Cigarette smoking inhibits myoblast regeneration by promoting proteasomal degradation of NPAT protein and hindering cell cycle progression.

Cigarette smoking (CS) causes skeletal muscle dysfunction, leading to sarcopenia and worse prognosis of patients with diverse systemic diseases. Here, we found that CS exposure prevented C2C12 myoblasts proliferation in a dose-dependent manner. Immunoblotting assays verified that CS exposure promoted the expression of cell cycle suppressor protein p21. Furthermore, CS exposure significantly inhibited replication-dependent (RD) histone transcription and caused S phase arrest in the cell cycle during C2C12 proliferation. Mechanistically, CS deregulated the expression levels of Nuclear Protein Ataxia-Telangiectasia Locus (NPAT/p220). Notably, the proteasome inhibitor MG132 was able to reverse the expression of NPAT in myoblasts, implying that the degradation of CS-mediated NPAT is proteasome-dependent. Overexpression of NPAT also rescued the defective proliferation phenotype induced by CS in C2C12 myoblasts. Taken together, we suggest that CS exposure induces NPAT degradation in C2C12 myoblasts and impairs myogenic proliferation through NPAT associated proteasomal-dependent mechanisms. As an application of the proteasome inhibitor MG132 or overexpression of NPAT could reverse the impaired proliferation of myoblasts induced by CS, the recovery of myoblast proliferation may be potential strategies to treat CS-related skeletal muscle dysfunction.

Dimension Evolution of Self-Assembled Organic Microcrystal for Laser and Polarization-Rotation Function.

Multidimensional integrated micro/nanostructures are vitally important for the implementation of versatile photonic functionalities, whereas current material structures still suffer undesired surface defects and contaminations in either multistep micro/nanofabrications or extreme synthetic conditions. Herein, the dimension evolution of organic self-assembled structures 2D microrings and 3D microhelixes for multidimensional photonic devices is realized via a protic/aprotic solvent-directed molecular assembly method based on a multiaxial confined-assisted growth mechanism. The 2D microrings with consummate circle boundaries and molecular-smooth surfaces function as high-quality whispering-gallery-mode microcavities for dual-wavelength energy-influence-dependent switchable lasing. Moreover, the 3D microhelixes with smooth surfaces and natural twistable characteristics act as active photon-transport materials and polarization rotators. These results will broaden the horizon of constructing multidimensional microstructures for integrated photonic circuits.

ELONGATED HYPOCOTYL 5a modulates FLOWERING LOCUS T2 and gibberellin levels to control dormancy and bud break in poplar.

Photoperiod is a crucial environmental cue for phenological responses, including growth cessation and winter dormancy in perennial woody plants. Two regulatory modules within the photoperiod pathway explain bud dormancy induction in poplar (Populus spp.): the circadian oscillator LATE ELONGATED HYPOCOTYL 2 (LHY2) and GIGANTEA-like genes (GIs) both regulate the key target for winter dormancy induction FLOWERING LOCUS T2 (FT2). However, modification of LHY2 and GIs cannot completely prevent growth cessation and bud set under short-day conditions, indicating that additional regulatory modules are likely involved. We identified PtoHY5a, an orthologs of the photomorphogenesis regulatory factor ELONGATED HYPOCOTYL 5 (HY5) in poplar (Populus tomentosa), that directly activates PtoFT2 expression and represses the circadian oscillation of LHY2, indirectly activating PtoFT2 expression. Thus, PtoHY5a suppresses short day-induced growth cessation and bud set. Accordingly, PtoHY5a knockout facilitates dormancy induction. PtoHY5a also inhibits bud-break in poplar by controlling gibberellic acid (GA) levels in apical buds. Additionally, PtoHY5a regulates the photoperiodic control of seasonal growth downstream of phytochrome PHYB2. Thus, PtoHY5a modulates seasonal growth in poplar by regulating the PtoPHYB2-PtoHY5a-PtoFT2 module to determine the onset of winter dormancy, and by fine-tuning GA levels to control bud-break.

Engineering a transposon-associated TnpB-ωRNA system for efficient gene editing and phenotypic correction of a tyrosinaemia mouse model.

Transposon-associated ribonucleoprotein TnpB is known to be the ancestry endonuclease of diverse Cas12 effector proteins from type-V CRISPR system. Given its small size (408 aa), it is of interest to examine whether engineered TnpB could be used for efficient mammalian genome editing. Here, we showed that the gene editing activity of native TnpB from Deinococcus radiodurans (ISDra2 TnpB) in mouse embryos was already higher than previously identified small-sized Cas12f1. Further stepwise engineering of noncoding RNA (ωRNA or reRNA) component of TnpB significantly elevated the nuclease activity of TnpB. Notably, an optimized TnpB-ωRNA system could be efficiently delivered in vivo with single adeno-associated virus (AAV) and corrected the disease phenotype in a tyrosinaemia mouse model. Thus, the engineered miniature TnpB system represents a new addition to the current genome editing toolbox, with the unique feature of the smallest effector size that facilitate efficient AAV delivery for editing of cells and tissues.

Time-dependent regulation of respiration is widespread across plant evolution.

Establishing the temperature dependence of respiration is critical for accurate predictions of the global carbon cycle under climate change. Diurnal temperature fluctuations, or changes in substrate availability, lead to variations in leaf respiration. Additionally, recent studies hint that the thermal sensitivity of respiration could be time-dependent. However, the role for endogenous processes, independent from substrate availability, as drivers of temporal changes in the sensitivity of respiration to temperature across phylogenies has not yet been addressed. Here, we examined the diurnal variation in the response of respiration to temperatures (R-T relationship) for different lycophyte, fern, gymnosperm and angiosperm species. We tested whether time-dependent changes in the R-T relationship would impact leaf level respiration modelling. We hypothesized that interactions between endogenous processes, like the circadian clock, and leaf respiration would be independent from changes in substrate availability. Overall, we observed a time-dependent sensitivity in the R-T relationship across phylogenies, independent of temperature, that affected modelling parameters. These results are compatible with circadian gating of respiration, but further studies should analyse the possible involvement of the clock. Our results indicate time-dependent regulation of respiration might be widespread across phylogenies, and that endogenous regulation of respiration is likely affecting leaf-level respiration fluxes.

Overexpression of PtoMYB99 diminishes poplar tolerance to osmotic stress by suppressing ABA and JA biosynthesis.

Drought poses a serious challenge to sustained plant growth and crop yields in the context of global climate change. Drought tolerance in poplars and their underlying mechanisms still remain largely unknown. In this article, we investigated the overexpression of PtoMYB99 - both a drought and abscisic acid (ABA) induced gene constraining drought tolerance in poplars (as compared with wild type poplars). First, we found that PtoMYB99-OE lines exhibited increased stomatal opening and conductance, higher transpiration and photosynthetic rates, as well as reduced levels of ABA and jasmonic acid (JA). Second, PtoMYB99-OE lines accumulated more reactive oxygen species (ROS), including H2O2 and O2-, as well as malonaldehyde (MDA), proline, and soluble sugar under osmotic stress; conversely, the activity of antioxidant enzymes (SOD, POD, and CAT), was weakened in the PtoMYB99-OE lines. Third, the expression of ABA biosynthetic genes, PtoNCED3.1 and PtoNCED3.2, as well as JA biosynthetic genes, PtoOPR3.1 and PtoOPR3.2, was significantly reduced in the PtoMYB99-OE lines under both normal conditions and osmotic stress. Based on our results, we conclude that the overexpression of PtoMYB99 compromises tolerance to osmotic stress in poplar. These findings contribute to the understanding of the role of the MYB genes in drought stress and the biosynthesis of ABA and JA.

The heat response regulators HSFA1s promote Arabidopsis thermomorphogenesis via stabilizing PIF4 during the day.

During summer, plants often experience increased light inputs and high temperatures, two major environmental factors with contrasting effects on thermomorphological traits. The integration of light and temperature signaling to control thermomorphogenesis in plants is critical for their acclimation in such conditions, but the underlying mechanisms remain largely unclear. We found that heat shock transcription factor 1d (HSFA1d) and its homologs are necessary for plant thermomorphogenesis during the day. In response to warm daytime temperature, HSFA1s markedly accumulate and move into the nucleus where they interact with phytochrome-interacting factor 4 (PIF4) and stabilize PIF4 by interfering with phytochrome B-PIF4 interaction. Moreover, we found that the HSFA1d nuclear localization under warm daytime temperature is mediated by constitutive photomorphogenic 1-repressed GSK3-like kinase BIN2. These results support a regulatory mechanism for thermomorphogenesis in the daytime mediated by the HSFA1s-PIF4 module and uncover HSFA1s as critical regulators integrating light and temperature signaling for a better acclimation of plants to the summer high temperature.

A Cost-Driven Method for Deep-Learning-Based Hardware Trojan Detection.

The Cyber-Physical System and even the Metaverse will become the second space in which human beings live. While bringing convenience to human beings, it also brings many security threats. These threats may come from software or hardware. There has been a lot of research on managing malware, and there are many mature commercial products, such as antivirus software, firewalls, etc. In stark contrast, the research community on governing malicious hardware is still in its infancy. Chips are the core component of hardware, and hardware Trojans are the primary and complex security issue faced by chips. Detection of hardware Trojans is the first step for dealing with malicious circuits. Due to the limitation of the golden chip and the computational consumption, the existing traditional detection methods are not applicable to very large-scale integration. The performances of traditional machine-learning-based methods depend on the accuracy of the multi-feature representation, and most of the methods may lead to instability because of the difficulty of extracting features manually. In this paper, employing deep learning, a multiscale detection model for automatic feature extraction is proposed. The model is called MHTtext and provides two strategies to balance the accuracy and computational consumption. After selecting a strategy according to the actual situations and requirements, the MHTtext generates the corresponding path sentences from the netlist and employs TextCNN for identification. Further, it can also obtain non-repeated hardware Trojan component information to improve its stability performance. Moreover, a new evaluation metric is established to intuitively measure the model's effectiveness and balance: the stabilization efficiency index (SEI). In the experimental results for the benchmark netlists, the average accuracy (ACC) in the TextCNN of the global strategy is as high as 99.26%, and one of its stabilization efficiency index values ranks first with a score of 71.21 in all comparison classifiers. The local strategy also achieved an excellent effect, according to the SEI. The results show that the proposed MHTtext model has high stability, flexibility, and accuracy, in general.

Transcriptome and Low-Affinity Sodium Transport Analysis Reveals Salt Tolerance Variations between Two Poplar Trees.

Salinity stress severely hampers plant growth and productivity. How to improve plants' salt tolerance is an urgent issue. However, the molecular basis of plant resistance to salinity still remains unclear. In this study, we used two poplar species with different salt sensitivities to conduct RNA-sequencing and physiological and pharmacological analyses; the aim is to study the transcriptional profiles and ionic transport characteristics in the roots of the two Populus subjected to salt stress under hydroponic culture conditions. Our results show that numerous genes related to energy metabolism were highly expressed in Populus alba relative to Populus russkii, which activates vigorous metabolic processes and energy reserves for initiating a set of defense responses when suffering from salinity stress. Moreover, we found the capacity of Na+ transportation by the P. alba high-affinity K+ transporter1;2 (HKT1;2) was superior to that of P. russkii under salt stress, which enables P. alba to efficiently recycle xylem-loaded Na+ and to maintain shoot K+/Na+ homeostasis. Furthermore, the genes involved in the synthesis of ethylene and abscisic acid were up-regulated in P. alba but downregulated in P. russkii under salt stress. In P. alba, the gibberellin inactivation and auxin signaling genes with steady high transcriptions, several antioxidant enzymes activities (such as peroxidase [POD], ascorbate peroxidase [APX], and glutathione reductase [GR]), and glycine-betaine content were significantly increased under salt stress. These factors altogether confer P. alba a higher resistance to salinity, achieving a more efficient coordination between growth modulation and defense response. Our research provides significant evidence to improve the salt tolerance of crops or woody plants.

Thrombospondin-1 mimic peptide PKHB1 induced endoplasmic reticulum stress-mediated but CD47-independent apoptosis in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the most common malignancies with high morbidity and mortality. PKHB1, a serum-stable Thrombospondin-1 (TSP-1) mimic peptide, has shown some effective ability in triggering cell death against several cancers. Here, we aimed to study the potential biological function of PKHB1 and its molecular mechanism in NSCLC. Our results revealed that PKHB1 significantly suppressed NSCLC cell proliferation, cell migration, and induced apoptosis in a dose-dependent manner. Additionally, we found that PKHB1 treatment resulted in mitochondrial transmembrane potential depolarization, Ca2+ overloading as well as the upregulation of proapoptotic proteins. Mechanistically, PKHB1 induced NSCLC cells apoptosis in a CD47-independent manner. Further study revealed that PKHB1 provoked endoplasmic reticulum (ER) stress principally through the activation of CHOP and JNK signaling, which could be alleviated in the presence of 4-PBA, an ER stress inhibitor. Furthermore, xenograft tumor models showed that PKHB1 treatment could notably inhibit NSCLC tumor growth in vivo. In conclusion, these findings suggested that PKHB1 exerted antitumor efficacy in NSCLC via triggering ER stress-mediated but CD47-independent apoptosis, potentially functioned as a promising peptide-based therapeutic agent for NSCLC.

North-south antiphase of wildfire activity across the pyroregions of continental China driven by NAO and the Antarctic oscillation.

Wildfires are a natural disturbance in many parts of the world, but fire regimes are changing as a result of anthropogenic pressures. A key uncertainty towards anticipating future changes in burned area lies in understanding the effects of climate teleconnections (CTs). Here we test how different CTs impact burned area in China, a large country comprising different biomes and where similar fire-suppression and post-fire afforestation policies are implemented. We observed diverging temporal trends in burned area across the different pyroregions of China, from increases in the Northeastern grasslands and mixed forests pyroregion to decreases in the Southern tropical forests pyroregion. This North-South antiphase in fire activity was being partly driven by joint effects of the North Atlantic Oscillation and the Antarctic Oscillation, which exerted contrasting effects on fire weather across latitude. El Niño Southern Oscillation and the other examined teleconnections had minor effects over burned area. The increasing burned area in the NE-mixed forests pyroregion indicates that mega-fires may increase under global warming but their occurrence may be modulated by potential strengthening or weakening of NAO and AAO.

Clinical outcomes and risk factor of immune checkpoint inhibitors-related pneumonitis in non-small cell lung cancer patients with chronic obstructive pulmonary disease.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is the most common co-morbidity associated with non-small cell lung cancer (NSCLC) patients. Immune checkpoint inhibitors related pneumonitis (CIP) is a common immune-related adverse event that can be life-threatening. The study aims to evaluate the association of COPD with the incidence and outcome of CIP in NSCLC patients receiving immune checkpoint inhibitors (ICIs). MATERIALS AND METHODS: We retrospectively collected data from 122 patients diagnosed with NSCLC and treated with ICIs in our department. Baseline pulmonary function was performed in the whole cohort. The incidence, risk factors, treatment and outcome of CIP patients were evaluated. Furthermore, the efficacy of ICIs in patients with COPD was analyzed. RESULTS: Nineteen patients (15.5%, 19/122) developed CIP during ICIs treatment, most patients with CIP were grade 1-2, and the incidence of CIP was comparable in patients with COPD and those without COPD (18.0% vs. 13.1%, P = 0.618). In addition, an increasing trend in the incidence of CIP among patients with pulmonary fibrosis on baseline chest CT scans (27.3% vs. 13.0%, P = 0.093). There is a longer progression-free survival in COPD patients than the non-COPD patients. CONCLUSION: Coexisting COPD did not predict the higher risk of CIP in NSCLC treated with ICIs therapy. Nevertheless, pre-existing pulmonary fibrosis on CT scan may increase the risk of CIP, close monitoring is advised in these patients during ICIs.

Adaptation to low nitrogen and salt stresses in the desert poplar by effective regulation of nitrogen assimilation and ion balance.

As a main desert plant from arid regions of Central Asia, Populus euphratica always encounters with nitrogen shortage in its long life, apart from salt or drought stress. However, it remains unknown how this species responds to low nitrogen and combined stresses of low nitrogen and salinity. Thus, saplings of P. euphratica with uniform size were exposed to normal or low nitrogen condition (150 and 15 ppm ammonium nitrate separately) individually or in combination with salinity. Under low nitrogen conditions we found a positive effect on P. euphratica root growth, which could be associated to high level of nitrogen allocation to support root growth and effective regulation of nitrogen assimilation in comparison with the other poplar species reported before. Under salt stress the root growth of P. euphratica was significantly inhibited, with the side effects of oxidative stress, as saplings stored higher Na+ and Cl- contents in roots. Under the combined stressors of both salinity and low nitrogen, P. euphratica undergo a risky strategy, as stimulated root growth is accompanied by further oxidative stress.The concentrations of root K+ and whole plant NO3- were increased to support the tolerance of the combined stressors in P. euphratica, showing same characteristics with halophytes. Overall, our results provide evidence that the desert poplar can adapt to the salt stress/low nitrogen bundle, by effective regulation of nitrogen assimilation and ion homoeostasis.

Interaction of BES1 and LBD37 transcription factors modulates brassinosteroid-regulated root forging response under low nitrogen in arabidopsis.

Brassinosteriod (BR) plays important roles in regulation of plant growth, development and environmental responses. BR signaling regulates multiple biological processes through controlling the activity of BES1/BZR1 regulators. Apart from the roles in the promotion of plant growth, BR is also involved in regulation of the root foraging response under low nitrogen, however how BR signaling regulate this process remains unclear. Here we show that BES1 and LBD37 antagonistically regulate root foraging response under low nitrogen conditions. Both the transcriptional level and dephosphorylated level of BES1, is significant induced by low nitrogen, predominantly in root. Phenotypic analysis showed that BES1 gain-of-function mutant or BES1 overexpression transgenic plants exhibits progressive outgrowth of lateral root in response to low nitrogen and BES1 negatively regulates repressors of nitrate signaling pathway and positively regulates several key genes required for NO3 - uptake and signaling. In contrast, BES1 knock-down mutant BES1-RNAi exhibited a dramatical reduction of lateral root elongation in response to low N. Furthermore, we identified a BES1 interacting protein, LBD37, which is a negative repressor of N availability signals. Our results showed that BES1 can inhibit LBD37 transcriptional repression on N-responsive genes. Our results thus demonstrated that BES1-LBD37 module acts critical nodes to integrate BR signaling and nitrogen signaling to modulate the root forging response at LN condition.

Overexpression of PeNAC122 gene promotes wood formation and tolerance to osmotic stress in poplars.

Finding the adequate balance between wood formation and abiotic stress resistance is still an important challenge for industrial woody crops. In this study, PeNAC122, a member of the NAC transcription factor (TF) family highly expressed in xylem, was cloned from Populus euphratica. Tissue expression and ß-glucuronidase (GUS) staining showed that PeNAC122 was exclusively expressed in phloem fiber and secondary xylem of stems. Subcellular and yeast transactivation assays confirmed that PeNAC122 protein existed in the nucleus and did not have transcriptional activation and inhibitory activity. Overexpression of PeNAC122 poplar lines exhibited reduced plant height, thickened xylem, and accumulated lignin content in stems, and also upregulates the expression of secondary cell wall biosynthetic genes. Moreover, overexpression of PeNAC122 lines displayed more tolerance to PEG6000-induced osmotic stress, with stronger photosynthetic performance, higher antioxidant enzyme activity, and less accumulation of reactive oxygen species in leaves, and higher expression levels of stress response genes DREB2A, RD29, and NCED3. These results indicate that PeNAC122 plays a crucial role in wood formation and abiotic stress tolerance, which, in addition to potential use in improving wood quality, provides further insight into the role of NAC family TFs in balancing wood development and abiotic stress resistance.

Th22 Cells/IL-22 Serves as a Protumor Regulator to Drive Poor Prognosis through the JAK-STAT3/MAPK/AKT Signaling Pathway in Non-Small-Cell Lung Cancer.

The interaction of immune cells and cytokines in the tumor microenvironment affects the development and prognosis of tumors with an unclear potential regulatory mechanism. Recent studies have elucidated the protumor role of Th22 cells and its lineage-specific cytokine IL-22 in different human cancers. The present study is aimed at investigating the biological effect of Th22 cells/IL-22 and its molecular mechanism in the pathogenesis process of non-small-cell lung cancer (NSCLC). It was initially found that Th22 cells were enriched in the peripheral blood of NSCLC patients. The level of Th22 cells in peripheral blood mononuclear cells (PBMCs) was positively correlated with the TNM stage, lymph node metastasis, and clinical tumor biomarkers. Furthermore, IL-22 not only antagonized the apoptosis inducing and cell cycle arresting effect by chemotherapy and molecular targeted drugs on NSCLC cell lines but also promoted tumor cell proliferation and tumor tissue growth. Moreover, IL-22 activated the JAK-STAT3/MAPK/AKT signaling pathway, both in vitro and in vivo. Conclusively, the present results confirm that Th22 cells/IL-22 may serve as a negative immune regulator in lung cancer.

Monoubiquitination in Homeostasis and Cancer.

Monoubiquitination is a post-translational modification (PTM), through which a single ubiquitin molecule is covalently conjugated to a lysine residue of the target protein. Monoubiquitination regulates the activity, subcellular localization, protein-protein interactions, or endocytosis of the substrate. In doing so, monoubiquitination is implicated in diverse cellular processes, including gene transcription, endocytosis, signal transduction, cell death, and DNA damage repair, which in turn regulate cell-cycle progression, survival, proliferation, and stress response. In this review, we summarize the functions of monoubiquitination and discuss how this PTM modulates homeostasis and cancer.

Ethylene activates poplar defense against Dothiorella gregaria Sacc by regulating reactive oxygen species accumulation.

Populus canker is a widespread disease that seriously threatens the survival of trees. Phytohormones are considered as effective chemical molecules improving plant resistance to various diseases. Ethylene is an important phytohormone that is extensively involved in the regulation of plant growth, development, and stress responses, but how ethylene and ethylene signaling regulates defense responses in woody plants is still unclear. Here, we showed that ethylene positively regulates the responses of poplar to canker caused by the hemibiotrophic fungus Dothiorella gregaria. Treatment of Populus tomentosa with 1-aminocyclopropane-1-carboxylic acid (ACC, the biosynthetic precursor of ethylene) significantly enhanced disease resistance, accompanied by the induction of pathogen-related protein (PR) gene expression and H2 O2 accumulation. Blocking ethylene biosynthesis using aminoethoxyvinyl glycine (AVG, a specific inhibitor of ethylene biosynthesis) repressed the disease resistance. Overexpression of the ethylene biosynthesis gene PtoACO7 in Populus tomentosa promoted defense responses and disease resistance. Furthermore, we demonstrated that the ethylene-induced defense response is independent of the salicylic acid pathway, but needs ROS signaling. ACC or PtoACO7 overexpression induced expressions of PtoRbohD/RbohF, which encode NADPH oxidases, and elevated H2 O2 levels in poplar. Inhibition of the NADPH oxidase compromised ethylene-induced disease resistance and PR gene expressions, while H2 O2 application could completely rescue the AVG-caused disease hypersensitivity. Therefore, the involvement of ethylene in disease resistance is done by activation of PR gene expressions and ROS production. Our results also showed that modifying ethylene biosynthesis or its signaling pathway has a great potential for improving disease resistance in woody plants.

Deguelin Attenuates Non-Small-Cell Lung Cancer Cell Metastasis by Upregulating PTEN/KLF4/EMT Signaling Pathway.

Non-small-cell lung cancer (NSCLC) is the most common lung cancer and a major cause of cancer mortality worldwide. Deguelin plays a vital inhibitory role in NSCLC initiation and development. However, the downstream mechanism of deguelin-suppressed metastasis of NSCLC cells is still not completely understood. Interestingly, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and Krüppel-like factor 4 (KLF4) also contribute to inhibition of metastasis in NSCLC cells. Here, we demonstrated that deguelin significantly upregulated PTEN and KLF4 expressions and PTEN positively upregulated KLF4 expression in NSCLC cells including A549 and PC9 cells. Moreover, overexpressions of PTEN and KLF4 inhibited the migration and invasion of NSCLC cells, an effect similar to that of deguelin. Furthermore, overexpressions of PTEN and KLF4 could suppress the epithelial-mesenchymal transition (EMT), an effect also similar to that of deguelin. Additionally, deguelin displayed a significant antitumor ability by upregulating PTEN and KLF4 expressions in mice model with NSCLC cells. Together, these results indicated that deguelin could be a potential therapeutic agent through upregulating PTEN and KLF4 expressions for NSCLC therapy.