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Photodynamic therapy (PDT) represents a promising strategy for tumor treatment. However, the development of PDT‐based antitumor therapies faces challenges stemming from the hypoxic nature of the tumor microenvironment and the limited penetration of photosensitizers. This study presents a novel class of antitumor nanoparticles, designated as ARLN‐FP, engineered to penetrate tumor tissues deeply and inhibit tumor growth through the generation of oxygen‐independent free radicals. With the encapsulation of IR780 and dimethyl 2,2′‐azobis(2‐methylpropionate) (AIBME) in the core of ARLN‐FP, near‐infrared (NIR) laser irradiation of ARLN‐FP with induced heat generation, which subsequentially led to the decomposition of AIBME and the production of free radicals without relying on oxygen. In vitro studies indicated that ARLN‐FP penetrated more than 100 µm into multicellular tumor spheroids, demonstrating its enhanced tissue permeability. Animal studies confirmed the anti‐tumor effects of ARLN‐FP‐mediated photonic thermodynamic therapy, where the oxygen‐independent radical formation contributed to successful tumor eradication, evidenced by a significant tumor inhibition rate of 90.8% after 22 days. This research presents a feasible method to overcome the limitations of traditional oxygen‐dependent photodynamic therapies, which offers a new approach to developing nanomedicines to overcome resistance in deep and hypoxic tumor regions. [ABSTRACT FROM AUTHOR]

Real‐time tracking of drug release from nanomedicine in vivo is crucial for optimizing its therapeutic efficacy in clinical settings, particularly in dosage control and determining the optimal therapeutic window. However, most current real‐time tracking systems require a tedious synthesis and purification process. Herein, a supramolecular nano‐tracker (SNT) capable of real‐time tracking of drug release in vivo based on non‐covalent host‐guest interactions is presented. By integrating multiple cavities into a single nanoparticle, SNT achieves co‐loading of drugs and probes while efficiently quenching the photophysical properties of the probe through host‐guest complexation. Moreover, SNT is readily degraded under hypoxic tumor tissues, leading to the simultaneous release of drugs and probes and the fluorescence recovery of probes. With this spatial and temporal consistency in drug loading and fluorescence quenching, as well as drug release and fluorescence recovery, SNT successfully achieves real‐time tracking of drug release in vivo (Pearson r = 0.9166, R2 = 0.8247). Furthermore, the released drugs can synergize effectively with fluorescent probes upon light irradiation, achieving potent chemo‐photodynamic combination therapy in 4T1‐bearing mice with a significantly improved survival rate (33%), providing a potential platform to significantly advance the development of nanomedicine and achieve optimal therapeutic effects in the clinic. [ABSTRACT FROM AUTHOR]

The cGAS‐STING pathway represents a crucial DNA‐sensing mechanism that has shown promise as a target for overcoming immunoresistance in solid tumors. Mn2+ and Zn2+ play crucial roles in innate immune sensing of cytosolic dsDNA, ultimately resulting in the activation of cGAS‐STING pathway. Unfortunately, efficient delivery of these metal ions to target cells remains a challenge, limiting their effectiveness in activating the STING pathway. Herein, a novel strategy based on nanoscale coordination polymer (NCP)/polymer nano‐hybrids is presented, which enables effective co‐delivery of metal ions and chemotherapeutics to tumor tissues, thereby activating the cGAS‐STING pathway to induce strong anti‐tumor immune responses. In this strategy, NCPs are water‐insoluble under physiological conditions, enabling efficient loading of metal ions while minimizing leakage in the bloodstream. In addition, designing the ligands of the NCPs to respond to different biological signals can enable rapid dissociation and metal ions/drugs release specifically at tumor sites. With this strategy, metal ion‐drug combinations such as Mn2+/PTX and Zn2+/Fe3+/DOX are co‐delivered to tumor successfully, leading to the effective synergy between dsDNA generation by chemo‐drugs and cGAS sensitization by Mn2+ and Zn2+. This efficiently activates the cGAS‐STING pathway, thereby inducing the anti‐tumor immune response and effectively inhibiting tumor growth, recurrence, and metastasis. [ABSTRACT FROM AUTHOR]

Photochemical regulation provides precise control over enzyme activities with high spatiotemporal resolution. A promising approach involves anchoring "photoswitches" at enzyme active sites to modulate substrate recognition. However, current methods often require genetic mutations and irreversible enzyme modifications for the site‐specific anchoring of "photoswitches", potentially compromising the enzyme activities. Herein, we present a pioneering reversible nano‐inhibitor based on molecular imprinting technique for bidirectional regulation of intracellular enzyme activity. The nano‐inhibitor employs a molecularly imprinted polymer nanoparticle as its body and azobenzene‐modified inhibitors ("photoswitches") as the arms. By using a target enzyme as the molecular template, the nano‐inhibitor acquires oriented binding sites on its surface, resulting in a high affinity for the target enzyme and non‐covalently firm anchoring of the azobenzene‐modified inhibitor to the enzyme active site. Harnessing the reversible isomerization of azobenzene units upon exposure to ultraviolet and visible light, the nano‐inhibitor achieves bidirectional enzyme activity regulation by precisely docking and undocking inhibitor at the active site. Notably, this innovative approach enables the facile in situ regulation of intracellular endogenous enzymes, such as carbonic anhydrase. Our results represent a practical and versatile tool for precise enzyme activity regulation in complex intracellular environments. [ABSTRACT FROM AUTHOR]

Cerebral soluble β‐amyloid aggregates (sAβs) accumulation is one of the most important causes in Alzheimer's disease (AD) progression. In order to mitigate the neurotoxicity induced by sAβs and achieve enhanced AD therapeutic outcomes, robust sAβs clearance become an emerging task. Herein, a self‐destructive nanoscavenger (SDNS) is reported based on multifunctional peptide‐polymer complexes that can capture extracellular sAβs via hydrogen‐bonding interactions and deliver them into microglial lysosomes. The internalized SDNS then occurs self‐destruction within lysosomes and upregulates autophagy, thereby promoting the degradation of neurotoxic sAβs. Importantly, the enhanced autophagy also significantly suppresses the secretion of inflammatory factors by microglia, which is induced by internalized sAβs. Given that cerebral persistent inflammatory environment disturbs microglia‐mediated phagocytosis and degradation, it is believed that this synergistic approach has valuable potential as a therapeutic strategy for AD. [ABSTRACT FROM AUTHOR]

SUMMARY: Peyote (Lophophora williamsii) is an entheogenic and medicinal cactus native to the Chihuahuan desert. The psychoactive and hallucinogenic properties of peyote are principally attributed to the phenethylamine derivative mescaline. Despite the isolation of mescaline from peyote over 120 years ago, the biosynthetic pathway in the plant has remained undiscovered. Here, we use a transcriptomics and homology‐guided gene discovery strategy to elucidate a near‐complete biosynthetic pathway from l‐tyrosine to mescaline. We identified a cytochrome P450 that catalyzes the 3‐hydroxylation of l‐tyrosine to l‐DOPA, a tyrosine/DOPA decarboxylase yielding dopamine, and four substrate‐specific and regiospecific substituted phenethylamine O‐methyltransferases. Biochemical assays with recombinant enzymes or functional analyses performed by feeding putative precursors to engineered yeast (Saccharomyces cerevisiae) strains expressing candidate peyote biosynthetic genes were used to determine substrate specificity, which served as the basis for pathway elucidation. Additionally, an N‐methyltransferase displaying broad substrate specificity and leading to the production of N‐methylated phenethylamine derivatives was identified, which could also function as an early step in the biosynthesis of tetrahydroisoquinoline alkaloids in peyote. [ABSTRACT FROM AUTHOR]

Here, we report a new multi‐optical maps scaffolder (MOMS) aiming at utilizing complementary information among optical maps labelled by distinct enzymes. This pipeline was designed for data structure organization, scaffolding by path traversal, gap‐filling and molecule reuse of optical maps. Our testing showed that this pipeline has uncapped enzyme tolerance in scaffolding. This means that there are no inbuilt limits as to the number of maps generated by different enzymes that can be utilized by MOMS. For the genome assembly of the human GM12878 cell line, MOMS significantly improved the contiguity and completeness with an up to 144‐fold increase of scaffold N50 compared with initial assemblies. Benchmarking on the genomes of human and O. sativa showed that MOMS is more effective and robust compared with other optical‐map‐based scaffolders. We believe this pipeline will contribute to high‐fidelity chromosome assembly and chromosome‐level evolutionary analysis. [ABSTRACT FROM AUTHOR]

Immunogenic cell death (ICD), which in situ generates cancer vaccines and elicits protective cognate anticancer immunity, has brought brightness to cancer immunotherapy. However, poor immunogenicity and low response rate of current ICD‐inducing strategies restrict the development and clinical application of ICD‐based immunotherapy. Herein, a novel calixarene, quaternary ammonium‐modified azocalix[4]arene (CA‐3) that drive bona fide ICD with high efficiency, is presented. In addition, the unique macrocyclic structure offers CA‐3 with great potential to bind with anticancer drugs via host–guest interactions. With these two functions in one molecule, CA‐3 effectively cooperates with various chemotherapeutics to improve their anticancer performance by activating ICD‐associated anti‐tumor immunity. These unique characteristics make CA‐3, a general platform for improving the prognosis of many chemotherapies commonly used in clinical practice. Furthermore, the structure‐activity relationship established in this study also provides insights for the design and synthesis of more efficient calixarene‐based ICD inducers. [ABSTRACT FROM AUTHOR]

Photodynamic therapy has emerged as a promising tool for inducing immunogenic cell death (ICD), which shows the potential to convert tumor cells into in situ vaccines. However, large amounts of as‐generated tumor‐associated antigens (TAAs) are entrapped in the endo‐lysosomes of tumor‐infiltrating dendritic cells (DCs), resulting in unsatisfactory TAA cross‐presentation and poor or moderate ICD‐associated antitumor responses. Herein, an immune‐enhancing polymer‐reinforced liposome (IERL) with a stable nanostructure and a bioactive surface is developed and it demonstrates its capability to collect TAAs, facilitates TAA endo‐lysosomal escape in DCs, and enhances cross‐presentation of TAAs, which results in the amplification of ICD‐associated antitumor immune responses. By loading photosensitizers, IERLs are able to induce robust antitumor immune responses and immune memory after local irradiation, thereby inhibiting the growth of both primary and distant/metastatic tumors. Additionally, considering the wide applications of liposomal carriers, photosensitizers in IERLs can be easily replaced with photothermal agents and radiosensitizers (or their combinations), which provides a general platform for the rapid development of combined cancer immunotherapy. [ABSTRACT FROM AUTHOR]

rGO/Mg(OH)2 composite films were fabricated on AZ61 alloy by the hydrothermal method in alkaline solutions containing deionized water and graphene oxide (GO). During the hydrothermal reaction, the Mg(OH)2 nanosheets and GO plates grew freely on the AZ61 substrate without any special orientation, and the GO was simultaneously reduced to rGO. With the increase of GO content in the hydrothermal solution, the corrosion resistance of the prepared composite films showed a trend of increasing first and then decreasing. When the content of GO incorporated in the hydrothermal solution is 5 mg, the corrosion current density (icorr) of the composite coating is reduced to the minimum (4.9 μA/cm2), which is seven times lower than that of the substrate and 3.5 times lower than that of the Mg(OH)2 monolayer. Based on experimental and molecular dynamics simulation results, the enhancement mechanism of the composite film was proposed, which is related to the growth of Mg(OH)2 layer, the "tortuous path" effect of GO and the slowing of chloride ion diffusion by GO functional groups. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disease in elderly population. Pterostilbene (PTS) is a resveratrol analog with neuroprotective activity. However, the biological mechanisms of PTS in AD progression are largely uncertain. An animal model of AD was established using streptozotocin (STZ)‐treated C57BL/6J mice. Monoamine oxidase B (MAOB) expression was analyzed by bioinformatics analysis and detected by western blotting assay. The memory impairment was investigated by Morris water maze test. The levels of Tau hyperphosphorylation and death‐related proteins were detected by western blotting analysis. The levels of amyloid β (Aβ)1–42 accumulation, oxidative stress‐related markers (ROS, MDA, SOD, and GSH), and inflammation‐relative markers (TNF‐α, IL‐1β, IL‐6, and p‐NF‐κB) were measured by ELISA. MAOB expression was increased in hippocampus of AD mice, and it was decreased by PTS. PTS attenuated STZ‐induced body weight loss and memory impairment by regulating MAOB. PTS mitigated Aβ1–42 accumulation and Tau hyperphosphorylation by regulating MAOB in STZ‐treated mice. PTS attenuated neuronal death by decreasing cleaved caspase‐3 and Bax levels and increasing Bcl2 expression in hippocampus by regulating MAOB in STZ‐treated mice. PTS weakened STZ‐induced oxidative stress in hippocampus by decreasing ROS and MDA levels and increasing SOD and GSH levels by regulating MAOB. PTS protected against STZ‐induced neuroinflammation in hippocampus by inhibiting TNF‐α, IL‐1β, IL‐6, and p‐NF‐κB levels through regulating MAOB. In conclusion, PTS alleviates STZ‐induced memory impairment, Aβ1–42 accumulation, Tau hyperphosphorylation, neuronal death, oxidative stress, and inflammation by decreasing MAOB in AD mice, proving anti‐AD potential of PTS. The biological mechanisms of pterostilbene (PTS) in Alzheimer's disease (AD) progression are largely uncertain. PTS alleviates streptozotocin (STZ)‐induced memory impairment, Aβ1–42 accumulation, Tau hyperphosphorylation, neuronal death, oxidative stress, and inflammation by decreasing MAOB in AD mice. This study might provide new pharmacological activity of PTS in treating AD. [ABSTRACT FROM AUTHOR]

Transfer learning has drawn growing attention with the target of improving statistical efficiency of one study (dataset) by digging up information from similar and related auxiliary studies (datasets). In this article, we consider transfer learning problem in estimating undirected semiparametric graphical model. We propose an algorithm called Trans‐Copula‐CLIME for estimating an undirected graphical model while uncovering information from similar auxiliary studies, characterizing the similarity between the target graph and each auxiliary graph by the sparsity of a divergence matrix. The proposed method relaxes the restrictive Gaussian distribution assumption, which deviates from reality for the fMRI dataset related to attention deficit hyperactivity disorder (ADHD) considered here. Nonparametric rank‐based correlation coefficient estimators are utilized in the Trans‐Copula‐CLIME procedure to achieve robustness against normality. We establish the convergence rate of the Trans‐Copula‐CLIME estimator under some mild conditions, which demonstrates that if the similarity between the auxiliary studies and the target study is sufficiently high and the number of informative auxiliary samples is sufficiently large, the Trans‐Copula‐CLIME estimator shows great advantage over the existing non‐transfer‐learning ones. Simulation studies also show that Trans‐Copula‐CLIME estimator has better performance especially when data are not from Gaussian distribution. Finally, the proposed method is applied to infer functional brain connectivity pattern for ADHD patients in the target Beijing site by leveraging the fMRI datasets from some other sites. [ABSTRACT FROM AUTHOR]

Photochemical regulation provides a promising approach for controlling enzyme activity on demand owing to its high spatiotemporal resolution. However, reversible regulation of the enzyme activity by light usually requires genetic mutations and covalent modifications of the target enzymes, which may lead to irreversible changes in the enzyme structure and subsequent loss of the enzymatic activity. Herein, we have developed a novel strategy based on a polymeric inhibitor‐encapsulated enzyme, which noncovalently anchors the azobenzene‐modified inhibitors to the enzyme active site, thereby achieving reversible control of the activity of native enzymes using light. As neither genetic mutation nor chemical modification of enzymes is required for this method, negligible loss of the enzymatic activity was observed for the encapsulated enzymes compared to their native counterparts. Thus, this approach has demonstrated a promising strategy for achieving reversible regulation of the activity of native enzymes. [ABSTRACT FROM AUTHOR]

Comparing genome scans among species is a powerful approach for investigating the patterns left by evolutionary processes. In particular, this offers a way to detect candidate genes that drive convergent evolution. We compared genome scan results to investigate if patterns of genetic diversity and divergence are shared among divergent species within the stickleback order (Gasterosteiformes): the threespine stickleback (Gasterosteus aculeatus), ninespine stickleback (Pungitius pungitus), and tubesnout (Aulorhynchus flavidus). Populations were sampled from the southern and northern edges of each species' range, to identify patterns associated with latitudinal changes in genetic diversity. Weak correlations in genetic diversity (FST and expected heterozygosity) and three different patterns in the genomic landscape were found among these species. Additionally, no candidate genes for convergent evolution were detected. This is a counterexample to the growing number of studies that have shown overlapping genetic patterns, demonstrating that genome scan comparisons can be noisy due to the effects of several interacting evolutionary forces. [ABSTRACT FROM AUTHOR]

Titanium alloys are widely accepted as orthopedic or dental implant materials in the medical field. It is important to evaluate the biocompatibility of an implant material prior to use. A new β‐type ultrafine‐grained Ti–28Nb–2Zr–8Sn (TNZS) alloy with low Young's modulus of 31.6 GPa was fabricated. This study aims to evaluate the biocompatibility of TNZS alloy. In this study, we examined the microstructure, chemical composition and surface wettability of the TNZS alloy. The mouse embryonic osteoblast MC3T3‐E1 cells and human umbilical vein endothelial cells (HUVECs) were cultured to study the cytocompatibility of TNZS alloy. Also, we evaluated the proinflammatory response of TNZS alloy in vitro and in vivo. The results show that the TNZS did not cause cytotoxicity, genotoxicity to MC3T3‐E1 cells and HUVECs. Whereas, the TNZS alloy could significantly promote the cell proliferation, cell spreading and cell adhesion of MC3T3‐E1 cells and HUVECs, as well as facilitate the osteogenic differentiation of MC3T3‐E1 cells. Moreover, the TNZS alloy did not induce any remarkable proinflammatory response in vitro and in vivo. Thus, the novel TNZS alloy with an elasticity closer to that of human bone is biologically safe and could be a potential candidate for biomedical implant application. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1628–1639, 2019. [ABSTRACT FROM AUTHOR]

A circular consensus sequencing ( CCS) strategy involving single molecule, real-time ( SMRT) DNA sequencing technology was applied to de novo assembly and single nucleotide polymorphism ( SNP) detection of chloroplast genomes., Chloroplast DNA was purified from enriched chloroplasts of pooled individuals to construct a shotgun library for each species. The sequencing reactions were performed on a PacBio RS platform. CCS sub-reads were generated from polymerase reads that passed the native dumbbell-shaped DNA templates multiple times. The complete chloroplast genome sequence was generated by mapping all reads to the draft sequence constructed in a step-by-step manner., The full-chain, PCR-free approach eliminates the possible context-specific biases in library construction and sequencing reaction. The chloroplast genome was easily and completely assembled using the data generated from one SMRT Cell without requiring a reference genome. Comparisons of the three assembled Fritillaria genomes to 34.1 kb of validation Sanger sequences revealed 100% concordance, and the detected intraspecies SNPs at a minimum variant frequency of 15% were all confirmed., This simple approach with potential for parallel sequencing yields high-quality chloroplast genomes for sensitive SNP detection and comparative analyses. We recommend this approach for its powerful applicability for evolutionary genetics and genomics studies in plants based on the sequences of chloroplast genomes. [ABSTRACT FROM AUTHOR]