Radiotherapy activates picolinium prodrugs in tumours.

Radiotherapy-induced prodrug activation provides an ideal solution to reduce the systemic toxicity of chemotherapy in cancer therapy, but the scope of the radiation-activated protecting groups is limited. Here we present that the well-established photoinduced electron transfer chemistry may pave the way for developing versatile radiation-removable protecting groups. Using a functional reporter assay, N-alkyl-4-picolinium (NAP) was identified as a caging group that efficiently responds to radiation by releasing a client molecule. When evaluated in a competition experiment, the NAP moiety is more efficient than other radiation-removable protecting groups discovered so far. Leveraging this property, we developed a NAP-derived carbamate linker that releases fluorophores and toxins on radiation, which we incorporated into antibody-drug conjugates (ADCs). These designed ADCs were active in living cells and tumour-bearing mice, highlighting the potential to use such a radiation-removable protecting group for the development of next-generation ADCs with improved stability and therapeutic effects.

Nanoplastics aggravated TDCIPP-induced transgenerational developmental neurotoxicity in zebrafish depending on the involvement of the dopamine signaling pathway.

Plastics pose a hazard to the environment. Although plastics have toxicity, microplastics (MPs) and nanoplastics (NPs) are capable of interacting with the rest pollutants in the environment, so they serve as the carriers and interact with organic pollutants to modulate their toxicity, thus resulting in unpredictable ecological risks. PS-NPs and TDCIPP were used expose from 2 h post-fertilization (hpf) to 150 days post-fertilization (dpf) to determine the bioaccumulation of tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and its potential effects on neurodevelopment in F1 zebrafish (Danio rerio) offspring under the action of polystyrene nano plastics (PS-NPs). The exposure groups were assigned to TDCIPP (0, 0.4, 2 or 10 µg/L) alone group and the PS-NPs (100 µg/L) and TDCIPP co-exposed group. F1 embryos were collected and grown in clean water to 5 dpf post-fertilization. PS-NPs facilitated the bioaccumulation of TDCIPP in the gut, gill, head，gonad and liver of zebrafish in a sex-dependent manner and promoted the transfer of TDCIPP to their offspring, thus contributing to PS-NPs aggravated the inhibition of offspring development and neurobehavior of TDCIPP-induced. In comparison with TDCIPP exposure alone, the combination could notably down-regulate the levels of the dopamine neurotransmitter, whereas the levels of serotonin or acetylcholine were not notably different. This result was achieved probably because PS-NPs interfered with the TDCIPP neurotoxic response of zebrafish F1 offspring not through the serotonin or acetylcholine neurotransmitter pathway. The increased transfer of TDCIPP to the offspring under the action of PS-NPs increased TDCIPP-induced transgenerational developmental neurotoxicity, which was proven by a further up-regulation/down-regulation the key gene and protein expression related to dopamine synthesis, transport, and metabolism in F1 larvae, in contrast to TDCIPP exposure alone. The above findings suggested that dopaminergic signaling involvement could be conducive to the transgenerational neurodevelopmental toxicity of F1 larval upon parental early co-exposure to PS-NPs and TDCIPP.

Electrical Transport and Dynamics of Confined DNA through Highly Conductive 2D Graphene Nanochannels.

Confining DNA in nanochannels is an important approach to studying its structure and transportation dynamics. Graphene nanochannels are particularly attractive for studying DNA confinement due to their atomic flatness, precise height control, and excellent mechanical strength. Here, using femtosecond laser etching and wetting transfer, we fabricate graphene nanochannels down to less than 4.3 nm in height, with the length-to-height ratios up to 103. These channels exhibit high stability, low noise, and self-cleaning ability during the long-term ionic current recording. We report a clear linear relationship between DNA length and the residence time in the channel and further utilize this relationship to differentiate DNA fragments based on their lengths, ranging widely from 200 bps to 48.5 kbps. The graphene nanochannel presented here provides a potential platform for label-free analyses and reveals fundamental insights into the conformational dynamics of DNA and proteins in confined space.

B-Glycine as a marker for ß cell imaging and ß cell mass evaluation.

PURPOSE: ß cell mass (BCM) and function are essential to the diagnosis and therapy of diabetes. Diabetic patients serve ß cell loss is, and damage of ß cells leads to severe insulin deficiency. Our understanding of the role of BCM in diabetes progression is extremely limited by lacking efficient methods to evaluate BCM in vivo. In vitro methods of labeling islets, including loading of contrast reagent or integration of exogenous biomarker, require artificial manipulation on islets, of which the clinical application is limited. Imaging methods targeting endogenous biomarkers may solve the above problems. However, traditional reagents targeting GLP-1R and VAMT2 result in a high background of adjacent tissues, complicating the identification of pancreatic signals. Here, we report a non-invasive and quantitative imaging technique by using radiolabeled glycine mimics ([18F]FBG, a boron-trifluoride derivative of glycine) to assay islet function and monitor BCM changes in living animals. METHODS: Glycine derivatives, FBG, FBSa, 2Me-FBG, 3Me-FBG, were successfully synthesized and labeled with 18F. Specificity of glycine derivatives were characterized by in vitro experiment. PET imaging and biodistribution studies were performed in animal models carring GLYT over-expressed cells. In vivo evaluation of BCM with [18F]FBG were performed in STZ (streptozocin) induced T1D (type 1 diabetes) models. RESULTS: GLYT responds to excess blood glycine levels and transports glycine into islet cells to maintain the activity of the glycine receptor (GLYR). Best PET imaging condition was 80 min after given a total of 240 ~ 250 nmol imaging reagent (a mixture of [18F]FBG and natural glycine) intravenously. [18F]FBG can detect both endogenous and exogenous islets clearly in vivo. When applied to STZ induced T1D mouse models, total uptake of [18F]FBG in the pancreas exhibited a linear correlation with survival BCM. CONCLUSION: [18F]FBG targeting the endogenous glycine transporter (GLYT), which is highly expressed on islet cells, avoiding extra modification on islet cells. Meanwhile the highly restricted expression pattern of GLYT excluded the background in adjacent tissues. This [18F]FBG-based imaging technique provides a non-invasive method to quantify BCM in vivo, implying a new evaluation index for diabetic assessment.

Retrieval of broken K-wires by overdrilling using hypodermic needle.

Breakage of K-wires within the metacarpals and phalanges due to metal fatigue and overly aggressive joint movements are encountered occasionally. We established a simple and feasible technique for K-wire retrieval by overdrilling using a hypodermic needle.Level of evidence: IV.

A Curcumin-Decorated Nanozyme with ROS Scavenging and Anti-Inflammatory Properties for Neuroprotection.

Disordered reactive oxygen/nitrogen species are a common occurrence in various diseases, which usually cause cellular oxidative damage and inflammation. Despite the wide range of applications for biomimetic nanoparticles with antioxidant or anti-inflammatory properties, designs that seamlessly integrate these two abilities with a synergistic effect in a simple manner are seldom reported. In this study, we developed a novel PEI-Mn composite nanoparticle (PM NP) using a chelation method, and the curcumin was loaded onto PM NPs via metal-phenol coordination to form PEI-Mn@curcumin nanoparticles (PMC NPs). PMC NPs possessed excellent dispersibility and cytocompatibility, was engineered to serve as an effective nanozyme, and exhibited specific SOD-like and CAT-like activities. In addition, the incorporation of curcumin granted PMC NPs the ability to effectively suppress the expression of inflammatory cytokines in microglia induced by LPS. As curcumin also has antioxidant properties, it further amplified the synergistic efficiency of ROS scavenging. Significantly, PMC NPs effectively scavenged ROS triggered by H2O2 in SIM-A9 microglia cells and Neuro-2a cells. PMC NPs also considerably mitigated DNA and lipid oxidation in Neuro-2a cells and demonstrated an increase in cell viability under various H2O2 concentrations. These properties suggest that PMC NPs have significant potential in addressing excessive ROS and inflammation related to neural diseases.

A modified shuffled frog leaping algorithm with inertia weight.

The shuffled frog leaping algorithm (SFLA) is a promising metaheuristic bionics algorithm, which has been designed by the shuffled complex evolution and the particle swarm optimization (PSO) framework. However, it is easily trapped into local optimum and has the low optimization accuracy when it is used to optimize complex engineering problems. To overcome the shortcomings, a novel modified shuffled frog leaping algorithm (MSFLA) with inertia weight is proposed in this paper. To extend the scope of the direction and length of the updated worst frog (vector) of the original SFLA, the inertia weight α was introduced and its meaning and range of the new parameters are fully explained. Then the convergence of the MSFLA is deeply analyzed and proved theoretically by a new dynamic equation formed by Z-transform. Finally, we have compared the solution of the 7 benchmark functions with the original SFLA, other improved SFLAs, genetic algorithm, PSO, artificial bee colony algorithm, and the grasshopper optimization algorithm with invasive weed optimization. The testing results showed that the modified algorithms can effectively improve the solution accuracy and convergence property, and exhibited an excellent ability of global optimization in high-dimensional space and complex function problems.

A bis-boron boramino acid PET tracer for brain tumor diagnosis.

PURPOSE: Boramino acids are a class of amino acid biomimics that replace the carboxylate group with trifluoroborate and can achieve the 18F-labeled positron emission tomography (PET) and boron neutron capture therapy (BNCT) with identical chemical structure. METHODS: This study reports a trifluoroborate-derived boronophenylalanine (BBPA), a derived boronophenylalanine (BPA) for BNCT, as a promising PET tracer for tumor imaging. RESULTS: Competition inhibition assays in cancer cells suggested the cell accumulation of [18F]BBPA is through large neutral amino acid transporter type-1 (LAT-1). Of note, [18F]BBPA is a pan-cancer probe that shows notable tumor uptake in B16-F10 tumor-bearing mice. In the patients with gliomas and metastatic brain tumors, [18F]BBPA-PET shows good tumor uptake and notable tumor-to-normal brain ratio (T/N ratio, 18.7 ± 5.5, n = 11), higher than common amino acid PET tracers. The [18F]BBPA-PET quantitative parameters exhibited no difference in diverse contrast-enhanced status (P = 0.115-0.687) suggesting the [18F]BBPA uptake was independent from MRI contrast-enhancement. CONCLUSION: This study outlines a clinical trial with [18F]BBPA to achieve higher tumor-specific accumulation for PET, provides a potential technique for brain tumor diagnosis, and might facilitate the BNCT of brain tumors.

An "AND" Logic-Gated Prodrug Micelle Locally Stimulates Antitumor Immunity.

Materials that can respond to multiple biomarkers simultaneously, acting as an "AND" gate, have the potential to enhance tumor-targeting for drug delivery. In this study, an "AND" logic-controlled release prodrug micelle is developed for codelivering the chemotherapeutic and the stimulator of interferon genes (STING) agonist, enabling precise combinatorial therapy. The drug release is programmed by tumor-enriched boramino acids (BAA) in the tumor microenvironment and intracellular reactive oxygen species (ROS), resulting in enhanced tumor targeting. STING agonist is successfully encapsulated into prodrug micelles through π-π stacking and hydrophobic interactions. These AND logic-gated prodrug micelles can achieve tumor-targeted delivery of STING agonist, leading to significantly enhanced immune activation and antitumor efficacy in vivo. It is expected that this clinically relevant nanoplatform will provide a rational design of an effective immunotherapy combination regimen to convert immunologically "cold" tumors to immunogenic "hot" tumors, addressing the major challenges faced by immunotherapies.

Impact of Metagenomic Next-Generation Sequencing of Bronchoalveolar Lavage Fluid on Antimicrobial Stewardship in Patients With Lower Respiratory Tract Infections: A Retrospective Cohort Study.

BACKGROUND: The impact of metagenomic next-generation sequencing (mNGS) on antimicrobial stewardship in patients with lower respiratory tract infections (LRTIs) is still unknown. METHODS: This retrospective cohort study included patients who had LRTIs diagnosed and underwent bronchoalveolar lavage between September 2019 and December 2020. Patients who underwent both mNGS and conventional microbiologic tests were classified as the mNGS group, while those with conventional tests only were included as a control group. A 1:1 propensity score match for baseline variables was conducted, after which changes in antimicrobial stewardship between the 2 groups were assessed. RESULTS: A total of 681 patients who had an initial diagnosis of LRTIs and underwent bronchoalveolar lavage were evaluated; 306 patients were finally included, with 153 in each group. mNGS was associated with lower rates of antibiotic escalation than in the control group (adjusted odds ratio, 0.466 [95% confidence interval, .237-.919]; P = .02), but there was no association with antibiotic de-escalation. Compared with the control group, more patients discontinued the use of antivirals in the mNGS group. CONCLUSIONS: The use of mNGS was associated with lower rates of antibiotic escalation and may facilitate the cessation of antivirals, but not contribute to antibiotic de-escalation in patients with LRTIs.

Prolonged sleep deprivation induces a cytokine-storm-like syndrome in mammals.

Most animals require sleep, and sleep loss induces serious pathophysiological consequences, including death. Previous experimental approaches for investigating sleep impacts in mice have been unable to persistently deprive animals of both rapid eye movement sleep (REMS) and non-rapid eye movement sleep (NREMS). Here, we report a "curling prevention by water" paradigm wherein mice remain awake 96% of the time. After 4 days of exposure, mice exhibit severe inflammation, and approximately 80% die. Sleep deprivation increases levels of prostaglandin D2 (PGD2) in the brain, and we found that elevated PGD2 efflux across the blood-brain-barrier-mediated by ATP-binding cassette subfamily C4 transporter-induces both accumulation of circulating neutrophils and a cytokine-storm-like syndrome. Experimental disruption of the PGD2/DP1 axis dramatically reduced sleep-deprivation-induced inflammation. Thus, our study reveals that sleep-related changes in PGD2 in the central nervous system drive profound pathological consequences in the peripheral immune system.

Outcomes After Double-Layer Repair Versus En Masse Repair for Delaminated Rotator Cuff Injury: A Systematic Review and Meta-analysis.

Background: Delamination of rotator cuff tears during arthroscopic shoulder surgery has an incidence of 38% to 92%. Double-layer (DL) repair and en masse (EM) repair are most commonly used in this situation. Purpose: To compare the clinical results of the DL versus EM repair techniques for delaminated rotator cuff tears using a meta-analysis. Study Design: Systematic review; level of evidence, 3. Methods: We identified relevant studies comparing the clinical results of DL and EM repair for delaminated rotator cuff injuries in the PubMed, Embase, and Cochrane databases after the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The primary outcomes were the Constant score and retear rate. Additionally, we compared other postoperative shoulder functional scores, shoulder range of motion, and visual analog scale (VAS) pain scores between the 2 suture methods using a meta-analysis. The mean difference (MD) was compared for continuous outcomes, and the odds ratios (ORs) were compared for categorical outcomes. Results: Of the 197 studies initially identified, 6 studies were included in this analysis. There were significant differences in the Constant score (MD, 8.64 [95% CI, 4.47 to 12.8]; P < .05) and external rotation (MD, 5.10 [95% CI, 2.63 to 7.56]; P < .05) between the 2 techniques, with DL repair having superior outcomes. No significant differences were observed between the 2 techniques in forward flexion (MD, 0.62 [95% CI, -1.18 to 2.43]; P = .50), VAS pain (MD, -0.03 [95% CI, -0.34 to 0.27]; P = .84), or retear rate (OR, 0.73 [95% CI, 0.37 to 1.41]; P = .35). Conclusion: Results of this review and meta-analysis suggest that DL repair was more beneficial than EM repair in terms of the Constant score and shoulder external rotation in patients with delaminated rotator cuff injuries.

CD9 exacerbates pathological cardiac hypertrophy through regulating GP130/STAT3 signaling pathway.

CD9 is a member of the tetraspanin protein family, which has been widely studied in inflammation and cancer, but not in pathological cardiac hypertrophy. In this study, we found that the expression of CD9 was increased in transaortic constriction (TAC) myocardial tissue. Knockdown of CD9 alleviated damage to cardiac function in the TAC model and reduced heart weight, cardiomyocyte size, and degree of fibrosis, and vice versa. Mechanistically, co-immunoprecipitation results showed that CD9 and GP130 can bind to each other in cardiomyocytes, and knockdown of CD9 can reduce the protein level of GP130 and the phosphorylation of STAT3 in vivo and in vitro, and vice versa. GP130 knockdown reversed the aggravating effects of CD9 on pathological cardiac hypertrophy. Therefore, we conclude that CD9 exacerbates pathological cardiac hypertrophy by regulating the GP130/STAT3 signaling pathway and may serve as a therapeutic target for pathological cardiac hypertrophy.

Bioorthogonal chemistry for prodrug activation in vivo.

Prodrugs have emerged as a major strategy for addressing clinical challenges by improving drug pharmacokinetics, reducing toxicity, and enhancing treatment efficacy. The emergence of new bioorthogonal chemistry has greatly facilitated the development of prodrug strategies, enabling their activation through chemical and physical stimuli. This "on-demand" activation using bioorthogonal chemistry has revolutionized the research and development of prodrugs. Consequently, prodrug activation has garnered significant attention and emerged as an exciting field of translational research. This review summarizes the latest advancements in prodrug activation by utilizing bioorthogonal chemistry and mainly focuses on the activation of small-molecule prodrugs and antibody-drug conjugates. In addition, this review also discusses the opportunities and challenges of translating these advancements into clinical practice.

Lexical density, lexical diversity, and lexical sophistication in simultaneously interpreted texts: a cognitive perspective.

Simultaneous interpreting (SI) is a cognitively demanding task that imposes a heavy cognitive load on interpreters. Interpreting into one's native (A language) or non-native language (B language), known as interpreting directionality, involves different cognitive demands. The cognitive requirements of simultaneous interpreting as well as interpreting directionality affect the interpreting process and product. This current study focused on the lexical features of a specially designed corpus of United Nations Security Council speeches. The corpus included non-interpreted speeches in US English (SubCorpusE), and texts interpreted from Chinese into English (A-into-B interpreted texts, SubCorpusC-E) and from Russian into English (B-into-A interpreted texts, SubCorpusR-E). Ten measures were used to analyze the lexical features of each subcorpus in terms of lexical density, lexical diversity, and lexical sophistication. The three subcorpora were regrouped into two pairs for the two research questions: SubCorpusR-E versus SubCorpusE and SubCorpusR-E versus SubCorpusC-E. The results showed that the interpreted texts in SubCorpusR-E exhibited simpler vocabulary features than the non-interpreted texts in SubCorpusE. In addition, compared with the A-into-B interpreted texts, the B-into-A interpreted texts demonstrated simplified lexical characteristics. The lexical features of the interpreted texts reflect that experienced simultaneous interpreters consciously adopt a simplified vocabulary approach to manage the cognitive load during simultaneous interpreting. This study provides new insights into the cognitive aspects of simultaneous interpreting, the impact of directionality, and the role of lexical strategies. These findings have practical implications for interpreter training, professional growth, and maintaining interpreting quality in diverse settings.

Simulating Chern insulators on a superconducting quantum processor.

The quantum Hall effect, fundamental in modern condensed matter physics, continuously inspires new theories and predicts emergent phases of matter. Here we experimentally demonstrate three types of Chern insulators with synthetic dimensions on a programable 30-qubit-ladder superconducting processor. We directly measure the band structures of the 2D Chern insulator along synthetic dimensions with various configurations of Aubry-André-Harper chains and observe dynamical localisation of edge excitations. With these two signatures of topology, our experiments implement the bulk-edge correspondence in the synthetic 2D Chern insulator. Moreover, we simulate two different bilayer Chern insulators on the ladder-type superconducting processor. With the same and opposite periodically modulated on-site potentials for two coupled chains, we simulate topologically nontrivial edge states with zero Hall conductivity and a Chern insulator with higher Chern numbers, respectively. Our work shows the potential of using superconducting qubits for investigating different intriguing topological phases of quantum matter.

Identification and Analysis of Neutrophil Extracellular Trap-Related Genes in Osteoarthritis by Bioinformatics and Experimental Verification.

Background: Osteoarthritis (OA) is a common joint disease with long-term pain and dysfunction that negatively affects the quality of life of patients. Neutrophil extracellular traps (NETs), consisting of DNA, proteins and cytoplasm, are released by neutrophils and play an important role in a variety of diseases. However, the relationship between OA and NETs is unclear. Methods: In our study, we used bioinformatics to explore the relationship between OA and NETs and the potential biological markers. GSE55235, GSE55457, GSE117999 and GSE98918 were downloaded from the Gene Expression Omnibus (GEO) database for subsequent analysis.After differential analysis of OA expression matrices, intersection with NET-related genes (NRGs) was taken to identify Differentially expressed NRGs (DE-NRGs) in OA processes. Evaluation of immune cell infiltration by ssGSEA and CIBERSORT algorithm. The GSVA method was used to analyze the activity changes of Neutrophils pathway, Neutrophil degranulation and Neutrophil granule constituents pathway. Results: Based on RandomForest (RF), Least Absolute Shrinkage and Selection Operator (LASSO), and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) learning algorithms, five core genes (CRISPLD2, IL1B, SLC25A37, MMP9, and TLR7) were identified to construct an OA-related nomogram model for predicting OA progression. ROC curve results for these genes validated the nomogram's reliability. Correlation analysis, functional enrichment, and drug predictions were performed for the core genes. TLR7 emerged as a key focus due to its high importance ranking in RF and SVM-RFE analyses. Gene Set Enrichment Analysis (GSEA) revealed a strong association between TLR7 and the Neutrophil extracellular trap pathway. Expression of core genes was demonstrated in mice OA models and human OA samples. TLR7 expression in ATDC5 cell line was significantly higher than control after TNFα induction, along with increased IL6 and MMP13. Conclusion: TLR7 may be related to NETs and affects OA.