TOX2 nuclear-cytosol translocation is linked to leukemogenesis of acute T-cell leukemia by repressing TIM3 transcription.

Nuclear factors TOX and TOX2 upregulate TIM3 expression and lead to T-cell exhaustion in malignancies. Here, we demonstrate two distinct TIM3 expression patterns (high & low) with high TOX and TOX2 levels in T-cell acute lymphoblastic leukemia (T-ALL) specimens and cell lines. However, the mechanisms regulated by TOX and TIM3 signaling in leukemogenesis are unclear. We found that TOX and TOX2 proteins each directly upregulated HAVCR2 transcription, while the cellular localization of TOX2 was different in Jurkat and MOLT3 cells (nucleus) and lymphoblastic cell T2 and normal T cells (cytoplasm). Nuclear TOX and TOX2 formed a protein complex and repressed HAVCR2 promoter activity by recruiting transcriptional corepressor LCOR and deacetylase HDAC3. The nuclear-cytosol translocation of TOX2 was deacetylation-dependent and cooperatively mediated by deacetylase Sirt1 and kinase TBK1. Radiation damage induced TOX2 nuclear translocation and decreased Sirt1, TIM3, and caspase 1 expression in normal T cells. Accordingly, knockdown of TOX, TOX2 or LCOR; HDAC3 inhibition; or TIM3 overexpression induced Jurkat cell apoptosis in vitro and slow growth in vivo. Thus, our findings demonstrate a novel regulatory mechanism involving TOX-TOX2 and the TIM3 pathway in the leukemogenesis of T-ALL.

Plasma-generated RONS in liquid transferred into cryo-microneedles patch for skin treatment of melanoma.

Malignant melanoma is the most lethal form of skin cancer. As a promising anti-cancer agent, plasma-activated water (PAW) rich in reactive oxygen and nitrogen species (RONS) has shown significant potential for melanoma treatment. However, rapid decay of RONS and inefficient delivery of PAW in conventional injection methods limit its practical applications. To address this issue, here we report a new approach for the production of plasma-activated cryo-microneedles (PA-CMNs) patches using custom-designed plasma devices and processes. Our innovation is to incorporate PAW into the PA-CMNs that are fabricated using a fast cryogenic micro-molding method. It is demonstrated that PA-CMNs can be easily inserted into skin to release RONS and slow the decay of RONS thereby prolonging their bioactivity and effectiveness. The new insights into the effective melanoma treatment suggest that the rich mixture of RONS within PA-CMNs prepared by custom-developed hybrid plasma-assisted configuration induces both ferroptosis and apoptosis to selectively kill tumor cells. A significant inhibition of subcutaneous A375 melanoma growth was observed in PA-CMNs-treated tumor-bearing nude mice without any signs of systemic toxicity. The new approach based on PA-CMNs may potentially open new avenues for a broader range of disease treatments.

Integration of Hollow Microneedle Arrays with Jellyfish-Shaped Electrochemical Sensor for the Detection of Biomarkers in Interstitial Fluid.

This study integrates hollow microneedle arrays (HMNA) with a novel jellyfish-shaped electrochemical sensor for the detection of key biomarkers, including uric acid (UA), glucose, and pH, in artificial interstitial fluid. The jellyfish-shaped sensor displayed linear responses in detecting UA and glucose via differential pulse voltammetry (DPV) and chronoamperometry, respectively. Notably, the open circuit potential (OCP) of the system showed a linear variation with pH changes, validating its pH-sensing capability. The sensor system demonstrates exceptional electrochemical responsiveness within the physiological concentration ranges of these biomarkers in simulated epidermis sensing applications. The detection linear ranges of UA, glucose, and pH were 0~0.8 mM, 0~7 mM, and 4.0~8.0, respectively. These findings highlight the potential of the HMNA-integrated jellyfish-shaped sensors in real-world epidermal applications for comprehensive disease diagnosis and health monitoring.

FOXA2 rewires AP-1 for transcriptional reprogramming and lineage plasticity in prostate cancer.

FOXA family proteins act as pioneer factors by remodeling compact chromatin structures. FOXA1 is crucial for the chromatin binding of the androgen receptor (AR) in both normal prostate epithelial cells and the luminal subtype of prostate cancer (PCa). Recent studies have highlighted the emergence of FOXA2 as an adaptive response to AR signaling inhibition treatments. However, the role of the FOXA1 to FOXA2 transition in regulating cancer lineage plasticity remains unclear. Our study demonstrates that FOXA2 binds to distinct classes of developmental enhancers in multiple AR-independent PCa subtypes, with its binding depending on LSD1. Moreover, we reveal that FOXA2 collaborates with JUN at chromatin and promotes transcriptional reprogramming of AP-1 in lineage-plastic cancer cells, thereby facilitating cell state transitions to multiple lineages. Overall, our findings underscore the pivotal role of FOXA2 as a pan-plasticity driver that rewires AP-1 to induce the differential transcriptional reprogramming necessary for cancer cell lineage plasticity.

CSRP1 gene: a potential novel prognostic marker in acute myeloid leukemia with implications for immune response.

BACKGROUND: Acute myeloid leukemia, constituting a majority of leukemias, grapples with a 24% 5-year survival rate. Recent strides in research have unveiled fresh targets for drug therapies. LIM-only, a pivotal transcription factor within LIM proteins, oversees cell development and is implicated in tumor formation. Among these critical LIM proteins, CSRP1, a Cysteine-rich protein, emerges as a significant player in various diseases. Despite its recognition as a potential prognostic factor and therapeutic target in various cancers, the specific link between CSRP1 and acute myeloid leukemia remains unexplored. Our previous work, identifying CSRP1 in a prognostic model for AML patients, instigates a dedicated exploration into the nuanced role of CSRP1 in acute myeloid leukemia. METHODS: R tool was conducted to analyze the public data. qPCR was applied to evaluate the expression of CSRP1 mRNA for clinical samples and cell line. Unpaired t test, Wilcoxon Rank Sum test, KM curves, spearman correlation test and Pearson correlation test were included in this study. RESULTS: CSRP1 displays notable expression variations between normal and tumor samples in acute myeloid leukemia (AML). It stands out as an independent prognostic factor for AML patients, showing correlations with clinical factors like age and cytogenetics risk. Additionally, CSRP1 correlates with immune-related pathways, immune cells, and immune checkpoints in AML. Furthermore, the alteration of CSRP1 mRNA levels is observed upon treatment with a DNMT1 inhibitor for THP1 cells. CONCLUSION: The CSRP1 has potential as a novel prognostic factor and appears to influence the immune response in acute myeloid leukemia. Additionally, there is an observed association between CSRP1 and DNA methylation in acute myeloid leukemia.

In vitro Antibacterial Effect Study of Plasma-Activated Saline on Mycobacterium Tuberculosis.

Purpose: This study aimed to investigate the antibacterial effects of plasma-activated saline (PAS) on My-cobacterium tuberculosis (Mtb). Methods: We conducted a growth assay on 3 strains of Mtb and an antibiotic sensitivity test on 4 strains of Mtb. Both tests included groups treated with normal saline (NS), PAS, and hydrochloric acid (HCl). The test of antibiotic sensitivity consisted of parallel tests with two concentrations of bacteria suspension: 10-2 and 10-4. The selected antibiotics were rifampicin (RIF), isoniazid (INH), ethambutol (EMB), and streptomycin (SM). The number of bacteria was determined after one month of culture under different conditions. The Kruskal-Wallis test was used to analyze the differences in grouping factors at representative time points. Results: The growth assay indicated that PAS significantly inhibited the growth of 3 strains of Mtb compared with NS and HCl treatment groups. Furthermore, except for the initial observation time point, the remaining three observation time points consistently demonstrate no significant differences between the NS group and the HCl group. The antibiotic sensitivity test of INH, SM, and RIF indicated that PAS could inhibit the growth of antibiotic-resistant Mtb, and the antibiotic sensitivity test of INH and SM with bacterial suspension concentration of 10-2 and SM with bacterial suspension concentration of 10-4 showed statistically different results. The antibiotic sensitivity test of EMB indicated that the growth of Mtb in PAS was slower than that in NS and HCl in both antibiotic-resistant and sensitive Mtb, but there was no statistical difference. Conclusion: The study indicates that PAS contains a significant amount of active substances and exhibits high oxidizability and an acidic pH state. The unique physicochemical properties of PAS significantly delayed the growth of Mtb, compared to the NS and the HCl. PAS not only inhibited the growth of drug-sensitive strains but also significantly enhanced the sensitivity of drug-resistant strains to anti-tuberculosis drugs, which may provide a new therapeutic strategy for the treatment of tuberculosis.

Electrochemical biosensor based on RNA aptamer and ferrocenecarboxylic acid signal probe for C-reactive protein detection.

Monitoring health-related biomarkers using fast and facile detection techniques provides key physicochemical information for disease diagnosis or reflects body health status. Among them, electrochemical detection of various bio-macromolecules, e.g., the C-reactive protein (CRP), is of great interest in offering potential diagnosis for acute inflammation caused by infections, heart diseases, etc. Herein, a novel electrochemical aptamer biosensor was constructed from Ti3C2Tx MXene and in-situ reduced Au NPs for thiolated-RNA aptamer immobilization and CRP protein detection using Fc(COOH) as the signal probe. The sensory performances for CRP detection were optimized based on working conditions, including the incubation times and the pH. The large surface area offered by Ti3C2Tx MXene and high electrical conductivity originating from Au NPs endowed the as-fabricated aptamer biosensor with a decent sensitivity for CRP in a wide linear range of 0.05-80.0 ng/mL, good selectivity over interfering substances, and a low detection limit of 0.026 ng/mL. Such aptamer biosensors also detected CRP in serum samples using the spike & recovery method with reasonable recovery rates. The results demonstrated the potential of the as-fabricated electrochemical aptamer biosensor for fast and facile CRP detection in practical applications.

Multiomics profiling reveals VDR as a central regulator of mesenchymal stem cell senescence with a known association with osteoporosis after high-fat diet exposure.

The consumption of a high-fat diet (HFD) has been linked to osteoporosis and an increased risk of fragility fractures. However, the specific mechanisms of HFD-induced osteoporosis are not fully understood. Our study shows that exposure to an HFD induces premature senescence in bone marrow mesenchymal stem cells (BMSCs), diminishing their proliferation and osteogenic capability, and thereby contributes to osteoporosis. Transcriptomic and chromatin accessibility analyses revealed the decreased chromatin accessibility of vitamin D receptor (VDR)-binding sequences and decreased VDR signaling in BMSCs from HFD-fed mice, suggesting that VDR is a key regulator of BMSC senescence. Notably, the administration of a VDR activator to HFD-fed mice rescued BMSC senescence and significantly improved osteogenesis, bone mass, and other bone parameters. Mechanistically, VDR activation reduced BMSC senescence by decreasing intracellular reactive oxygen species (ROS) levels and preserving mitochondrial function. Our findings not only elucidate the mechanisms by which an HFD induces BMSC senescence and associated osteoporosis but also offer new insights into treating HFD-induced osteoporosis by targeting the VDR-superoxide dismutase 2 (SOD2)-ROS axis.

Fabrication and mechanical modelling of dissolvable PVA/PVP composite microneedles with biocompatibility for efficient transdermal delivery of ibuprofen.

Microneedles offer minimally invasive, user-friendly, and subcutaneously accessible transdermal drug delivery and have been widely investigated as an effective transdermal delivery system. Ibuprofen is a common anti-inflammatory drug to treat chronic inflammation. It is crucial to develop microneedle patches capable of efficiently delivering ibuprofen through the skin for the effective treatment of arthritis patients requiring repeated medication. In this study, the mechanical properties of a new type of polymer microneedle were studied by finite element analysis, and the experimental results showed that the microneedle could effectively deliver drugs through the skin. In addition, a high ibuprofen-loaded microneedle patch was successfully prepared by micromolding and subjected to evaluation of its infrared spectrum morphology and dissolve degree. The morphology of microneedles was characterized by scanning electron microscopy, and the mechanical properties were assessed using a built linear stretching system. In the in-vitro diffusion cell drug release test, the microneedle released 85.2 ± 1.52% (210 ± 3.7 µg) ibuprofen in the modified Franz diffusion within 4 h, exhibiting a higher drug release compared to other drug delivery methods. This study provides a portable, safe and efficient treatment approach for arthritis patients requiring daily repeated medication.

Androgen receptor splice variants drive castration-resistant prostate cancer metastasis by activating distinct transcriptional programs.

One critical mechanism through which prostate cancer (PCa) adapts to treatments targeting androgen receptor (AR) signaling is the emergence of ligand-binding domain-truncated and constitutively active AR splice variants, particularly AR-V7. While AR-V7 has been intensively studied, its ability to activate distinct biological functions compared with the full-length AR (AR-FL), and its role in regulating the metastatic progression of castration-resistant PCa (CRPC), remain unclear. Our study found that, under castrated conditions, AR-V7 strongly induced osteoblastic bone lesions, a response not observed with AR-FL overexpression. Through combined ChIP-seq, ATAC-seq, and RNA-seq analyses, we demonstrated that AR-V7 uniquely accesses the androgen-responsive elements in compact chromatin regions, activating a distinct transcription program. This program was highly enriched for genes involved in epithelial-mesenchymal transition and metastasis. Notably, we discovered that SOX9, a critical metastasis driver gene, was a direct target and downstream effector of AR-V7. Its protein expression was dramatically upregulated in AR-V7-induced bone lesions. Moreover, we found that Ser81 phosphorylation enhanced AR-V7's pro-metastasis function by selectively altering its specific transcription program. Blocking this phosphorylation with CDK9 inhibitors impaired the AR-V7-mediated metastasis program. Overall, our study has provided molecular insights into the role of AR splice variants in driving the metastatic progression of CRPC.

Squalene-epoxidase-catalyzed 24(S),25-epoxycholesterol synthesis promotes trained-immunity-mediated antitumor activity.

The importance of trained immunity in antitumor immunity has been increasingly recognized, but the underlying metabolic regulation mechanisms remain incompletely understood. In this study, we find that squalene epoxidase (SQLE), a key enzyme in cholesterol synthesis, is required for ß-glucan-induced trained immunity in macrophages and ensuing antitumor activity. Unexpectedly, the shunt pathway, but not the classical cholesterol synthesis pathway, catalyzed by SQLE, is required for trained immunity induction. Specifically, 24(S),25-epoxycholesterol (24(S),25-EC), the shunt pathway metabolite, activates liver X receptor and increases chromatin accessibility to evoke innate immune memory. Meanwhile, SQLE-induced reactive oxygen species accumulation stabilizes hypoxia-inducible factor 1α protein for metabolic switching into glycolysis. Hence, our findings identify 24(S),25-EC as a key metabolite for trained immunity and provide important insights into how SQLE regulates trained-immunity-mediated antitumor activity.

Inactivation of microorganisms on fabrics using plasma-activated nebulized mist driven by different plasma gases.

The disinfection of fabrics is crucial in preventing the spread of infectious diseases caused by pathogenic microorganisms to maintain public health. A previous study proved that plasma-activated nebulized mist (PANM) could effectively inactivate microorganisms both in aerosol and attached to the surface. In this study, the PANM driven by different plasma gases were employed to inactivate microorganisms on diverse fabrics. The PANM could efficiently inactivate a variety of microorganisms, including bacteria, fungi, and viruses, contaminating different fabrics, and even across covering layers of different fabrics. The mites residing on the cotton fabrics both uncovered and covered with various types of fabrics were also effectively inactivated by the PANM. After 30 times repeated treatments of the PANM, notable changes were observed in the color of several fabrics while the structural integrity and mechanical strength of the fabrics were unaffected and maintained similarly to the untreated fabrics with slight changes in elemental composition. Additionally, only trace amounts of nitrate remained in the fabrics after the PANM treatment. Therefore, the PANM treatment supplied an efficient, broad-spectrum, and environmentally friendly strategy for industrial and household disinfection of fabrics.

AURKA emerges as a vulnerable target for KEAP1-deficient non-small cell lung cancer by activation of asparagine synthesis.

AURKA is an established target for cancer therapy; however, the efficacy of its inhibitors in clinical trials is hindered by differential response rates across different tumor subtypes. In this study, we demonstrate AURKA regulates amino acid synthesis, rendering it a vulnerable target in KEAP1-deficient non-small cell lung cancer (NSCLC). Through CRISPR metabolic screens, we identified that KEAP1-knockdown cells showed the highest sensitivity to the AURKA inhibitor MLN8237. Subsequent investigations confirmed that KEAP1 deficiency heightens the susceptibility of NSCLC cells to AURKA inhibition both in vitro and in vivo, with the response depending on NRF2 activation. Mechanistically, AURKA interacts with the eIF2α kinase GCN2 and maintains its phosphorylation to regulate eIF2α-ATF4-mediated amino acid biosynthesis. AURKA inhibition restrains the expression of asparagine synthetase (ASNS), making KEAP1-deficient NSCLC cells vulnerable to AURKA inhibitors, in which ASNS is highly expressed. Our study unveils the pivotal role of AURKA in amino acid metabolism and identifies a specific metabolic indication for AURKA inhibitors. These findings also provide a novel clinical therapeutic target for KEAP1-mutant/deficient NSCLC, which is characterized by resistance to radiotherapy, chemotherapy, and targeted therapy.

Cold atmospheric plasma for chronic kidney disease-related skin disorders.

BACKGROUND AND HYPOTHESIS: An estimated 80% of individuals with chronic kidney disease (CKD) experience concomitant skin disorders, yet experimental research that elucidates the pathological changes in CKD-affected skin is limited. Cold atmospheric plasma (CAP) has shown promise in regulating keratinocyte proliferation, skin barrier function, and anti-inflammatory activity. We hypothesize that CAP emerges as a promising therapeutic avenue for CKD-related skin diseases. METHODS: Male and female C57/BL6 mice were administered a 0.2% adenine diet to generate a CKD mouse model. Skin samples from dialysis patients were also collected. These models were used to investigate the pathological alterations in the renal glomeruli, tubules, and epidermis. Subsequently, the potential impact of CAP on the stratum corneum, keratinocytes, skin hydration, and inflammation in mice with CKD were examined. RESULTS: Renal biopsies revealed glomerular and tubular atrophy, epithelial degeneration and necrosis in uriniferous tubules, and significant renal interstitial fibrosis. Skin biopsies from patients with CKD and mice showed stratum corneum thickening, epidermis atrophy, skin hydration dysfunction, and excessive inflammation. CAP attenuated skin atrophy, hydration dysfunction, and inflammation in mice with CKD, as evidenced by the activated level of YAP1/ß-catenin and Nrf-2/OH-1, enhanced expression of K5 and Ki67, increased levels of AQP3, collagen I, and GLUT1, reduced infiltration of CD3+ T cells, and diminished levels of IL-6 and TNF-α. CONCLUSION: This study provides valuable insights into the pathological changes in skin associated with CKD in both patients and animal models. It also establishes that CAP has the potential to effectively mitigate skin atrophy, hydration dysfunction, and inflammation, suggesting a novel therapeutic avenue for the treatment of CKD-related skin disorders.

Fully Transient 3D Origami Paper-Based Ammonia Gas Sensor Obtained by Facile MXene Spray Coating.

Developing high-performance chemiresistive gas sensors with mechanical compliance for environmental or health-related biomarker monitoring has recently drawn increasing research attention. Among them, two-dimensional MXene materials hold great potential for room-temperature hazardous gas (e.g., NH3) monitoring regardless of the complicated fabrication process, insufficient 2D/3D flexibilities, and poor environmental sustainability. Herein, a Ti3C2Tx MXene/gelatin ink was developed for patterning electrodes through a facile spray coating. Particularly, the patterned Ti3C2Tx-based coating exhibited good adhesion on the paper substrate against repeated peeling-off and excellent mechanical flexibility against 1000 cyclic stretching. The porous morphology of the coating facilitated the NH3 sensing ability. As a result, the 2D kirigami-shaped NH3 sensor exhibited a good response of 7% to 50 ppm of NH3 with detectable concentrations ranging from 5-500 ppm, decent selectivity over interferences, etc., which could be well-maintained even at 50% stretched state. In addition, with the help of mechanically guided compressive buckling, 3D mesostructured MXene origamis could be obtained, holding promise for detecting the coming direction and height distribution of hazardous gas, e.g., the NH3. More importantly, the as-fabricated MXene/gelatin origami paper could be fully degraded in PBS/H2O2/cellulase solution within 19 days, demonstrating its potential as a high-performance, shape morphable, and environmentally friendly wearable gas sensor.

Microneedle Patches-Integrated Transdermal Bioelectronics for Minimally Invasive Disease Theranostics.

Wearable epidermal electronics with non- or minimally-invasive characteristics can collect, transduce, communicate, and interact with accessible physicochemical health indicators on the skin. However, due to the stratum corneum layer, rich information about body health is buried under the skin stratum corneum layer, for example, in the skin interstitial fluid. Microneedle patches are typically designed with arrays of special microsized needles of length within 1000 µm. Such characteristics potentially enable the access and sample of biomolecules under the skin or give therapeutical treatment painlessly and transdermally. Integrating microneedle patches with various electronics allows highly efficient transdermal bioelectronics, showing their great promise for biomedical and healthcare applications. This comprehensive review summarizes and highlights the recent progress on integrated transdermal bioelectronics based on microneedle patches. The design criteria and state-of-the-art fabrication techniques for such devices are initially discussed. Next, devices with different functions, including but not limited to health monitoring, drug delivery, and therapeutical treatment, are highlighted in detail. Finally, key issues associated with current technologies and future opportunities are elaborated to sort out the state of recent research, point out potential bottlenecks, and provide future research directions.

Constrained Origami Artificial Muscle-Driven Robotic Manipulator Capable of Coordinating Twisting and Grasping Motions for Object Manipulation.

Grasping and twisting motions are vital when manipulating objects due to their fundamental role in enabling precision, adaptability, and effective interaction. However, few studies in soft robotics exploiting artificial muscles have achieved object manipulation in situ through the coordination of twisting and grasping motions akin to our forearm and hand's capabilities. Especially, when using the same artificial muscle module to achieve these two motions will greatly simplify the manufacturing and control complexity. Here, we introduce identical origami artificial muscle modules (OAMMs) subjected to distinct end constraints into the design of the robotic manipulator, allowing it to achieve independent grasping and twisting motions to achieve effective, precise object manipulation. Applying different end constraints to the identical OAMMs yields distinct motions at their ends, where utilizing a fixed end and a sliding end realizes pure translation, while opting for a fixed end and a rotating end enables pure rotation. The differentially constrained OAMMs then serve as soft actuators for the manipulator's torsional mechanism and grasping mechanism to accomplish independent, controllable twisting and grasping motions. The coordination of twisting and grasping motions finally enables the manipulator to complete various tasks, including installing a light bubble, pouring the water from a lidded bottle into a cup, and sorting and stacking puzzle blocks. Our study pioneers the utilization of OAMMs for precise and versatile object manipulation through the coordination of independent twisting and grasping motions.

Characterization and Application of an Aspartate Dehydrogenase from Achromobacter denitrificans.

A novel gene encoding aspartate dehydrogenase (ASPDH) has been discovered in Achromobacter denitrificans. The product of this gene has a strict dependence on NADH and demonstrated significant reductive activity towards not only oxaloacetate (OAA) but also 2-ketobutyric acid. Further enzymatic characterization revealed the kinetic parameters of ASPDH for OAA and 2-ketobutyric acid were as follows: Km values of 4.25 mM and 0.89 mM, Vmax values of 10.67 U mg-1 and 2.10 U mg-1, and Kcat values of 3.70 s-1 and 0.72 s-1, respectively. The enzyme also showed a dependency on metal ions, with EDTA and Cu2+ exerting strong inhibitory effects, while Ca2+ and Fe2+ exhibited pronounced enhancing effects. By utilizing a whole-cell biocatalyst system comprising glucose dehydrogenase (GDH) and ASPDH as a coupled system to replenish cofactors by oxidizing glucose, enabling the effective conversion of 2-ketobutyric acid to L-2-aminobutyric acid (L-2-ABA) with 97.2% yield.

LncRNA CHROMR/miR-27b-3p/MET axis promotes the proliferation, invasion, and contributes to rituximab resistance in diffuse large B-cell lymphoma.

Long non-coding RNAs (LncRNAs) could regulate chemoresistance through sponging microRNAs (miRNAs) and sequestering RNA binding proteins. However, the mechanism of lncRNAs in rituximab resistance in diffuse large B-cell lymphoma (DLBCL) is largely unknown. Here, we investigated the functions and molecular mechanisms of lncRNA CHROMR in DLBCL tumorigenesis and chemoresistance. LncRNA CHROMR is highly expressed in DLBCL tissues and cells. We examined the oncogenic functions of lncRNA CHROMR in DLBCL by a panel of gain-or-loss-of-function assays and in vitro experiments. LncRNA CHROMR suppression promotes CD20 transcription in DLBCL cells and inhibits rituximab resistance. RNA immunoprecipitation, RNA pull-down, and dual luciferase reporter assay reveal that lncRNA CHROMR sponges with miR-27b-3p to regulate mesenchymal-epithelial transition factor (MET) levels and Akt signaling in DLBCL cells. Targeting the lncRNA CHROMR/miR-27b-3p/MET axis reduces DLBCL tumorigenesis. Altogether, these findings provide a new regulatory model, lncRNA CHROMR/miR-27b-3p/MET, which can serve as a potential therapeutic target for DLBCL.

Aurora kinase A-mediated phosphorylation triggers structural alteration of Rab1A to enhance ER complexity during mitosis.

Morphological rearrangement of the endoplasmic reticulum (ER) is critical for metazoan mitosis. Yet, how the ER is remodeled by the mitotic signaling remains unclear. Here, we report that mitotic Aurora kinase A (AURKA) employs a small GTPase, Rab1A, to direct ER remodeling. During mitosis, AURKA phosphorylates Rab1A at Thr75. Structural analysis demonstrates that Thr75 phosphorylation renders Rab1A in a constantly active state by preventing interaction with GDP-dissociation inhibitor (GDI). Activated Rab1A is retained on the ER and induces the oligomerization of ER-shaping protein RTNs and REEPs, eventually triggering an increase of ER complexity. In various models, from Caenorhabditis elegans and Drosophila to mammals, inhibition of Rab1AThr75 phosphorylation by genetic modifications disrupts ER remodeling. Thus, our study reveals an evolutionarily conserved mechanism explaining how mitotic kinase controls ER remodeling and uncovers a critical function of Rab GTPases in metaphase.