The GATAD2B-NuRD complex drives DNA:RNA hybrid-dependent chromatin boundary formation upon DNA damage.

Double-strand breaks (DSBs) are the most lethal form of DNA damage. Transcriptional activity at DSBs, as well as transcriptional repression around DSBs, are both required for efficient DNA repair. The chromatin landscape defines and coordinates these two opposing events. However, how the open and condensed chromatin architecture is regulated remains unclear. Here, we show that the GATAD2B-NuRD complex associates with DSBs in a transcription- and DNA:RNA hybrid-dependent manner, to promote histone deacetylation and chromatin condensation. This activity establishes a spatio-temporal boundary between open and closed chromatin, which is necessary for the correct termination of DNA end resection. The lack of the GATAD2B-NuRD complex leads to chromatin hyperrelaxation and extended DNA end resection, resulting in homologous recombination (HR) repair failure. Our results suggest that the GATAD2B-NuRD complex is a key coordinator of the dynamic interplay between transcription and the chromatin landscape, underscoring its biological significance in the RNA-dependent DNA damage response.

HiFun: homology independent protein function prediction by a novel protein-language self-attention model.

Protein function prediction based on amino acid sequence alone is an extremely challenging but important task, especially in metagenomics/metatranscriptomics field, in which novel proteins have been uncovered exponentially from new microorganisms. Many of them are extremely low homology to known proteins and cannot be annotated with homology-based or information integrative methods. To overcome this problem, we proposed a Homology Independent protein Function annotation method (HiFun) based on a unified deep-learning model by reassembling the sequence as protein language. The robustness of HiFun was evaluated using the benchmark datasets and metrics in the CAFA3 challenge. To navigate the utility of HiFun, we annotated 2 212 663 unknown proteins and discovered novel motifs in the UHGP-50 catalog. We proved that HiFun can extract latent function related structure features which empowers it ability to achieve function annotation for non-homology proteins. HiFun can substantially improve newly proteins annotation and expand our understanding of microorganisms' adaptation in various ecological niches. Moreover, we provided a free and accessible webservice at http://www.unimd.org/HiFun, requiring only protein sequences as input, offering researchers an efficient and practical platform for predicting protein functions.

An entropy-based approach for assessing the directional persistence of cell migration.

Cell migration, which is primarily characterized by directional persistence, is essential for the development of normal tissues and organs, as well as for numerous pathological processes. However, there is a lack of simple and efficient tools to analyze the systematic properties of persistence based on cellular trajectory data. Here, we present a novel approach, the entropy of angular distribution , which combines cellular turning dynamics and Shannon entropy to explore the statistical and time-varying properties of persistence that strongly correlate with cellular migration modes. Our results reveal the changes in the persistence of multiple cell lines that are tightly regulated by both intra- and extracellular cues, including Arpin protein, collagen gel/substrate, and physical constraints. Significantly, some previously unreported distinctive details of persistence have also been captured, helping to elucidate how directional persistence is distributed and evolves in different cell populations. The analysis suggests that the entropy of angular distribution-based approach provides a powerful metric for evaluating directional persistence and enables us to better understand the relationships between cellular behaviors and multiscale cues, which also provides some insights into the migration dynamics of cell populations, such as collective cell invasion.

Excitation-Selective and Double-Emissive Lead-Free Binary Hybrid Metal Halides for White Light-Emitting Diode and X-Ray Scintillation.

Zero-dimensional (0D) organic metal halides comprising heterogeneous metal cations in single phase can achieve multiple luminous emissions enabling them toward multifunctional light-emitting applications. Herein, A novel single crystal of (C8H20N)4SbMnCl9 containing two luminescent centers of [SbCl5]2- pentahedrons and [MnCl4]2- tetrahedrons is reported. The large distance between Sb-Sb, Mn-Mn, and Sb-Mn as well as theory calculation indicate negligible interaction between individual centers, thus endowing (C8H20N)4SbMnCl9 with excitation-dependable and efficient luminescence. Under near-UV excitation, only orange emission originates from self-trapped excitons recombination in [SbCl5]2- pentahedron occurs with photoluminescence quantum yield (PLQY) of 91.5%. Under blue-light excitation, only green emission originating from 4T1-6A1 transition of Mn2+ in [MnCl4]2- tetrahedrons occurs with PLQY of 66.8%. Interestingly, upon X-ray illumination, both emissions can be fully achieved due to the high-energy photon absorption. Consequently, (C8H20N)4SbMnCl9 is employed as phosphors to fabricate white light-emitting diodes optically pumped by n-UV chip and blue-chip thanks to its excitation-dependable property. Moreover, it also shows promising performance as X-ray scintillator with low detection limit of 60.79 nGyair S-1, steady-state light yield ≈54% of commerical scintillaotr LuAG:Ce, high resolution of 13.5 lp mm-1 for X-ray imaging. This work presents a new structural design to fabricate 0D hybrids with multicolor emissions.

Best practice and reproducible science are required to advance artificial intelligence in real-world applications.

Drug-induced liver injury (DILI) is one of the most significant concerns in medical practice but yet it still cannot be fully recapitulated with existing in vivo, in vitro and in silico approaches. To address this challenge, Chen et al. [ 1] developed a deep learning-based DILI prediction model based on chemical structure information alone. The reported model yielded an outstanding prediction performance (i.e. 0.958, 0.976, 0.935, 0.947, 0.926 and 0.913 for AUC, accuracy, recall, precision, F1-score and specificity, respectively, on a test set), far outperforming all publicly available and similar in silico DILI models. This extraordinary model performance is counter-intuitive to what we know about the underlying biology of DILI and the principles and hypothesis behind this type of in silico approach. In this Letter to the Editor, we raise awareness of several issues concerning data curation, model validation and comparison practices, and data and model reproducibility.

PLM-ARG: antibiotic resistance gene identification using a pretrained protein language model.

MOTIVATION: Antibiotic resistance presents a formidable global challenge to public health and the environment. While considerable endeavors have been dedicated to identify antibiotic resistance genes (ARGs) for assessing the threat of antibiotic resistance, recent extensive investigations using metagenomic and metatranscriptomic approaches have unveiled a noteworthy concern. A significant fraction of proteins defies annotation through conventional sequence similarity-based methods, an issue that extends to ARGs, potentially leading to their under-recognition due to dissimilarities at the sequence level. RESULTS: Herein, we proposed an Artificial Intelligence-powered ARG identification framework using a pretrained large protein language model, enabling ARG identification and resistance category classification simultaneously. The proposed PLM-ARG was developed based on the most comprehensive ARG and related resistance category information (>28K ARGs and associated 29 resistance categories), yielding Matthew's correlation coefficients (MCCs) of 0.983 ± 0.001 by using a 5-fold cross-validation strategy. Furthermore, the PLM-ARG model was verified using an independent validation set and achieved an MCC of 0.838, outperforming other publicly available ARG prediction tools with an improvement range of 51.8%-107.9%. Moreover, the utility of the proposed PLM-ARG model was demonstrated by annotating resistance in the UniProt database and evaluating the impact of ARGs on the Earth's environmental microbiota. AVAILABILITY AND IMPLEMENTATION: PLM-ARG is available for academic purposes at https://github.com/Junwu302/PLM-ARG, and a user-friendly webserver (http://www.unimd.org/PLM-ARG) is also provided.

Does a new case-based payment system promote the construction of the ordered health delivery system? Evidence from a pilot city in China.

BACKGROUND: The construction of the ordered health delivery system in China aims to enhance equity and optimize the efficient use of medical resources by rationally allocating patients to different levels of medical institutions based on the severity of their condition. However, superior hospitals have been overcrowded, and primary healthcare facilities have been underutilized in recent years. China has developed a new case-based payment method called "Diagnostic Intervention Package" (DIP). The government is trying to use this economic lever to encourage medical institutions to actively assume treatment tasks consistent with their functional positioning and service capabilities. METHODS: This study takes Tai'an, a DIP pilot city, as a case study and uses an interrupted time series analysis to analyze the impact of DIP reform on the case severity and service scope of medical institutions at different levels. RESULTS: The results show that after the DIP reform, the proportion of patients receiving complicated procedures (tertiary hospitals: ß3 = 0.197, P < 0.001; secondary hospitals: ß3 = 0.132, P = 0.020) and the case mix index (tertiary hospitals: ß3 = 0.022, P < 0.001; secondary hospitals: ß3 = 0.008, P < 0.001) in tertiary and secondary hospitals increased, and the proportion of primary-DIP-groups cases decreased (tertiary hospitals: ß3 = -0.290, P < 0.001; secondary hospitals: ß3 = -1.200, P < 0.001), aligning with the anticipated policy objectives. However, the proportion of patients receiving complicated procedures (ß3 = 0.186, P = 0.002) and the case mix index (ß3 = 0.002, P < 0.001) in primary healthcare facilities increased after the reform, while the proportion of primary-DIP-groups cases (ß3 = -0.515, P = 0.005) and primary-DIP-groups coverage (ß3 = -2.011, P < 0.001) decreased, which will reduce the utilization efficiency of medical resources and increase inequity. CONCLUSION: The DIP reform did not effectively promote the construction of the ordered health delivery system. Policymakers need to adjust economic incentives and implement restraint mechanisms to regulate the behavior of medical institutions.

Switchable asymmetric transmission with broadband polarization conversion in vanadium dioxide-assisted terahertz metamaterials.

In this paper, we theoretically present a vanadium dioxide (VO2)-integrated metamaterial, which can achieve switchable single- and double-band asymmetric transmission (AT) in terahertz regions. When VO2 acts as a metal, the presented metamaterial device exhibits a single-band AT effect. In contrast, when VO2 transitions from the metal to the insulating state, a dual-band AT effect can be realized for the presented metamaterials. Also, it is demonstrated that there is a broadband near-perfect orthogonal polarization conversion associated with the AT effect. And the operating mechanisms are elucidated by using the Fabry-Pérot-like cavity model and the electromagnetic field distributions. Moreover, the presented nanostructure exhibits a robust tolerance for the incidence angle. Our designed metamaterial may have potential applications for switchable multi-functional devices in terahertz regimes.

Impact of operative time on textbook outcome after minimally invasive esophagectomy, a risk-adjusted analysis from a high-volume center.

BACKGROUND: We aimed to study the impact of operative time on textbook outcome (TO), especially postoperative complications and length of postoperative stay in minimally invasive esophagectomy. METHODS: Patients undergoing esophagectomy for curative intent within a prospectively maintained database from 2016 to 2022 were retrieved. Relationships between operative time and outcomes were quantified using multivariable mixed-effects models with medical teams random effects. A restricted cubic spline (RCS) plotting was used to characterize correlation between operative time and the odds for achieving TO. RESULTS: Data of 2210 patients were examined. Median operative time was 270 mins (interquartile range, 233-313) for all cases. Overall, 902 patients (40.8%) achieved TO. Among non-TO patients, 226 patients (10.2%) had a major complication (grade ≥ III), 433 patients (19.6%) stayed postoperatively longer than 14 days. Multivariable analysis revealed operative time was associated with higher odds of major complications (odds ratio 1.005, P < 0.001) and prolonged postoperative stay (≥ 14 days) (odds ratio 1.003, P = 0.006). The relationship between operative time and TO exhibited an inverse-U shape, with 298 mins identified as the tipping point for the highest odds of achieving TO. CONCLUSIONS: Longer operative time displayed an adverse influence on postoperative morbidity and increased lengths of postoperative stay. In the present study, the TO displayed an inverse U-shaped correlation with operative time, with a significant peak at 298 mins. Potential factors contributing to prolonged operative time may potentiate targets for quality metrics and risk-adjustment process.

Predictive Role of Platelet and Inflammation Markers for Severe COVID-19 by Propensity Score Matching.

BACKGROUND: This study aims to ascertain the predictive value of platelet and inflammation markers in severe cases of COVID-19. METHODS: A retrospective real-world cohort study was conducted using propensity score matching (PSM). Patients were classified into severe and non-severe COVID-19 groups based on the severity of the disease, and the correlation between severe COVID-19 and laboratory parameters at admission was analyzed. RESULTS: The study included 397 adult patients, comprising 212 (53%) males and 185 (47%) females. Among these, 309 were non-severe and 88 were severe cases. The severe group had a higher median age than the non-severe group (60 vs. 42 years, p < 0.001). Independent risk factors for severe COVID-19 included age, diabetes comorbidity, fever, respiratory symptoms, platelet count, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and the ratio of arterial oxygen partial pressure (PaO2) to the fraction of inspired oxygen (FiO2) (P/F ratio). After one-to-one PSM, adjusted for age, diabetes comorbidities, fever, and respiratory symptoms, significant differences in laboratory parameters at admission were observed. Compared to the non-severe group (n = 71), in the severe group (n = 71), elevated levels of hsCRP (median: 27.1 mg/L vs. 14.6 mg/L, p = 0.005) and IL-6 (median: 16.2 pg/mL vs. 15.3 pg/mL, p = 0.005) were observed, while platelet count (164 ± 36 × 109 vs. 180 ± 50 × 109, p = 0.02) and P/F ratio (median: 351 vs. 397, p = 0.001) were reduced. CONCLUSIONS: Elevated levels of hsCRP and IL-6, along with reduced platelet count and P/F ratio at admission, were significantly associated with severe COVID-19 and may serve as predictive indicators.

Arsenic mobilization across the sediment-water interface of the Three Gorges Reservoir as a function of water depth using DGT and HR-Peepers, a preliminary study.

The artificial regulation of the Three Gorges Reservoir (TGR) creates large water level fluctuation zones (WLFZ) that may change the behavior of metals and metalloid in sediment, particularly redox sensitive elements. Mobilization of As, Fe and Mn across the sediment-water interface (SWI) in the TGR as a function of different water depth (periodically and permanently submerged sediments, respectively) was in situ determined by diffusive gradients in thin films (DGT) and high-resolution dialysis technique (HR-Peeper), respectively. The results showed that the mobilization of As was significantly affected by Fe/Mn especially Mn, across the SWI. Duo to the oxic-anoxic transitional state in near bottom water, the reduced Fe and Mn in sediment pore water could be oxidized and precipitated again, leading to the co-precipitation of As with Fe/Mn oxides (hydroxides). Consequently, concentrations of As, Fe and Mn in labile phases and pore water were generally low across the SWI, then they sharply increased at a few centimeters below the SWI. Considering different water depth, various trends were found in labile phase, whereas concentrations of As, Fe and Mn in pore water in permanently submerged sediments were significantly higher than those in periodically submerged sediments. The dry-re-wetting alternation processes in the WLFZ may play vital roles in the resupply capacity of sediments as it was found that periodically submerged sediments with longer re-wetting time had higher Fe/Mn resupply capacity than those with shorter re-wetting times and permanently submerged sediments.

Anatomy and function of the canalis sinuosus and its injury prevention and treatment strategies in implant surgery. / çª¦ç®¡çš„è§£å‰–ä¸ŽåŠŸèƒ½åŠå ¶åœ¨ç§æ¤æœ¯ä¸­æŸä¼¤çš„é˜²æ²»ç­–ç•¥.

The canalis sinuosus, a canal containing the anterior superior alveolar nerve bundle, originates from the infraorbital canal and extends along the maxillary sinus and nasal cavity edges to the anterior maxilla. It was once regarded as an anatomical variation. However, with the widespread application of cone beam computed tomography (CBCT), the detection rate of canalis sinuosus in the population has increased. The canalis sinuosus exhibits diverse courses, branching into multiple accessory canals and terminating at the nasal floor or the anterior tooth region, with the majority traversing the palatal side of the central incisor. The anterior superior alveolar nerve bundle within the canalis sinuosus not only innervates and nourishes the maxillary anterior teeth, their corresponding soft tissues, and the maxillary sinus mucosa, but also relates to the nasal septum, lateral nasal wall, and parts of the palatal mucosa. To minimize surgical complications, implantologists need to investigate strategies for preventing and treating canalis sinuosus injuries. Preoperatively, implantologists should use CBCT to identify the canalis sinuosus and virtually design implant placement at a distance of more than 2 mm from the canalis sinuosus. Intraoperatively, implantologists should assess bleeding and patient comfort, complemented by precision surgical techniques such as the use of implant surgical guide plates. Postoperatively, CBCT can be employed to examine the relationship between the implant and the canalis sinuosus, and treatment of canalis sinuosus injuries can be tailored based on the patient's symptoms. This review summarizes the detection of canalis sinuosus in the population, its anatomical characteristics, and its physiological functions in the anterior maxilla, and discusses strategies for effectively avoiding canalis sinuosus injuries during implant surgery, thereby enhancing implantologists' awareness and providing references for clinical decision-making.

Real-Time Tracking of Electrical Signals and an Accurate Quantification of Chemical Signals with Long-Term Stability in the Live Brain.

The development of in vivo analytical tools and methods for recording electrical signals and accurately quantifying chemical signals is a key issue for a comprehensive understanding of brain events. The electrophysiological microelectrode was invented to monitor electrical signals in free-moving brains. On the other hand, electrochemical assays with excellent spatiotemporal resolution provide an effect way to monitor chemical signals in vivo. Unfortunately, the in vivo electrochemical biosensors still have three limitations. First, many biological species such as reactive oxygen species (ROS) and neurotransmitters demonstrate large overpotentials at conventional electrodes. Thus, it is hard to convert the chemical/electrochemical signals of these molecules into electric signals. Second, the interfacial properties of the recognition molecules assembled onto the electrode surfaces have a great influence on the transmission of electric charge through the interface and the stability of the modified recognition molecules. Meanwhile, the surface of biosensors implanted in the brain is easily absorbed by many proteins present in the brain, resulting in the loss of signals. Finally, activities in the brain including neuron discharges and electrophysiological signals may be affected by electrochemical measurements due to the application of extra potentials and/or currents.This Account presents a deep view of the fundamental design principles and solutions in response to the above challenges for developing in vivo biosensors with high performance while meeting the growing requirements, including high selectivity, long-time stability, and simultaneously monitoring electrical and chemical signals. We aim to highlight the basic criteria based on a double-recognition strategy for the selective biosensing of ROS, H2S, and HnS through the rational design of specific recognition molecules followed by electrochemical oxidation or reduction. Recent developments in designing functionalized surfaces through a systematic investigation of self-assembly with Au-S bonds, Au-Se bonds, and Au≡C bonds for facilitating electrochemical properties as well as improving the stability are summarized. More importantly, this Account highlights the novel methodologies for simultaneously monitoring electrical and chemical signals ascribed to the dynamic changes in K+, Na+, and Ca2+ and pH values in vivo. Additionally, SERS-based photophysiological microarray probes have been developed for quantitatively tracking chemical changes in the live brain together with recording electrophysiological signals.The design principles and novel strategies presented in this Account can be extended to the real-time tracking of electrical signals and the accurate quantification of more chemical signals such as amino acids, neurotransmitters, and proteins to understand the brain events. The final part also outlines potential future directions in constructing high-density microarrays, eventually enabling the large-scale dynamic recording of the chemical expression of multineuronal signals across the whole brain. There is still room to develop a multifiber microarray which can be coupled with photometric methods to record chemical signals both inside and outside neurons in the live brains of freely moving animals to understand physiological processes and screen drugs.

Evolution of the point defects involved under the action of mechanical forces on mechanically machined fused silica surfaces.

Point defects with different species are concentrated on most mechanically machined fused silica optical surfaces with surface defects, which would sharply decrease the laser damage resistance under intense laser irradiation. Various point defects have distinct roles in affecting the laser damage resistance. Especially, the proportions of various point defects have not been identified, posing the challenge in relating the intrinsic quantitative relationship among various point defects. To fully reveal the comprehensive effect of various point defects, it is necessary to systematically explore the origins, evolution laws and especially the quantitative relationship among point defects. Herein, seven types of point defects are determined. The unbonded electrons in point defects are found to tend to be ionized to induce laser damage and there is a definite quantitative relationship between the proportions of oxygen-deficient point defects and that of peroxide point defects. The conclusions are further verified based on the photoluminescence (PL) emission spectra and the properties (e.g., reaction rule and structural feature) of the point defects. On basis of the fitted Gaussian components and electronic-transition theory, the quantitative relationship between PL and the proportions of various point defects is constructed for the first time. E'-Center accounts for the highest proportion among them. This work is beneficial for fully revealing the comprehensive action mechanisms of various point defects and providing new insights in elucidating the defect-induced laser damage mechanisms of optical components under intense laser irradiation from the atomic scale.

Formation mechanism of DKDP surface in single point diamond fly-cutting process and the resulting degradation of laser-induced damage performance.

Laser damage performance of DKDP (KD2xH2(1-x)PO4) crystal is largely determined by the surface microstructures generated in the manufacturing process, more specifically, single point diamond fly-cutting process. However, because of the lack of knowledge about the formation mechanism and damage performance of the microstructures, laser induced damage of DKDP crystal remains a key issue limiting the output energy of the high power laser systems. In this paper, the influence of fly-cutting parameters on the generation of DKDP surface and the underlying material deformation mechanism have been investigated. Except for cracks, two kinds of new microstructures, namely micro grains and ripples, have been found on the processed DKDP surfaces. GIXRD, nano-indentation and nano-scratch test results prove that the micro grains are generated by the slip motion of the crystal, while the simulation results show that the cracks are induced by the tensile stress formed behind the cutting edge. Moreover, the formation of micro grains can facilitate the plastic chip flow through the mechanism of grain boundary sliding, which will further lead to a periodic fluctuation of the chip separation point and the formation of micro ripples. Finally, laser damage test results demonstrate that cracks will degrade the damage performance of DKDP surface significantly, while the formation of micro grains and micro ripples has little impact. The results of this study can deepen the understanding of the formation mechanism of the DKDP surface during the cutting process and provide guidance to improve the laser-induced damage performance of the crystal.

Phase-type diffractive micro-optics elements in sulfur-based polymeric glass by femtosecond laser direct writing.

Sulfur-based polymeric glasses are promising alternative low-cost IR materials due to their profoundly high IR transparency. In this Letter, femtosecond-laser-induced refractive index change (RIC) was investigated in one typical sulfur-based polymeric glass material, poly(S-r-DIB), for the first time, to the best of our knowledge. The RIC in the laser-engineered region was quantitively characterized, which laid a foundation for phase-type optical element design. By the integration of RIC traces, embedded phase-type micro-optics elements, including Fresnel zone plates, and a Dammann grating were fabricated in bulk poly(S-r-DIB) polymeric glass substrate via the femtosecond laser direct writing technique. The imaging and beam shaping performance were demoed in the near-infrared (NIR) region.

Evolution of intrinsic defects and ring structures on the surface of fused silica optics after CO2 laser conditioning.

Recently and interestingly, experiments show that the CO2 laser conditioning can significantly increase the laser-induced damage threshold (LIDT) of fused silica optics, but its underlying mechanism has not been clearly revealed. This Letter reports the experimental studies on the evolution of the intrinsic point defects and intrinsic ring structures on the surface of fused silica optics under the CO2 laser irradiation. The laser conditioning can effectively reduce the intrinsic defect contents in the surface layer of mechanically processed fused silica. However, the suppression effect of defects can be affected by the initial surface state. If there are micro-cracks on the component surface, the effect of the laser conditioning would be limited. The evolution of the intrinsic ring structures indicate that most of the intrinsic defects tend to recombine as short (Si-O)n ring structures during the laser healing of the micro-fractures. The observed recombination behavior and suppression of the intrinsic defects can help find out the reason for the increase of the LIDT of the fused silica optics.

TransOrGAN: An Artificial Intelligence Mapping of Rat Transcriptomic Profiles between Organs, Ages, and Sexes.

Animal studies are required for the evaluation of candidate drugs to ensure patient and volunteer safety. Toxicogenomics is often applied in these studies to gain understanding of the underlying mechanisms of toxicity, which is usually focused on critical organs such as the liver or kidney in young male rats. There is a strong ethical reason to reduce, refine and replace animal use (the 3Rs), where the mapping of data between organs, sexes and ages could reduce the cost and time of drug development. Herein, we proposed a generative adversarial network (GAN)-based framework entitled TransOrGAN that allowed the molecular mapping of gene expression profiles in different rodent organ systems and across sex and age groups. We carried out a proof-of-concept study based on rat RNA-seq data from 288 samples in 9 different organs of both sexes and 4 developmental stages. First, we demonstrated that TransOrGAN could infer transcriptomic profiles between any 2 of the 9 organs studied, yielding an average cosine similarity of 0.984 between synthetic transcriptomic profiles and their corresponding real profiles. Second, we found that TransOrGAN could infer transcriptomic profiles observed in females from males, with an average cosine similarity of 0.984. Third, we found that TransOrGAN could infer transcriptomic profiles in juvenile, adult, and aged animals from adolescent animals with an average cosine similarity of 0.981, 0.983, and 0.989, respectively. Altogether, TransOrGAN is an innovative approach to infer transcriptomic profiles between ages, sexes, and organ systems, offering the opportunity to reduce animal usage and to provide an integrated assessment of toxicity in the whole organism irrespective of sex or age.

PES1 reduces CD8+ T cell infiltration and immunotherapy sensitivity via interrupting ILF3-IL15 complex in esophageal squamous cell carcinoma.

BACKGROUND: Although immune checkpoint blockade (ICB) therapy has brought survival benefits to patients with specific cancer types, most of cancer patients remain refractory to the ICB therapy, which is largely attributed to the immunosuppressive tumor microenvironment. Thereby, it is urgent to profile key molecules and signal pathways responsible for modification of tumor microenvironment. METHODS: Multiple databases of esophageal squamous cell carcinoma (ESCC) were integratively analyzed to screen candidate genes responsible for infiltration of CD8+ T cells. Expression of pescadillo ribosomal biogenesis factor 1 (PES1) in clinical ESCC samples was examined by qRT-PCR, western blotting, and immunohistochemistry. The mechanisms of PES1 were investigated via RNA sequencing and mass spectrometry followed by immunoprecipitation and proximity ligation assay. The clinical and therapeutic significance of PES1 in ESCC was comprehensively investigated using ESCC cells and mouse model. RESULTS: PES1 was significantly upregulated and correlated with poor prognosis in ESCC patients. PES1 knockdown decreased ESCC cell growth in vitro and in vivo and enhanced the efficacy of ICB therapy in mouse model, which was established through subcutaneous inoculation with ESCC cells. Analyses on RNA sequencing and mass spectrometry suggested that PES1 expression was negatively correlated with IL15 and ILF3 was one of the PES1-associated proteins. It has been known that ILF3 interacts with and stabilizes IL15 mRNA to increase IL15 protein level. Our data further indicated that PES1 interfered with the interaction between ILF3 and IL15 mRNA and impaired ILF3-mediated stabilization of IL15 mRNA, which eventually reduced the protein level of IL15. Interestingly, the inhibitory effect of ICB therapy boosted by PES1 knockdown dramatically antagonized by knockdown of IL15, which suppressed the tumor-infiltrated CD8+ T cells in ESCC. Finally, we confirmed the relationships among PES1, IL15, and CD8+ T cell infiltration in 10 locally advanced ESCC patients receiving ICB neoadjuvant therapy and demonstrated that ICB therapy would be more effective in those with low expression of PES1. CONCLUSIONS: Altogether, our findings herein provided novel insights on biological function and clinical significance of PES1 and suggested that high expression of PES1 could suppress ILF3-IL15 axis-mediated immunosurveillance and promote resistance to ICB through restraining tumor-infiltrated CD8+ T cells.

Tailor Traps in Bi3+-Doped NaGdGeO4 Phosphors by Introducing Eu3+ Ions to Switch Multimodal Phosphorescence Emission.

Featured with a tunable excitation/emission wavelength and excellent physicochemical stability, inorganic fluorescent materials are widely used in the fields of anti-counterfeiting. Here, we design a multi-stimuli-responsive dynamic fluorescence and phosphorescence anti-counterfeiting material by introducing Eu3+ ions in NaGdGeO4: Bi3+ to tailor the trap structure. The photoluminescence (PL), long persistent luminescence (LPL), and photo-stimulated luminescence (PSL) colors of NaGdGeO4: Bi3+, Eu3+ can be switched by varying the excitation modes (ultraviolet, near infrared, and X-ray light). Especially, the LPL and PSL colors of NaGdGeO4: Bi3+, Eu3+ vary with increasing decay and stimulation times. In addition, X-ray excitation ensures the specificity of the luminescence of NaGdGeO4: Bi3+, Eu3+ compared with ultraviolet excitation. This rapidly-changing-color fluorescent material offers the possibility of sophisticated anti-counterfeiting applications in the future.