A Radical Activation Strategy for Versatile and Stereoselective N-Glycosylation.

Previous N-glycosylation approaches have predominately involved acidic conditions, facing challenges of low stereoselectivity and limited scope. Herein, we introduce a radical activation strategy that enables versatile and stereoselective N-glycosylation using readily accessible glycosyl sulfinate as a donor under basic conditions and exhibits exceptional tolerance towards various N-aglycones containing alkyl, aryl, heteroaryl and nucleobase functionalities. Preliminary mechanistic studies indicate a pivotal role of iodide, which orchestrates the formation of a glycosyl radical from the glycosyl sulfinate and subsequent generation of the key intermediate, a configurationally well-defined glycosyl iodide, which is subsequently attacked by an N-aglycone in a stereospecific SN2 manner to give the desired N-glycosides. An alternative route involving the coupling of a glycosyl radical and a nitrogen-centered radical is also proposed, affording the exclusive 1,2-trans product. This novel approach promises to broaden the synthetic landscape of N-glycosides, offering a powerful tool for the construction of complex glycosidic structures under mild conditions.

Fast Pure Shift NMR Spectroscopy Using Attention-Assisted Deep Neural Network.

Pure shift NMR spectroscopy enables the robust probing on molecular structure and dynamics, benefiting from great resolution enhancements. Despite extensive application landscapes in various branches of chemistry, the long experimental times induced by the additional time dimension generally hinder its further developments and practical deployments, especially for multi-dimensional pure shift NMR. Herein, this study proposes and implements the fast, reliable, and robust reconstruction for accelerated pure shift NMR spectroscopy with lightweight attention-assisted deep neural network. This deep learning protocol allows one to regain high-resolution signals and suppress undersampling artifacts, as well as furnish high-fidelity signal intensities along with the accelerated pure shift acquisition, benefitting from the introduction of the attention mechanism to highlight the spectral feature and information of interest. Extensive results of simulated and experimental NMR data demonstrate that this attention-assisted deep learning protocol enables the effective recovery of weak signals that are almost drown in the serious undersampling artifacts, and the distinction and recognition of close chemical shifts even though using merely 5.4% data, highlighting its huge potentials on fast pure shift NMR spectroscopy. As a result, this study affords a promising paradigm for the AI-assisted NMR protocols toward broader applications in chemistry, biology, materials, and life sciences, and among others.

TORSEL, a 4EBP1-based mTORC1 live-cell sensor, reveals nutrient-sensing targeting by histone deacetylase inhibitors.

BACKGROUND: Mammalian or mechanistic target of rapamycin complex 1 (mTORC1) is an effective therapeutic target for diseases such as cancer, diabetes, aging, and neurodegeneration. However, an efficient tool for monitoring mTORC1 inhibition in living cells or tissues is lacking. RESULTS: We developed a genetically encoded mTORC1 sensor called TORSEL. This sensor changes its fluorescence pattern from diffuse to punctate when 4EBP1 dephosphorylation occurs and interacts with eIF4E. TORSEL can specifically sense the physiological, pharmacological, and genetic inhibition of mTORC1 signaling in living cells and tissues. Importantly, TORSEL is a valuable tool for imaging-based visual screening of mTORC1 inhibitors. Using TORSEL, we identified histone deacetylase inhibitors that selectively block nutrient-sensing signaling to inhibit mTORC1. CONCLUSIONS: TORSEL is a unique living cell sensor that efficiently detects the inhibition of mTORC1 activity, and histone deacetylase inhibitors such as panobinostat target mTORC1 signaling through amino acid sensing.

Insights into comparative genomics, structural features, and phylogenetic relationship of species from Eurasian Aster and its related genera (Asteraceae: Astereae) based on complete chloroplast genome.

Aster L. is an economically and phylogenetically important genus in the tribe Astereae. Here, the complete plastomes of the eight Aster species were assembled and characterized using next-generation sequencing datasets. The results indicated the complete plastomes of Aster had a quadripartite structure. These genomes were 152,045-152,729 bp in length and contained 132-133 genes, including 87 protein-coding genes, 37-38 tRNA genes, and eight rRNA genes. Expansion or contraction of inverted repeat regions and forward, palindromic, complement, and reverse repeats were detected in the eight Aster species. Additionally, our analyses showed the richest type of simple sequence repeats was A/T mononucleotides, and 14 highly variable regions were discovered by analyzing the border regions, sequence divergence, and hotspots. Phylogenetic analyses indicated that 27 species in Astereae were clustered into six clades, i.e., A to D, North American, and outgroup clades, and supported that the genera Heteropappus, Kalimeris, and Heteroplexis are nested within Aster. The results indicated the clades B to D might be considered as genera. Divergence time estimate showed the clades A, B, C, and D diverged at 23.15 Mya, 15.13 Mya, 24.29 Mya, and 21.66 Mya, respectively. These results shed light on the phylogenetic relationships of Aster and provided new information on species identification of Aster and its related genera.

Effect of dental chew on reducing dental plaque, dental calculus and halitosis in beagle dogs.

Periodontosis is the most common clinical disease in adult dogs, which is mainly caused by plaque accumulation and seriously endangers the oral health of dogs and even cause kidney, myocardial, and liver problems in severe cases. The aim of this study was to determine the clinical efficacy of dental chew (Cature Brushing Treats product) with mechanical and chemical properties in beagles. The dogs in the experimental group were fed with a dental chew twice a day after meals; The control group had no treatment. Dental plaque was evaluated on the 14th day and 29th day, respectively. The concentration of volatile sulfur compounds (VSC) in the breath and dental calculus were also evaluated on the 29th day. The results showed that there was no significant difference in the indexes of dental plaque on the 14th day. While they had significantly reduced accumulation of plaque (37.63%), calculus (37.61%), and VSC concentration (81.08%) compared to when receiving no chew on the 29th day.

Optical biomarker analysis for renal cell carcinoma obtained from preoperative and postoperative patients using ATR-FTIR spectroscopy.

Renal cell carcinoma (RCC) is the most common malignant tumor in the urinary system, accounting for 80 % to 90 % for all renal malignancies. Traditional diagnostic methods like magnetic resonance imaging (MRI) and computed tomography (CT) lack the sensitivity and specificity as they lack specific biomarkers. These limitations impede effective monitoring of tumor recurrence. This study aims to employ Attenuated Total Reflection (ATR)-Fourier transform infrared (FTIR) spectroscopy, an optical technology sensitive to molecular groups, to analyze the potential optical biomarkers in urine and plasma samples from RCC patients pre- and post-surgery. The results reveal distinctive spectral information from both plasma and urine samples. Post-surgery urine spectra exhibit complexity compared to plasma, showing reduced content at 1072 cm-1, 1347 cm-1 and 1654 cm-1 bands, while increased content at 1112 cm-1, 1143 cm-1, 1447 cm-1, 3334 cm-1 and 3420 cm-1 bands. Utilizing machine learning models such as eXtreme Gradient Boosting (XGBoost), support vector machine (SVM), partial least squares (PLS), and artificial neural network (ANN), the study evaluated plasma and urine samples pre- and post-surgery. Remarkably, the XGBoost method excelled in distinguishing between tumor conditions and recovery, achieving an impressive AUC value of 0.99. These results underscore the potential of ATR-FTIR technology in identifying RCC optical biomarkers, with XGBoost showing promise as a valuable screening tool for RCC recurrence diagnosis.

Bioinspired Mechanochromic Liquid Crystal Materials: from Fundamentals to Functionalities and Applications.

Inspired by intriguing color changeable ability of natural animals, the design and fabrication of artificial mechanochromic materials capable of changing colors upon stretching or pressing have attracted intense scientific interest. Liquid crystal (LC) is a self-organized soft matter with anisotropic molecular alignment. Due to the sensitivity to various external stimulations, LC has been considered as an emerging and appealing responsive building block to construct intelligent materials and advanced devices. Recently, mechanochromic LC materials have becoming a hot topic in multi fields from flexible artificial skins to visualized sensors and smart biomimetic devices. In this review, the recent progress of mechanochromic LCs is comprehensively summarized. Firstly, the mechanism and functionalities of mechanochromic LC is introduced, followed by preparation of various functional materials based on mechanochromic LCs. Then the applications of mechanochromic LCs are provided. Finally, the conclusion and outlooks of this field is given. This overview is hoped to provide inspiration in fabrication of advanced functional soft materials for scientists and engineers from multidisciplines including materials science, elastomers, chemistry and physical science. This article is protected by copyright. All rights reserved.

R3 strain and Fe-Mn modified biochar reduce Cd absorption capacity of roots and available Cd content of soil by affecting rice rhizosphere and endosphere key flora.

Microorganisms have a significant role in regulating the absorption and transportation of Cd in the soil-plant system. However, the mechanism by which key microbial taxa play a part in response to the absorption and transportation of Cd in rice under Cd stress requires further exploration. In this study, the cadmium-tolerant endophytic bacterium Herbaspirillum sp. R3 (R3) and Fe-Mn-modified biochar (Fe-Mn) were, respectively, applied to cadmium-contaminated rice paddies to investigate the effects of key bacterial taxa in the soil-rice system on the absorption and transportation of Cd in rice under different treatments. The results showed that both R3 and Fe-Mn treatments considerably decreased the content of cadmium in roots, stems and leaves of rice at the peak tillering stage by 17.24-49.28% in comparison to the control (CK). The cadmium content reduction effect of R3 treatment is better than that of Fe-Mn treatment. Further analysis revealed that the key bacterial taxa in rice roots under R3 treatment were Sideroxydans and Actinobacteria, and that their abundance showed a substantial positive correlation and a significant negative correlation with the capacity of rice roots to assimilate Cd from the surroundings, respectively. The significant increase in soil pH under Fe-Mn treatment, significant reduction in the relative abundances of Acidobacteria, Verrucomicrobia, Subdivision3 genera incertae sedis, Sideroxydans, Geobacter, Gp1, and Gp3, and the significant increase in the relative abundance of Thiobacillus among the soil bacterial taxa may be the main reasons for the decrease in available Cd content of the soil. In addition, both the R3 and Fe-Mn treatments showed some growth-promoting effects on rice, which may be related to their promotion of transformations of soil available nutrients. This paper describes the possible microbial mechanisms by which strain R3 and Fe-Mn biochar reduce Cd uptake in rice, providing a theoretical basis for the remediation of Cd contamination in rice and soil by utilizing key microbial taxa.

In Situ Synthesis of an Immune-Checkpoint Blocker from Engineered Bacteria Elicits a Potent Antitumor Response.

Immune-checkpoint blockade (ICB) reinvigorates T cells from exhaustion and potentiates T-cell responses to tumors. However, most patients do not respond to ICB therapy, and only a limited response can be achieved in a "cold" tumor with few infiltrated lymphocytes. Synthetic biology can be used to engineer bacteria as controllable bioreactors to synthesize biotherapeutics in situ. We engineered attenuated Salmonella VNP20009 with synthetic gene circuits to produce PD-1 and Tim-3 scFv to block immunosuppressive receptors on exhausted T cells to reinvigorate their antitumor response. Secreted PD-1 and Tim-3 scFv bound PD-1+ Tim-3+ T cells through their targeting receptors in vitro and potentiated the T-cell secretion of IFN-γ. Engineered bacteria colonized the hypoxic core of the tumor and synthesized PD-1 and Tim-3 scFv in situ, reviving CD4+ T cells and CD8+ T cells to execute an antitumor response. The bacteria also triggered a strong innate immune response, which stimulated the expansion of IFN-γ+ CD4+ T cells within the tumors to induce direct and indirect antitumor immunity.

In situ phytoextraction of Mn and NH4+-N from aqueous electrolytic manganese residue solution by Pistia stratiotes: Effects of Fe/Co presence and rhizospheric microbe synergistic involvement.

The electrolytic manganese industry produces a large amount of electrolytic manganese residue (EMR). Soluble Mn, NH4+-N, and other pollutants may be released from the open-air stacked EMR and transported to the environment along with rainfall or surface runoff. Aqueous EMR solution (AES) generally contains various elements required for plant growth, and phytoremediation can be applied to remove these pollutants from AES. Since the contents of Fe and Co vary greatly in AES depending on the ore sources as well as the pre-treatment processes, the presence of bioavailable Fe and Co at different levels may affect plant growth, the rhizosphere microbes, and pollutant removal. The present study investigated the in-situ removal of Mn(II) and NH4+-N from AES solution using free floating aquatic plant Pistia stratiotes, focusing especially on the effects of Fe/Co presence and rhizospheric microbe synergistic involvement on contaminant removal. The results showed that 69.08% of Mn and 94.99% of NH4+-N were removed by P. stratiotes in 24 d. Both the presence of Fe(II) and Co(II) facilitated the Mn(II) immobilization and increased Mn(II) removal by 19-31% due to the enhanced peroxidase activity and the increased Mn accumulating in roots The complete removal of Mn from AES was found in the presence of Fe(II) at 2 mg L-1 or Co(II) at 0.5 mg L-1 and more than 51% accumulated Mn in the roots was stored in the vacuole and cytoplasm. BioMnOx was found on the surface of the roots, revealing that rhizofiltration, rhizospheric plaque/biofilm formation, and Mn biogeochemical cycle exert synergic effects on Mn(II) immobilization. The findings of the present study demonstrate the feasibility of using P. stratiotes in the treatment of aqueous EMR solutions and the presence of an appropriate amount of bio-available Fe and Co can promote the removal of Mn(II) and NH4+-N.

Comprehensive molecular characterization of long-term glioblastoma survivors.

Fewer than 5 % glioblastoma (GBM) patients survive over five years and are termed long-term survivors (LTS), yet their molecular background is unclear. The present cohort included 72 isocitrate dehydrogenase (IDH)-wildtype GBM patients, consisting of 35 LTS and 37 short-term survivors (STS), and we employed whole exome sequencing, RNA-seq and DNA methylation array to delineate this largest LTS cohort to date. Although LTS and STS demonstrated analogous clinical characters and classical GBM biomarkers, CASC5 (P = 0.002) and SPEN (P = 0.013) mutations were enriched in LTS, whereas gene-to-gene fusions were concentrated in STS (P = 0.007). Importantly, LTS exhibited higher tumor mutation burden (P < 0.001) and copy number (CN) increase (P = 0.013), but lower mutant-allele tumor heterogeneity score (P < 0.001) and CN decrease (P = 0.026). Additionally, LTS demonstrated hypermethylated genome (P < 0.001) relative to STS. Differentially expressed and methylated genes both enriched in olfactory transduction. Further, analysis of the tumor microenvironment revealed higher infiltration of M1 macrophages (P = 0.043), B cells (P = 0.016), class-switched memory B cells (P = 0.002), central memory CD4+ T cells (P = 0.031) and CD4+ Th1 cells (P = 0.005) in LTS. We also separately analyzed a subset of patients who were methylation class-defined GBM, contributing 70.8 % of the entire cohort, and obtained similar results relative to prior analyses. Finally, we demonstrated that LTS and STS could be distinguished using a subset of molecular features. Taken together, the present study delineated unique molecular attributes of LTS GBM.

Jagged1-Notch1 Signaling Pathway Induces M1 Microglia to Disrupt the Barrier Function of Retinal Microvascular Endothelial Cells.

PURPOSE: Microglia-related inflammation is closely linked to the pathogenesis of retinal diseases. The primary objective of this research was to investigate the impact and mechanism of M1 phenotype microglia on the barrier function of retina microvascular endothelial cells. METHODS: Quantitative polymerase chain reactions and western blot techniques were utilized to analysis the mRNA and protein expressions of M1 and M2 markers of human microglial clone 3 cell line (HMC3), as well as the levels of Notch ligands and receptors under the intervention of lipopolysaccharide (LPS) or interleukin (IL)-4. ELISA was utilized to detect the pro-inflammatory and anti-inflammatory cytokines from HMC3 cells. The cellular tight junction and apoptosis of human retinal microvascular endothelial cells (HRMECs) were assessed by western blot and fluorescein isothiocyanate-dextran permeability assay. The inhibitors of Notch1 and RNA interference (RNAi) targeting Jagged1 were used to assess their contribution to the barrier function of vascular endothelial cells. RESULTS: Inducible nitric oxide synthase (iNOS) and IL-1ß were considerably elevated in LPS-treated HMC3, while CD206 and Arg-1 markedly elevated under IL-4 stimulation. The conditioned medium derived from LPS-treated HMC3 cells promoted permeability, diminished the expression of zonula occludens-1 and Occludin, and elevated the expression of Cleaved caspase-3 in HRMECs. RNAi targeting Jagged1 or Notch1 inhibitor could block M1 HMC3 polarization and maintain barrier function of HRMECs. CONCLUSION: Our findings suggest that Jagged1-Notch1 signaling pathway induces M1 microglial cells to disrupt the barrier function of HRMECs, which may lead to retinal diseases.

Effects of different assembly strategies on gene annotation in activated sludge.

Activated sludge comprises diverse bacteria, fungi, and other microorganisms, featuring a rich repertoire of genes involved in antibiotic resistance, pollutant degradation, and elemental cycling. In this regard, hybrid assembly technology can revolutionize metagenomics by detecting greater gene diversity in environmental samples. Nonetheless, the optimal utilization and comparability of genomic information between hybrid assembly and short- or long-read technology remain unclear. To address this gap, we compared the performance of the hybrid assembly, short- and long-read technologies, abundance and diversity of annotated genes, and taxonomic diversity by analysing 46, 161, and 45 activated sludge metagenomic datasets, respectively. The results revealed that hybrid assembly technology exhibited the best performance, generating the most contiguous and longest contigs but with a lower proportion of high-quality metagenome-assembled genomes than short-read technology. Compared with short- or long-read technologies, hybrid assembly technology can detect a greater diversity of microbiota and antibiotic resistance genes, as well as a wider range of potential hosts. However, this approach may yield lower gene abundance and pathogen detection. Our study revealed the specific advantages and disadvantages of hybrid assembly and short- and long-read applications in wastewater treatment plants, and our approach could serve as a blueprint to be extended to terrestrial environments.

High-Sensitivity Seawater Refraction Index Optical Measurement Sensor Based on a Position-Sensitive Detector.

The refractive index of seawater is one of the essential parameters in ocean observation, so it is necessary to achieve high-precision seawater refractive index measurements. In this paper, we propose a method for measuring the refractive index of seawater, based on a position-sensitive detector (PSD). A theoretical model was established to depict the correlation between laser spot displacement and refractive index change, utilizing a combination of a position-sensitive detector and laser beam deflection principles. Based on this optical measurement method, a seawater refractive index measurement system was established. To effectively enhance the sensitivity of refractive index detection, a focusing lens was incorporated into the optical path of the measuring system, and simulations were conducted to investigate the impact of focal length on refractive index sensitivity. The calibration experiment of the measuring system was performed based on the relationship between the refractive index of seawater and underwater pressure (depth). By measuring laser spot displacement at different depths, changes in displacement, with respect to both refractive index and depth, were determined. The experimental results demonstrate that the system exhibits a sensitivity of 9.93×10-9 RIU (refractive index unit), and the refractive index deviation due to stability is calculated as ±7.54×10-9 RIU. Therefore, the feasibility of this highly sensitive measurement of seawater refractive index is verified. Since the sensitivity of the refractive index measurement of this measurement system is higher than the refractive index change caused by the wake of underwater vehicles, it can also be used in various applications for underwater vehicle wake measurement, as well as seawater refractive index measurement, such as the motion state monitoring of underwater navigation targets such as AUVs and ROVs.

UAV and Satellite Synergies for Mapping Grassland Aboveground Biomass in Hulunbuir Meadow Steppe.

Aboveground biomass (AGB) is an important indicator of the grassland ecosystem. It can be used to evaluate the grassland productivity and carbon stock. Satellite remote sensing technology is useful for monitoring the dynamic changes in AGB across a wide range of grasslands. However, due to the scale mismatch between satellite observations and ground surveys, significant uncertainties and biases exist in mapping grassland AGB from satellite data. This is also a common problem in low- and medium-resolution satellite remote sensing modeling that has not been effectively solved. The rapid development of uncrewed aerial vehicle (UAV) technology offers a way to solve this problem. In this study, we developed a method with UAV and satellite synergies for estimating grassland AGB that filled the gap between satellite observation and ground surveys and successfully mapped the grassland AGB in the Hulunbuir meadow steppe in the northeast of Inner Mongolia, China. First, based on the UAV hyperspectral data and ground survey data, the UAV-based AGB was estimated using a combination of typical vegetation indices (VIs) and the leaf area index (LAI), a structural parameter. Then, the UAV-based AGB was aggregated as a satellite-scale sample set and used to model satellite-based AGB estimation. At the same time, spatial information was incorporated into the LAI inversion process to minimize the scale bias between UAV and satellite data. Finally, the grassland AGB of the entire experimental area was mapped and analyzed. The results show the following: (1) random forest (RF) had the best performance compared with simple regression (SR), partial least squares regression (PLSR) and back-propagation neural network (BPNN) for UAV-based AGB estimation, with an R2 of 0.80 and an RMSE of 76.03 g/m2. (2) Grassland AGB estimation through introducing LAI achieved higher accuracy. For UAV-based AGB estimation, the R2 was improved by an average of 10% and the RMSE was reduced by an average of 9%. For satellite-based AGB estimation, the R2 was increased from 0.70 to 0.75 and the RMSE was decreased from 78.24 g/m2 to 72.36 g/m2. (3) Based on sample aggregated UAV-based AGB and an LAI map, the accuracy of satellite-based AGB estimation was significantly improved. The R2 was increased from 0.57 to 0.75, and the RMSE was decreased from 99.38 g/m2 to 72.36 g/m2. This suggests that UAVs can bridge the gap between satellite observations and field measurements by providing a sufficient training dataset for model development and AGB estimation from satellite data.

Zeb1-controlled metabolic plasticity enables remodeling of chromatin accessibility in the development of neuroendocrine prostate cancer.

Cell plasticity has been found to play a critical role in tumor progression and therapy resistance. However, our understanding of the characteristics and markers of plastic cellular states during cancer cell lineage transition remains limited. In this study, multi-omics analyses show that prostate cancer cells undergo an intermediate state marked by Zeb1 expression with epithelial-mesenchymal transition (EMT), stemness, and neuroendocrine features during the development of neuroendocrine prostate cancer (NEPC). Organoid-formation assays and in vivo lineage tracing experiments demonstrate that Zeb1+ epithelioid cells are putative cells of origin for NEPC. Mechanistically, Zeb1 transcriptionally regulates the expression of several key glycolytic enzymes, thereby predisposing tumor cells to utilize glycolysis for energy metabolism. During this process, lactate accumulation-mediated histone lactylation enhances chromatin accessibility and cellular plasticity including induction of neuro-gene expression, which promotes NEPC development. Collectively, Zeb1-driven metabolic rewiring enables the epigenetic reprogramming of prostate cancer cells to license the adeno-to-neuroendocrine lineage transition.

Endogenous mutant Huntingtin alters the corticogenesis via lowering Golgi recruiting ARF1 in cortical organoid.

Pathogenic mutant huntingtin (mHTT) infiltrates the adult Huntington's disease (HD) brain and impairs fetal corticogenesis. However, most HD animal models rarely recapitulate neuroanatomical alterations in adult HD and developing brains. Thus, the human cortical organoid (hCO) is an alternative approach to decode mHTT pathogenesis precisely during human corticogenesis. Here, we replicated the altered corticogenesis in the HD fetal brain using HD patient-derived hCOs. Our HD-hCOs had pathological phenotypes, including deficient junctional complexes in the neural tubes, delayed postmitotic neuronal maturation, dysregulated fate specification of cortical neuron subtypes, and abnormalities in early HD subcortical projections during corticogenesis, revealing a causal link between impaired progenitor cells and chaotic cortical neuronal layering in the HD brain. We identified novel long, oriented, and enriched polyQ assemblies of HTTs that hold large flat Golgi stacks and scaffold clathrin+ vesicles in the neural tubes of hCOs. Flat Golgi stacks conjugated polyQ assemblies by ADP-ribosylation factor 1 (ARF1). Inhibiting ARF1 activation with Brefeldin A (BFA) disassociated polyQ assemblies from Golgi. PolyQ assembles with mHTT scaffolded fewer ARF1 and formed shorter polyQ assembles with fewer and shorter Golgi and clathrin vesicles in neural tubes of HD-hCOs compared with those in hCOs. Inhibiting the activation of ARF1 by BFA in healthy hCOs replicated impaired junctional complexes in the neural tubes. Together, endogenous polyQ assemblies with mHTT reduced the Golgi recruiting ARF1 in the neuroepithelium, impaired the Golgi structure and activities, and altered the corticogenesis in HD-hCO.

Current understanding of the molecular mechanisms of chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is the most common off-target adverse effects caused by various chemotherapeutic agents, such as cisplatin, oxaliplatin, paclitaxel, vincristine and bortezomib. CIPN is characterized by a substantial loss of primary afferent sensory axonal fibers leading to sensory disturbances in patients. An estimated of 19-85% of patients developed CIPN during the course of chemotherapy. The lack of preventive measures and limited treatment options often require a dose reduction or even early termination of life-saving chemotherapy, impacting treatment efficacy and patient survival. In this Review, we summarized the current understanding on the pathogenesis of CIPN. One prominent change induced by chemotherapeutic agents involves the disruption of neuronal cytoskeletal architecture and axonal transport dynamics largely influenced by the interference of microtubule stability in peripheral neurons. Due to an ineffective blood-nerve barrier in our peripheral nervous system, exposure to some chemotherapeutic agents causes mitochondrial swelling in peripheral nerves, which lead to the opening of mitochondrial permeability transition pore and cytochrome c release resulting in degeneration of primary afferent sensory fibers. The exacerbated nociceptive signaling and pain transmission in CIPN patients is often linked the increased neuronal excitability largely due to the elevated expression of various ion channels in the dorsal root ganglion neurons. Another important contributing factor of CIPN is the neuroinflammation caused by an increased infiltration of immune cells and production of inflammatory cytokines. In the central nervous system, chemotherapeutic agents also induce neuronal hyperexcitability in the spinal dorsal horn and anterior cingulate cortex leading to the development of central sensitization that causes CIPN. Emerging evidence suggests that the change in the composition and diversity of gut microbiota (dysbiosis) could have direct impact on the development and progression of CIPN. Collectively, all these aspects contribute to the pathogenesis of CIPN. Recent advances in RNA-sequencing offer solid platform for in silico drug screening which enable the identification of novel therapeutic agents or repurpose existing drugs to alleviate CIPN, holding immense promises for enhancing the quality of life for cancer patients who undergo chemotherapy and improve their overall treatment outcomes.

Development and Initial Characterization of the First 18F-CXCR2-Targeting Radiotracer for PET Imaging of Neutrophils.

The interleukin-8 receptor beta (CXCR2) is a highly promising target for molecular imaging of inflammation and inflammatory diseases. This is due to its almost exclusive expression on neutrophils. Modified fluorinated ligands were designed based on a squaramide template, with different modification sites and synthetic strategies explored. Promising candidates were then tested for affinity to CXCR2 in a NanoBRET competition assay, resulting in tracer candidate 16b. As direct 18F-labeling using established tosyl chemistry did not yield the expected radiotracer, an indirect labeling approach was developed. The radiotracer [18F]16b was obtained with a radiochemical yield of 15% using tert-butyl (S)-3-(tosyloxy)pyrrolidine carboxylate and a pentafluorophenol ester. The subsequent time-dependent uptake of [18F]16b in CXCR2-negative and CXCR2-overexpressing human embryonic kidney cells confirmed the radiotracer's specificity. Further studies with human neutrophils revealed its diagnostic potential for functional imaging of neutrophils.

Hydroxylase-like Biomimetic Nanozyme Synthesized via a Urea-Mediated MOF Pyrolytic Reconstruction Strategy for Non-"o-Phenol hydroxyl"-Dependent Dopamine Electrochemical Sensing.

Dopamine (DA), an essential neurotransmitter, is closely associated with various neurological disorders, whose real-time dynamic monitoring is significant for evaluating the physiological activities of neurons. Electrochemical sensing methods are commonly used to determine DA, but they mostly rely on the redox reaction of its o-phenolic hydroxyl group, which makes it difficult to distinguish it from substances with this group. Here, we design a biomimetic nanozyme inspired by the coordination structure of the copper-based active site of dopamine ß-hydroxylase, which was successfully synthesized via a urea-mediated MOF pyrolysis reconstruction strategy. Experimental studies and theoretical calculations revealed that the nanozyme with Cu-N3 coordination could hydroxylate the carbon atom of the DA ß-site at a suitable potential and that the active sites of this Cu-N3 structure have the lowest binding energy for the DA ß-site. With this property, the new oxidation peak achieves the specific detection of DA rather than the traditional electrochemical signal of o-phenol hydroxyl redox, which would effectively differentiate it from neurotransmitters, such as norepinephrine and epinephrine. The sensor exhibited good monitoring capability in DA concentrations from 0.05 to 16.7 µM, and its limit of detection was 0.03 µM. Finally, the sensor enables the monitoring of DA released from living cells and can be used to quantitatively analyze the effect of polystyrene microplastics on the amount of DA released. The research provides a method for highly specific monitoring of DA and technical support for initial screening for neurocytotoxicity of pollutants.