Structure and Mechanisms of Assembly-Line Polyketide Synthases.

Three decades of studies on the multifunctional 6-deoxyerythronolide B synthase have laid a foundation for understanding the chemistry and evolution of polyketide antibiotic biosynthesis by a large family of versatile enzymatic assembly lines. Recent progress in applying chemical and structural biology tools to this prototypical assembly-line polyketide synthase (PKS) and related systems has highlighted several features of their catalytic cycles and associated protein dynamics. There is compelling evidence that multiple mechanisms have evolved in this enzyme family to channel growing polyketide chains along uniquely defined sequences of 10-100 active sites, each of which is used only once in the overall catalytic cycle of an assembly-line PKS. Looking forward, one anticipates major advances in our understanding of the mechanisms by which the free energy of a repetitive Claisen-like reaction is harnessed to guide the growing polyketide chain along the assembly line in a manner that is kinetically robust yet evolutionarily adaptable.

Multisubstrate specificity shaped the complex evolution of the aminotransferase family across the tree of life.

Aminotransferases (ATs) are an ancient enzyme family that play central roles in core nitrogen metabolism, essential to all organisms. However, many of the AT enzyme functions remain poorly defined, limiting our fundamental understanding of the nitrogen metabolic networks that exist in different organisms. Here, we traced the deep evolutionary history of the AT family by analyzing AT enzymes from 90 species spanning the tree of life (ToL). We found that each organism has maintained a relatively small and constant number of ATs. Mapping the distribution of ATs across the ToL uncovered that many essential AT reactions are carried out by taxon-specific AT enzymes due to wide-spread nonorthologous gene displacements. This complex evolutionary history explains the difficulty of homology-based AT functional prediction. Biochemical characterization of diverse aromatic ATs further revealed their broad substrate specificity, unlike other core metabolic enzymes that evolved to catalyze specific reactions today. Interestingly, however, we found that these AT enzymes that diverged over billion years share common signatures of multisubstrate specificity by employing different nonconserved active site residues. These findings illustrate that AT family enzymes had leveraged their inherent substrate promiscuity to maintain a small yet distinct set of multifunctional AT enzymes in different taxa. This evolutionary history of versatile ATs likely contributed to the establishment of robust and diverse nitrogen metabolic networks that exist throughout the ToL. The study provides a critical foundation to systematically determine diverse AT functions and underlying nitrogen metabolic networks across the ToL.

CELA-MFP: a contrast-enhanced and label-adaptive framework for multi-functional therapeutic peptides prediction.

Functional peptides play crucial roles in various biological processes and hold significant potential in many fields such as drug discovery and biotechnology. Accurately predicting the functions of peptides is essential for understanding their diverse effects and designing peptide-based therapeutics. Here, we propose CELA-MFP, a deep learning framework that incorporates feature Contrastive Enhancement and Label Adaptation for predicting Multi-Functional therapeutic Peptides. CELA-MFP utilizes a protein language model (pLM) to extract features from peptide sequences, which are then fed into a Transformer decoder for function prediction, effectively modeling correlations between different functions. To enhance the representation of each peptide sequence, contrastive learning is employed during training. Experimental results demonstrate that CELA-MFP outperforms state-of-the-art methods on most evaluation metrics for two widely used datasets, MFBP and MFTP. The interpretability of CELA-MFP is demonstrated by visualizing attention patterns in pLM and Transformer decoder. Finally, a user-friendly online server for predicting multi-functional peptides is established as the implementation of the proposed CELA-MFP and can be freely accessed at http://dreamai.cmii.online/CELA-MFP.

Realizing the multifunctional metamaterial for fluid flow in a porous medium.

Metamaterials are artificial materials that can achieve unusual properties through unique structures. In particular, their "invisibility" property has attracted enormous attention due to its little or negligible disturbance to the background field that avoids detection. This invisibility feature is not only useful for the optical field, but it is also important for any field manipulation that requires minimum disturbance to the background, such as the flow field manipulation inside the human body. There are several conventional invisible metamaterial designs: a cloak can isolate the influence between the internal and external fields, a concentrator can concentrate the external field to form an intensified internal field, and a rotator can rotate the internal field by a specific angle with respect to the external field. However, a multifunctional invisible device that can continuously tune across all these functions has never been realized due to its challenging requirements on material properties. Inside a porous medium flow, however, we overcome these challenges and realize such a multifunctional metamaterial. Our hydrodynamic device can manipulate both the magnitude and the direction of the internal flow and, at the same time, make negligible disturbance to the external flow. Thus, we integrate the functions of the cloak, concentrator, and rotator within one single hydrodynamic metamaterial, and such metamaterials may find potential applications in biomedical areas such as tissue engineering and drug release.

Cryo-EM structures show the mechanistic basis of pan-peptidase inhibition by human α2-macroglobulin.

Human α2-macroglobulin (hα2M) is a multidomain protein with a plethora of essential functions, including transport of signaling molecules and endopeptidase inhibition in innate immunity. Here, we dissected the molecular mechanism of the inhibitory function of the ∼720-kDa hα2M tetramer through eight cryo­electron microscopy (cryo-EM) structures of complexes from human plasma. In the native complex, the hα2M subunits are organized in two flexible modules in expanded conformation, which enclose a highly porous cavity in which the proteolytic activity of circulating plasma proteins is tested. Cleavage of bait regions exposed inside the cavity triggers rearrangement to a compact conformation, which closes openings and entraps the prey proteinase. After the expanded-to-compact transition, which occurs independently in the four subunits, the reactive thioester bond triggers covalent linking of the proteinase, and the receptor-binding domain is exposed on the tetramer surface for receptor-mediated clearance from circulation. These results depict the molecular mechanism of a unique suicidal inhibitory trap.

Dynamic multifunctional devices enabled by ultrathin metal nanocoatings with optical/photothermal and morphological versatility.

Inspired by the intriguing adaptivity of natural life, such as squids and flowers, we propose a series of dynamic and responsive multifunctional devices based on multiscale structural design, which contain metal nanocoating layers overlaid with other micro-/nanoscale soft or rigid layers. Since the optical/photothermal properties of a metal nanocoating are thickness dependent, metal nanocoatings with different thicknesses were chosen to integrate with other structural design elements to achieve dynamic multistimuli responses. The resultant devices demonstrate 1) strain-regulated cracked and/or wrinkled topography with tunable light-scattering properties, 2) moisture/photothermal-responsive structural color coupled with wrinkled surface, and 3) mechanically controllable light-shielding properties attributed to the strain-dependent crack width of the nanocoating. These devices can adapt external stimuli, such as mechanical strain, moisture, light, and/or heat, into corresponding changes of optical signals, such as transparency, reflectance, and/or coloration. Therefore, these devices can be applied as multistimuli-responsive encryption devices, smart windows, moisture/photothermal-responsive dynamic optics, and smartphone app-assisted pressure-mapping sensors. All the devices exhibit high reversibility and rapid responsiveness. Thus, this hybrid system containing ultrathin metal nanocoatings holds a unique design flexibility and adaptivity and is promising for developing next-generation multifunctional devices with widespread application.

Multiwavelength Achromatic Deflector in the Visible Using a Single-Layer Freeform Metasurface.

Deflectors are essential for modulating beam direction in optical systems but often face form factor issues or chromatic aberration with conventional optical elements, such as prisms, mirrors, and diffractive/holographic optical elements. Despite recent efforts to address such issues using metasurfaces, their practicality remains limited due to operation wavelengths in the near-infrared or the fabrication difficulties inherent in the multilayer scheme. Here, we propose a novel single-layer metasurface achieving multiwavelength chromatic aberration-free deflection across the visible spectrum by employing the robust freeform design strategy to simplify the fabrication process. By properly selecting diffraction orders for red, green, and blue wavelengths to achieve identical wavelength-diffraction-order products, the metasurface deflects light at a consistent angle of 41.3° with a high efficiency. The coupled Bloch mode analysis explains the physical properties, and experimental fabrication and characterization confirm its effectiveness. This approach holds potential for various applications such as AR/VR, digital cameras, and high-quality optical systems.

Microenvironment with NIR-Controlled ROS and Mechanical Tensions for Manipulating Cell Activities in Wound Healing.

The extracellular matrix (ECM) orchestrates cell behavior and tissue regeneration by modulating biochemical and mechanical signals. Manipulating cell-material interactions is crucial for leveraging biomaterials to regulate cell functions. Yet, integrating multiple cues in a single material remains a challenge. Here, near-infrared (NIR)-controlled multifunctional hydrogel platforms, named PIC/CM@NPs, are introduced to dictate fibroblast behavior during wound healing by tuning the matrix oxidative stress and mechanical tensions. PIC/CM@NPs are prepared through cell adhesion-medicated assembly of collagen-like polyisocyanide (PIC) polymers and cell-membrane-coated conjugated polymer nanoparticles (CM@NPs), which closely mimic the fibrous structure and nonlinear mechanics of ECM. Upon NIR stimulation, PIC/CM@NPs composites enhance fibroblast cell proliferation, migration, cytokine production, and myofibroblast activation, crucial for wound closure. Moreover, they exhibit effective and toxin removal antibacterial properties, reducing inflammation. This multifunctional approach accelerates healing by 95%, highlighting the importance of integrating biochemical and biophysical cues in the biomaterial design for advanced tissue regeneration.

Physiological Microenvironment Dependent Self-Cross-Linking of Multifunctional Nanohybrid for Prolonged Antibacterial Therapy via Synergistic Chemodynamic-Photothermal-Biological Processes.

Herein, a multifunctional nanohybrid (PL@HPFTM nanoparticles) was fabricated to perform the integration of chemodynamic therapy, photothermal therapy, and biological therapy over the long term at a designed location for continuous antibacterial applications. The PL@HPFTM nanoparticles consisted of a polydopamine/hemoglobin/Fe2+ nanocomplex with comodification of tetrazole/alkene groups on the surface as well as coloading of antimicrobial peptides and luminol in the core. During therapy, the PL@HPFTM nanoparticles would selectively cross-link to surrounding bacteria via tetrazole/alkene cycloaddition under chemiluminescence produced by the reaction between luminol and overexpressed H2O2 at the infected area. The resulting PL@HPFTM network not only significantly damaged bacteria by Fe2+-catalyzed ROS production, effective photothermal conversion, and sustained release of antimicrobial peptides but dramatically enhanced the retention time of these therapeutic agents for prolonged antibacterial therapy. Both in vitro and in vivo results have shown that our PL@HPFTM nanoparticles have much higher bactericidal efficiency and remarkably longer periods of validity than free antibacterial nanoparticles.

Comprehensive insight on protein modification by V-type agent: A chemical proteomic approach employing bioorthogonal reaction.

Organophosphorus compounds (OPs) such as chemical agents and pesticides are posing critical threats to civilians due to their irreversible phosphonylation of diverse amino acids residues forming different protein adducts. However, traditional analytical approaches are quite limited in capturing the myriad of post-translational events that affect protein functions, especially in identifying the low-abundance OP adducts. Herein a systematic proteomic strategy based on a typical click-enrich-release-identify bioorthogonal operation was firstly developed by employing an alkynyl-tagged V-type agent probe (AVP) and a biotin-based azido-enrichment linker (BTP-N3 ). AVP targeting peptides from human serum albumin (HSA) or plasma were captured by BTP-N3 via CuAAC click reaction, enriched by streptavidin beads, released by selective alkaline hydrolysis of phenacyl ester bond, and subsequently sequenced by LC-MS/MS. This strategy has helped identifying 1115 unique OP adduction sites on 163 proteins in human plasma, and covers lots of OP adducts that cannot be achieved by traditional detection methods. The comprehensive coverage of novel OP substrates provided a general and sensitive approach to retrospective verification and/or dose assessment of toxic OPs.

Novel exported fusion enzymes with chorismate mutase and cyclohexadienyl dehydratase activity: Shikimate pathway enzymes teamed up in no man's land.

Chorismate mutase (CM) and cyclohexadienyl dehydratase (CDT) catalyze two subsequent reactions in the intracellular biosynthesis of l-phenylalanine (Phe). Here, we report the discovery of novel and extremely rare bifunctional fusion enzymes, consisting of fused CM and CDT domains, which are exported from the cytoplasm. Such enzymes were found in only nine bacterial species belonging to non-pathogenic γ- or ß-Proteobacteria. In γ-proteobacterial fusion enzymes, the CM domain is N-terminal to the CDT domain, whereas the order is inverted in ß-Proteobacteria. The CM domains share 15% to 20% sequence identity with the AroQγ class CM holotype of Mycobacterium tuberculosis (∗MtCM), and the CDT domains 40% to 60% identity with the exported monofunctional enzyme of Pseudomonas aeruginosa (PheC). In vitro kinetics revealed a Km <7 µM, much lower than for ∗MtCM, whereas kinetic parameters are similar for CDT domains and PheC. There is no feedback inhibition of CM or CDT by the pathway's end product Phe, and no catalytic benefit of the domain fusion compared with engineered single-domain constructs. The fusion enzymes of Aequoribacter fuscus, Janthinobacterium sp. HH01, and Duganella sacchari were crystallized and their structures refined to 1.6, 1.7, and 2.4 Å resolution, respectively. Neither the crystal structures nor the size-exclusion chromatography show evidence for substrate channeling or higher oligomeric structure that could account for the cooperation of CM and CDT active sites. The genetic neighborhood with genes encoding transporter and substrate binding proteins suggests that these exported bifunctional fusion enzymes may participate in signaling systems rather than in the biosynthesis of Phe.

Surprising multifunctionality of a Tritonia swim CPG neuron: C2 drives the early phase of postswim crawling despite being silent during the behavior.

In response to a suitably aversive skin stimulus, the marine mollusk Tritonia diomedea launches an escape swim followed by several minutes of high-speed crawling. The two escape behaviors are highly dissimilar: whereas the swim is a muscular behavior involving alternating ventral and dorsal whole body flexions, the crawl is a nonrhythmic gliding behavior mediated by the beating of foot cilia. The serotonergic dorsal swim interneurons (DSIs) are members of the swim central pattern generator (CPG) and also strongly drive crawling. Although the swim network is very well understood, the Tritonia crawling network to date comprises only three neurons: the DSIs and pedal neurons 5 and 21 (Pd5 and Pd21). Since Tritonia's swim network has been suggested to have arisen from a preexisting crawling network, we examined the possible role that another swim CPG neuron, C2, may play in crawling. Because of its complete silence in the postswim crawling period, C2 had not previously been considered to play a role in driving crawling. However, semi-intact preparation experiments demonstrated that a brief C2 spike train surprisingly and strongly drives the foot cilia for ∼30 s, something that cannot be explained by its synaptic connections to Pd5 and Pd21. Voltage-sensitive dye (VSD) imaging in the pedal ganglion identified many candidate crawling motor neurons that fire at an elevated rate after the swim and also revealed several pedal neurons that are strongly excited by C2. It is intriguing that unlike the DSIs, which fire tonically after the swim to drive crawling, C2 does so despite its postswim silence.NEW & NOTEWORTHY Tritonia swim central pattern generator (CPG) neuron C2 surprisingly and strongly drives the early phase of postswim crawling despite being silent during this period. In decades of research, C2 had not been suspected of driving crawling because of its complete silence after the swim. Voltage-sensitive dye imaging revealed that the Tritonia crawling motor network may be much larger than previously known and also revealed that many candidate crawling neurons are excited by C2.

The Emerging Star of Carbon Luminescent Materials: Exploring the Mysteries of the Nanolight of Carbon Dots for Optoelectronic Applications.

Carbon dots (CDs), a class of carbon-based nanomaterials with dimensions less than 10 nm, have attracted significant interest since their discovery. They possess numerous excellent properties, such as tunability of photoluminescence, environmental friendliness, low cost, and multifunctional applications. Recently, a large number of reviews have emerged that provide overviews of their synthesis, properties, applications, and their composite functionalization. The application of CDs in the field of optoelectronics has also seen unprecedented development due to their excellent optical properties, but reviews of them in this field are relatively rare. With the idea of deepening and broadening the understanding of the applications of CDs in the field of optoelectronics, this review for the first time provides a detailed summary of their applications in the field of luminescent solar concentrators (LSCs), light-emitting diodes (LEDs), solar cells, and photodetectors. In addition, the definition, categories, and synthesis methods of CDs are briefly introduced. It is hoped that this review can bring scholars more and deeper understanding in the field of optoelectronic applications of CDs to further promote the practical applications of CDs.

Recent Advances in Reprogramming Strategy of Tumor Microenvironment for Rejuvenating Photosensitizers-Mediated Photodynamic Therapy.

Photodynamic therapy (PDT) has recently been considered a potential tumor therapy due to its time-space specificity and non-invasive advantages. PDT can not only directly kill tumor cells by using cytotoxic reactive oxygen species but also induce an anti-tumor immune response by causing immunogenic cell death of tumor cells. Although it exhibits a promising prospect in treating tumors, there are still many problems to be solved in its practical application. Tumor hypoxia and immunosuppressive microenvironment seriously affect the efficacy of PDT. The hypoxic and immunosuppressive microenvironment is mainly due to the abnormal vascular matrix around the tumor, its abnormal metabolism, and the influence of various immunosuppressive-related cells and their expressed molecules. Thus, reprogramming the tumor microenvironment (TME) is of great significance for rejuvenating PDT. This article reviews the latest strategies for rejuvenating PDT, from regulating tumor vascular matrix, interfering with tumor cell metabolism, and reprogramming immunosuppressive related cells and factors to reverse tumor hypoxia and immunosuppressive microenvironment. These strategies provide valuable information for a better understanding of the significance of TME in PDT and also guide the development of the next-generation multifunctional nanoplatforms for PDT.

Advancements in Functional Nanomaterials Inspired by Viral Particles.

Virus-like particles (VLPs) are nanostructures composed of one or more structural proteins, exhibiting stable and symmetrical structures. Their precise compositions and dimensions provide versatile opportunities for modifications, enhancing their functionality. Consequently, VLP-based nanomaterials have gained widespread adoption across diverse domains. This review focuses on three key aspects: the mechanisms of viral capsid protein self-assembly into VLPs, design methods for constructing multifunctional VLPs, and strategies for synthesizing multidimensional nanomaterials using VLPs. It provides a comprehensive overview of the advancements in virus-inspired functional nanomaterials, encompassing VLP assembly, functionalization, and the synthesis of multidimensional nanomaterials. Additionally, this review explores future directions, opportunities, and challenges in the field of VLP-based nanomaterials, aiming to shed light on potential advancements and prospects in this exciting area of research.

Lead-Free Perovskite With Efficient Tellurium Ion Activation for Multifunctional Applications.

Lead-free perovskite materials have received extensive attention due to their non-toxicity, super environmental stability and adjustable photoelectric properties. However, the inherent problems of low luminous efficiency and low photoluminescence quantum yields (PLQYs) limit its development in multifunctional applications. Here, Te4+ doped Cs2ZrCl6 with high luminous efficiency and stability for multifunctional applications are developed. Te4+ ions are used as emission centers to improve the optical properties of Cs2ZrCl6 to make efficient and stable single-component white light-emitting diodes (WLEDs), and can be used as scintillator materials to improve scintillation performance to achieve high-resolution and low-dose X-ray imaging detection. In addition, it is found for the first time that Te4+ ions can be introduced into the trap center, so that the Cs2ZrCl6:Te4+ perovskite material exhibits excellent persistent luminescence (PersL) and mechanoluminescence (ML) after X-ray radiation, which has potential applications in the fields of delayed imaging and stress sensing. This work provides a method for designing lead-free perovskites with high optical performance and scintillating properties, as well as developing multifunctional applications.

Flexible, Reliable, and Lightweight Multiwalled Carbon Nanotube/Polytetrafluoroethylene Membranes with Dual-Nanofibrous Structure for Outstanding EMI Shielding and Multifunctional Applications.

In this study, lightweight, flexible, and environmentally robust dual-nanofibrous membranes made of carbon nanotube (CNT) and polytetrafluoroethylene (PTFE) are fabricated using a novel shear-induced in situ fibrillation method for electromagnetic interference (EMI) shielding. The unique spiderweb-like network, constructed from fine CNTs and PTFE fibrils, integrates the inherent characteristics of these two materials to achieve high conductivity, superhydrophobicity, and extraordinary chemical resistance. The dual-nanofibrous membranes demonstrate a high EMI shielding effectiveness (SE) of 25.7-42.2 dB at a thickness range of 100-520 µm and the normalized surface-specific SE can reach up to 9931.1 dB·cm2·g-1, while maintaining reliability even under extremely harsh conditions. In addition, distinct electrothermal and photothermal conversion properties can be achieved easily. Under the stimulation of a modest electrical voltage (5 V) and light power density (400 mW·cm-2), the surface temperatures of the CNT/PTFE membranes can reach up to 135.1 and 147.8 °C, respectively. Moreover, the CNT/PTFE membranes exhibit swift, stable, and highly efficient thermal conversion capabilities, endowing them with self-heating and de-icing performance. These versatile, flexible, and breathable membranes, coupled with their efficient and facile fabrication process, showcase tremendous application potential in aerospace, the Internet of Things, and the fabrication of wearable electronic equipment for extreme environments.

Broadband Sound Absorption and High Damage Resistance in a Turtle Shell-Inspired Multifunctional Lattice: Neural Network-Driven Design and Optimization.

Incorporating acoustic and mechanical properties into a single multifunctional structure has attracted considerable attention in engineering. However, effectively integrating these sound absorption properties and damage resistance to achieve multifunctional structural designs remains a great challenge due to imperfect design methods. In this study, the inherent mechanical properties of turtle shells by introducing dissipative pores are leveraged to present a lattice structure that possesses both excellent sound-absorg and high damage-resistant characteristics. To achieve acoustic optimization design, a universal high-fidelity neural network correction model is proposed to address the impedance calculation challenge in complex structures. Building upon this foundation, a multi-cell combination design enables to achieve high absorption through optimization with a low thickness of 50 mm, resulting in average sound absorption coefficients reaching 0.88 and 0.93 within the frequency ranges of 300-600 Hz and 500-1000 Hz, respectively. It is also found that the optimized structures exhibit exceptional damage resistance under varying relative densities via the coupling effect of the shell thickness on the acoustic and mechanical properties. Overall, this work introduces a novel paradigm for designing intricate multifunctional structures with acoustic and mechanical properties while providing valuable inspiration for future research on multifunctional structure design.

Diagnostic, Therapeutic, and Theranostic Multifunctional Microneedles.

Microneedles (MNs) have maintained their popularity in therapeutic and diagnostic medical applications throughout the past decade. MNs are originally designed to gently puncture the stratum corneum layer of the skin and have lately evolved into intelligent devices with functions including bodily fluid extraction, biosensing, and drug administration. MNs offer limited invasiveness, ease of application, and minimal discomfort. Initially manufactured solely from metals, MNs are now available in polymer-based varieties. MNs can be used to create systems that deliver drugs and chemicals uniformly, collect bodily fluids, and are stimulus-sensitive. Although these advancements are favorable in terms of biocompatibility and production costs, they are insufficient for the therapeutic use of MNs. This is the first comprehensive review that discusses individual MN functions toward the evolution and development of smart and multifunctional MNs for a variety of novel and impactful future applications. The study examines fabrication techniques, application purposes, and experimental details of MN constructs that perform multiple functions concurrently, including sensing, drug-molecule release, sampling, and remote communication capabilities. It is highly likely that in the near future, MN-based smart devices will be a useful and important component of standard medical practice for different applications.

MXene-Layered Double Hydroxide Reinforced Epoxy Nanocomposite with Enhanced Electromagnetic Wave Absorption, Thermal Conductivity, and Flame Retardancy in Electronic Packaging.

Due to the increased integration and miniaturization of electronic devices, traditional electronic packaging materials, such as epoxy resin (EP), cannot solve electromagnetic interference (EMI) in electronic devices. Thus, the development of multifunctional electronic packaging materials with superior electromagnetic wave absorption (EMA), high heat dissipation, and flame retardancy is critical for current demand. This study employs an in-situ growth method to load layered double hydroxides (LDH) onto transition metal carbides (MXene), synthesizing a novel composite material (MXene@LDH). MXene@LDH possesses a sandwich structure and exhibits excellent EMA performance, thermal conductivity, and flame retardancy. By adjusting the load of LDH, under the synergistic effect of multiple factors, such as dielectric and polarization losses, this work achieves an EMA material with a remarkable minimum reflection loss (RL) of -52.064 dB and a maximum effective absorption bandwidth (EAB) of 4.5 GHz. Furthermore, MXene@LDH emerges a bridging effect in EP, namely MXene@LDH/EP, leading to a 118.75% increase in thermal conductivity compared to EP. Simultaneously, MXene@LDH/EP contributes to the enhanced flame retardancy compared to EP, resulting in a 46.5% reduction in the total heat release (THR). In summary, this work provides a promising candidate advanced electronic packaging material for high-power density electronic packaging.