Cationized orthogonal triad as a photosensitizer with enhanced synergistic antimicrobial activity.

Single-molecule-based synergistic phototherapy holds great potential for antimicrobial treatment. Herein, we report an orthogonal molecular cationization strategy to improve the reactive oxygen species (ROS) and hyperthermia generation of heptamethine cyanine (Cy7) for photodynamic and photothermal treatments of bacterial infections. Cationic pyridine (Py) is introduced at the meso­position of the asymmetric Cy7 with intramolecular charge transfer (ICT) to construct an atypical electron-transfer triad, which reduces ΔES1-S0, circumvents rapid charge recombination, and simultaneously enhances intersystem crossing (ISC) based on spin-orbit charge-transfer ISC (SOCT-ISC) mechanism. This unique molecular construction produces anti-Stokes luminescence (ASL) because the rotatable CN bond enriched in high vibrational-rotational energy levels improves hot-band absorption (HBA) efficiency. The obtained triad exhibits higher singlet oxygen quantum yield and photothermal conversion efficiency compared to indocyanine green (ICG) under irradiation above 800 nm. Cationization with Py enables the triad to target bacteria via intense electrostatic attractions, as well as biocidal property against a broad spectrum of bacteria in the dark. Moreover, the triad under irradiation can enhance biofilm eradication performance in vitro and statistically improve healing efficacy of MRSA-infected wound in mice. Thus, this work provides a simple but effective strategy to design small-molecule photosensitizers for synergistic phototherapy of bacterial infections. STATEMENT OF SIGNIFICANCE: We developed an orthogonal molecular cationization strategy to enhance the reactive oxygen species and thermal effects of heptamethine cyanine (Cy7) for photodynamic and photothermal treatments of bacterial infections. Specifically, cationic pyridine (Py) was introduced at the meso­position of the asymmetric Cy7 to construct an atypical electron-transfer triad, which reduced ΔES1-S0, circumvented rapid charge recombination, and simultaneously enhanced intersystem crossing (ISC). This triad, with a rotatable CN bond, produced anti-Stokes luminescence due to hot-band absorption. The triad enhanced antimicrobial performance and statistically improved the healing efficacy of MRSA-infected wounds in mice. This site-specific cationization strategy may provide insights into the design of small molecule-based photosensitizers for synergistic phototherapy of bacterial infections.

Supramolecular prodrug-like nanotheranostics with dynamic and activatable nature for synergistic photothermal immunotherapy of metastatic cancer.

Synergistic photothermal immunotherapy has attracted widespread attention due to the mutually reinforcing therapeutic effects on primary and metastatic tumors. However, the lack of clinical approval nanomedicines for spatial, temporal, and dosage control of drug co-administration underscores the challenges facing this field. Here, a photothermal agent (Cy7-TCF) and an immune checkpoint blocker (NLG919) are conjugated via disulfide bond to construct a tumor-specific small molecule prodrug (Cy7-TCF-SS-NLG), which self-assembles into prodrug-like nano-assemblies (PNAs) that are self-delivering and self-formulating. In tumor cells, over-produced GSH cleaves disulfide bonds to release Cy7-TCF-OH, which re-assembles into nanoparticles to enhance photothermal conversion while generate reactive oxygen species (ROSs) upon laser irradiation, and then binds to endogenous albumin to activate near-infrared fluorescence, enabling multimodal imaging-guided phototherapy for primary tumor ablation and subsequent release of tumor-associated antigens (TAAs). These TAAs, in combination with the co-released NLG919, effectively activated effector T cells and suppressed Tregs, thereby boosting antitumor immunity to prevent tumor metastasis. This work provides a simple yet effective strategy that integrates the supramolecular dynamics and reversibility with stimuli-responsive covalent bonding to design a simple small molecule with synergistic multimodal imaging-guided phototherapy and immunotherapy cascades for cancer treatment with high clinical value.

Cell-Membrane Coated Self-Immolative Poly(thiourethane) for Cysteine/Homocysteine-Triggered Intracellular H2S Delivery.

Hydrogen sulfide (H2S) is an important gaseous signaling molecule with unique pleiotropic pharmacological effects, but may be limited for clinical translation due to the lack of a reliable delivery form that delivers exogenous H2S to cells at action site with precisely controlled dosage. Herein, we report the design of a poly(thiourethane) (PTU) self-immolative polymer terminally caged with an acrylate moiety to trigger release of H2S in response to cysteine (Cys) and homocysteine (Hcy), the most used and independent indicators of neurodegenerative diseases. The synthesized PTU polymer was then coated with the red-blood-cell (RBC) membrane in the presence of solubilizing agent to self-assemble into nanoparticles with enhanced stability and cytocompatibility. The Hcy/Cys mediated addition/cyclization chemistry actuated the biomimetic polymeric nanoparticles to disintegrate into carbonyl sulfide (COS), and finally convert into H2S via the ubiquitous carbonic anhydrase (CA). H2S released in a controlled manner exhibited a strong antioxidant ability to resist Alzheimer's disease (AD)-related oxidative stress factors in BV-2 cells, a neurodegenerative disease model in vitro. Thus, this work may provide an effective strategy to construct H2S donors that can degrade in response to a specific pathological microenvironment for the treatment of neurodegenerative diseases.

Near-Infrared Molecular Logic Gate for In Situ Construction and Quantification of Cell-Macromolecule Conjugates.

Engineering cell surfaces with macromolecules offers the potential to manipulate and control their phenotype and function for cell-based therapies. In situ construction and real-time evaluation of cell-macromolecule conjugates are vital for characterizing their dynamics, mobility, and function but remain a great challenge. Herein, we design a near-infrared (NIR) heptamethine cyanine (LS)-bearing dibenzocyclooctyne (DBCO) and norbornene (NB) in its structure for rapid and selective bioorthogonal "click" coupling to azide-labeled cells and tetrazine-functionalized macromolecular precursors. Specifically, only orthogonal dual "click" cell-macromolecule conjugates turn on NIR fluorescence, in which LS behaves as an AND logic gate, with azide- and tetrazine-derivatives being "input" and the emission intensity as the output. LS enables in situ construction and real-time evaluation of the process and functional effects that macromolecules "graft to" cells with high cytocompatibility. This probe is tailor-made for live-cell microscopy technologies, which may open new opportunities for promoting further developments in cell-tracking and cell-based therapies.

Multi-objective cluster based bidding algorithm for E-commerce search engine marketing system.

Search engine marketing (SEM) is an important channel for the success of e-commerce. With the increasing scale of catalog items, designing an efficient modern industrial-level bidding system usually requires overcoming the following hurdles: 1. the relevant bidding features are of high sparsity, preventing an accurate prediction of the performances of many ads. 2. the large volume of bidding requests induces a significant computation burden to offline and online serving. In this article, we introduce an end-to-end structure of a multi-objective bidding system for search engine marketing for Walmart e-commerce, which successfully handles tens of millions of bids each day. The system deals with multiple business demands by constructing an optimization model targeting a mixture of metrics. Moreover, the system extracts the vector representations of ads via the Transformer model. It leverages their geometric relation to building collaborative bidding predictions via clustering to address performance features' sparsity issues. We provide theoretical and numerical analyzes to discuss how we find the proposed system as a production-efficient solution.

Temporal and seasonal variations in incidence of stage II and III NEC-a 28-year epidemiologic study from tertiary NICUs in Connecticut, USA.

OBJECTIVE: To investigate seasonality and temporal trends in the incidence of NEC. STUDY DESIGN: A retrospective cohort study from two tertiary NICUs in northern and central Connecticut involving 16,761 infants admitted over a 28-year period. Various perinatal and neonatal risk factors were evaluated by univariate, multivariate, and spectral density analyses. RESULTS: Incidence of NEC was unchanged over the 28 years of study. Gestational age, birth weight, and birth-months (birth in April/May) were independently associated with stage II or III NEC even after adjusting for confounding factors (p < 0.05). Yearly NEC incidence showed a multi-modal distribution with spectral density spikes approximately every 10 years. CONCLUSION(S): Temporal and seasonal factors may play a role in NEC with a peak incidence in infants born in April/May and periodicity spikes approximately every 10 years. These trends suggest non-random and possibly environmental factors influencing NEC.

Semi-Automated evidence synthesis in health psychology: current methods and future prospects.

The evidence base in health psychology is vast and growing rapidly. These factors make it difficult (and sometimes practically impossible) to consider all available evidence when making decisions about the state of knowledge on a given phenomenon (e.g., associations of variables, effects of interventions on particular outcomes). Systematic reviews, meta-analyses, and other rigorous syntheses of the research mitigate this problem by providing concise, actionable summaries of knowledge in a given area of study. Yet, conducting these syntheses has grown increasingly laborious owing to the fast accumulation of new evidence; existing, manual methods for synthesis do not scale well. In this article, we discuss how semi-automation via machine learning and natural language processing methods may help researchers and practitioners to review evidence more efficiently. We outline concrete examples in health psychology, highlighting practical, open-source technologies available now. We indicate the potential of more advanced methods and discuss how to avoid the pitfalls of automated reviews.

Nanoscale insight on the durability of magnesium phosphate cement: a molecular dynamics study.

The sustainable green building material magnesium phosphate cement (MPC) is widely used in the fields of solidifying heavy metals and nuclear waste and repair and reinforcement. Magnesium potassium phosphate hexahydrate (MKP) is the main hydration product of MPC. The transport of water and ions in MKP nanochannels determines the mechanical properties and durability of MPC materials. Herein, the interface models of MKP crystals with sodium chloride solution in the [001], [010] and [100] direction were established by molecular dynamics. The interaction of the MKP interface with water and ions was studied and the durability of MPC in sodium chloride solution was explained at the molecular level. The results show that a large number of water molecules are adsorbed on the MKP crystal surface through hydrogen bonds and Coulomb interactions; the surface water molecules have the bigger dipole moment and the dipole vector of most of the water molecules points to the solid matrix, when the crystal surfaces of the three models all show hydrophilicity. In addition, plenty of sodium ions are adsorbed at the MKP interface, and some potassium ions are desorbed from the matrix. In the MKP[001] model, the amount of potassium ions separated from the matrix and diffused into the solution is the highest and the interface crystal is the most disordered. Due to the attack of water and ions, the K-Os bond loses its chemical stability and the order of the MKP crystal is destroyed, which explains the decline of MPC performance after the erosion of sodium chloride solution at the molecular level. Besides, in the three models, the Na-Cl ion bond is more unstable than the K-Cl ion bond due to the smaller radius of the sodium atom. The stability of ionic bonds in the models is as follows: MKP[010] > MKP[100] > MKP[001].