Dihydrocelastrol induces cell death and suppresses angiogenesis through BCR/AP-1/junb signalling in diffuse large B cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Although treatment options have improved, a large proportion of patients show low survival rates, highlighting an urgent need for novel therapeutic strategies. The aim of this study was to investigate the efficacy of the new small-molecule compound dihydrocelastrol (DHCE), acquired through the structural modification of celastrol (CE), in the treatment of DLBCL. DHCE showed potent anti-lymphoma efficacy and synergistic effects with doxorubicin. DHCE triggered DLBCL cell apoptosis and G0/G1-phase blockade, thereby hindering angiogenesis. DHCE inhibited B-cell receptor cascade signalling and Jun B and p65 nuclear translocation, thereby suppressing pro-tumourigenic signalling. Finally, DHCE exerted lower toxicity than CE, which showed severe hepatic, renal, and reproductive toxicity in vivo. Our findings support further investigation of the clinical efficacy of DHCE against DLBCL.

Intraocular mRNA delivery with endogenous MmPEG10-based virus-like particles.

Virus-like particles (VLP) are a promising tool for intracellular gene delivery, yet their potential in ocular gene therapy remains underexplored. In this study, we bridged this knowledge gap by demonstrating the successful generation and application of vesicular stomatitis virus glycoprotein (VSVG)-pseudotyped mouse PEG10 (MmPEG10)-VLP for intraocular mRNA delivery. Our findings revealed that PEG10-VLP can efficiently deliver GFP mRNA to adult retinal pigment epithelial cell line-19 (ARPE-19) cells, leading to transient expression. Moreover, we showed that MmPEG10-VLP can transfer SMAD7 to inhibit epithelial-mesenchymal transition (EMT) in RPE cells effectively. In vivo experiments further substantiated the potential of these vectors, as subretinal delivery into adult mice resulted in efficient transduction of retinal pigment epithelial (RPE) cells and GFP reporter gene expression without significant immune response. However, intravitreal injection did not yield efficient ocular expression. We also evaluated the transduction characteristics of MmPEG10-VLP following intracameral delivery, revealing transient GFP protein expression in corneal endothelial cells without significant immunotoxicities. In summary, our study established that VSVG pseudotyped MmPEG10-based VLP can transduce mitotically inactive RPE cells and corneal endothelial cells in vivo without triggering an inflammatory response, underscoring their potential utility in ocular gene therapy.

Design, synthesis, and biological evaluation of novel 1-amido-2-one-4-thio-deoxypyranose as potential antitumor agents for multiple myeloma.

This study reported the design and synthesis of novel 1-amido-2-one-4-thio-deoxypyranose as inhibitors of potential drug target TRIP13 for developing new mechanism-based therapeutic agents in the treatment of multiple myeloma (MM). In comparison with the positive control DCZ0415, the most active compounds C16, C18, C20 and C32 exhibited strong anti-proliferative activity against human MM cell lines (ARP-1 and NCI-H929) with IC50 values of 1 âˆ¼ 2 µM. While the surface plasmon resonance (SPR) and ATPase activity assays demonstrated that the representative compound C20 is a potent inhibitor of TRIP13, C20 also showed good antitumor activity in vivo on BALB/c nude mice xenografted with MM tumor cells. An initial structure-activity study showed that the carbonyl group is crucial for anticancer activity. Overall, this study provided novel 1-amido-2-one-4-thio-deoxypyranoses, which are entirely different from previously reported potent inhibitor structures of TRIP13, and thus would aid the development of carbohydrate-based novel agents in MM pharmacotherapy.

Deciphering the impact of aging on splenic endothelial cell heterogeneity and immunosenescence through single-cell RNA sequencing analysis.

BACKGROUND: Aging is associated with significant structural and functional changes in the spleen, leading to immunosenescence, yet the detailed effects on splenic vascular endothelial cells (ECs) and their immunomodulatory roles are not fully understood. In this study, a single-cell RNA (scRNA) atlas of EC transcriptomes from young and aged mouse spleens was constructed to reveal age-related molecular changes, including increased inflammation and reduced vascular development and also the potential interaction between splenic endothelial cells and immune cells. RESULTS: Ten clusters of splenic endothelial cells were identified. DEGs analysis across different EC clusters revealed the molecular changes with aging, showing the increase in the overall inflammatory microenvironment and the loss in vascular development function of aged ECs. Notably, four EC clusters with immunological functions were identified, suggesting an Endothelial-to-Immune-like Cell Transition (EndICLT) potentially driven by aging. Pseudotime analysis of the Immunology4 cluster further indicated a possible aging-induced transitional state, potentially initiated by Ctss gene activation. Finally, the effects of aging on cell signaling communication between different EC clusters and immune cells were analyzed. CONCLUSIONS: This comprehensive atlas elucidates the complex interplay between ECs and immune cells in the aging spleen, offering new insights into endothelial heterogeneity, reprogramming, and the mechanisms of immunosenescence.

EZH2 inhibition induces senescence via ERK1/2 signaling pathway in multiple myeloma.

Epigenetic modifications play an important role in cellular senescence, and enhancer of zeste homolog 2 (EZH2) is a key methyltransferase involved in epigenetic remodeling in multiple myeloma (MM) cells. We have previously demonstrated that GSK126, a specific EZH2 inhibitor, exhibits anti-MM therapeutic efficacy and safety in vivo and in vitro; however, its specific mechanism remains unclear. This study shows that GSK126 induces cellular senescence in MM, which is characterized by the accumulation of senescence-associated heterochromatin foci (SAHF) and p21, and increased senescence-associated ß galactosidase activity. Furthermore, EZH2 is inhibited in ribonucleotide reductase regulatory subunit M2 (RRM2)-overexpressing OCI-MY5 and RPMI-8226 cells. RRM2 overexpression inhibits the methyltransferase function of EZH2 and promotes its degradation through the ubiquitin-proteasome pathway, thereby inducing cellular senescence. In this senescence model, Lamin B1, a key component of the nuclear envelope and a marker of senescence, does not decrease but instead undergoes aberrant accumulation. Meanwhile, phosphorylation of extracellular signal-regulated protein kinase (ERK1/2) is significantly increased. The inhibition of ERK1/2 phosphorylation in turn partially restores Lamin B1 level and alleviates senescence. These findings suggest that EZH2 inhibition increases Lamin B1 level and induces senescence by promoting ERK1/2 phosphorylation. These data indicate that EZH2 plays an important role in MM cellular senescence and provide insights into the relationships among Lamin B1, p-ERK1/2, and cellular senescence.

Enhancement of Large Language Models' Performance in Diabetes Education: Retrieval-Augmented Generation Approach.

BACKGROUND: Large language models (LLMs) demonstrated advanced performance in processing clinical information. However, commercially available LLMs lack specialized medical knowledge and remain susceptible to generating inaccurate information. Given the need for self-management in diabetes, patients commonly seek information online. We introduce the RISE framework and evaluate its performance in enhancing LLMs to provide accurate responses to diabetes-related inquiries. OBJECTIVE: This study aimed to evaluate the potential of RISE framework, an information retrieval and augmentation tool, to improve the LLM's performance to accurately and safely respond to diabetes-related inquiries. METHODS: The RISE, an innovative retrieval augmentation framework, comprises four steps: Rewriting Query, Information Retrieval, Summarization, and Execution. Using a set of 43 common diabetes-related questions, we evaluated three base LLMs (GPT-4, Anthropic Claude 2, Google Bard) and their RISE-enhanced versions. Assessments were conducted by clinicians for accuracy and comprehensiveness, and by patients for understandability. RESULTS: The integration of RISE significantly improved the accuracy and comprehensiveness of responses from all three based LLMs. On average, the percentage of accurate responses increased by 12% (122 - 107/129) with RISE. Specifically, the rates of accurate responses increased by 7% (42 - 39/43) for GPT-4, 19% (39 - 31/43) for Claude 2, and 9% (41 - 37/43) for Google Bard. The framework also enhanced response comprehensiveness, with mean scores improving by 0.44. Understandability was also enhanced by 0.19 on average. Data collection was conducted from Sept. 30, 2023, to Feb. 05, 2024. CONCLUSIONS: RISE significantly improves LLMs' performance in responding to diabetes-related inquiries, enhancing accuracy, comprehensiveness, and understandability. These improvements have crucial implications for RISE's future role in patient education and chronic illness self-management, which contributes to relieving medical resource pressures and raising public awareness of medical knowledge.

Enhanced photocatalytic performance of Bi2O2CO3/Bi4O5Br2/reduced graphene oxide Z-schemehe terojunction via a one-pot room-temperature synthesis.

Bi2O2CO3(BOC)/Bi4O5Br2(BOB)/reduced graphene oxide (rGO) Z-scheme heterojunction with promising photocatalytic properties was synthesized via a facile one-pot room-temperature method. Ultra-thin nanosheets of BOC and BOB were grown in situ on rGO. The formed 2D/2D direct Z-scheme heterojunction of BOC/BOB with oxygen vacancies (OVs) effectively leads to lower negative electron reduction potential of BOB as well as higher positive hole oxidation potential of BOC, showing improved reduction/oxidation ability. Particularly, rGO is an acceptor of the electrons from the conduction band of BOC. Its dual roles significantly improve the transfer performance of photo-induced charge carriers and accelerate their separation. With layered nanosheet structure, rich OVs, high specific surface area, and increased utilization efficiency of visible light, the multiple synergistic effects of BOC/BOB/rGO can achieve effective generation and separation of the electron-holes, thereby generating more •O2- and h+. The photocatalytic reduction efficiency of CO2 to CO (12.91 µmol/(g·hr)) is three times higher than that of BOC (4.18 µmol/(g·hr)). Moreover, it also achieved almost 100% removal of Rhodamine B and cyanobacterial cells within 2 hours.

Molecular mechanism by which RRM2-inhibitor (cholagogue osalmid) plus bafilomycin A1 cause autophagic cell death in multiple myeloma.

Despite significant improvement in the prognosis of multiple myeloma (MM), the disease remains incurable; thus, more effective therapies are required. Ribonucleoside-diphosphate reductase subunit M2 (RRM2) is significantly associated with drug resistance, rapid relapse, and poor prognosis. Previously, we found that 4-hydroxysalicylanilide (osalmid), a specific inhibitor of RRM2, exhibits anti-MM activity in vitro, in vivo, and in human patients; however, the mechanism remains unclear. Osalmid inhibits the translocation of RRM2 to the nucleus and stimulates autophagosome synthesis but inhibits subsequent autophagosome-lysosome fusion. We confirm that RRM2 binds to receptor-interacting protein kinase 3 (RIPK3) and reduces RIPK3, inhibiting autophagosome-lysosome fusion. Interestingly, the combination of osalmid and bafilomycin A1 (an autophagy inhibitor) depletes RIPK3 and aggravates p62 and autophagosome accumulation, leading to autophagic cell death. Combination therapy demonstrates synergistic cytotoxicity both in vitro and in vivo. Therefore, we propose that combining osalmid and bafilomycin A1(BafA1) may have clinical benefits against MM.

NOD2 silencing promotes cell apoptosis and inhibits drug resistance in chronic lymphocytic leukemia by inhibiting the NF-κB signaling pathway.

Recent years have witnessed increasing studies on the effect of epigenetic silencing of genes in the progression of chronic lymphocytic leukemia (CLL). This study investigates whether the nucleotide binding oligomerization domain containing 2 (NOD2) participates in the cell apoptosis and drug resistance of CLL cells. Cells were treated with adriamycin (ADR), etoposide, aclacinomycin and daunorubicin. After treatment, drug resistance and cell proliferation were examined to detect the inhibitory effect of ADR on cell proliferation; flow cytometry to identify ADR accumulation, the cell cycle distribution and apoptosis after transfection, and rhodamine 123 accumulation and efflux tests to assess P-glycoprotein (P-gp) function. NOD2 silencing or inhibition of the nuclear factor kappa-B (NF-κB) signaling pathway suppressed the multidrug resistance level in CLL, the inhibition rate, and cell proliferation caused by ADR at concentrations of approximately 0.25-1.5 µmol/L. Greater accumulation of ADR was observed in the CLL-AAT cell line than in the CLL-AAT/A02 cell line, but NOD2 silencing or inhibition of the NF-κB signaling pathway further increased the accumulation of ADR drugs in the CLL-AAT cell line and inhibited the drug efflux pump function of P-gp. Additionally, NOD2 silencing or NF-κB signaling pathway inhibition increased the apoptotic rate. The results of this study indicate that NOD2 promotes cell apoptosis and reduces the drug resistance of CLL by inhibiting the NF-κB signaling pathway.

The molecular identification, odor binding characterization, and immunolocalization of odorant-binding proteins in Liriomyza trifolii.

The Liriomyza trifolii is a highly invasive polyphagia pest. Understanding the physiological functions of odorant binding proteins (OBPs) in the chemical communication of L. trifolii can lead to effective pest management strategies. Seven full-length OBPs were identified by transcriptome screening of L. trifolii adults. Bioinformatics analyses classified the seven OBPs into two subfamilies (six classic OBPs, one minus-C OBP). The analysis of their expression in different development stages revealed that LtriOBP5 was highly expressed in the larval stage, LtriOBP4 in the pupa stage, and LtriOBP1, 2, 3, 6, 7 in the adult stage; the expression levels were higher in male adults than in females. The analysis of different tissues showed high expression of LtriOBP1, 3, 6, 7 in the antennae, which were selected for in vitro purification. To explore the ligand compounds of OBPs, fluorescence competitive binding experiments were performed. Immunofluorescence localization revealed that LtriOBP1, 3, 6, 7 showed strong binding abilities to plant volatiles and were located in the antennae, implying that LtriOBP1, 3, 6, 7 may play key roles in olfaction, such as host location. LtriOBP6 and LtriOBP7 had strong binding abilities to specific herbivore-induced plant volatiles, suggesting LtriOBP6 and LtriOBP7 may also play critical roles in chemoreception. This study provides preliminary exploration of the olfactory perception mechanism of L. trifolii, which can be used as a basis to design insect behavior regulators and develop highly effective insecticides using mixture of ligands and known pesticides.

O-Glycosylation Induces Amyloid-ß To Form New Fibril Polymorphs Vulnerable for Degradation.

Brain accumulation of amyloid-ß (Aß) peptides (resulting from a disrupted balance between biosynthesis and clearance) occurs during the progression of Alzheimer's disease (AD). Aß peptides have diverse posttranslational modifications (PTMs) that variously modulate Aß aggregation into fibrils, but understanding the mechanistic roles of PTMs in these processes remains a challenge. Here, we chemically synthesized three homogeneously modified isoforms of Aß (1-42) peptides bearing Tyr10 O-glycosylation, an unusual PTM initially identified from the cerebrospinal fluid samples of AD patients. We discovered that O-glycans significantly affect both the aggregation and degradation of Aß42. By combining cryo-EM and various biochemical assays, we demonstrate that a Galß1-3GalNAc modification redirects Aß42 to form a new fibril polymorphic structure that is less stable and more vulnerable to Aß-degrading enzymes (e.g., insulin-degrading enzyme). Thus, beyond showing how particular O-glycosylation modifications affect Aß42 aggregation at the molecular level, our study provides powerful experimental tools to support further investigations about how PTMs affect Aß42 fibril aggregation and AD-related neurotoxicity.

Semiquantitative Visual Detection of Lead Ions with a Smartphone via a Colorimetric Paper-Based Analytical Device.

A simple, instrument-free, paper-based analytical device with dual-emission carbon dots (CDs) (blue CDs and red CDs) was developed for the semiquantitative, visual, and sensitive speciation analysis of lead ions in a real sample with a sensitive detection limit of 2.89 nM. When a paper strip was immersed into the sample solution, the blue fluorescence was quenched by Pb2+ in solution, while the red fluorescence served as a background reference without color change, and significant color evolutions from blue to red were observed under the ultraviolet lamp, resulting in a semiquantitative visual detection. Furthermore, a smartphone was used in the visual detection of lead ions by identifying the RGB value of the fluorescent probe solution and corresponding paper strip. The application of smartphones and fluorescent paper strips has greatly shortened the detection time and reduced the cost of detection, providing a new strategy for the on-site and semiquantitative detection of heavy-metal ions in water samples.

Dynamic expression of α6 integrin indicates epidermal cell behaviors.

Skin epidermis is a stratified epithelium that composed of interfollicular epidermis (IFE) and hair follicles (HFs). Integrins are cell-cell and cell-matrix adhesive ligands that play important roles in epidermal cell proliferation, migration and differentiation behaviors. Here, we analyzed the expression of both α6 and ß1 integrins. In vitro epidermal cell culture, both α6 and ß1 integrins displayed downregulation upon high Ca2+ induced differentiation. During wound healing (WH), α6 integrin showed dynamic expression, first greatly upregulated in unclosed wounds and then downregulated upon re-epithelialization. Further analysis of different wound regions confirmed α6 integrin significantly increased in migratory cells and migration was coupled with differentiation. However, expression level of ß1 integrin did not show significant correlation with migration. We discovered that α6 integrin directly indicates epidermal cell differentiation and wound directed migration behaviors with its expression level.

Boron: Functions and Approaches to Enhance Its Availability in Plants for Sustainable Agriculture.

Boron (B) is an essential trace element required for the physiological functioning of higher plants. B deficiency is considered as a nutritional disorder that adversely affects the metabolism and growth of plants. B is involved in the structural and functional integrity of the cell wall and membranes, ion fluxes (H⁺, K⁺, PO43−, Rb⁺, Ca2+) across the membranes, cell division and elongation, nitrogen and carbohydrate metabolism, sugar transport, cytoskeletal proteins, and plasmalemma-bound enzymes, nucleic acid, indoleacetic acid, polyamines, ascorbic acid, and phenol metabolism and transport. This review critically examines the functions of B in plants, deficiency symptoms, and the mechanism of B uptake and transport under limited B conditions. B deficiency can be mitigated by inorganic fertilizer supplementation, but the deleterious impact of frequent fertilizer application disrupts soil fertility and creates environmental pollution. Considering this, we have summarized the available information regarding alternative approaches, such as root structural modification, grafting, application of biostimulators (mycorrhizal fungi (MF) and rhizobacteria), and nanotechnology, that can be effectively utilized for B acquisition, leading to resource conservation. Additionally, we have discussed several new aspects, such as the combination of grafting or MF with nanotechnology, combined inoculation of arbuscular MF and rhizobacteria, melatonin application, and the use of natural and synthetic chelators, that possibly play a role in B uptake and translocation under B stress conditions.

Interpreted Recognition Process: A Highly Sensitive and Selective Luminescence Chemosensor.

A luminescence-sensing process based on coordination compound [H2 N(CH3 )2 ]3 [Tb(dipic)3 ] was developed. It shows fast response (within 1 min), high selectivity, and is ultrasensitive to detect Fe(3+) or Cr(3+) in aqueous solution and living cells (KSV values are calculated to be 3.6×10(4)  L mol(-1) for Fe(3+) and 1.9×10(4)  L mol(-1) for Cr(3+) ). The whole recognition process has been witnessed through electrospray ionization mass spectrometry (ESI-MS) analysis, and the ligand-transfer-induced luminescence-quenching mechanism is interpreted. This work contributes to extend the potential applications of lanthanide coordination compounds (LnCCs) in the fields of biological and environmental technologies.

Microsaccades reflect attention shifts: a mini review of 20 years of microsaccade research.

Microsaccades are small, involuntary eye movements that occur during fixation. Since the 1950s, researchers have conducted extensive research on the role of microsaccades in visual information processing, and found that they also play an important role in human advanced visual cognitive activities. Research over the past 20 years further suggested that there is a close relationship between microsaccades and visual attention, yet lacking a timely review. The current article aims to provide a state-of-the-art review and bring microsaccades studies into the sight of attention research. We firstly introduce basic characteristics about microsaccades, then summarized the empirical evidence supporting the view that microsaccades can reflect both external (perception) and internal (working memory) attention shifts. We finally conclude and highlight three promising avenues for future research.

Seasonal migration pattern of an important rice pest, Nilaparvata lugens (Hemiptera: Delphacidae), on Hainan Island, China.

The brown planthopper, Nilaparvata lugens (Hemiptera: Delphacidae) (BPH), is a major, regionally migratory pest of rice in Asia. Despite intensive migratory studies, the seasonal migratory pattern of this species in the year-round breeding region (i.e., Hainan Island) remains largely unknown. To understand the migration dynamics, we conducted relevant research based on BPH light trap catches on Hainan in 2017-2022. Results showed that the occurrence dynamics of BPH in Hainan oscillated in different years and seasons. Overall, there are 4 migration peak periods on Hainan, with outbound peak periods in April-May and August-September and inbound peak periods in June and October. Trajectory and wind fields showed that in August-September, Hainan had complex meteorological conditions, and the outbound paths of BPH were variable, mainly landing in southeastern Guangxi and southwestern Guangdong. In contrast, April-May was influenced by southeasterly winds, with a wider outbound range and a further distance, landing along northeastern Vietnam from west to east toward Guangxi and Guangdong areas with time. Wind-rain fields, trajectory, and hydrogen isotope showed that in June, southwesterly winds transported BPH northward from the Indochina peninsula, where it was hindered by rainfall in the Leizhou Peninsula area and the migrants will be "rained out" into Hainan. Identically, in October, the interactions between northeasterly winds and rainfall belts on the southwest shore of Hainan increased the opportunities for BPH to migrate southward to reach Hainan. Our results suggest that Hainan is not only an important source of BPH migrating from East Asia but also plays the role of a bridge.

CD169+ classical monocyte as an important participant in Graves' ophthalmopathy through CXCL12-CXCR4 axis.

Patients with Graves' disease (GD) can develop Graves' ophthalmopathy (GO), but the underlying pathological mechanisms driving this development remain unclear. In our study, which included patients with GD and GO, we utilized single-cell RNA sequencing (scRNA-seq) and multiplatform analyses to investigate CD169+ classical monocytes, which secrete proinflammatory cytokines and are expanded through activated interferon signaling. We found that CD169+ clas_mono was clinically significant in predicting GO progression and prognosis, and differentiated into CD169+ macrophages that promote inflammation, adipogenesis, and fibrosis. Our murine model of early-stage GO showed that CD169+ classical monocytes accumulated in orbital tissue via the Cxcl12-Cxcr4 axis. Further studies are needed to investigate whether targeting circulating monocytes and the Cxcl12-Cxcr4 axis could alleviate GO progression.

Substrate-borne vibrational signals and stridulatory organs for sexual communication in leafminer, Liriomyza sativae (Diptera: Agromyzidae).

The vegetable leafminer (Liriomyza sativae [Burgess]) is a highly polyphagous pest that threatens vegetables and horticultural plants. Although sexual communication is a key component of the animal behavioral repertoire, the mechanism underlying sexual communication in L. sativae remains to be elucidated. Here, we used laser vibrometry to characterize the vibrational signals emitted by L. sativae during pair formation. By emitting trains of vibrational pulses (male calling) the male initiated communication on the host plant. The female then became immobile and responded to the male calling by emitting replies (female replies), which in turn triggered male replies consisting of a rapid series of chirps and trills. If the female replied, a continuous exchange of male and female replies ensued, representing a duet. In playback trials, a playback signal caused responses from the opposite sex. Moreover, scanning electron microscopy revealed vibration-producing stridulatory organs in both male and female individuals. The files in males were more developed than those in females, and older male specimens had more signs of abrasion. The results provide new insight into the mating biology of L. sativae.

The RBPMSCreERT2-tdTomato mouse line for studying retinal and vascular relevant diseases.

RNA-binding protein with multiple splicing (RBPMS) plays a crucial role in cardiac mesoderm specification and cardiovascular development, as well as being a typical marker for whole retinal ganglion cells (RGCs). However, there is a lack of animal models to spatiotemporally trace the location and function of RBPMS-expressing cells in vivo. In this study, we develop a tamoxifen-inducible RBPMS-tdTomato reporter mouse line to track RBPMS-expressing cells during embryogenesis and adulthood. This mouse line allows us to identify and locate RBPMS-tdTomato-positive cells among various tissues, especially in RGCs and smooth muscle cells, which assist to simulate related retinal degenerative diseases, model and examine choroidal neovascularization non-invasively in vivo. Our results show that the RBPMSCreERT2-tdTomato mouse line is a valuable tool for lineage tracing, disease modeling, drug screening, as well as isolating specific target cells.