Modular Platform Research Articles

Rapid Synthesis of Chiral Figure-Eight Macrocycles Using a Preorganized Natural Product-Based Scaffold.

Chiral D2 -symmetric figure-eight shaped macrocycles are promising scaffolds for amplifying the chiroptical properties of π-conjugated systems. By harnessing the inherent and adaptable conformational dynamics of a chiral C2 -symmetric bispyrrolidinoindoline (BPI) manifold, we developed an enantio-divergent modular synthetic platform to rapidly generate a diverse range of chiral macrocycles, spanning from 14- to 66-membered rings, eliminating the need for optical resolution. Notably, a 32-membered figure-eight macrocycle showed excellent circularly polarized luminescence (CPL: |glum |=1.1×10-2 ) complemented by a robust emission quantum yield (Φfl =0.74), to achieve outstanding CPL brightness (BCPL : ϵ×Φfl ×|glum |/2=480). Using quadruple Sonogashira couplings, this versatile synthetic platform enables precise adjustments of the angle, distance, and length among intersecting π-conjugated chromophores. Our synthetic strategy offers a streamlined and systematic approach to significantly enhance BCPL values for a variety of chiral D2 -symmetric figure-eight macrocycles.

MBPPE: A Modular Batch Processing Platform for Electroencephalography

To ensure the accuracy and reliability of subsequent analysis, research on electroencephalogram (EEG) signals typically requires preliminary processing of large datasets to eliminate noise and artifacts. Traditional batch processing methods require substantial hardware resources while lacking flexible automated workflows and user-friendly interactions. To address these challenges, we have implemented a modular batch processing platform for EEG (MBPPE) that offers both local execution and private deployment options to meet the demands of efficient signal processing from individuals to laboratories. We modularize the processing methods and organize them into pluggable multi-task batch processes, providing asynchronous processing solutions. In addition, we extend user functions by introducing plugins and promoting collaborative interaction through data sharing, access control, and comment communication. Simultaneously, interactive features are integrated into the visualization design, enabling users to process and analyze data more intuitively and naturally. Currently, the platform integrates several commonly used data preprocessing and analysis techniques, providing a novel solution for batch processing of EEG signals.

Enabling Personalization for Digital Cognitive Stimulation to Support Communication With People With Dementia: Pilot Intervention Study as a Prelude to AI Development.

Maintaining good communication and engagement between people with dementia and their caregivers is a major challenge in dementia care. Cognitive stimulation is a psychosocial intervention that supports communication and engagement, and several digital applications for cognitive stimulation have been developed. Personalization is an important factor for obtaining sustainable benefits, but the time and effort required to personalize and optimize applications often makes them difficult for routine use by nonspecialist caregivers and families. Although artificial intelligence (AI) has great potential to support automation of the personalization process, its use is largely unexplored because of the lack of suitable data from which to develop and train machine learning models. This pilot study aims to evaluate a digital application called Aikomi in Japanese care homes for its potential to (1) create and deliver personalized cognitive stimulation programs to promote communication and engagement between people with dementia and usual care staff and (2) capture meaningful personalized data suitable for the development of AI systems. A modular technology platform was developed and used to create personalized programs for 15 people with dementia living in 4 residential care facilities in Japan with the cooperation of a family member or care staff. A single intervention with the program was conducted with the person with dementia together with a care staff member, and for some participants, smell stimulation was provided using selected smell sticks in conjunction with the digital program. All sessions were recorded using a video camera, and the combined personalized data obtained by the platform were analyzed. Most people with dementia (10/15, 67%) showed high levels of engagement (>40 on Engagement of a Person with Dementia Scale), and there were no incidences of negative reactions toward the programs. Care staff reported that some participants showed extended concentration and spontaneous communication while using Aikomi, which was not their usual behavior. Smell stimulation promoted engagement for some participants even when they were unable to identify the smell. No changes in well-being were observed following the intervention according to the Mental Function Impairment Scale. The level of response to each type of content in the stimulation program varied greatly according to the person with dementia, and personalized data captured by the Aikomi platform enabled understanding of correlations between stimulation content and responses for each participant. This study suggests that the Aikomi digital application is acceptable for use by persons with dementia and care staff and may have the potential to promote communication and engagement. The platform captures personalized data, which can provide suitable input for machine learning. Further investigation of Aikomi will be conducted to develop AI systems and create personalized digital cognitive stimulation applications that can be easily used by nonspecialist caregivers.

Development of a Smart Wireless Multisensor Platform for an Optogenetic Brain Implant.

Implantable cell replacement therapies promise to completely restore the function of neural structures, possibly changing how we currently perceive the onset of neurodegenerative diseases. One of the major clinical hurdles for the routine implementation of stem cell therapies is poor cell retention and survival, demanding the need to better understand these mechanisms while providing precise and scalable approaches to monitor these cell-based therapies in both pre-clinical and clinical scenarios. This poses significant multidisciplinary challenges regarding planning, defining the methodology and requirements, prototyping and different stages of testing. Aiming toward an optogenetic neural stem cell implant controlled by a smart wireless electronic frontend, we show how an iterative development methodology coupled with a modular design philosophy can mitigate some of these challenges. In this study, we present a miniaturized, wireless-controlled, modular multisensor platform with fully interfaced electronics featuring three different modules: an impedance analyzer, a potentiostat and an optical stimulator. We show the application of the platform for electrical impedance spectroscopy-based cell monitoring, optical stimulation to induce dopamine release from optogenetically modified neurons and a potentiostat for cyclic voltammetry and amperometric detection of dopamine release. The multisensor platform is designed to be used as an opto-electric headstage for future in vivo animal experiments.

Reductive Radical-Polar Crossover Enabled Carboxylative Alkylation of Aryl Thianthrenium Salts with CO2 and Styrenes.

Carboxylic functionalities are among the pivotal groups in bioactive molecules and in the synthesis of new lead compounds because of their unique character in the formation of hydrogen bonds and the possibility of constructing molecular complexes via amide couplings. We adopt the reductive radical-polar crossover strategy to introduce carboxyalkyl groups into arenes with styrenes and CO2 via thianthrenium salts. This protocol exhibits excellent potential as a straightforward and modular platform for site-selective carboxylative derivation of bioactive molecules.

Inhalable point-of-care urinary diagnostic platform.

Although low-dose computed tomography screening improves lung cancer survival in at-risk groups, inequality remains in lung cancer diagnosis due to limited access to and high costs of medical imaging infrastructure. We designed a needleless and imaging-free platform, termed PATROL (point-of-care aerosolizable nanosensors with tumor-responsive oligonucleotide barcodes), to reduce resource disparities for early detection of lung cancer. PATROL formulates a set of DNA-barcoded, activity-based nanosensors (ABNs) into an inhalable format. Lung cancer-associated proteases selectively cleave the ABNs, releasing synthetic DNA reporters that are eventually excreted via the urine. The urinary signatures of barcoded nanosensors are quantified within 20 min at room temperature using a multiplexable paper-based lateral flow assay. PATROL detects early-stage tumors in an autochthonous lung adenocarcinoma mouse model with high sensitivity and specificity. Tailoring the library of ABNs may enable not only the modular PATROL platform to lower the resource threshold for lung cancer early detection tools but also the rapid detection of chronic pulmonary disorders and infections.

Max Well-Being: a modular platform for the gamification of rehabilitation.

This study proposes a modular platform to improve the adoption of gamification in conventional physical rehabilitation programs. The effectiveness of rehabilitation is correlated to a patient's adherence to the program. This adherence can be diminished due to factors such as motivation, feedback, and isolation. Gamification is a means of adding game-like elements to a traditionally non-game activity. This has been shown to be effective in providing a more engaging experience and improving adherence. The platform is made of three main parts; a central hardware hub, various wired and wireless sensors, and a software program with a stream-lined user interface. The software interface and hardware peripherals were all designed to be simple to use by either a medical specialist or an end-user patient without the need for technical training. A usability study was performed using a group of university students and a group of medical specialists. Using the System Usability Scale, the system received an average score of 69.25 ± 20.14 and 72.5 ± 17.16 by the students and medical specialists, respectively. We also present a framework that attempts to assist in selecting commercial games that are viable for physical rehabilitation.

Autonomous nanomanufacturing of lead-free metal halide perovskite nanocrystals using a self-driving fluidic lab.

Lead-based metal halide perovskite (MHP) nanocrystals (NCs) have emerged as a promising class of semiconducting nanomaterials for a wide range of optoelectronic and photoelectronic applications. However, the intrinsic lead toxicity of MHP NCs has significantly hampered their large-scale device applications. Copper-base MHP NCs with composition-tunable optical properties have emerged as a prominent lead-free MHP NC candidate. However, comprehensive synthesis space exploration, development, and synthesis science studies of copper-based MHP NCs have been limited by the manual nature of flask-based synthesis and characterization methods. In this study, we present an autonomous approach for the development of lead-free MHP NCs via seamless integration of a modular microfluidic platform with machine learning-assisted NC synthesis modeling and experiment selection to establish a self-driving fluidic lab for accelerated NC synthesis science studies. For the first time, a successful and reproducible in-flow synthesis of Cs3Cu2I5 NCs is presented. Autonomous experimentation is then employed for rapid in-flow synthesis science studies of Cs3Cu2I5 NCs. The autonomously generated experimental NC synthesis dataset is then utilized for fast-tracked synthetic route optimization of high-performing Cs3Cu2I5 NCs.

Modularized supramolecular assemblies for hypoxia-activatable fluorescent visualization and image-guided theranostics.

Rationale: Molecular imaging of microenvironment by hypoxia-activatable fluorescence probes has emerged as an attractive approach to tumor diagnosis and image-guided treatment. Difficulties remain in its translational applications due to hypoxia heterogeneity in tumor microenvironments, making it challenging to image hypoxia as a reliable proxy of tumor distribution. Methods: We report a modularized theranostics platform to fluorescently visualize hypoxia via light-modulated signal compensation to overcome tumor heterogeneity, thereby serving as a diagnostic tool for image-guided surgical resection and photodynamic therapy. Specifically, the platform integrating dual modules of fluorescence indicator and photodynamic moderator using supramolecular host-guest self-assembly, which operates cooperatively as a cascaded "AND" logic gate. First, tumor enrichment and specific fluorescence turn-on in hypoxic regions were accessible via tumor receptors and cascaded microenvironment signals as simultaneous inputs of the "AND" gate. Second, image guidance by a lighted fluorescence module and light-mediated endogenous oxygen consumption of a photodynamic module as dual inputs of "AND" gate collaboratively enabled light-modulated signal compensation in situ, indicating homogeneity of enhanced hypoxia-related fluorescence signals throughout a tumor. Results: In in vitro and in vivo analyses, the biocompatible platform demonstrated several strengths including a capacity for dual tumor targeting to progressively facilitate specific fluorescence turn-on, selective signal compensation, imaging-time window extension conducive to precise normalized image-guided treatment, and the functionality of tumor glutathione depletion to improve photodynamic efficacy. Conclusion: The hypoxia-activatable, image-guided theranostic platform demonstrated excellent potential for overcoming hypoxia heterogeneity in tumors.

A Modular Co-Simulation Platform for Comparing Flexibility Solutions in District Heating Under Variable Operating Conditions

A Modular Co-Simulation Platform for Comparing Flexibility Solutions in District Heating Under Variable Operating Conditions

Vaccination against neoantigens induced in cross-priming cDC1 in vivo

The conventional type 1 dendritic cells (cDC1) play a pivotal role in protective immunity against pathogens and cancer. However, their low frequency in the blood and tissues limits their use in immune therapy. We have recently described a method to vaccinate against neoantigens that are induced in tumor cells by targeted delivery of a TAP siRNA to dendritic cells using a TLR9 binding CpG oligonucleotide. Since TLR9 is also expressed in immune suppressive myeloid populations TLR9 targeting could reduce the effectiveness of this approach. Here, we describe a modular multivalent antibody platform to target the TAP siRNA to resident Clec9a expressing cDC1 and show that it leads to selective and sustained TAP downregulation in cDC1 and inhibits tumor growth in mice more effectively than CpG targeted siRNA. To induce DC maturation an agonistic CD40 antibody was administered to the siRNA treated mice. To obviate the need for a second drug formulation and reduce the risk of toxicity, we exploited the multivalent nature of this targeting platform to co-deliver the TAP siRNA and a DC maturation agent, a CpG containing oligonucleotide, to cDC1 in vivo and show that it was more effective than Clec9a targeting of TAP siRNA in combination with CD40 antibody. This study describes a way to manipulate the function of cDC1 cells in vivo using a broadly applicable antibody-based targeting platform to deliver multiple biological agents to specific cells in vivo to potentiate (immune) therapy and to probe the biology of specific cell types in their natural settings.

Design, modeling, and experimental analysis of the Crawler Unit for inspection in constrained space

Inspections of industrial and civil infrastructures prevent unexpected failures that may lead to loss of life. Although inspection robotics is gaining momentum, most of field operations are still performed by human workers. For inspection robots, the main limiting factors are the low versatility and reliability in dynamic, non-structured and highly complex environments. To tackle these issues, we have designed a modular and self-reconfigurable hybrid platform, which consists of three units: the mobile Main Base and two Crawler Units with docking interfaces. The Crawler Unit operates in constrained environments and narrow spaces, while the Main Base will inspect wide areas and deploy/recover the Crawler Units near/from inspection sites, as in marsupial robots. Docking interfaces will allow the Crawler Units to reconfigure into a snake robot or mobile manipulators. In particular, the Crawler Units consist of four modules connected by three kinematic chains for nine active joints in total. Each module is equipped with half active, half passive tracks for moving. This paper discusses in detail the dynamic model of the Crawler Unit, especially focusing on the definition of effective constraint equations, which closely model the system features avoiding common simplifications. Numerical simulations and physical experiments validate the proposed dynamic model of the Crawler Unit.

Regulating H2S release from self-assembled peptide H2S-donor conjugates using cysteine derivatives.

Self-assembled peptides provide a modular and diverse platform for drug delivery, and innovative delivery methods are needed for delivery of hydrogen sulfide (H2S), an endogenous signaling molecule (gasotransmitter) with significant therapeutic potential. Of the available types of H2S donors, peptide/protein H2S donor conjugates (PHDCs) offer significant versatility. Here we discuss the design, synthesis, and in-depth study of a PHDC containing three covalently linked components: a thiol-triggered H2S donor based on an S-aroylthiooxime (SATO), a GFFF tetrapeptide, and a tetraethylene glycol (TEG) dendron. Conventional transmission electron microscopy showed that the PHDC self-assembled into spherical structures without heat or stirring, but it formed nanofibers with gentle heat (37 °C) and stirring. Circular dichroism (CD) spectroscopy data collected during self-assembly under nanofiber-forming conditions suggested an increase in β-sheet character and a decrease in organization of the SATO units. Release of H2S from the nanofibers was studied through triggering with various thiols. The release rate and total amount of H2S released over both short (5 h) and long (7 d) time scales varied with the charge state: negatively charged and zwitterionic thiols (e.g., Ac-Cys-OH and H-Cys-OH) triggered release slowly while a neutral thiol (Ac-Cys-OMe) showed ∼10-fold faster release, and a positively charged thiol (H-Cys-OMe) triggered H2S release nearly 50-fold faster than the negatively charged thiols. CD spectroscopy studies monitoring changes in secondary structure over time during H2S release showed similar trends. This study sheds light on the driving forces behind self-assembling nanostructures and offers insights into tuning H2S release through thiol charge state modulation.

Bioluminescent detection of viral surface proteins using branched multivalent protein switches

Modular virus diagnostics is key to prevent virus spread. Here, we combine state-of-the-art synthetic biology tools to create a modular bioluminescent sensor platform of branched, multivalent protein switches for detecting viral surface proteins.

AMPERE: automated modular platform for expedited and reproducible electrochemical testing

AMPERE automates sample preparation and electrochemical testing at large scale, enhancing speed, reliability, and openness. It uses a liquid-handling robot with modular reactors to measure metal dissolution for electrochemical stability assessment.

Synthesis of axially chiral diaryl ethers via NHC-catalyzed atroposelective esterification.

Axially chiral diaryl ethers bearing two potential axes find unique applications in bioactive molecules and catalysis. However, only very few catalytic methods have been developed to construct structurally diverse diaryl ethers. We herein describe an NHC-catalyzed atroposelective esterification of prochiral dialdehydes, leading to the construction of enantioenriched axially chiral diaryl ethers. Mechanistic studies indicate that the matched kinetic resolutions play an essential role in the challenging chiral induction of flexible dual-axial chirality by removing minor enantiomers via over-functionalization. This protocol features mild conditions, excellent enantioselectivity, broad substrate scope, and applicability to late-stage functionalization, and provides a modular platform for the synthesis of axially chiral diaryl ethers and their derivatives.

Validation of Snaptics: A Modular Approach to Low-Cost Wearable Multi-Sensory Haptics.

Wearable haptic devices provide touch feedback to users for applications including virtual reality, prosthetics, and navigation. When these devices are designed for experimental validation in research settings, they are often highly specialized and customized to the specific application being studied. As such, it can be difficult to replicate device hardware due to the associated high costs of customized components and the complexity of their design and construction. In this work, we present Snaptics, a simple and modular platform designed for rapid prototyping of fully wearable multi-sensory haptic devices using 3D-printed modules and inexpensive off-the-shelf components accessible to the average hobbyist. We demonstrate the versatility of the modular system and the salience of haptic cues produced by wearables constructed with Snaptics modules in two human subject experiments. First, we report on the identification accuracy of multi-sensory haptic cues delivered by a Snaptics device. Second, we compare the effectiveness of the Snaptics Vibrotactile Bracelet to the Syntacts Bracelet, a high-fidelity wearable vibration feedback bracelet, in assisting participants with a virtual reality sorting task. Results indicate that participant performance was comparable in perceiving cue sets and in completing tasks when interacting with low-cost Snaptics devices as compared to a similar research-grade haptic wearables.

Impact of synthesis methods on the functionality of antibody-conjugated gold nanoparticles for targeted therapy.

Gold nanoparticles (GNPs) are emerging as promising modular platforms for antibody-based cancer therapeutics. Their unique physiochemical properties enable efficient binding of multiple antibodies upon a single particle, thereby enhancing therapeutic potential. However, the effect of widely used synthesis techniques on the characteristics and functionality of antibody-GNP platforms has yet to be fully understood. Here, we investigated the effect of key synthesis approaches, namely, covalent binding and physical adsorption, on the properties and anti-cancer functionality of antibody-coated GNPs. By carefully manipulating synthesis variables, including antibody mass in reaction and linker compositions, we revealed a direct impact of these synthesis methods on antibody binding efficiency and anti-cancer functionality. We found that covalent binding of antibodies to GNPs generated a platform with increased cancer cell killing functionality as compared to the adsorption approach. Additionally, a higher antibody mass in the synthesis reaction and a higher polyethylene glycol linker ratio upon covalently bound antibody-GNPs led to increased cell death. Our findings emphasize the critical role of synthesis strategies in determining the functionality of targeted GNPs for effective cancer therapy.

Chemo-, regio-, and stereoselective tetrafunctionalization of fluoroalkynes enables divergent synthesis of 5-7-membered azacycles.

Alkyne annulation has been widely used in organic synthesis for the construction of azacycles with unique structural and physicochemical properties. However, the analogous transformation of fluoroalkynes remains a challenge and has seen limited progress. Herein we report a 1,2,3,4-tetrafunctionalization of polyfluoroalkynes for the divergent construction of 5-7-membered (E)-1,2-difluorovinyl azacycles. The use of the fluorine atom as a detachable "activator" not only obviates the use of any transition metal catalysts and oxidizing reagents, but also ensures the [3-5 + 2]-annulation and defluorinative functionalization of fluoroalkynes with high chemo-, regio-, and stereoselectivities. This method exhibits a broad substrate scope, good functional group tolerance, and excellent scalability, providing a modular platform for accessing fluorinated skeletons of medicinal and biological interest. The late-stage modification of complex molecules, the multi-component 1,2-diamination of fluoroalkyne, and the synthesis of valuable organofluorides from the obtained products further highlight the real-world utility of this fluoroalkyne annulation technology.

Biomineralized in situ catalytic nanoreactor integrated microneedle patch for on demand immunomodulator supply to combat psoriasis.

The endogenous immunomodulator adenosine (ADO) was expected to be potentialized as an efficacious mediator to combat psoriasis. However, its efficacy is severely hindered by its poor metabolic stability and insufficient accumulation at the dermatological lesions. Methods: In this study, a biomineralized in situ catalytic nanoreactor was delicately customized by encapsulating ADO precursor (adenosine monophosphate, AMP) within the internal porous skeleton of zeolitic imidazolate framework-90, followed by the biomineralization of the AMP catabolic enzyme on the outer layer. The nanocrystals were then incorporated into a dissolving microneedles patch, which was designed to deliver drugs with precision into the cutaneous lesion and enhance the efficacy of psoriasis treatment. Results: Upon penetration into the skin, the nanoreactors were released and underwent a gradual collapse of their structure, releasing AMP when exposed to the acidic microenvironment. Meanwhile, the acidic pH could trigger an in situ catalytic reaction to continuously produce ADO. This system yielded remarkable results in a psoriasis-like mouse model. The mechanism study demonstrated that this system could substantially reshape the inflammatory ecosystem by inhibiting the keratinocyte hyperplasia, reducing inflammatory cytokine expression, and regulating the infiltration of immune cells. Conclusion: The in situ catalytic nanoreactor integrated microneedle patch is a promising modular platform for co-delivery of prodrugs and their catabolic enzymes, offering a potential solution for various diseases.