NSUN5/TET2-directed chromatin-associated RNA modification of 5-methylcytosine to 5-hydroxymethylcytosine governs glioma immune evasion.

Malignant glioma exhibits immune evasion characterized by highly expressing the immune checkpoint CD47. RNA 5-methylcytosine(m5C) modification plays a pivotal role in tumor pathogenesis. However, the mechanism underlying m5C-modified RNA metabolism remains unclear, as does the contribution of m5C-modified RNA to the glioma immune microenvironment. In this study, we demonstrate that the canonical 28SrRNA methyltransferase NSUN5 down-regulates ß-catenin by promoting the degradation of its mRNA, leading to enhanced phagocytosis of tumor-associated macrophages (TAMs). Specifically, the NSUN5-induced suppression of ß-catenin relies on its methyltransferase activity mediated by cysteine 359 (C359) and is not influenced by its localization in the nucleolus. Intriguingly, NSUN5 directly interacts with and deposits m5C on CTNNB1 caRNA (chromatin-associated RNA). NSUN5-induced recruitment of TET2 to chromatin is independent of its methyltransferase activity. The m5C modification on caRNA is subsequently oxidized into 5-hydroxymethylcytosine (5hmC) by TET2, which is dependent on its binding affinity for Fe2+ and α-KG. Furthermore, NSUN5 enhances the chromatin recruitment of RBFOX2 which acts as a 5hmC-specific reader to recognize and facilitate the degradation of 5hmC caRNA. Notably, hmeRIP-seq analysis reveals numerous mRNA substrates of NSUN5 that potentially undergo this mode of metabolism. In addition, NSUN5 is epigenetically suppressed by DNA methylation and is negatively correlated with IDH1-R132H mutation in glioma patients. Importantly, pharmacological blockage of DNA methylation or IDH1-R132H mutant and CD47/SIRPα signaling synergistically enhances TAM-based phagocytosis and glioma elimination in vivo. Our findings unveil a general mechanism by which NSUN5/TET2/RBFOX2 signaling regulates RNA metabolism and highlight NSUN5 targeting as a potential strategy for glioma immune therapy.

Optical single-pixel volumetric imaging by three-dimensional light-field illumination.

Three-dimensional single-pixel imaging (3D SPI) has become an attractive imaging modality for both biomedical research and optical sensing. 3D-SPI techniques generally depend on time-of-flight or stereovision principle to extract depth information from backscattered light. However, existing implementations for these two optical schemes are limited to surface mapping of 3D objects at depth resolutions, at best, at the millimeter level. Here, we report 3D light-field illumination single-pixel microscopy (3D-LFI-SPM) that enables volumetric imaging of microscopic objects with a near-diffraction-limit 3D optical resolution. Aimed at 3D space reconstruction, 3D-LFI-SPM optically samples the 3D Fourier spectrum by combining 3D structured light-field illumination with single-element intensity detection. We build a 3D-LFI-SPM prototype that provides an imaging volume of ∼390 × 390 × 3,800 µm3 and achieves 2.7-µm lateral resolution and better than 37-µm axial resolution. Its capability of 3D visualization of label-free optical absorption contrast is demonstrated by imaging single algal cells in vivo. Our approach opens broad perspectives for 3D SPI with potential applications in various fields, such as biomedical functional imaging.

Cervical cancer cell-derived Tie1 expression via PI3K/AKT signaling pathway promotes tumor progression.

BACKGROUND: Tie1 orphan receptor has become a focus of research, Tie1 can form a polymer with Tie2, regulate the Ang/Tie2 pathway and play a vital role in pathological angiogenesis and tumor progression, the function of Tie1 has remained uncertain in the progression of cervical cancer (CC). Here, we investigated the functional influences of Tie1 overexpress on CC in vitro and in vivo. METHODS: We used Immunohistochemistry (IHC) analysis to detect the relative expression of Tie1 in CC, and we analyzed its connection with the overall survival (OS) and progression free survival (PFS)of CC patients. To prove the role of Tie1 in cell proliferation and metastatic, Tie1 expression in CC cell lines was upregulated by lentivirus. RESULTS: The high expression of Tie1 in tumor cells of cervical cancer tissues is significantly correlated with FIGO stage, differentiated tumors, tumors with diameters, deep stromal invasion. We found that cell progression was promoted in Tie1-overexpress CC cell lines in vivo and in vitro. Tie1 potentially exerts a commanding influence on the expression of markers associated with epithelial-mesenchymal transition (EMT) and the PI3K/AKT signaling pathway. CONCLUSIONS: Our research indicates that Tie1 is highly connected to CC progression as it may play a role in the EMT process through the PI3K/AKT signaling pathway.

The dual role of FSP1 in programmed cell death: resisting ferroptosis in the cell membrane and promoting necroptosis in the nucleus of THP-1 cells.

BACKGROUND: Acute monocytic leukemia-M5 (AML-M5) remains a challenging disease due to its high morbidity and poor prognosis. In addition to the evidence mentioned earlier, several studies have shown that programmed cell death (PCD) serves a critical function in treatment of AML-M5. However, the role and relationship between ferroptosis and necroptosis in AML-M5 remains unclear. METHODS: THP-1 cells were mainly treated with Erastin and IMP-366. The changes of ferroptosis and necroptosis levels were detected by CCK-8, western blot, quantitative real-time PCR, and electron microscopy. Flow cytometry was applied to detect the ROS and lipid ROS levels. MDA, 4-HNE, GSH and GSSG were assessed by ELISA kits. Intracellular distribution of FSP1 was studied by immunofluorescent staining and western blot. RESULTS: The addition of the myristoylation inhibitor IMP-366 to erastin-treated acute monocytic leukemia cell line THP-1 cell not only resulted in greater susceptibility to ferroptosis characterized by lipid peroxidation, glutathione (GSH) depletion and mitochondrial shrinkage, as the FSP1 position on membrane was inhibited, but also increased p-RIPK1 and p-MLKL protein expression, as well as a decrease in caspase-8 expression, and triggered the characteristic necroptosis phenomena, including cytoplasmic translucency, mitochondrial swelling, membranous fractures by FSP1 migration into the nucleus via binding importin α2. It is interesting to note that ferroptosis inhibitor fer-1 reversed necroptosis. CONCLUSION: We demonstrated that inhibition of myristoylation by IMP-366 is capable of switching ferroptosis and ferroptosis-dependent necroptosis in THP-1 cells. In these findings, FSP1-mediated ferroptosis and necroptosis are described as alternative mechanisms of PCD of THP-1 cells, providing potential therapeutic strategies and targets for AML-M5.

Chiral-Achiral Cations Intercalation Induced Lead-Free Chiral-Polar Hybrid Perovskites Enable Self-Powered X-Ray and Ultraviolet-Visible-Near-Infrared Photo Detection.

Lead halide hybrid perovskites have made great progress in direct X-ray detection and broadband photodetection, but the existence of toxic Pb and the demand for external operating voltage have severely limited their further applications and operational stability improvements. Therefore, exploring "green" lead-free hybrid perovskite that can both achieve X-ray detection and broadband photodetection without external voltage is of great importance, but remains severely challenging. Herein, using centrosymmetric (BZA)3BiI6 (1, BZA = benzylamine) as a template, a pair of chiral-polar lead-free perovskites, (BZA)2(R/S-PPA)BiI6 (2-R/S, R/S-PPA = (R/S)-1-Phenylpropylamine) are successfully obtained by introducing chiral aryl cations of (R/S)-1-Phenylpropylamine. Compared to 1, chiral-polar 2-R presents a significant irradiation-responsive bulk photovoltaic effect (BPVE) with an open circuit photovoltage of 0.4 V, which enables it with self-powered X-ray, UV-vis-NIR broadband photodetection. Specifically, 2-R device exhibits an ultralow detection limit of 18.5 nGy s-1 and excellent operational stability. Furthermore, 2-R as the first lead-free perovskite achieves significant broad-spectrum (377-940 nm) photodetection via light-induced pyroelectric effect. This work sheds light on the rational crystal reconstruction engineering and design of "green" hybrid perovskite toward high-demanded self-powered radiation detection and broadband photodetection.

Dion-Jacobson Type Lead-Free Double Perovskite with Ultra-Narrow Aromatic Interlayer Spacing for Highly Sensitive and Stable X-ray Detection.

The low-toxic and environmentally friendly 2D lead-free perovskite has made significant progress in the exploration of "green" X-ray detectors. However, the gap in detection performance between them and their lead-based analogues remains a matter of concern that cannot be ignored. To reduce this gap, shortening the interlayer spacing to accelerate the migration and collection of X-ray carriers is a promising strategy. Herein, a Dion-Jacobson (DJ) lead-free double perovskite (4-AP)2AgBiBr8 (1, 4-AP = 4-amidinopyridine) with an ultra-narrow interlayer spacing of 3.0 Å, is constructed by utilizing π-conjugated aromatic spacers. Strikingly, the subsequent enhanced carrier transport and increased crystal density lead to X-ray detectors based on bulk single crystals of 1 with a high sensitivity of 1117.3 µC Gy-1 cm-2, superior to the vast majority of similar double perovskites. In particular, the tight connection of the inorganic layers by the divalent cations enhances structural rigidity and stability, further endowing 1 detector with ultralow dark current drift (3.06 × 10-8 nA cm-1 s-1 V-1, 80 V), excellent multiple cycles switching X-ray irradiation stability, as well as long-term environmental stability (maintains over 94% photoresponse after 90 days). This work brings lead-free double perovskites one step closer to realizing efficient practical green applications.

Ultra-broadband TM-pass polarizer based on anisotropic metamaterials in lithium niobate on an insulator.

An ultra-broadband TM-pass polarizer is designed, fabricated, and experimentally demonstrated based on subwavelength grating (SWG) metamaterials in a lithium niobate on an insulator (LNOI) platform. According to our simulation, the designed device is predicted to work at a 220 nm wavelength range from 1460 to 1680 nm, covering the S-, C-, L-, U-bands of optical fiber communication. By depositing and subsequently etching a silicon nitride thin film atop the LNOI chip, the SWG structures are formed successfully by using complementary metal-oxide semiconductor (CMOS)-compatible fabrication processes. The measured results show a high polarization extinction ratio larger than 20 dB and a relatively low insertion loss below 2.5 dB over a 130 nm wavelength range from 1500 to 1630 nm, mainly limited by the operation bandwidth of our laser source.

Ubiquitin-specific protease 52 as a prognostic biomarker correlates with tumor microenvironment and therapy response in colorectal cancer.

INTRODUCTION: As the primary members of the deubiquitinases (DUBs) family, ubiquitin-specific peptidases (USPs) can regulate the efficacy of immunotherapy and mediate immune evasion. However, further research is needed to explore the influence of USP52 on the prognosis of colorectal cancer (CRC), the tumor immune microenvironment, and therapeutic response. METHODS: The differential expression of USP52 between colorectal cancer and normal tissues was analyzed using multiple public databases. The relationship between USP52 with the prognosis and clinicopathological characteristics of CRC patients was evaluated, and a nomogram was constructed to predict patient survival based on USP52 expression. Subsequently, Gene set variation analysis (GSVA) was used to explore the potential biological functions of USP52 in CRC. The impact of USP52 on the tumor microenvironment (TME) was estimated. Moreover, the effect of USP52 on the response to immunotherapy and chemotherapeutic drugs in CRC was investigated. Finally, the correlation between tumor mutation burden (TMB)/microsatellite instability (MSI) status and USP52 was explored. RESULTS: The expression of USP52 was markedly upregulated in CRC, correlating with a poor prognosis in patients. GSVA uncovered a strong association between high USP52 and immune suppression. Furthermore, high USP52 was found to be correlated with a non-inflamed TME, resulting in reduced immune cell infiltration levels. Additionally, it was observed that patients with high USP52 exhibited low sensitivity to both immunotherapy and chemotherapeutic drugs. Lastly, high USP52 was negatively associated with high TMB and MSI. CONCLUSION: This study revealed the significance of USP52 in TME, efficacy of therapy, and clinical prognosis in CRC, offering novel insights for the therapeutic advancements in CRC.

Controllable Microparticle Spinning via Light without Spin Angular Momentum.

The spin angular momentum (SAM) of an elliptically or circularly polarized light beam can be transferred to matter to drive a spinning motion. It is counterintuitive to find that a light beam without SAM can also cause the spinning of microparticles. Here, we demonstrate controllable spinning of birefringent microparticles via a tightly focused radially polarized vortex beam that has no SAM prior to focusing. To this end, the orbital Hall effect is proposed to control the radial separation of two spin components in the focused field, and tunable transfer of local SAM to microparticles is achieved by manipulating the twisted wavefront of the source light. Our work broadens the perspectives for controllable exertion of optical torques via the spin-orbit interactions.

LAMA5 promotes cell proliferation and migration in ovarian cancer by activating Notch signaling pathway.

LAMA5 (laminin α5) is a member of the laminin family. Despite the recent research implicating LAMA5 in cancer, the function of LAMA5 has remained uncertain in the progression of ovarian cancer (OC). Here, we investigated the functional influences of LAMA5 knockdown on OC in vitro and in vivo. In this study, we used immunohistochemistry (IHC) analysis to detect the relative expression of LAMA5 in OC and non-cancer tissues, and we analyzed its connection with the overall survival (OS) of OC patients. To prove the role of LAMA5 in cell proliferation, migration, and invasion, LAMA5 expression in OC cell lines was inhibited by lentivirus. Compared with normal fallopian tube tissue, epithelial ovarian cancer (EOC) tissue showed critically higher LAMA5 expression levels; additionally, high LAMA5 levels were a poor predictor of OS. We found that cell progression was restrained in LAMA5-knockdown OC cell lines in vivo and in vitro. Finally, LAMA5 might be a commanding inducer of the expression of epithelial-mesenchymal transition (EMT) and Notch signaling pathway-related markers. Together, our research indicates that LAMA5 is highly connected to OC progression as it may play a role in the EMT process through the Notch signaling pathway.

Optothermal Microparticle Oscillator Induced by Marangoni and Thermal Convection.

The light-fueled microparticle oscillator, exemplifying sustained driving in a static light source, potentially holds applications in fundamental physics, cellular manipulation, fluid dynamics, and various other soft-matter systems. The challenges of photodamage due to laser focusing on particles and the control of the oscillation direction have always been two major issues for microparticle oscillators. Here, we present an optical-thermal method for achieving a 3D microparticle oscillator with a fixed direction by employing laser heating of the gold film surface. First, the microparticle oscillation without direction limitation is studied. The photothermal conversion originates from the laser heating of a gold film. The oscillation mechanism is the coordination of the forces exerted on the particles, including the thermal convective force, thermophoresis force, and gravity. Subsequently, the additional Marangoni convection force, generated by the temperature gradient on the surface of a microbubble, is utilized to control the oscillation direction of the microparticle. Finally, a dual-channel oscillation mode is achieved by utilizing two microbubbles. During the oscillation process, the microparticle is influenced by flow field forces and temperature gradient force, completely avoiding optical damage to the oscillating microparticle.

Multi-axial Self-driven X-ray Detection by a Two-dimensional Biaxial Hybrid Organic-Inorganic Perovskite Ferroelectric.

Metal halide perovskite ferroelectrics combining spontaneous polarization and excellent semiconducting properties is an ideal platform for enabling self-driven X-ray detection, however, achievements to date have been only based on uniaxiality, which increases the complexity of device fabrication. Multi-axial ferroelectric materials have multiple equivalent polarization directions, making them potentially amenable to multi-axial self-driven X-ray detection, but the report on these types of materials is still a huge blank. Herein, a high-quality (BA)2(EA)2Pb3I10 (1) biaxial ferroelectric single crystal was successfully grown, which exhibited significant spontaneous polarization along the c-axis and b-axis. Under X-ray irradiation, bulk photovoltaic effect (BPVE) was exhibited along both the c-axis and b-axis, with open circuit voltages (Voc) of 0.23 V and 0.22 V, respectively. Then, the BPVE revealed along the inversion of polarized direction with the polarized electric fields. Intriguingly, due to the BPVE of 1, 1 achieved multi-axial self-driven X-ray detection for the first time (c-axis and b-axis) with relatively high sensitivities and ultralow detection limits (17.2 nGyair s-1 and 19.4 nGyair s-1, respectively). This work provides a reference for the subsequent use of multi-axial ferroelectricity for multi-axial self-driven optoelectronic detection.

Circularly Polarized Light-Dependent Pyro-Phototronic Effect from 2D Chiral-Polar Double Perovskites.

Chiral hybrid perovskites combine the advantages of chiral materials and halide perovskites, offering an ideal platform for the design of circularly polarized light (CPL) detectors. The pyro-phototronic effect, as a special mechanism of the photoexcited pyroelectric signal, can significantly improve the performance of photodetectors, whereas it remains a great challenge to achieve pyroelectricity-based CPL detection. In this work, the chiroptical phenomena and the pyro-phototronic effect are combined in chiral-polar perovskites to achieve unprecedented pyroelectric-based CPL detection. Two novel two-dimensional (2D) lead-free chiral-polar double perovskites, S/R-[(4-aminophenyl)ethylamine]2AgBiI8·0.5H2O, are successfully designed and synthesized by introducing chiral organic ligands into metal halide frameworks. Strikingly, the photoresponse is substantially boosted with the support of the pyro-phototronic effect, showing an increased pyro-phototronic current that is 40 times greater than the photovoltaic current. Furthermore, the pyroelectric-based detector possesses excellent CPL detection capacity to distinguish different polarization states of CPL photons, which achieve an impressive glph of up to 0.27 at zero bias. This study provides a brand new process for CPL detection by utilizing the pyro-phototronic effect in chiral-polar perovskites, which opens a new avenue for chiral materials in optoelectronic applications.

Larotrectinib induces autophagic cell death through AMPK/mTOR signalling in colon cancer.

Larotrectinib (Lar) is a highly selective and potent small-molecule inhibitor used in patients with tropomyosin receptor kinase (TRK) fusion-positive cancers, including colon cancer. However, the underlying molecular mechanisms specifically in patients with colon cancer have not yet been explored. Our data showed that Lar significantly suppressed proliferation and migration of colon cancer cells. In addition, Lar suppressed the epithelial-mesenchymal transition (EMT) process, as evidenced by elevation in E-cadherin (E-cad), and downregulation of vimentin and matrix metalloproteinase (MMP) 2/9 expression. Furthermore, Lar was found to activate autophagic flux, in which Lar increased the ratio between LC3II/LC3I and decreased the expression of p62 in colon cancer cells. More importantly, Lar also increased AMPK phosphorylation and suppressed mTOR phosphorylation in colon cancer cells. However, when we silenced AMPK in colon cancer cells, Lar-induced accumulation of autolysomes as well as Lar-induced suppression of the EMT process were significantly diminished. An in vivo assay also confirmed that tumour volume and weight decreased in Lar-treated mice than in control mice. Taken together, this study suggests that Lar significantly suppresses colon cancer proliferation and migration by activating AMPK/mTOR-mediated autophagic cell death.

The lipid phosphatase-like protein PLPPR1 associates with RhoGDI1 to modulate RhoA activation in response to axon growth inhibitory molecules.

Phospholipid Phosphatase-Related Protein Type 1 (PLPPR1) is a member of a family of lipid phosphatase related proteins, integral membrane proteins characterized by six transmembrane domains. This family of proteins is enriched in the brain and recent data indicate potential pleiotropic functions in several different contexts. An inherent ability of this family of proteins is to induce morphological changes, and we have previously reported that members of this family interact with each other and may function co-operatively. However, the function of PLPPR1 is not yet understood. Here we show that the expression of PLPPR1 reduces the inhibition of neurite outgrowth of cultured mouse hippocampal neurons by chondroitin sulfate proteoglycans and the retraction of neurites of Neuro-2a cells by lysophosphatidic acid (LPA). Further, we show that PLPPR1 reduces the activation of Ras homolog family member A (RhoA) by LPA in Neuro-2a cells, and that this is because of an association of PLPPR1with the Rho-specific guanine nucleotide dissociation inhibitor (RhoGDI1). These results establish a novel signaling pathway for the PLPPR1 protein.

1D Mixed-Stack Cocrystals Based on Perylene Diimide toward Ambipolar Charge Transport.

There is very limited repertoire of organic ambipolar semiconductors to date. Electron donor-acceptor alternative stacking is a unique and important binary motif for 1D mixed-stack cocrystals, opening up possibilities for the development of organic ambipolar semiconductors. Herein, four 1D mixed-stack cocrystals using N,N'-bis(perfluorobutyl)-1,7-dicyanoperylene-3,4:9,10-bis(dicarboximide) (PDICNF) as the acceptor and anthracene, pyrene, perylene, and meso-diphenyl tetrathia[22]annulene[2,1,2,1] (DPTTA) as the donors are achieved in a stoichiometric ratio (D:A = 1:1) through solution or vapor processed methods. Their packing structures, energy levels, charge transfer interactions, coassembling behaviors, and molecular orientations are systematically investigated by single-crystal X-ray analysis, absorption spectra, fluorescence quenching, Job's curve plot, and polarized photoluminescence measurements with the help of theoretical calculations. The donor-acceptor alternative stacking direction coincides with the long axis for all the four cocrystals. The field-effect transistors based on Pyrene-PDICNF show the electron mobility up to 0.19 cm2 V-1 s-1 , which is the highest value among perylene diimide-based cocrystals. Moreover, DPTTA-PDICNF cocrystals possess well-balanced electron and hole mobility with 1.7 × 10-2 and 2.0 × 10-2  cm2 V-1 s-1 respectively due to both hole and electron strong superexchange interactions, shedding light on the design of 1D mixed-stack cocrystals with excellent ambipolar transport behaviors.

Effects of Exogenous Biliverdin Treatment on Neurobehaviors in Mice.

The neuroprotective effects of heme oxygenase (HO) have been well investigated. The potential effects of exogenous supplementation of biliverdin (BVD), one of the main products catalyzed by HO, on neurobehaviors are still largely unknown. The present study aimed to investigate the effects of BVD treatment on depression, anxiety, and memory in adult mice. Mice were injected with BVD through tail vein daily for a total 5 d, and depression- and anxiety-like behaviors were conducted by using open field test (OFT), novelty suppressed feeding (NSF), forced swimming test (FST) and tail suspension test (TST) since the third day of BVD administration. Novel object recognition (NOR) paradigm was used for memory formation test. After the final test, serum and hippocampal levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) of mice were analyzed by enzyme-linked immunosorbent assay (ELISA). The results showed that BVD treatment at low dose (2 mg/kg) induced depression-like behaviors, and high dose (8 mg/kg) BVD injection increased anxiety-like behaviors and impaired memory formation in mice. ELISA data showed that BVD treatment significantly increased hippocampal IL-6 and TNF-α level while only decreasing serum IL-6 level of mice. The present data suggest that exogenous BVD treatment induced depression- and anxiety-like phenotypes, which may be related to inflammatory factors, providing BVD may be a potential target for the prevention of mental disorders.

Single-pixel spiral phase contrast imaging.

In this Letter, we present single-pixel spiral phase contrast imaging that enables optical edge detection of both amplitude and phase objects. This technique utilizes single-pixel detection to directly acquire the Fourier spectrum of the edge-enhanced object by scanning spiral phase-encoded plane waves in k-space. Experimentally, we exploit a digital micromirror device to simultaneously generate the plane wave and reference field for illuminating the object and scan the plane wave for spectrum sampling. During the process, four-step phase-shifting is adopted, and synchronized intensity measurements are made with a single-pixel detector. Applying an inverse Fourier transform to the obtained spectrum directly yields the edge information of objects. As a demonstration, digital and real objects are imaged, and results verify that isotropic edge detection can be achieved with our technique for both amplitude and phase objects.

Neonatal exposure to organophosphorus flame retardant TDCPP elicits neurotoxicity in mouse hippocampus via microglia-mediated inflammation in vivo and in vitro.

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is a phosphorus-based flame retardant common in consumer goods and baby products. Concerns have been raised about TDCPP exposure and neurodevelopmental toxicity. However, the mechanism and early response for TDCPP-induced neurotoxicity are poorly understood. This study investigates the role of microglia-mediated neuroinflammation in TDCPP-induced neurotoxicity in mice and primary cells. TDCPP was administered to C57BL/6 pups (0, 5, or 50 mg/kg/day) via an oral gavage from postnatal days 10-38 (28 days). The results showed that TDCPP exposure for 28 days altered the gene expression of neuronal markers Tubb3, Nefh, and Nes, and led to apoptosis in the hippocampus. The mRNA levels of pro-inflammatory factors Il-1ß, Tnfα and Ccl2 dose dependently increased in the hippocampus at both 24 h and 28 days following exposure, accompanied by microglia activation characterized by an amoeboid-like phenotype. In in vitro studies using the primary microglia isolated from neonatal mice, exposure to TDCPP (0-100 µM) for 24 h resulted in cellular activation. It also increased the expression of genes responsible for inflammatory responses including surface markers and pro-inflammatory cytokines. These changes occurred in a dose-dependent fashion. Neurite outgrowth of primary mouse hippocampal neurons was inhibited by treatment with the conditioned medium harvested from microglia exposed to TDCPP. These results reveal that neonatal exposure to TDCPP induces neuronal damage through microglia-mediated inflammation. This provides insight into the mechanism of TDCPP's neurodevelopmental toxicity, and suggests that microglial cell is a sensitive responder for OPFRs exposure.

Identification of novel binding sites for heparin in receptor protein-tyrosine phosphatase (RPTPσ): Implications for proteoglycan signaling.

Receptor protein-tyrosine phosphatase RPTPσ has important functions in modulating neural development and regeneration. Compelling evidence suggests that both heparan sulfate (HS) and chondroitin sulfate (CS) glycosaminoglycans (GAGs) bind to a series of Lys residues located in the first Ig domain of RPTPσ. However, HS promotes and CS inhibits axonal growth. Mutation of these Lys residues abolished binding and signal transduction of RPTPσ to CS, whereas HS binding was reduced, and signaling persisted. This activity was mediated through novel heparin-binding sites identified in the juxtamembrane region. Although different functional outcomes of HS and CS have been previously attributed to the differential oligomeric state of RPTPσ upon GAG binding, we found that RPTPσ was clustered by both heparin and CS GAG rich in 4,6-O-disulfated disaccharide units. We propose an additional mechanism by which RPTPσ distinguishes between HS and CS through these novel binding sites.