Establishment of a humanized mouse model using steady-state peripheral blood-derived hematopoietic stem and progenitor cells facilitates screening of cancer-targeted T-cell repertoires.

Background: Cancer-targeted T-cell receptor T (TCR-T) cells hold promise in treating cancers such as hematological malignancies and breast cancers. However, approaches to obtain cancer-reactive TCR-T cells have been unsuccessful. Methods: Here, we developed a novel strategy to screen for cancer-targeted TCR-T cells using a special humanized mouse model with person-specific immune fingerprints. Rare steady-state circulating hematopoietic stem and progenitor cells were expanded via three-dimensional culture of steady-state peripheral blood mononuclear cells, and then the expanded cells were applied to establish humanized mice. The human immune system was evaluated according to the kinetics of dendritic cells, monocytes, T-cell subsets, and cytokines. To fully stimulate the immune response and to obtain B-cell precursor NAML-6- and triple-negative breast cancer MDA-MB-231-targeted TCR-T cells, we used the inactivated cells above to treat humanized mice twice a day every 7 days. Then, human T cells were processed for TCR ß-chain (TRB) sequencing analysis. After the repertoires had been constructed, features such as the fraction, diversity, and immune signature were investigated. Results: The results demonstrated an increase in diversity and clonality of T cells after treatment. The preferential usage and features of TRBV, TRBJ, and the V-J combination were also changed. The stress also induced highly clonal expansion. Tumor burden and survival analysis demonstrated that stress induction could significantly inhibit the growth of subsequently transfused live tumor cells and prolong the survival of the humanized mice. Conclusions: We constructed a personalized humanized mouse model to screen cancer-targeted TCR-T pools. Our platform provides an effective source of cancer-targeted TCR-T cells and allows for the design of patient-specific engineered T cells. It therefore has the potential to greatly benefit cancer treatment.

A diphenylphosphine oxide decorated multi-resonance TADF emitter for narrowband green electroluminescence with an EQE of 32.4.

A new narrowband thermally activated delayed fluorescence emitter, PhCzBN-PO, was developed by incorporating the diphenylphosphine oxide (DPPO) group into a multi-resonance core. The unique properties of DPPO enabled PhCzBN-PO to achieve pure green emission and a nonplanar structure. The resulting electroluminescent devices achieved high external quantum efficiencies up to 32.4% with extremely low efficiency roll-off and pure-green emission with Commission Internationale de L'Eclairage (CIE) coordinates of (0.24, 0.67).

B‒N covalent bond-involved π-extension of multiple resonance emitters enables high-performance narrowband electroluminescence.

Multi-boron-embedded multiple resonance thermally activated delayed fluorescence (MR-TADF) emitters show promise for achieving both high color-purity emission and high exciton utilization efficiency. However, their development is often impeded by a limited synthetic scope and excessive molecular weights, which challenge material acquisition and organic light-emitting diode (OLED) fabrication by vacuum deposition. Herein, we put forward a B‒N covalent bond-involved π-extension strategy via post-functionalization of MR frameworks, leading to the generation of high-order B/N-based motifs. The structurally and electronically extended π-system not only enhances molecular rigidity to narrow emission linewidth but also promotes reverse intersystem crossing to mitigate efficiency roll-off. As illustrated examples, ultra-narrowband sky-blue emitters (full-width at half-maximum as small as 8 nm in n-hexane) have been developed with multi-dimensional improvement in photophysical properties compared to their precursor emitters, which enables narrowband OLEDs with external quantum efficiencies (EQEmax) of up to 42.6%, in company with alleviated efficiency decline at high brightness, representing the best efficiency reported for single-host OLEDs. The success of these emitters highlights the effectiveness of our molecular design strategy for advanced MR-TADF emitters and confirms their extensive potential in high-performance optoelectronic devices.

Development and validation of prediction model for technique failure in peritoneal dialysis patients: An observational study.

AIM: This study aimed to establish a prediction model in peritoneal dialysis patients to estimate the risk of technique failure and guide clinical practice. METHODS: Clinical and laboratory data of 424 adult peritoneal dialysis patients were retrospectively collected. The risk prediction models were built using univariate Cox regression, best subsets approach and LASSO Cox regression. Final nomogram was constructed based on the best model selected by the area under the curve. RESULTS: After comparing three models, the nomogram was built using the LASSO Cox regression model. This model included variables consisting of hypertension and peritonitis, serum creatinine, low-density lipoprotein, fibrinogen and thrombin time, and low red blood cell count, serum albumin, triglyceride and prothrombin activity. The predictive model constructed performed well using receiver operating characteristic curve and area under the curve value, C-index and calibration curve. CONCLUSION: This study developed and verified a new prediction instrument for the risk of technique failure among peritoneal dialysis patients.

LncRNA HOTTIP regulates TLR4 promoter methylation by recruiting H3K4 methyltransferase MLL1 to affect apoptosis and inflammatory response of fibroblast-like synoviocyte in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, and the role of HOXA transcript at the distal tip (HOTTIP) in its pathogenesis remains underexplored. This study investigates the mechanism by which HOTTIP influences apoptosis and the inflammatory response of fibroblast-like synoviocytes (FLS). An RA mouse model was established, and clinical scores were analyzed. Pathological changes in synovial tissues, bone mineral density (BMD) of the paws, serum tartrate-resistant acid phosphatase (TRAP) activity, and TNF-α and IL-1ß levels were assessed. FLS were transfected, and cell proliferation and apoptosis were examined. The RNA-pull-down assay determined HOTTIP's interaction with mixed-lineage leukemia 1 (MLL1), while RNA immunoprecipitation assay measured HOTTIP expression pulled down by MLL1. The levels of MLL1 and toll-like receptor 4 (TLR4) after MLL1 overexpression based on HOTTIP silencing were determined. Chromatin immunoprecipitation (ChIP) was performed with H3K4me3 as an antibody, followed by the evaluation of TLR4 expression. HOTTIP expression was elevated in RA mouse synovial tissues. Inhibition of HOTTIP led to reduced clinical scores, inflammatory infiltration, synovial hyperplasia, TRAP activity, and TNF-α and IL-1ß levels, along with increased BMD. In vitro Interference with HOTTIP suppressed RA-FLS apoptosis and inflammation. HOTTIP upregulated TLR4 expression by recruiting MLL1 to facilitate TLR4 promoter methylation. MLL1 overexpression reversed HOTTIP silencing-mediated repression of RA-FLS apoptosis. Activation of H3K4 methylation counteracted HOTTIP knockout, ameliorating the inflammatory response. HOTTIP regulates TLR4 expression by recruiting MLL1, leading to TLR4 promoter methylation, thereby suppressing RA-FLS proliferation and inducing cell apoptosis and inflammatory response in RA.

CAS Landslide Dataset: A Large-Scale and Multisensor Dataset for Deep Learning-Based Landslide Detection.

In this work, we present the CAS Landslide Dataset, a large-scale and multisensor dataset for deep learning-based landslide detection, developed by the Artificial Intelligence Group at the Institute of Mountain Hazards and Environment, Chinese Academy of Sciences (CAS). The dataset aims to address the challenges encountered in landslide recognition. With the increase in landslide occurrences due to climate change and earthquakes, there is a growing need for a precise and comprehensive dataset to support fast and efficient landslide recognition. In contrast to existing datasets with dataset size, coverage, sensor type and resolution limitations, the CAS Landslide Dataset comprises 20,865 images, integrating satellite and unmanned aerial vehicle data from nine regions. To ensure reliability and applicability, we establish a robust methodology to evaluate the dataset quality. We propose the use of the Landslide Dataset as a benchmark for the construction of landslide identification models and to facilitate the development of deep learning techniques. Researchers can leverage this dataset to obtain enhanced prediction, monitoring, and analysis capabilities, thereby advancing automated landslide detection.

Nlrc3 signaling is indispensable for hematopoietic stem cell emergence via Notch signaling in vertebrates.

Hematopoietic stem and progenitor cells generate all the lineages of blood cells throughout the lifespan of vertebrates. The emergence of hematopoietic stem and progenitor cells is finely tuned by a variety of signaling pathways. Previous studies have revealed the roles of pattern-recognition receptors such as Toll-like receptors and RIG-I-like receptors in hematopoiesis. In this study, we find that Nlrc3, a nucleotide-binding domain leucine-rich repeat containing family gene, is highly expressed in hematopoietic differentiation stages in vivo and vitro and is required in hematopoiesis in zebrafish. Mechanistically, nlrc3 activates the Notch pathway and the downstream gene of Notch hey1. Furthermore, NF-kB signaling acts upstream of nlrc3 to enhance its transcriptional activity. Finally, we find that Nlrc3 signaling is conserved in the regulation of murine embryonic hematopoiesis. Taken together, our findings uncover an indispensable role of Nlrc3 signaling in hematopoietic stem and progenitor cell emergence and provide insights into inflammation-related hematopoietic ontogeny and the in vitro expansion of hematopoietic stem and progenitor cells.

Deep-Blue Narrowband Hetero[6]helicenes Showing Circularly Polarized Thermally Activated Delayed Fluorescence Toward High-Performance OLEDs.

Helicenes exhibit substantial potential as circularly polarized luminescence (CPL) active molecules. However, their application in circularly polarized organic light-emitting diodes (CP-OLEDs) is typically hindered by the challenge of integrating both high color purity and efficient triplet-harvesting capability, particularly in the blue spectral region. Herein, a series of hetero[6]helicene-based emitters that is strategically engineered through the helical extension of a deep-blue double-boron-based multiple resonance thermally activated delayed fluorescence (MR-TADF) motif, is introduced. Importantly, the helical extension does not cause apparent structural deformation or perturb frontier molecular orbitals; thus, preserving the deep-blue emission and MR-TADF characteristics of the parent molecule. This approach also leads to reduced reorganization energy, resulting in emitters with narrower linewidth and higher photoluminescence quantum yield. Further, the helical motif enhances the racemization barrier and leads to improved CPL performance with luminescence dissymmetry factor values up to 1.5 × 10-3 . Exploiting these merits, devices incorporating the chiral dopants demonstrate deep-blue emission within the Broadcast Service Television 2020 color-gamut range, record external quantum efficiencies (EQEs) up to 29.3%, and have distinctive circularly polarized electroluminescence (CPEL) signals. Overall, the authors' findings underscore the helical extension as a promising strategy for designing narrowband chiroptical materials and advancing high-definition displays.

Mitochondrial dysfunction: a new molecular mechanism of intervertebral disc degeneration.

OBJECTIVE: Intervertebral disc degeneration (IVDD) is a chronic degenerative orthopedic illness that causes lower back pain as a typical clinical symptom, severely reducing patients' quality of life and work efficiency, and imposing a significant economic burden on society. IVDD is defined by rapid extracellular matrix breakdown, nucleus pulposus cell loss, and an inflammatory response. It is intimately related to the malfunction or loss of myeloid cells among them. Many mechanisms have been implicated in the development of IVDD, including inflammatory factors, oxidative stress, apoptosis, cellular autophagy, and mitochondrial dysfunction. In recent years, mitochondrial dysfunction has become a hot research topic in age-related diseases. As the main source of adenosine triphosphate (ATP) in myeloid cells, mitochondria are essential for maintaining myeloid cell survival and physiological functions. METHODS: We searched the PUBMED database with the search term "intervertebral disc degeneration and mitochondrial dysfunction" and obtained 82 articles, and after reading the abstracts and eliminating 30 irrelevant articles, we finally obtained 52 usable articles. RESULTS: Through a review of the literature, it was discovered that IVDD and cellular mitochondrial dysfunction are also linked. Mitochondrial dysfunction contributes to the advancement of IVDD by influencing a number of pathophysiologic processes such as mitochondrial fission/fusion, mitochondrial autophagy, cellular senescence, and cell death. CONCLUSION: We examine the molecular mechanisms of IVDD-associated mitochondrial dysfunction and present novel directions for quality management of mitochondrial dysfunction as a treatment approach to IVDD.

Generating hematopoietic cells from human pluripotent stem cells: approaches, progress and challenges.

Human pluripotent stem cells (hPSCs) have been suggested as a potential source for the production of blood cells for clinical application. In two decades, almost all types of blood cells can be successfully generated from hPSCs through various differentiated strategies. Meanwhile, with a deeper understanding of hematopoiesis, higher efficiency of generating progenitors and precursors of blood cells from hPSCs is achieved. However, how to generate large-scale mature functional cells from hPSCs for clinical use is still difficult. In this review, we summarized recent approaches that generated both hematopoietic stem cells and mature lineage cells from hPSCs, and remarked their efficiency and mechanisms in producing mature functional cells. We also discussed the major challenges in hPSC-derived products of blood cells and provided some potential solutions. Our review summarized efficient, simple, and defined methodologies for developing good manufacturing practice standards for hPSC-derived blood cells, which will facilitate the translation of these products into the clinic.

Multiple Porcine Innate Immune Signaling Pathways Are Involved in the Anti-PEDV Response.

Porcine epidemic diarrhea virus (PEDV) has caused great damage to the global pig industry. Innate immunity plays a significant role in resisting viral infection; however, the exact role of innate immunity in the anti-PEDV response has not been fully elucidated. In this study, we observed that various porcine innate immune signaling adaptors are involved in anti-PEDV (AJ1102-like strain) activity in transfected Vero cells. Among these, TRIF and MAVS showed the strongest anti-PEDV activity. The endogenous TRIF, MAVS, and STING were selected for further examination of anti-PEDV activity. Agonist stimulation experiments showed that TRIF, MAVS, and STING signaling all have obvious anti-PEDV activity. The siRNA knockdown assay showed that TRIF, MAVS, and STING are also all involved in anti-PEDV response, and their remarkable effects on PEDV replication were confirmed in TRIF-/-, MAVS-/- and STING-/- Vero cells via the CRISPR approach. For further verification, the anti-PEDV activity of TRIF, MAVS, and STING could be reproduced in porcine IPEC-DQ cells treated with siRNAs. In summary, this study reveals that multiple pattern-recognition receptor (PRR) signaling pathways of porcine innate immunity play an important role in the anti-PEDV infection, providing new and useful antiviral knowledge for prevention and control of PEDV spreading.

Naphthalene-Embedded Multi-Resonance Emitters Enabling Efficient Narrow Emissive Blue OLEDs.

Great achievements have been made in the development of organic light-emitting diodes in recent decades. However, achieving high color purity for blue emitters remains a challenge. In this study, we have designed and synthesized three naphthalene (NA)-embedded multi-resonance (MR) emitters, named SNA, SNB and SNB1, based on N-B-O frameworks with isomer variations for finely adjusting the photophysical properties. These emitters show tunable blue emission with emission peaks of 450-470 nm. Small full width of half maximum (FWHM) of 25-29 nm are achieved in these emitters, indicating the well maintaining of molecular rigidity and MR effect with NA extension. Such design also ensures a fast radiative decay. However, no obvious delayed fluorescence is observed in all three emitters due to the relatively large energy differences between the first singlet and triplet excited states. Both SNA and SNB enable high electroluminescent (EL) performance in doped devices with external quantum efficiency (EQE) of 7.2 and 7.9 %, respectively. When applying the sensitized strategy, devices based on SNA and SNB show huge improvement with EQE of 29.3 and 29.1 %. More importantly, SNB with twist geometry enables stable EL spectra with almost unchanged FWHM under different doping concentrations. This work demonstrates the potential of NA extension design in constructing narrowband emissive blue emitters.

Multi-spiro junctions enable efficient thermally activated delayed fluorescent emitter.

A new acridine donor with trispiro junctions is developed for assembling a highly efficient thermally activated delayed fluorescence emitter. The multispiro junctions ensure a rigid geometry that leads to a well-suppressed nonradiative decay. The resulting electroluminescent devices achieve a high external quantum efficiency of 34.2%.

Untargeted GC-MS and FT-NIR study of the effect of 14 processing methods on the volatile components of Polygonatum kingianum.

Introduction: Polygonatum kingianum is a traditional medicinal plant, and processing has significantly impacts its quality. Methods: Therefore, untargeted gas chromatography-mass spectrometry (GC-MS) and Fourier transform-near-infrared spectroscopy (FT-NIR) were used to analyze the 14 processing methods commonly used in the Chinese market.It is dedicated to analyzing the causes of major volatile metabolite changes and identifying signature volatile components for each processing method. Results: The untargeted GC-MS technique identified a total of 333 metabolites. The relative content accounted for sugars (43%), acids (20%), amino acids (18%), nucleotides (6%), and esters (3%). The multiple steaming and roasting samples contained more sugars, nucleotides, esters and flavonoids but fewer amino acids. The sugars are predominantly monosaccharides or small molecular sugars, mainly due to polysaccharides depolymerization. The heat treatment reduces the amino acid content significantly, and the multiple steaming and roasting methods are not conducive to accumulating amino acids. The multiple steaming and roasting samples showed significant differences, as seen from principal component analysis (PCA) and hierarchical cluster analysis (HCA) based on GC-MS and FT-NIR. The partial least squares discriminant analysis (PLS-DA) based on FT-NIR can achieve 96.43% identification rate for the processed samples. Discussion: This study can provide some references and options for consumers, producers, and researchers.

Scientific and regulatory challenges of environmentally persistent free radicals: From formation theory to risk prevention strategies.

EPFRs (Environmentally Persistent Free Radicals) are a class of pollutants that have been identified as potential environmental contaminants due to their persistence and ability to generate reactive oxygen species (ROS) that can cause oxidative stress in living organisms. However, no study has comprehensively summarized the production conditions, influencing factors and toxic mechanisms of EPFRs, impeding exposure toxicity assessments and risk prevention strategies. To bridge the gap between theoretical research and practical application, a thorough literature review to summarize the formation, environmental effects, and biotoxicity of EPFRs are conducted. A total of 470 relevant papers were screened in Web of Science Core collection databases. The transfer of electrons between interfaces and the cleavage of covalent bonds of persistent organic pollutants is crucial to the generation of EPFRs, which is induced by external sources of energy, including thermal energy, light energy, transition metal ions, and others. In the thermal system, the stable covalent bond of organic matter can be destroyed by heat energy at low temperature to form EPFRs, while the formed EPFRs can be destroyed at high temperature. Light can also accelerate the production of free radicals and promote the degradation of organic matter. The persistence and stability of EPFRs are synergistically influenced by individual environmental factors such as environmental humidity, oxygen content, organic matter content, and environmental pH. Studying the formation mechanism of EPFRs and their biotoxicity is essential for fully understanding the hazards posed by these emerging environmental contaminants.

Reduced adsorption of norfloxacin on UV aging microplastics in anoxic environment.

Over recent years, much attention has been paid to aging problem of microplastics and adsorption behavior of antibiotic on microplastics. In this study, four microplastics, including polystyrene (PS), polypropylene (PP), polyamide (PA) and polyethylene (PE), were photoaged by UV light in anoxic environment. The surface characteristics of microplastics and adsorption behavior of norfloxacin (NOR) on microplastics were investigated. Results indicated that the specific surface area and crystallinity increased, and hydrophobicity weakened of microplastics after UV aging. The content of C element decreased and the content of O barely changed in the aged microplastics. In addition, the adsorption of NOR on microplastics yielded a better fitness for the pseudo-second-order kinetics, Langmuir and Freundlich models. The adsorption capacities of NOR on PS, PA, PP, and PE at 288 K were 16.01, 15.12, 14.03, and 13.26 mg·g-1, respectively, while the adsorption capacities of NOR on aged microplastics were reduced to 14.20, 14.19, 11.50, and 10.36 mg·g-1, respectively, due to decrease of hydrophobicity and increase of crystallinity of microplastics after UV aging. The adsorption of NOR on microplastics decreased with the increase of temperature, implying the adsorption process was exothermic. Adsorption mechanism analysis showed that Van der Waals force was the main influential mechanism of the adsorption of NOR on PP and PE, and hydrogen bond was the main factor affecting the adsorption of NOR on PA, while the π-π interaction was the main mechanism impacting the adsorption of NOR on PS. Aging time and salinity significantly affect the adsorption of NOR on microplastics. With the increase of humic acid concentration and pH, the adsorption of NOR on microplastics first reduced and then rose. This study provides a basis for further clarifying the mechanism of UV aging microplastics and a reference for the study of combined pollution behavior of microplastics and antibiotics.

Glia maturation factor-γ is required for initiation and maintenance of hematopoietic stem and progenitor cells.

BACKGROUND: In vertebrates, hematopoietic stem and progenitor cells (HSPCs) emerge from hemogenic endothelium in the floor of the dorsal aorta and subsequently migrate to secondary niches where they expand and differentiate into committed lineages. Glia maturation factor γ (gmfg) is a key regulator of actin dynamics that was shown to be highly expressed in hematopoietic tissue. Our goal is to investigate the role and mechanism of gmfg in embryonic HSPC development. METHODS: In-depth bioinformatics analysis of our published RNA-seq data identified gmfg as a cogent candidate gene implicated in HSPC development. Loss and gain-of-function strategies were applied to study the biological function of gmfg. Whole-mount in situ hybridization, confocal microscopy, flow cytometry, and western blotting were used to evaluate changes in the number of various hematopoietic cells and expression levels of cell proliferation, cell apoptosis and hematopoietic-related markers. RNA-seq was performed to screen signaling pathways responsible for gmfg deficiency-induced defects in HSPC initiation. The effect of gmfg on YAP sublocalization was assessed in vitro by utilizing HUVEC cell line. RESULTS: We took advantage of zebrafish embryos to illustrate that loss of gmfg impaired HSPC initiation and maintenance. In gmfg-deficient embryos, the number of hemogenic endothelium and HSPCs was significantly reduced, with the accompanying decreased number of erythrocytes, myelocytes and lymphocytes. We found that blood flow modulates gmfg expression and gmfg overexpression could partially rescue the reduction of HSPCs in the absence of blood flow. Assays in zebrafish and HUVEC showed that gmfg deficiency suppressed the activity of YAP, a well-established blood flow mediator, by preventing its shuttling from cytoplasm to nucleus. During HSPC initiation, loss of gmfg resulted in Notch inactivation and the induction of Notch intracellular domain could partially restore the HSPC loss in gmfg-deficient embryos. CONCLUSIONS: We conclude that gmfg mediates blood flow-induced HSPC maintenance via regulation of YAP, and contributes to HSPC initiation through the modulation of Notch signaling. Our findings reveal a brand-new aspect of gmfg function and highlight a novel mechanism for embryonic HSPC development.

Manganese Mediates Its Antiviral Functions in a cGAS-STING Pathway Independent Manner.

The innate immune system is the first line of host defense sensing viral infection. Manganese (Mn) has recently been found to be involved in the activation of the innate immune DNA-sensing cGAS-STING pathway and subsequent anti-DNA virus function. However, it is still unclear whether Mn2+ mediates host defense against RNA viruses. In this study, we demonstrate that Mn2+ exhibited antiviral effects against various animal and human viruses, including RNA viruses such as PRRSVs and VSV, as well as DNA viruses such as HSV1, in a dose-dependent manner. Moreover, cGAS and STING were both investigated in the Mn2+ mediated antiviral roles using the knockout cells made by the CRISPR-Cas9 approach. Unexpectedly, the results revealed that neither cGAS knockout nor STING knockout had any effect on Mn2+-mediated antiviral functions. Nevertheless, we verified that Mn2+ promoted the activation of the cGAS-STING signaling pathway. These findings suggest that Mn2+ has broad-spectrum antiviral activities in a cGAS-STING pathway independent manner. This study also provides significant insights into redundant mechanisms participating in the Mn2+ antiviral functions, and also indicates a new target for Mn2+ antiviral therapeutics.