EMT activates exocytotic Rabs to coordinate invasion and immunosuppression in lung cancer.

Epithelial-to-mesenchymal transition (EMT) underlies immunosuppression, drug resistance, and metastasis in epithelial malignancies. However, the way in which EMT orchestrates disparate biological processes remains unclear. Here, we identify an EMT-activated vesicular trafficking network that coordinates promigratory focal adhesion dynamics with an immunosuppressive secretory program in lung adenocarcinoma (LUAD). The EMT-activating transcription factor ZEB1 drives exocytotic vesicular trafficking by relieving Rab6A, Rab8A, and guanine nucleotide exchange factors from miR-148a-dependent silencing, thereby facilitating MMP14-dependent focal adhesion turnover in LUAD cells and autotaxin-mediated CD8+ T cell exhaustion, indicating that cell-intrinsic and extrinsic processes are linked through a microRNA that coordinates vesicular trafficking networks. Blockade of ZEB1-dependent secretion reactivates antitumor immunity and negates resistance to PD-L1 immune checkpoint blockade, an important clinical problem in LUAD. Thus, EMT activates exocytotic Rabs to drive a secretory program that promotes invasion and immunosuppression in LUAD.

Pd-Adsorbed SiN3 Monolayer as a Promising Gas Scavenger for SF6 Partial Discharge Decomposition Components: Insights from the First-Principles Study.

Gas-insulated switchgear (GIS) equipment must be protected by detecting and eliminating the toxic SF6 partial discharge decomposition components. This study employs first-principles calculations to thoroughly investigate the interaction between a Pd-adsorbed SiN3 monolayer (Pd-SiN3) and four typical SF6 decomposition gases (H2S, SO2, SOF2, and SO2F2). The study also investigates the associated geometric, electrical, and optical characteristics along with the sensing sensitivity and desorption efficiency. The ab initio molecular dynamics (AIMD) simulations demonstrated the favorable stability of the Pd-SiN3 monolayer. Furthermore, the Pd-SiN3 monolayer exhibited strong chemisorption behavior toward H2S, SO2, SOF2, and SO2F2 gases because of the higher adsorption energies of -2.717, -2.917, -2.457, and -2.025 eV, respectively. Furthermore, significant changes occur in the electronic and optical characteristics of the Pd-SiN3 monolayer following the adsorption of these gases, resulting in remarkable sensitivity of the Pd-SiN3 monolayer in relation to electrical conductivity and optical absorption. Meanwhile, all of these gas adsorption systems exhibited extremely long recovery times. The aforementioned theoretical findings suggest that the Pd-SiN3 monolayer has the potential to be an effective gas scavenger for the storage or removal of the SF6 decomposition components. Additionally, it might function as a reliable one-time sensor for detecting these gases. The results potentially provide valuable theoretical guidance for maintaining the normal operation of the SF6 insulation devices.

Addiction to Golgi-resident PI4P synthesis in chromosome 1q21.3-amplified lung adenocarcinoma cells.

A chromosome 1q21.3 region that is frequently amplified in diverse cancer types encodes phosphatidylinositol (PI)-4 kinase IIIß (PI4KIIIß), a key regulator of secretory vesicle biogenesis and trafficking. Chromosome 1q21.3-amplified lung adenocarcinoma (1q-LUAD) cells rely on PI4KIIIß for Golgi-resident PI-4-phosphate (PI4P) synthesis, prosurvival effector protein secretion, and cell viability. Here, we show that 1q-LUAD cells subjected to prolonged PI4KIIIß antagonist treatment acquire tolerance by activating an miR-218-5p-dependent competing endogenous RNA network that up-regulates PI4KIIα, which provides an alternative source of Golgi-resident PI4P that maintains prosurvival effector protein secretion and cell viability. These findings demonstrate an addiction to Golgi-resident PI4P synthesis in a genetically defined subset of cancers.

Piezoelectric tuning of narrowband perfect plasmonic absorbers via an optomechanic cavity.

Optical antennas enable the control of light-matter interaction on the nanometer scale. Efficient on-chip electrical switching of plasmonic resonances is a crucial step toward the integration of optical antennas into practical optoelectronic circuits. We propose and numerically investigate the on-chip low-voltage linear electrical tuning of a narrowband optical antenna perfect absorber via a piezoelectric optomechanic cavity. Near unity absorption is realized by an array of gold nanostrip antennas separated from a membrane-based deformable backreflector by a small gap. A narrow linewidth of 33 nm at 2.58 µm is realized through the coupling between the plasmonic mode and photonic mode in the cavity-enhanced antenna structure. An aluminum nitride piezoelectric layer enabled efficient actuation of the backreflector and therefore changed the gap size, allowing for the tuning of the spectral absorption. The peak wavelength can be shifted linearly by 250 nm with 10 V of tuning voltage, and the tuning range is not limited by the pull-in effect. The polarization dependence of the nanostrip antenna coupled with the optomechanic cavity allows the use of our device as a voltage tunable polarization control device.

PTBP1 induces ADAR1 p110 isoform expression through IRES-like dependent translation control and influences cell proliferation in gliomas.

Internal ribosomal entry site (IRES)-mediated translation initiation is constitutively activated during stress conditions such as tumorigenesis and hypoxia. The RNA editing enzyme ADAR1 plays an important role in physiology and pathology. Initially, we found that the ADAR1 p150 or p110 transcript levels were decreased in glioma cells compared with normal astrocyte cells. In contrast, protein levels of ADAR1 p110 were significantly upregulated in glioma tissues and cells. This expression pattern indicated translationally controlled regulation. We identified an 885-nt sequence that was located between AUG1 and AUG2 within the ADAR1 mRNA that exhibited IRES-like activity. Furthermore, we confirmed that the translational mode of ADAR1 p110 was mediated by PTBP1 in glioma cells. The protein levels of PTBP1 and ADAR1 were cooperatively expressed in glioma tissues and cells. Knocking down ADAR1 p110 significantly decreased cell proliferation in three types of glioma cells (T98G, U87MG and A172). The removal of a minimal IRES-like sequence in a p150-overexpression construct could effectively abolish p110 induction and resulted in the slight suppression of cell proliferation compared with ADAR1-p150 overexpression in siPTBP1-treated T98G cells. In summary, our study revealed a mechanism whereby ADAR1 p110 can be activated by PTBP1 through an IRES-like element in glioma cells, and ADAR1 is essential for the maintenance of gliomagenesis.

cAMP response element-binding protein promotes gliomagenesis by modulating the expression of oncogenic microRNA-23a.

Gliomas are the most common and deadly type of primary brain tumor. In this study, we showed that cAMP response element-binding protein (CREB), a proto-oncogenic transcription factor that is overexpressed in gliomas, can promote gliomagenesis by modulating the expression of oncogenic microRNA-23a (mir-23a). First, we found that CREB is highly expressed in glioma tissues and cell lines. CREB is also essential for glioma cell growth and cell survival in vitro and is critical for gliomagenesis in vivo. Second, microRNA microarray, ChIP-chip, ChIP-quantitative PCR, and luciferase reporter assays showed that CREB directly binds to the regulatory sequences of mir-23a and enhance the expression of mir-23a. Moreover, mir-23a was confirmed as a functional downstream target of CREB in glioma cell growth and cell survival. Finally, using computational prediction followed by experimental confirmation, we identified PTEN, which is frequently silenced in gliomas, as a downstream target of mir-23a. Taken together, we propose that CREB promotes gliomagenesis and acts as a modulator of oncogenic mir-23a, which represses the tumor suppressor PTEN.

Amino-modified nanoplastics at predicted environmental concentrations cause transgenerational toxicity through activating germline EGF signal in Caenorhabditis elegans.

In the real environment, some chemical functional groups are unavoidably combined on the nanoplastic surface. Reportedly, amino-modified polystyrene nanoparticles (PS-A NPs) exposure in parents can induce severe transgenerational toxicity, but the underlying molecular mechanisms remain largely unclear. Using Caenorhabditis elegans as the animal model, this study was performed to investigate the role of germline epidermal growth factor (EGF) signal on modulating PS-A NPs' transgenerational toxicity. As a result, 1-10 µg/L PS-A NPs exposure transgenerationally enhanced germline EGF ligand/LIN-3 and NSH-1 levels. Germline RNAi of lin-3 and nsh-1 was resistant against PS-A NPs' transgenerational toxicity, implying the involvement of EGF ligand activation in inducing PS-A NPs' transgenerational toxicity. Furthermore, LIN-3 overexpression transgenerationally enhanced EGF receptor/LET-23 expression in the progeny, and let-23 RNAi in F1-generation notably suppressed PS-A NPs' transgenerational toxicity in the exposed worms overexpressing germline LIN-3 at P0 generation. Finally, LET-23 functioned in neurons and intestine for regulating PS-A NPs' transgenerational toxicity. LET-23 acted at the upstream DAF-16/FOXO within the intestine in response to PS-A NPs' transgenerational toxicity. In neurons, LET-23 functioned at the upstream of DAF-7/DBL-1, ligands of TGF-ß signals, to mediate PS-A NPs' transgenerational toxicity. Briefly, this work revealed the exposure risk of PS-A NPs' transgenerational toxicity, which was regulated through activating germline EGF signal in organisms.

Long-term exposure to 6-PPD quinone at environmentally relevant concentrations causes neurotoxicity by affecting dopaminergic, serotonergic, glutamatergic, and GABAergic neuronal systems in Caenorhabditis elegans.

6-PPD quinone (6-PPDQ), an emerging environmental pollutant, is converted based on 6-PPD via ozonation. However, a systematic evaluation on possible neurotoxicity of long-term and low-dose 6-PPDQ exposure and the underlying mechanism remain unknown. In the present work, 0.1-10 µg/L 6-PPDQ was added to treat Caenorhabditis elegans for 4.5 days, with locomotion behavior, neuronal development, sensory perception behavior, neurotransmitter content, and levels of neurotransmission-related genes being the endpoints. 6-PPDQ exposure at 0.1-10 µg/L significantly reduced locomotion behavior, and that at 1-10 µg/L decreased sensory perception behavior in nematodes. Moreover, 6-PPDQ exposure at 10 µg/L notably induced damage to the development of dopaminergic, glutamatergic, serotonergic, and GABAergic neurons. Importantly, nematodes with chronic 6-PPDQ exposure at 10 µg/L were confirmed to suffer obviously decreased dopamine, serotonin, glutamate, dopamine, and GABA contents and altered neurotransmission-related gene expression. Meanwhile, the potential binding sites of 6-PPDQ and neurotransmitter synthesis-related proteins were further shown by molecular docking method. Lastly, Pearson's correlation analysis showed that locomotion behavior and sensory perception behavior were positively correlated with the dopaminergic, serotonergic, glutamatergic, and GABAergic neurotransmission. Consequently, 6-PPDQ exposure disturbed neurotransmitter transmission, while such changed molecular foundation for neurotransmitter transmission was related to 6-PPDQ toxicity induction. The present work sheds new lights on the mechanisms of 6-PPDQ and its possible neurotoxicity to organisms at environmentally relevant concentrations.

Effects of chronic low-level lead (Pb) exposure on cognitive function and hippocampal neuronal ferroptosis: An integrative approach using bioinformatics analysis, machine learning, and experimental validation.

Lead (Pb), a pervasive and ancient toxic heavy metal, continues to pose significant neurological health risks, particularly in regions such as Southeast Asia. While previous research has primarily focused on the adverse effects of acute, high-level lead exposure on neurological systems, studies on the impacts of chronic, low-level exposure are less extensive, especially regarding the precise mechanisms linking ferroptosis - a novel type of neuron cell death - with cognitive impairment. This study aims to explore the potential effects of chronic low-level lead exposure on cognitive function and hippocampal neuronal ferroptosis. This research represents the first comprehensive investigation into the impact of chronic low-level lead exposure on hippocampal neuronal ferroptosis, spanning clinical settings, bioinformatic analyses, and experimental validation. Our findings reveal significant alterations in the expression of genes associated with iron metabolism and Nrf2-dependent ferroptosis following lead exposure, as evidenced by comparing gene expression in the peripheral blood of lead-acid battery workers and workers without lead exposure. Furthermore, our in vitro and in vivo experimental results strongly suggest that lead exposure may precipitate cognitive dysfunction and induce hippocampal neuronal ferroptosis. In conclusion, our study indicates that chronic low-level lead exposure may activate microglia, leading to the promotion of ferroptosis in hippocampal neurons.

Chromosomal 3q amplicon encodes essential regulators of secretory vesicles that drive secretory addiction in cancer.

Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identify a chromosome 3q amplicon that serves as a platform for secretory regulation in cancer. The 3q amplicon encodes multiple Golgi-resident proteins, including the scaffold Golgi integral membrane protein 4 (GOLIM4) and the ion channel ATPase Secretory Pathway Ca2+ Transporting 1 (ATP2C1). We show that GOLIM4 recruits ATP2C1 and Golgi phosphoprotein 3 (GOLPH3) to coordinate calcium-dependent cargo loading and Golgi membrane bending and vesicle scission. GOLIM4 depletion disrupts the protein complex, resulting in a secretory blockade that inhibits the progression of 3q-amplified malignancies. In addition to its role as a scaffold, GOLIM4 maintains intracellular manganese (Mn) homeostasis by binding excess Mn in the Golgi lumen, which initiates the routing of Mn-bound GOLIM4 to lysosomes for degradation. We show that Mn treatment inhibits the progression of multiple types of 3q-amplified malignancies by degrading GOLIM4, resulting in a secretory blockade that interrupts pro-survival autocrine loops and attenuates pro-metastatic processes in the tumor microenvironment. Potentially underlying the selective activity of Mn against 3q-amplified malignancies, ATP2C1 co-amplification increases Mn influx into the Golgi lumen, resulting in a more rapid degradation of GOLIM4. These findings show that functional cooperativity between co-amplified genes underlies heightened secretion and a targetable secretory addiction in 3q-amplified malignancies.