Ligand-Receptor Interaction-Induced Intracellular Phase Separation: A Global Disruption Strategy for Resistance-Free Lethality of Pathogenic Bacteria.

Addressing the global challenge of bacterial resistance demands innovative approaches, among which multitargeting is a widely used strategy. Current strategies of multitargeting, typically achieved through drug combinations or single agents inherently aiming at multiple targets, face challenges such as stringent pharmacokinetic and pharmacodynamic requirements and cytotoxicity concerns. In this report, we propose a bacterial-specific global disruption approach as a vastly expanded multitargeting strategy that effectively disrupts bacterial subcellular organization. This effect is achieved through a pioneering chemical design of ligand-receptor interaction-induced aggregation of small molecules, i.e., DNA-induced aggregation of a diarginine peptidomimetic within bacterial cells. These intracellular aggregates display affinity toward various proteins and thus substantially interfere with essential bacterial functions and rupture bacterial cell membranes in an "inside-out" manner, leading to robust antibacterial activities and suppression of drug resistance. Additionally, biochemical analysis of macromolecule binding affinity, cytoplasmic localization patterns, and bacterial stress responses suggests that this bacterial-specific intracellular aggregation mechanism is fundamentally different from nonselective classic DNA or membrane binding mechanisms. These mechanistic distinctions, along with the peptidomimetic's selective permeation of bacterial membranes, contribute to its favorable biocompatibility and pharmacokinetic properties, enabling its in vivo antimicrobial efficacy in several animal models, including mice-based superficial wound models, subcutaneous abscess models, and septicemia infection models. These results highlight the great promise of ligand-receptor interaction-induced intracellular aggregation in achieving a globally disruptive multitargeting effect, thereby offering potential applications in the treatment of malignant cells, including pathogens, tumor cells, and infected tissues.

Binder-Responsive DNA Strand Displacement Enables High-Throughput and High-Fidelity Discovering of Small Molecular DNA Binders.

High-throughput screening (HTS) is pivotal in the discovery of small molecules that bind to DNA, yet there are limited sensing mechanisms available for designing HTS assays for DNA binders. Herein, we introduce a binder-responsive toehold-mediated DNA strand displacement (BR-TMSD) technique featuring programmable reaction kinetics in response to DNA-binder interactions. When two DNA binders are used, BR-TMSD is initiated through a rapid binder displacement, followed by the DNA strand displacement. The orthogonal displacement reactions of BR-TMSD enables a high-fidelity, dual-channel HTS assay, returning 19 new DNA binders from a library of 1,170 compounds.

Multi-targeting oligopyridiniums: Rational design for biofilm dispersion and bacterial persister eradication.

The development of effective antibacterial drugs to combat bacterial infections, particularly the biofilm-related infections, remains a challenge. There are two important features of bacterial biofilms, which are well-known critical factors causing biofilms hard-to-treat in clinical, including the dense and impermeable extracellular polymeric substances (EPS) and the metabolically repressed dormant and persistent bacterial population embedded. These characteristics largely increase the difficulty for regular antibiotic treatment due to insufficient penetration into EPS. In addition, the dormant bacteria are insensitive to the growth-inhibiting mechanism of traditional antibiotics. Herein, we explore the potential of a series of new oligopyridinium-based oligomers bearing a multi-biomacromolecule targeting function as the potent bacterial biofilm eradication agent. These oligomers were rationally designed to be "charge-on-backbone" that can offer a special alternating amphiphilicity. This novel and unique feature endows high affinity to bacterial membrane lipids, DNAs as well as proteins. Such a broad multi-targeting nature of molecules not only enables its penetration into EPS, but also plays vital roles in the bactericidal mechanism of action that is highly effective against dormant and persistent bacteria. Our in vitro, ex vivo, and in vivo studies demonstrated that OPc3, one of the most effective derivatives, was able to offer excellent antibacterial potency against a variety of bacteria and effectively eliminate biofilms in zebrafish models and mouse wound biofilm infection models.

Chemical Biology Approach to Reveal the Importance of Precise Subcellular Targeting for Intracellular Staphylococcus aureus Eradication.

Intracellular bacterial pathogens, such as Staphylococcus aureus, that may hide in intracellular vacuoles represent the most significant manifestation of bacterial persistence. They are critically associated with chronic infections and antibiotic resistance, as conventional antibiotics are ineffective against such intracellular persisters due to permeability issues and mechanistic reasons. Direct subcellular targeting of S. aureus vacuoles suggests an explicit opportunity for the eradication of these persisters, but a comprehensive understanding of the chemical biology nature and significance of precise S. aureus vacuole targeting remains limited. Here, we report an oligoguanidine-based peptidomimetic that effectively targets and eradicates intracellular S. aureus persisters in the phagolysosome lumen, and this oligomer was utilized to reveal the mechanistic insights linking precise targeting to intracellular antimicrobial efficacy. The oligomer has high cellular uptake via a receptor-mediated endocytosis pathway and colocalizes with S. aureus persisters in phagolysosomes as a result of endosome-lysosome interconversion and lysosome-phagosome fusion. Moreover, the observation of a bacterium's altered susceptibility to the oligomer following a modification in its intracellular localization offers direct evidence of the critical importance of precise intracellular targeting. In addition, eradication of intracellular S. aureus persisters was achieved by the oligomer's membrane/DNA dual-targeting mechanism of action; therefore, its effectiveness is not hampered by the hibernation state of the persisters. Such precise subcellular targeting of S. aureus vacuoles also increases the agent's biocompatibility by minimizing its interaction with other organelles, endowing excellent in vivo bacterial targeting and therapeutic efficacy in animal models.

Three-electrode germanium-on-silicon avalanche photodiode array.

In this Letter, we report a bridge-connected three-electrode germanium-on-silicon (Ge-on-Si) avalanche photodiode (APD) array compatible with the complementary metal-oxide semiconductor (CMOS) process. In addition to the two electrodes on the Si substrate, a third electrode is designed for Ge. A single three-electrode APD was tested and analyzed. By applying a positive voltage on the Ge electrode, the dark current of the device can be reduced, and yet the response of the device can be increased. Under a dark current of 100 nA, as the voltage on Ge increases from 0 V to 15 V, the light responsivity is increased from 0.6 A/W to 1.17 A/W. We report, for the first time to the best of our knowledge, the near-infrared imaging properties of an array of three-electrode Ge-on-Si APDs. Experiments show that the device can be used for LiDAR imaging and low-light detection.

Amphiphilic Nano-Swords for Direct Penetration and Eradication of Pathogenic Bacterial Biofilms.

Bacterial biofilms are major causes of persistent and recurrent infections and implant failures. Biofilms are formable by most clinically important pathogens worldwide, such as Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli, causing recalcitrance to standard antibiotic therapy or anti-biofilm strategies due to amphiphilic impermeable extracellular polymeric substances (EPS) and the presence of resistant and persistent bacteria within the biofilm matrix. Herein, we report our design of an oligoamidine-based amphiphilic "nano-sword" with high structural compacity and rigidity. Its rigid, amphiphilic structure ensures effective penetration into EPS, and the membrane-DNA dual-targeting mechanism exerts strong bactericidal effect on the dormant bacterial persisters within biofilms. The potency of this oligoamidine is shown in two distinct modes of application: it may be used as a coating agent for polycaprolactone to fully inhibit surface biofilm growth in an implant-site mimicking micro-environment; meanwhile, it cures model mice of biofilm infections in various ex vivo and in vivo studies.

On-chip generation of Bessel-Gaussian beam via concentrically distributed grating arrays for long-range sensing.

Bessel beam featured with self-healing is essential to the optical sensing applications in the obstacle scattering environment. Integrated on-chip generation of the Bessel beam outperforms the conventional structure by small size, robustness, and alignment-free scheme. However, the maximum propagation distance (Zmax) provided by the existing approaches cannot support long-range sensing, and thus, it restricts its potential applications. In this work, we propose an integrated silicon photonic chip with unique structures featured with concentrically distributed grating arrays to generate the Bessel-Gaussian beam with a long propagation distance. The spot with the Bessel function profile is measured at 10.24 m without optical lenses, and the photonic chip's operation wavelength can be continuously performed from 1500 to 1630 nm. To demonstrate the functionality of the generated Bessel-Gaussian beam, we also experimentally measure the rotation speeds of a spinning object via the rotational Doppler Effect and the distance through the phase laser ranging principle. The maximum error of the rotation speed in this experiment is measured to be 0.05%, indicating the minimum error in the current reports. By the compact size, low cost, and mass production potential of the integrated process, our approach is promising to readily enable the Bessel-Gaussian beam in widespread optical communication and micro-manipulation applications.

Fully Integrated Line Array Angular Displacement Sensing Chip.

The angular displacement sensor is a digital angular displacement measurement device that integrates optics, mechanics, and electronics. It has important applications in communication, servo control, aerospace, and other fields. Although conventional angular displacement sensors can achieve extremely high measurement accuracy and resolution, they cannot be integrated because complex signal processing circuitry is required at the photoelectric receiver, which limits their suitability for robotics and automotive applications. The design of a fully integrated line array angular displacement-sensing chip is presented for the first time using a combination of pseudo-random and incremental code channel designs. Based on the charge redistribution principle, a fully differential 12-bit, 1 MSPS sampling rate successive approximation analog-to-digital converter (SAR ADC) is designed for quantization and subdivision of the incremental code channel output signal. The design is verified with a 0.35 µm CMOS process and the area of the overall system is 3.5 × 1.8 mm2. The fully integrated design of the detector array and readout circuit is realized for the angular displacement sensing.

A severe complication of J-tip guide wire during catheterization: A case report and discussion.

J-tip guide wire entrapment within the heart is a serious and dangerous complication that is rarely mentioned. We present a case in which the J-tip guide wire was entrapped in the right atrium during tunneled cuffed venous catheterization. We were unable to remove the guide wire using previously reported methods and concluded with surgery. Owing to the special structure of the guide wire itself, a safe removal process needs to be discussed. Patient consent for publication was obtained prior to the submission of the manuscript.

Self-Supervised Learning for Point-Cloud Classification by a Multigrid Autoencoder.

It has become routine to directly process point clouds using a combination of shared multilayer perceptrons and aggregate functions. However, this practice has difficulty capturing the local information of point clouds, leading to information loss. Nevertheless, several recent works have proposed models that establish point-to-point relationships based on this procedure. However, to address the information loss, in this study we use self-supervised methods to enhance the network's understanding of point clouds. Our proposed multigrid autoencoder (MA) constrains the encoder part of the classification network so that it gains an understanding of the point cloud as it reconstructs it. With the help of self-supervised learning, we find the original network improves performance. We validate our model on PointNet++, and the experimental results show that our method improves overall classification accuracy by 2.0% and 4.7% with ModelNet40 and ScanObjectNN datasets, respectively.

Point Cloud Completion Network Applied to Vehicle Data.

With the development of autonomous driving, augmented reality, and other fields, it is becoming increasingly important for machines to more accurately and comprehensively perceive their surrounding environment. LiDAR is one of the most important tools used by machines to obtain information about the surrounding environment. However, because of occlusion, the point cloud data obtained by LiDAR are not the complete shape of the object, and completing the incomplete point cloud shape is of great significance for further data analysis, such as classification and segmentation. In this study, we examined the completion of a 3D point cloud and improved upon the FoldingNet auto-encoder. Specifically, we used the encoder-decoder architecture to design our point cloud completion network. The encoder part uses the transformer module to enhance point cloud feature extraction, and the decoder part changes the 2D lattice used by the A network into a 3D lattice so that the network can better fit the shape of the 3D point cloud. We conducted experiments on point cloud datasets sampled from the ShapeNet car-category CAD models to verify the effectiveness of the various improvements made to the network.

Multi-target free-space laser communication system based on a rotating double prism with an RF signal beacon.

Traditional free-space laser communication systems use beacon and signal lights for target detection and alignment. However, these approaches are inaccurate owing to signal dispersion errors. To overcome this difficulty, we propose a new method using transient radio frequency (RF) signals to achieve highly accurate target detection and alignment. To validate the feasibility of our proposed method, we built an experimental multi-target space-laser communication system based on a rotating double prism and applied it to achieve multi-target space-laser communication. The results demonstrate the efficiency of the proposed method to capture multi-target positions in the field of view using wireless RF signals and a rotating double prism. In addition, we show that the system is capable of rapid scanning and accurate pointing as well as establishing a one-way stable communication with multiple targets. When the target is 36 cm away, the pointing accuracy of the system motor is less than 0.8°, the pointing time is 1.2 s, and the average pointing lateral error is 0.666 mm.

Potentiation of Vancomycin: Creating Cooperative Membrane Lysis through a "Derivatization-for-Sensitization" Approach.

Gram-negative bacteria, especially the ones with multidrug resistance, post dire challenges to antibiotic treatments due to the presence of the outer membrane (OM), which blocks the entry of many antibiotics. Current solutions for such permeability issues, namely lipophilic-cationic derivatization of antibiotics and sensitization with membrane-active agents, cannot effectively potentiate the large, globular, and hydrophilic antibiotics such as vancomycin, due to ineffective disruption of the OM. Here, we present our solution for high-degree OM binding of vancomycin via a hybrid "derivatization-for-sensitization" approach, which features a combination of LPS-targeting lipo-cationic modifications on vancomycin and OM disruption activity from a sensitizing adjuvant. 106- to 107-fold potentiation of vancomycin and 20-fold increase of the sensitizer's effectiveness were achieved with a combination of a vancomycin derivative and its sensitizer. Such potentiation is the result of direct membrane lysis through cooperative membrane binding for the sensitizer-antibiotic complex, which strongly promotes the uptake of vancomycin and adds to the extensive antiresistance effectiveness. The potential of such derivatization-for-sensitization approach was also supported by the combination's potent in vivo antimicrobial efficacy in mouse model studies, and the expanded application of such strategy on other antibiotics and sensitizer structures.

Two-dimensional multi-layered SiN-on-SOI optical phased array with wide-scanning and long-distance ranging.

Silicon based optoelectronic integrated optical phased array is attractive owing to large-dense integration, large scanning range and CMOS compatibility. In this paper, we design and fabricate a SiN-on-SOI two-dimensional optical phased array chip. We demonstrate a two-dimensional scanning range of 96°×14.4° and 690 mW peak power of the main lobe. Additionally, we set up the time of flight (ToF) and frequency-modulated continuous-wave (FMCW) ranging systems by using this optical phased array chip, and achieve the objects detection at the range of 20 m in the ToF system and 109 m in the FMCW system, respectively.

Efficient Enzymatic Incorporation of Dehydroalanine Based on SAMDI-Assisted Identification of Optimized Tags for OspF/SpvC.

Site-specific modification of proteins has important applications in biological research and drug development. Reactive tags such as azide, alkyne, and tetrazine have been used extensively to achieve the abovementioned goal. However, bulky side-chain "ligation scars" are often left after the labeling and may hinder the biological application of such engineered protein products. Conjugation chemistry via dehydroalanine (Dha) may provide an opportunity for "traceless" ligation because the activated alkene moiety on Dha can then serve as an electrophile to react with radicalophile, thiol/amine nucleophile, and reactive phosphine probe to introduce a minimal linker in the protein post-translational modifications. In this report, we present a mild and highly efficient enzymatic approach to incorporate Dha with phosphothreonine/serine lyases, OspF and SpvC. These lyases originally catalyze an irreversible elimination reaction that converts a doubly phosphorylated substrate with phosphothreonine (pT) or phosphoserine (pS) to dehydrobutyrine (Dhb) or Dha. To generate a simple monophosphorylated tag for these lyases, we conducted a systematic approach to profile the substrate specificity of OspF and SpvC using peptide arrays and self-assembled monolayers for matrix-assisted laser desorption/ionization mass spectrometry. The optimized tag, [F/Y/W]-pT/pS-[F/Y/W] (where [F/Y/W] indicates an aromatic residue), results in a ∼10-fold enhancement of the overall peptide labeling efficiency via Dha chemistry and enables the first demonstration of protein labeling as well as live cell labeling with a minimal ligation linker via enzyme-mediated incorporation of Dha.

Genetic dissection of maize plant architecture using a novel nested association mapping population.

The leaf angle (LA), plant height (PH), and ear height (EH) are key plant architectural traits influencing maize (Zea mays L.) yield. However, their genetic determinants have not yet been well-characterized. Here, we developed a maize advanced backcross-nested association mapping population in Henan Agricultural University (HNAU-NAM1) comprised of 1,625 BC1 F4 /BC2 F4 lines. These were obtained by crossing a diverse set of 12 representative inbred lines with the common GEMS41 line, which were then genotyped using the MaizeSNP9.4K array. Genetic diversity and phenotypic distribution analyses showed considerable levels of genetic variation. We obtained 18-88 quantitative trait loci (QTLs) associated with LA, PH, and EH by using three complementary mapping methods, named as separate linkage mapping, joint linkage mapping, and genome-wide association studies. Our analyses enabled the identification of ten QTL hot-spot regions associated with the three traits, which were distributed on nine different chromosomes. We further selected 13 major QTLs that were simultaneously detected by three methods and deduced the candidate genes, of which eight were not reported before. The newly constructed HNAU-NAM1 population in this study will further broaden our insights into understanding of genetic regulation of plant architecture, thus will help to improve maize yield and provide an invaluable resource for maize functional genomics and breeding research.

Investigation and demonstration of a high-power handling and large-range steering optical phased array chip.

The optical power handling of an OPA scanning beam determines its targeted detection distance. So far, a limited number of investigations have been conducted on the restriction of the beam power. To the best of our knowledge, we for the first time in this paper explore the ability of the silicon photonics based OPA circuit for the high power application. A 64-channel SiN-Si based one-dimensional (1D) OPA chip has been designed to handle high beam power to achieve large scanning range. The chip was fabricated on the standard silicon photonics platform. The main lobe power of our chip can reach 720 mW and its peak side-lobe level (PSLL) is -10.33 dB. We obtain a wide scanning range of 110° in the horizontal direction at 1550 nm wavelength, with a compressed longitudinal divergence angle of each scanning beam of 0.02°.

Unidirectional large-scale waveguide grating with uniform radiation for optical phased array.

Two novel waveguide gratings for optical phased array transmitters are investigated. By offsetting the grating structures along the waveguide on the upper and lower surfaces of the silicon nitride (Si3N4) waveguide, the dual-level chain and dual-level fishbone structures can achieve 95% of unidirectional radiation with a single Si3N4 layer by design. With apodized perturbation along the gratings, both structures can achieve uniform radiation without compromising the unidirectional radiation performance. In experiment, both demonstrate ∼ 80-90% unidirectionality. With further analysis, it is found that the dual-level fishbone structure is more feasible and robust to process variations in uniform radiation.

Surface illuminated interdigitated Ge-on-Si photodetector with high responsivity.

To address the problem of traditional surface illuminated detectors being of low responsivity, this work proposes a large-size interdigitated "finger-type" germanium-on-silicon (Ge-on-Si) photodetector (PD) based on the surface illumination approach. For 1550 nm light with a surface incident power of -20 dBm at room temperature, the best responsivity of the PD achieved is ∼0.64 A/W at 0.5 V. At the same time, the optimal bandwidth reaches 1.537 MHz with 3.5 V applied voltage. In order to suppress the dark current induced noise, a Ge-on-Si avalanche photodiode (APD) with the interdigitated structure is designed. The avalanche voltage is designed ∼13.3 V at room temperature, and the dark current density in linear region is at mA/cm2 order. We believe this type of device can be applied in weak light detection condition.

An alternatingly amphiphilic, resistance-resistant antimicrobial oligoguanidine with dual mechanisms of action.

The increasing number of infections caused by multi-drug resistance (MDR) bacteria is an omen of a new global challenge. As one of the countermeasures under development, antimicrobial peptides (AMPs) and AMP mimics have emerged as a new family of antimicrobial agents with high potential, due to their low resistance generation rate and effectiveness against MDR bacterial strains resulted from their membrane-disrupting mechanism of action. However, most reported AMPs and AMP mimics have facially amphiphilic structures, which may lead to undesired self-aggregation and non-specific binding, as well as increased cytotoxicity toward mammalian cells, all of which put significant limits on their applications. Here, we report an oligomer with the size of short AMPs, with both hydrophobic carbon chain and cationic groups placed on its backbone, giving an alternatingly amphiphilic structure that brings better selectivity between mammalian and bacterial cell membranes. In addition, the oligomer shows affinity toward DNA, thus it can utilize bacterial DNA located in the vulnerable nucleoid as the second drug target. Benefiting from these designs, the oligomer shows higher therapeutic index and synergistic effect with other antibiotics, while its low resistance generation rate and effectiveness on multi-drug resistant bacterial strains can be maintained. We demonstrate that this alternatingly amphiphilic, DNA-binding oligomer is not only resistance-resistant, but is also able to selectively eliminate bacteria at the presence of mammalian cells. Importantly, the oligomer exhibits good in vivo activity: it cleans all bacteria on Caenorhabditis elegans without causing apparent toxicity, and significantly improves the survival rate of mice with severely infected wounds in a mice excision wound model study.