Polarity Signaling Research Articles

Model supports asymmetric regulation across the intercellular junction for collective cell polarization.

Symmetry breaking, which is ubiquitous in biological cells, functionally enables directed cell movement and organized embryogenesis. Prior to movement, cells break symmetry to form a well-defined cell front and rear in a process called polarization. In developing and regenerating tissues, collective cell movement requires the coordination of the polarity of the migration machineries of neighboring cells. Though several works shed light on the molecular basis of polarity, fewer studies have focused on the regulation across the cell-cell junction required for collective polarization, thus limiting our ability to connect tissue-level dynamics to subcellular interactions. Here, we investigated how polarity signals are communicated from one cell to its neighbor to ensure coordinated front-to-rear symmetry breaking with the same orientation across the group. In a theoretical setting, we systematically searched a variety of intercellular interactions and identified that co-alignment arrangement of the polarity axes in groups of two and four cells can only be achieved with strong asymmetric regulation of Rho GTPases or enhanced assembly of complementary F-actin structures across the junction. Our results held if we further assumed the presence of an external stimulus, intrinsic cell-to-cell variability, or larger groups. The results underline the potential of using quantitative models to probe the molecular interactions required for macroscopic biological phenomena. Lastly, we posit that asymmetric regulation is achieved through junction proteins and predict that in the absence of cytoplasmic tails of such linker proteins, the likeliness of doublet co-polarity is greatly diminished.

Moxibustion inhibits the macrophage M1 polarization toll-like receptor 4/myeloid differentiation factor 88/nuclear factor kappa B signaling pathway by regulating T-cell immunoglobulin and mucin-containing protein-3 in rheumatoid arthritis.

To explore whether moxibustion exerts therapeutic effects on rheumatoid arthritis (RA) by regulating the expression of T-cell immunoglobulin and mucin-containing protein-3 (TIM-3) and subsequently modulating the macrophage M1 polarization toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-nuclear factor kappa B (NF-κB) signaling pathway. We utilized moxibustion treatment in RA rat models using the Zusanli (ST36) and Shenshu (BL23) acupoints. Hematoxylin and eosin (HE) staining was used to observe the pathological changes of the synovial tissue under a section light microscope, and pathological scoring was performed according to the grading standard of the degree of synovial tissue disease. Enzyme-linked immunosorbent assay (ELISA) was applied to verify the efficacy of moxibustion in reducing inflammation. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of the TIM-3/TLR4-MyD88-NF-κB signaling pathway-related molecules, and Western blot was used to detect the contents of synovial NF-κB. We established the Freund's complete adjuvant (FCA)-induced RA model in rats. The expression level of M1 polarization signaling pathway TLR4-MyD88-NF-κB and the inflammatory factors interleukin-12(IL-12), tumor necrosis factor alpha (TNF-α), and tumor necrosis factor beta (TNF-β) were significantly increased in the RA model. After moxibustion treatment, the expression level of TLR4-MyD88-NF-κB was significantly decreased, and the inflammatory factors IL-12, TNF-α, and TNF-β were decreased, but the expression level was significantly increased in the RA model. When TIM-3 expression was inhibited, the expression level of TLR4-MyD88-NF-κB, and the inflammatory factors IL-12, TNF-α, and TNF-β were not suppressed, even after moxibustion treatment. Moxibustion regulates the key target TIM-3 by acting on the Zusanli (ST36) and Shenshu (BL23) points, thereby inhibiting the M1 polarization of macrophages; that is, it inhibits the TLR4-MyD88-NF-κB signaling pathway, and finally achieves alleviation of pathological changes and anti-inflammatory effects.

Scientific and technical ways of reducing quantitative indicators of false alarms during the operation of an airboard radar station on the background of the underlying surface (earth)

The purpose of the research is development of scientific and technical ways to reduce the quantitative indicators of false alarms when operating an on-board radar station against the background of the underlying surface (earth) against the background of passive interference.Methods. When conducting scientific research, methods of probability theory, mathematical statistics, statistical radio engineering and computational mathematics were used. The study identified a number of methods and technical solutions based on them that make it possible to increase the efficiency of the functioning of airborne radar stations against the background of passive interference. The paper proposes a method for expanding the signal spectrum to 1 GHz by reducing the resolved volume of airborne radar stations. Physically, this is determined by the fact that with a decrease in the resolved volume, the size of the underlying surface area from which the signal is reflected decreases. In order to improve the quality of detection of objects against the background of the underlying surface, a method of using polarization modes is proposed.Results. In the course of the research: a technical solution was proposed based on the method of expanding the signal spectrum to 1 GHz by reducing the resolution volume of airborne radar stations designed to convert radio frequency signals into digital form, using a mixed signal receiver with direct digitization at radio frequency, such as the AD6688 ; a design of a low-baseline radar system has been developed, consisting of two positions, the antennas of which are located within the average width of the lobe of the backscattering diagram of the irradiated object; a feature of the antenna is the ability to receive and emit signals of the same linear polarization, but orthogonal to the polarization of the first position (including . horizontal and vertical polarization signals); an important relation was obtained for a lowbaseline polarization measuring system (MPIS) when the distance between two partial antennas can be much less than the distance to the measured object. Conclusion. The scientific article proposes methods and technical solutions based on these methods to reduce the quantitative indicators of false alarms when operating an on-board radar station against the background of the underlying surface (ground) against the background of passive interference. The proposed approach allows us to move on to the synthesis of a low-baseline polarization measuring system.

Jing Si Herbal Tea Modulates Macrophage Polarization and Inflammatory Signaling in LPS-Induced Inflammation.

Background: Sepsis is a lethal disease due to uncontrolled inflammatory responses. Macrophages play an important role in sepsis-associated inflammation. Jing Si Herbal Tea (JSHT) is a plant-based regimen with anti-inflammatory properties designed to treat respiratory diseases; however, its underlying therapeutic mechanism remains unclear. This study aimed to investigate the effects of JSHT on macrophage polarization and inflammatory signaling in lipopolysaccharide (LPS)-induced inflammation to provide therapeutic approaches for inflammatory diseases. Methods: RAW264.7 cells were stimulated with LPS (1 µg/mL for 16 h) to induce inflammatory responses and treated by JSHT (0.0125% concentration for 4 h) in the experimental groups (Control, JSHT, LPS, Pre-JSHT, and Post-JSHT groups). We investigated the protein and cytokine expression levels using western blotting and enzyme-linked immunosorbent assay (ELISA). Macrophage morphology was observed using immunofluorescence staining. The polarization surface markers were detected by flow cytometry. Results: In the LPS group, the expressions of the inflammatory signaling (pERK, pJNK, and nuclear NFκB) and the pro-inflammatory cytokine levels (TNF-α, IL-1β, and IL-6) were significantly increased, with M1 polarization (CD68+/CD80+) compared to the Control group. In the Pre-JSHT and Post-JSHT groups, the expressions of the inflammatory signaling and the pro-inflammatory cytokine levels were significantly decreased, with a higher M2 polarization ratio (CD163+/CD206+) compared to the LPS group. RAW264.7 cells exhibited filopodia protruding from the cell surface in the LPS group, which were inhibited in the Pre-JSHT and Post-JSHT groups. Conclusions: LPS induced M1 polarization with elevated inflammatory signaling and cytokine levels, while JSHT not only decreased M1 polarization but also promoted M2 polarization with decreased inflammatory responses. We propose JSHT as a potential anti-inflammatory agent against LPS-induced inflammation.

Field monitoring of copepodamides using a new application for solid phase adsorption toxin tracking

AbstractChemical signaling is ubiquitous in the marine environment. Plankton rely on chemical signals to find mates, hunt prey, and respond to threats, and these small‐scale interactions can propagate into community‐wide cascades and large‐scale ecological changes. The chemical signaling exchange in the open ocean is poorly understood, and fundamental information about concentrations and spatiotemporal variability is lacking. Passive sampling has been used to monitor a wide range of dissolved chemicals, including anthropogenic pollutants and harmful algal toxins, but it is not generally applied to the study of marine chemical ecology. Here we test the compatibility of two resins commonly used for passive sampling via solid phase adsorption toxin tracking (SPATT), Diaion® HP20 and Sepabeads® SP207, with copepodamides, a group of polar lipid signaling compounds produced by copepods. We developed extraction and analysis methods that align with current SPATT practices for algal toxins and show the first measurements of copepodamides from Monterey Bay in California. In lab trials, mean copepodamide recovery from HP20 resin was approximately 240% greater than SP207. In addition, copepodamides were found to have a mean half‐life of 34 h in seawater. Adsorption to HP20 stabilized dissolved copepodamides, increasing the mean recovery after 168 h from 0.62% in seawater to 65.2% from SPATT. Results suggest that SPATT is a sensitive and effective tool for obtaining integrated copepodamide concentrations, spotlighting a novel method to include information from copepod mesozooplankton in time series and field studies.

Linking planar polarity signalling to actomyosin contractility during vertebrate neurulation.

Actomyosin contractility represents an ancient feature of eukaryotic cells participating in many developmental and homeostasis events, including tissue morphogenesis, muscle contraction and cell migration, with dysregulation implicated in various pathological conditions, such as cancer. At the molecular level, actomyosin comprises actin bundles and myosin motor proteins that are sensitive to posttranslational modifications like phosphorylation. While the molecular components of actomyosin are well understood, the coordination of contractility by extracellular and intracellular signals, particularly from cellular signalling pathways, remains incompletely elucidated. This study focuses on WNT/planar cell polarity (PCP) signalling, previously associated with actomyosin contractility during vertebrate neurulation. Our investigation reveals that the main cytoplasmic PCP proteins, Prickle and Dishevelled, interact with key actomyosin components such as myosin light chain 9 (MLC9), leading to its phosphorylation and localized activation. Using proteomics and microscopy approaches, we demonstrate that both PCP proteins actively control actomyosin contractility through Rap1 small GTPases in relevant in vitro and in vivo models. These findings unveil a novel mechanism of how PCP signalling regulates actomyosin contractility through MLC9 and Rap1 that is relevant to vertebrate neurulation.

Analysis and correction of crosstalk in the side-on transition radiation detector prototype for HERD

The side-on Transition Radiation Detector (TRD) is an essential component of the High Energy cosmic-Radiation Detection (HERD) facility aboard the China Space Station (CSS). Utilizing the proportional correlation between the Lorentz factor γ and Transition Radiation (TR) intensity, the side-on TRD collaborates with the HERD calorimeter for cross-calibration in the TeV energy range while orbiting. This paper focuses on analyzing and correcting signal crosstalk in the side-on TRD prototype. A signal caused by crosstalk, referred to as the “reversed polarity signal”, affects the particle signal and biases the prototype's energy measurement. To address the issue of energy deviation and select the most suitable capacitance for the prototype to correct crosstalk, we analyze the source of the reversed polarity signal and the effectiveness of adding a decoupling capacitor to the voltage divider circuit. Additionally, we use a combination of simulation and experimentation to investigate the specific relationship between the reversed polarity signal and the decoupling capacitance. The comparison between the simulation results and the experimental results show consistent trends. Measured energy spectra shows that correcting crosstalk eliminates a maximum measurement deviation of approximately 10.79% in the prototype. Following this correction, the side-on TRD prototype completed beam experiments in 2022.

YOD1 regulates microglial homeostasis by deubiquitinating MYH9 to promote the pathogenesis of Alzheimer's disease

Alzheimer's disease (AD) is the major form of dementia in the elderly and is closely related to the toxic effects of microglia sustained activation. In AD, sustained microglial activation triggers impaired synaptic pruning, neuroinflammation, neurotoxicity, and cognitive deficits. Accumulating evidence has demonstrated that aberrant expression of deubiquitinating enzymes is associated with regulating microglia function. Here, we use RNA sequencing to identify a deubiquitinase YOD1 as a regulator of microglial function and AD pathology. Further study showed that YOD1 knockout significantly improved the migration, phagocytosis, and inflammatory response of microglia, thereby improving the cognitive impairment of AD model mice. Through LC–MS/MS analysis combined with Co-IP, we found that Myosin heavy chain 9 (MYH9), a key regulator maintaining microglia homeostasis, is an interacting protein of YOD1. Mechanistically, YOD1 binds to MYH9 and maintains its stability by removing the K48 ubiquitin chain from MYH9, thereby mediating the microglia polarization signaling pathway to mediate microglia homeostasis. Taken together, our study reveals a specific role of microglial YOD1 in mediating microglia homeostasis and AD pathology, which provides a potential strategy for targeting microglia to treat AD.

DPP an extracellular matrix molecule induces Wnt5a mediated signaling to promote the differentiation of adult stem cells into odontogenic lineage

Dentin phosphophoryn (DPP) an extracellular matrix protein activates Wnt signaling in DPSCs (dental pulp stem cells). Wnt/β catenin signaling is essential for tooth development but the role of DPP-mediated Wnt5a signaling in odontogenesis is not well understood. Wnt5a is typically considered as a non-canonical Wnt ligand that elicits intracellular signals through association with a specific cohort of receptors and co-receptors in a cell and context–dependent manner. In this study, DPP facilitated the interaction of Wnt5a with Frizzled 5 and LRP6 to induce nuclear translocation of β-catenin. β-catenin has several nuclear binding partners that promote the activation of Wnt target genes responsible for odontogenic differentiation. Interestingly, steady increase in the expression of Vangl2 receptor suggest planar cell polarity signaling during odontogenic differentiation. In vitro observations were further strengthened by the low expression levels of Wnt5a and β-catenin in the teeth of DSPP KO mice which exhibit impaired odontoblast differentiation and defective dentin mineralization. Together, this study suggests that the DPP-mediated Wnt5a signaling could be exploited as a therapeutic approach for the differentiation of dental pulp stem cells into functional odontoblasts and dentin regeneration.

Differential Sensitivity of Midline Patterning to Mitosis during and after Primitive Streak Extension.

Midline establishment is a fundamental process during early embryogenesis for Bilaterians . Midline patterning in nonamniotes can occur without mitosis, through Planar Cell Polarity (PCP) signaling. By contrast, amniotes utilize both cell proliferation and PCP signaling for patterning early midline landmark, the primitive streak (PS). This study examined their roles for midline patterning at post PS-extension. In contrast to PS extension stages, embryos under mitotic arrest during the post PS-extension preserved notochord (NC) extension and Hensen's node (HN)/PS regression judged by both morphology and marker genes, although they became shorter, and laterality was lost. Remarkably, no or background level of expression was detected for the majority of PCP core components in the NC-HN-PS area at post PS-extension stages, except for robustly detected prickle-1 . Morpholino knockdown of Prickle-1 showed little influence on midline patterning, except for suppressed embryonic growth. Lastly, associated with mitotic arrest-induced size reduction, midline tissue cells displayed hypertrophy. Thus, the study has identified at least two distinct mitosis sensitivity phases during early midline pattering: One is PS extension that requires both mitosis and PCP, and the other is mitotic arrest-resistant midline patterning with little influence by PCP at post PS-extension stages.

Cluster Assembly Dynamics Drive Fidelity of Planar Cell Polarity Polarization.

The planar cell polarity (PCP) signaling pathway polarizes epithelial cells in the tissue plane by segregating distinct molecular subcomplexes to opposite sides of each cell, where they interact across intercellular junctions to form asymmetric clusters. The role of clustering in this process is unknown. We hypothesized that protein cluster size distributions could be used to infer the underlying molecular dynamics and function of cluster assembly and polarization. We developed a method to count the number of monomers of core PCP proteins within individual clusters in live animals, and made measurements over time and space in wild type and in strategically chosen mutants. The data demonstrate that clustering is required for polarization, and together with mathematical modeling provide evidence that cluster assembly dynamics dictate that larger clusters are more likely to be strongly asymmetric and correctly oriented. We propose that cluster assembly dynamics thereby drive fidelity of cell- and tissue-level polarization.

SLMAP3 is crucial for organogenesis through mechanisms involving primary cilia formation.

SLMAP3 is a constituent of the centrosome and is known to assemble with the striatin-interacting phosphatase and kinase (STRIPAK) complex, where it has been reported to repress Hippo signalling. The global knockout of SLMAP3 in mice results in embryonic/perinatal lethality and stunted growth without changes in the phosphorylation status of YAP. Diverse phenotypes present in the SLMAP3-/- embryos include reduced body axis, small and abnormal organs resembling defects in planar cell polarity (PCP) signalling, while also displaying the notable polycystic kidneys, a known manifestation of ciliopathies. Analysis of cell polarity in primary mouse embryonic fibroblasts (MEFs) including cell migration, orientation and mitotic spindle angle did not reveal any changes due to SLMAP3 loss in these cells, although the expression of DVL3 was significantly reduced. Furthermore, MEFs lacking FGFR1OP2 or STRN3, two other STRIPAK members, did not reveal any significant changes in any of these parameters either. Significant changes in the number of ciliated cells and primary cilium length in SLMAP3 and FGFR1OP2 deficient MEFs were evident, while a reduced primary cilium length was notable in chondrocytes of SLMAP3 deficient embryos. Our findings suggest that SLMAP3 is essential for mouse embryogenesis through novel mechanisms involving the primary cilium/PCP and protein stability independent of Hippo signalling.

Linkage between Fuz and Gpr161 genes regulates sonic hedgehog signaling during mouse neural tube development.

Sonic hedgehog (Shh) signaling regulates embryonic morphogenesis utilizing the primary cilium, the cell's antenna, which acts as a signaling hub. Fuz, an effector of planar cell polarity signaling, regulates Shh signaling by facilitating cilia formation, and the G protein-coupled receptor 161 (Gpr161) is a negative regulator of Shh signaling. The range of phenotypic malformations observed in mice bearing mutations in either of the genes encoding these proteins is similar; however, their functional relationship has not been previously explored. This study identified the genetic and biochemical linkage between Fuz and Gpr161 in mouse neural tube development. Fuz was found to be genetically epistatic to Gpr161 with respect to regulation of Shh signaling in mouse neural tube development. The Fuz protein biochemically interacts with Gpr161, and Fuz regulates Gpr161-mediated ciliary localization, a process that might utilize β-arrestin 2. Our study characterizes a previously unappreciated Gpr161-Fuz axis that regulates Shh signaling during mouse neural tube development.

Significant influence of winter Pacific-North American pattern on spring vegetation in mid-high latitude Asia

Abstract Given that the vegetation over mid-high latitude Asia (MHA) has been more variable in recent years, it is necessary to better understand the physical causes of vegetation variations in this region. Based on the normalized difference vegetation index (NDVI), this study reveals a close linkage of the variability of spring (April–May) vegetation in MHA to the winter (December–January–February) Pacific-North American (PNA) pattern. When the winter PNA pattern lies in the positive phase, the NDVI tends to decrease in most parts of the MHA region during the following spring. Further analysis suggests that the lagged influence of winter PNA on spring atmospheric circulations and hence the vegetation in MHA is accomplished by the stratospheric pathway. The positive PNA phase can enhance the upward transport of wave energy into the stratosphere over the high latitudes in winter through the linear constructive interference of zonal wavenumber 1 (WN1), consequently leading to a weaker polar vortex in the stratosphere during February-March. Subsequently, the weakened polar vortex signal propagates downward from the stratosphere to the troposphere, inducing the negative Arctic Oscillation-like circulation with an anomalous cyclonic circulation dominating the MHA region in spring. The anomalous cyclonic circulation further cools the surface air temperature in MHA via modulating downward solar radiation and temperature advection, resulting in a decrease of spring NDVI in situ.

Advances in Plant Auxin Biology: Synthesis, Metabolism, Signaling, Interaction with Other Hormones, and Roles under Abiotic Stress.

Auxin is a key hormone that regulates plant growth and development, including plant shape and sensitivity to environmental changes. Auxin is biosynthesized and metabolized via many parallel pathways, and it is sensed and transduced by both normal and atypical pathways. The production, catabolism, and signal transduction pathways of auxin primarily govern its role in plant growth and development, and in the response to stress. Recent research has discovered that auxin not only responds to intrinsic developmental signals, but also mediates various environmental signals (e.g., drought, heavy metals, and temperature stresses) and interacts with hormones such as cytokinin, abscisic acid, gibberellin, and ethylene, all of which are involved in the regulation of plant growth and development, as well as the maintenance of homeostatic equilibrium in plant cells. In this review, we discuss the latest research on auxin types, biosynthesis and metabolism, polar transport, signaling pathways, and interactions with other hormones. We also summarize the important role of auxin in plants under abiotic stresses. These discussions provide new perspectives to understand the molecular mechanisms of auxin's functions in plant development.

Development of the signal‐to‐noise paradox in subseasonal forecasting models: When? Where? Why?

AbstractSubseasonal forecast models are shown to suffer from the same inconsistency in the signal‐to‐noise ratio evident in climate models. Namely, predictable signals in these models are too weak, yet there is a relatively high level of agreement with observed variability of the atmospheric circulation. The net effect is subseasonal forecast models show higher correlation with observed variability than with their own simulations; that is, the signal‐to‐noise paradox. Also, similar to climate models, this paradox is particularly evident in the North Atlantic sector. The paradox is not evident in week 1 or week 2 forecasts, and hence is limited to subseasonal time‐scales. The paradox appears to be related to an overly fast decay of northern annular mode regimes. Three possible causes of this overly fast decay and for the paradox in the Northern Hemisphere are identified: a too‐fast decay of polar stratospheric signals, overly weak downward coupling from the stratosphere to the surface in some models, and overly weak transient synoptic eddy feedbacks. Though the paradox is clearly evident in the North Atlantic, it is relatively muted in the Southern Hemisphere: southern annular mode regimes persist realistically, the stratospheric signal is well maintained, and eddy feedback is, if anything, too strong and zonal.

Wnt7b acts in concert with Wnt5a to regulate tissue elongation and planar cell polarity via noncanonical Wnt signaling.

Intercellular signaling mediated by evolutionarily conserved planar cell polarity (PCP) proteins aligns cell polarity along the tissue plane and drives polarized cell behaviors during tissue morphogenesis. Accumulating evidence indicates that the vertebrate PCP pathway is regulated by noncanonical, β-catenin-independent Wnt signaling; however, the signaling components and mechanisms are incompletely understood. In the mouse hearing organ, both PCP and noncanonical Wnt (ncWnt) signaling are required in the developing auditory sensory epithelium to control cochlear duct elongation and planar polarity of resident sensory hair cells (HCs), including the shape and orientation of the stereociliary hair bundle essential for sound detection. We have recently discovered a Wnt/G-protein/PI3K pathway that coordinates HC planar polarity and intercellular PCP signaling. Here, we identify Wnt7b as a ncWnt ligand acting in concert with Wnt5a to promote tissue elongation in diverse developmental processes. In the cochlea, Wnt5a and Wnt7b are redundantly required for cochlear duct coiling and elongation, HC planar polarity, and asymmetric localization of core PCP proteins Fzd6 and Dvl2. Mechanistically, Wnt5a/Wnt7b-mediated ncWnt signaling promotes membrane recruitment of Daple, a nonreceptor guanine nucleotide exchange factor for Gαi, and activates PI3K/AKT and ERK signaling, which promote asymmetric Fzd6 localization. Thus, ncWnt and PCP signaling pathways have distinct mutant phenotypes and signaling components, suggesting that they act as separate, parallel pathways with nonoverlapping functions in cochlear morphogenesis. NcWnt signaling drives tissue elongation and reinforces intercellular PCP signaling by regulating the trafficking of PCP-specific Frizzled receptors.

Areca nut-induced metabolic reprogramming and M2 differentiation promote OPMD malignant transformation

BackgroundBetel quid and its major ingredient, areca nut, are recognized by IARC as major risk factors in oral cancer development. Areca nut extract (ANE) exposure has been linked to OPMD progression and malignant transformation to OSCC. However, the detailed mechanism through which ANE acts on other cell types in the oral microenvironment to promote oral carcinogenesis remains elusive.MethodsImmunoprofiling of macrophages associated with OPMD and OSCC was carried out by immunohistochemical and immunofluorescence staining. Phosphokinase and cytokine arrays and western blotting were performed to determine the underlying mechanisms. Transwell assays were used to evaluate the migration-promoting effect of ANE. Hamster model was finally applied to confirm the in vivo effect of ANE.ResultsWe reported that M2 macrophages positively correlated with oral cancer progression. ANE induced M2 macrophage differentiation, CREB phosphorylation and VCAM-1 secretion and increased mitochondrial metabolism. Conditioned medium and VCAM-1 from ANE-treated macrophages promoted migration and mesenchymal phenotypes in oral precancer cells. In vivo studies showed that ANE enhanced M2 polarization and related signaling pathways in the oral buccal tissues of hamsters.ConclusionOur study provides novel mechanisms for areca nut-induced oral carcinogenesis, demonstrating that areca nut promotes M2 macrophage differentiation and secretion of oncogenic cytokines that critically activate malignant transformation of oral premalignant cells.

The nonphototrophic hypocotyl 3 (NPH3) domain protein NRL5 is a trafficking-associated GTPase essential for drought resistance.

The mechanisms of plant drought resistance are unclear but may involve membrane trafficking and metabolic reprogramming, including proline accumulation. Forward genetic screening using a proline dehydrogenase 1 (ProDH1) promoter:reporter identified a drought hypersensitive mutant with a single-amino acid substitution (P335L) in the nonphototrophic hypocotyl 3 (NPH3) domain of NPH3/root phototropism 2-like 5 (NRL5)/naked pins in Yucca 8 (NPY8). Further experiments found that NRL5 and other NPH3 domain proteins are guanosine triphosphatases (GTPases). NRL5, but not NRL5P335L, interacted with the RABE1c and RABH1b GTPases and the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) Vesicle-Associated Membrane Protein (VAMP)721/722. These proteins controlled NRL5 localization and connection to trafficking while also being genetically downstream of, and potentially regulated by, NRL5. These data demonstrate that NRL5-mediated restraint of proline catabolism is required for drought resistance and also reveal unexpected functions of the NPH3 domain such that the role of NPH3 domain proteins in signaling, trafficking, and cellular polarity can be critically reevaluated.

Mxene-bpV plays a neuroprotective role in cerebral ischemia-reperfusion injury by activating the Akt and promoting the M2 microglial polarization signaling pathways

Studies have shown that the inhibition of phosphatase and tensin homolog deleted on chromosome 10 (PTEN)was neuroprotective against ischemia/reperfusion(I/R) injury. Bisperoxovanadium (bpV), a derivative of vanadate, is a well-established inhibitor of PTEN. However, its function islimited due to its general inadequacy in penetrating cell membranes. Mxene(Ti3C2Tx) is a novel two-dimensional lamellar nanomaterial with an excellent ability to penetrate the cell membrane. Yet, the effects of this nanomaterial on nervous system diseases have yet to be scrutinized. Here, Mxene(Ti3C2Tx) was used for the first time to carry bpV(HOpic), creating a new nanocomposite Mxene-bpV that was probed in a cerebral I/R injury model. The findings showed that this synthetic Mxene-bpV was adequately stable and can cross the cell membraneeasily. We observed that Mxene-bpV treatment significantly increased the survival rate of oxygen glucose deprivation/reperfusion(OGD/R)--insulted neurons, reduced infarct sizes and promoted the recovery of brain function after mice cerebral I/R injury. Crucially, Mxene-bpV treatment was more therapeutically efficient than bpV(HOpic) treatment alone over the same period. Mechanistically, Mxene-bpV inhibited the enzyme activity of PTEN in vitro and in vivo. It also promoted the expression of phospho-Akt (Ser473) by repressing PTEN and then activated the Akt pathway to boost cell survival. Additionally, in PTEN transgenic mice, Mxene-bpV suppressed I/R-induced inflammatory response by promoting M2 microglial polarization through PTEN inhibition. Collectively, the nanosynthetic Mxene-bpV inhibited PTEN’ enzymatic activity by activating Akt pathway and promoting M2 microglial polarization, and finally exerted neuroprotection against cerebral I/R injury.Graphical