photosynthesis, which enriches the topological database in reticular chemistry and promotes the exploration of structure-catalysis correlation.

1D Covalent Organic Frameworks Triggering Highly Efficient Photosynthesis of H2O2 via Controllable Modular Design

AbstractThe topological diversity of covalent organic frameworks (COFs) enables considerable space for exploring their structure‐performance relationships. In this study, we report a sequence of novel 1D COFs (EO, ES, and ESe‐COF) with typical 4‐c sql topology that can be interconnected with VIA group elements (O, S, and Se) via a modular design strategy. It is found that the electronic structures, charge delivery property, light harvesting ability, and hydrophilicity of these 1D COFs can be profoundly influenced by the bridge‐linked atom ordinal. Finally, EO‐COF, possessing the highest quantity of active sites, the longest lifetime of the active electron, the strongest interaction with O2, and the lowest energy barrier of O2 reduction, exhibits exceptional photocatalytic O2‐to‐H2O2 activity under visible light, with a production rate of 2675 μmol g−1 h−1 and a high apparent quantum yield of 6.57 % at 450 nm. This is the first systematic report on 1D COFs for H2O2 photosynthesis, which enriches the topological database in reticular chemistry and promotes the exploration of structure‐catalysis correlation.

Anti-tumor immunotherapy using engineered bacterial outer membrane vesicles fused to lysosome-targeting chimeras mediated by transferrin receptor

The lysosome-targeting chimera (LYTAC) approach has shown promise for the targeted degradation of secreted and membrane proteins via lysosomes. However, there have been challenges in design, development, and targeting. Here, we have designed a genetically engineered transferrin receptor (TfR)-mediated lysosome-targeting chimera (TfR-LYTAC) that is efficiently internalized via TfR-mediate endocytosis and targets PD-L1 for lysosomal degradation in cultured cells but not invivo due to short half-life and poor tumor targeting. A delivery platform was developed by fusing TfR-LYTAC to the surface of bacterial outer membrane vesicles (OMVs). The engineered OMV-LYTAC combines PD-1/PD-L1 pathway inhibition with LYTAC and immune activation by bacterial OMVs. OMV-LYTAC significantly reduced tumor growth invivo. We have provided a modular and simple genetic strategy for lysosomal degradation as well as a delivery platform for invivo tumor targeting. The study paves the way for the targeting and degradation of extracellular proteins using the TfR-LYTAC system.