1,2-Dichloroethane causes anxiety and cognitive dysfunction in mice by disturbing GABA metabolism and inhibiting the cAMP-PKA-CREB signaling pathway.

1,2-Dichloroethane (1,2-DCE) is a powerfully toxic neurotoxin, which is a common environmental pollutant. Studies have indicated that 1,2-DCE long-term exposure can result in adverse effects. Nevertheless, the precise mechanism remains unknown. In this study, behavioral results revealed that 1,2-DCE long-term exposure could cause anxiety and learning and memory ability impairment in mice. The contents of γ-aminobutyric acid (GABA) and glutamine (Gln) in mice's prefrontal cortex decreased, whereas that of glutamate (Glu) increased. With the increase in dose, the activities of glutamate decarboxylase (GAD) decreased and those of GABA transaminase (GABA-T) increased. The protein and mRNA expressions of GABA transporter-3 (GAT-3), vesicular GABA transporter (VGAT), GABA A receptor α2 (GABAARα2), GABAARγ2, K-Cl cotransporter isoform 2 (KCC2), GABA B receptor 1 (GABABR1), GABABR2, protein kinase A (PKA), cAMP-response element binding protein (CREB), p-CREB, brain-derived neurotrophic factor (BDNF), c-fos, c-Jun and the protein of glutamate dehydrogenase (GDH) and PKA-C were decreased, while the expression levels of GABA transporter-1 (GAT-1) and Na-K-2Cl cotransporter isoform 1 (NKCC1) were increased. However, there was no significant change in the protein content of succinic semialdehyde dehydrogenase (SSADH). The expressions of adenylate cyclase (AC) and cyclic adenosine monophosphate (cAMP) contents were also reduced. In conclusion, the results of this study show that exposure to 1,2-DCE could lead to anxiety and cognitive impairment in mice, which may be related to the disturbance of GABA metabolism and its receptors along with the cAMP-PKA-CREB pathway.

Sensitive Detection of Tumor Cells Using Protein Nanoparticles with Multiple Displays of DNA Aptamers and Bioluminescent Reporters.

Simple and effective detection methods for circulating tumor cells are essential for early detection and progression monitoring of tumors. The use of DNA aptamer and bioluminescence is expected to be a key tool for the simple, effective, and sensitive detection of tumor cells. Herein, we designed multifunctional protein nanoparticles for the detection of tumor cells using DNA aptamer and bioluminescence. Fusion proteins (ELP-poly(d)-POIs), composed of elastin-like polypeptide (ELP) fused with protein of interests (POIs) via poly(aspartic acid) (poly(d)), formed the protein nanoparticles based on the temperature responsivity of ELP sequences, leading to multiply displayed POIs on the protein nanoparticles. In the present study, we focused on porcine circovirus type 2 replication initiation protein (Rep), which covalently conjugated with DNA aptamers, and NanoLuc luciferase (Nluc), which emitted a strong bioluminescence, as POIs. ELP-poly(d)-Rep and ELP-poly(d)-Nluc were constructed and formed the protein nanoparticles with multiply displayed Nluc and Rep (DNA aptamer) that amplified the bioluminescence signal and tumor recognition ability. Mucin-1 (MUC1)-overexpressing human breast tumor MCF7 cells and MUC1-recognizing aptamer (MUC1 aptamer) were selected as models. The MUC1 aptamer-conjugated protein nanoparticles exhibited a 13.7-fold higher bioluminescence signal to MCF-7 cells than to human embryonic kidney 293 (HEK293) cells, which express low levels of MUC1. Furthermore, the protein nanoparticles could detect up to 70.7 cells/mL of MCF-7 cells from a cell suspension containing HEK-293. The protein nanoparticles with multiple Rep and Nluc show a great potential as a material for detecting CTCs.

Factors ameliorate pro-inflammatory microglia polarization through inhibition of reactive astrocytes induced by 2-chloroethanol.

Our previous studies have demonstrated that the crosstalk between astrocytes and microglia may trigger and amplify the neuroinflammatory response and, in turn, cause brain edema in 1,2-dichloroethane (1,2-DCE)-intoxicated mice. Moreover, findings from our in vitro studies showed that astrocytes are more sensitive to 2-chloroethanol (2-CE), an intermediate metabolite of 1,2-DCE, than microglia, and 2-CE-induced reactive astrocytes (RAs) can promote microglia polarization through releasing the pro-inflammatory mediators. Therefore, it is essential to explore therapeutic agents that may ameliorate microglia polarization through inhibition of 2-CE-induced RAs, which remains unclear till now. Results of this study revealed that exposure to 2-CE could induce RAs with pro-inflammatory effects, and fluorocitrate (FC), GIBH-130 (GI) and diacerein (Dia) pretreatment could all abolish the pro-inflammatory effects of 2-CE-induced RAs. FC and GI pretreatment might suppress 2-CE-induced RAs through inhibition of p38 mitogen-activated protein kinase (p38 MAPK)/activator protein-1 (AP-1) and nuclear factor-kappaB (NF-κB) signaling pathways, but Dia pretreatment might only inhibit p38 MAPK/NF-κB signaling pathway. FC, GI, and Dia pretreatment could all suppress the pro-inflammatory microglia polarization through inhibition of 2-CE-induced RAs. Meanwhile, GI and Dia pretreatment could also restored the anti-inflammatory microglia polarization via inhibition of 2-CE-induced RAs. However, FC pretreatment could not affect the anti-inflammatory polarization of microglia through inhibition of 2-CE-induced RAs. Taken together, findings from the present study demonstrated that FC, GI, and Dia might be the potential candidates with different characteristic for therapeutic use in 1,2-DCE poisoning.

"Is this blueberry ripe?": a blueberry ripeness detection algorithm for use on picking robots.

Blueberries are grown worldwide because of their high nutritional value; however, manual picking is difficult, and expert pickers are scarce. To meet the real needs of the market, picking robots that can identify the ripeness of blueberries are increasingly being used to replace manual operators. However, they struggle to accurately identify the ripeness of blueberries because of the heavy shading between the fruits and the small size of the fruit. This makes it difficult to obtain sufficient information on characteristics; and the disturbances caused by environmental changes remain unsolved. Additionally, the picking robot has limited computational power for running complex algorithms. To address these issues, we propose a new YOLO-based algorithm to detect the ripeness of blueberry fruits. The algorithm improves the structure of YOLOv5x. We replaced the fully connected layer with a one-dimensional convolution and also replaced the high-latitude convolution with a null convolution based on the structure of CBAM, and finally obtained a lightweight CBAM structure with efficient attention-guiding capability (Little-CBAM), which we embedded into MobileNetv3 while replacing the original backbone structure with the improved MobileNetv3. We expanded the original three-layer neck path by one to create a larger-scale detection layer leading from the backbone network. We added a multi-scale fusion module to the channel attention mechanism to build a multi-method feature extractor (MSSENet) and then embedded the designed channel attention module into the head network, which can significantly enhance the feature representation capability of the small target detection network and the anti-interference capability of the algorithm. Considering that these improvements will significantly extend the training time of the algorithm, we used EIOU_Loss instead of CIOU_Loss, whereas the k-means++ algorithm was used to cluster the detection frames such that the generated predefined anchor frames are better adapted to the scale of the blueberries. The algorithm in this study achieved a final mAP of 78.3% on the PC terminal, which was 9% higher than that of YOLOv5x, and the FPS was 2.1 times higher than that of YOLOv5x. By translating the algorithm into a picking robot, the algorithm in this study ran at 47 FPS and achieved real-time detection well beyond that achieved manually.

A Treg-specific long noncoding RNA maintains immune-metabolic homeostasis in aging liver.

Regulatory T (Treg) cells modulate several aging-related liver diseases. However, the molecular mechanisms regulating Treg function in this context are unknown. Here we identified a long noncoding RNA, Altre (aging liver Treg-expressed non-protein-coding RNA), which was specifically expressed in the nucleus of Treg cells and increased with aging. Treg-specific deletion of Altre did not affect Treg homeostasis and function in young mice but caused Treg metabolic dysfunction, inflammatory liver microenvironment, liver fibrosis and liver cancer in aged mice. Depletion of Altre reduced Treg mitochondrial integrity and respiratory capacity, and induced reactive oxygen species accumulation, thus increasing intrahepatic Treg apoptosis in aged mice. Moreover, lipidomic analysis identified a specific lipid species driving Treg aging and apoptosis in the aging liver microenvironment. Mechanistically, Altre interacts with Yin Yang 1 to orchestrate its occupation on chromatin, thereby regulating the expression of a group of mitochondrial genes, and maintaining optimal mitochondrial function and Treg fitness in the liver of aged mice. In conclusion, the Treg-specific nuclear long noncoding RNA Altre maintains the immune-metabolic homeostasis of the aged liver through Yin Yang 1-regulated optimal mitochondrial function and the Treg-sustained liver immune microenvironment. Thus, Altre is a potential therapeutic target for the treatment of liver diseases affecting older adults.

Identification of CircRNA signature associated with tumor immune infiltration to predict therapeutic efficacy of immunotherapy.

Circular RNAs (circRNAs) play important roles in the regulation of cancer. However, the clinical implications and regulatory networks of circRNAs in cancer patients receiving immune checkpoint blockades (ICB) have not been fully elucidated. Here, we characterize circRNA expression profiles in two independent cohorts of 157 ICB-treated advanced melanoma patients and reveal overall overexpression of circRNAs in ICB non-responders in both pre-treatment and early during therapy. Then, we construct circRNA-miRNA-mRNA regulatory networks to reveal circRNA-related signaling pathways in the context of ICB treatment. Further, we construct an ICB-related circRNA signature (ICBcircSig) score model based on progression-free survival-related circRNAs to predict immunotherapy efficacy. Mechanistically, the overexpression of ICBcircSig circTMTC3 and circFAM117B could increase PD-L1 expression via the miR-142-5p/PD-L1 axis, thus reducing T cell activity and leading to immune escape. Overall, our study characterizes circRNA profiles and regulatory networks in ICB-treated patients, and highlights the clinical utility of circRNAs as predictive biomarkers of immunotherapy.

Revisiting maize Brittle endosperm-2 reveals new insights in BETL development and starchy endosperm filling.

Rerouting the starch biosynthesis pathway in maize can generate specialty types, like sweet corn and waxy corn, with a drastically increasing global demand. Hence, a fine-tuning of starch metabolism is relevant to create diverse maize cultivars for end-use applications. Here, we characterized a new maize brittle endosperm mutant, referred to as bt1774, which exhibited decreased starch content but a dramatic increase of soluble sugars at maturity. Both endosperm and embryo development was impaired in bt1774 relative to the wild-type (WT), with a prominently arrested basal endosperm transfer layer (BETL). Map-based cloning revealed that BRITTLE ENDOSPERM2 (Bt2), which encodes a small subunit of ADP-glucose pyrophosphorylase (AGPase), is the causal gene for bt1774. A MuA2 element was found to be inserted into intron 2 of Bt2, leading to a severe decrease of its expression, in bt1774. This is in line with the irregular and loosely packed starch granules in the mutant. Transcriptome of endosperm at grain filling stage identified 1,013 differentially expressed genes in bt1774, which were notably enriched in the BETL compartment, including ZmMRP1, Miniature1, MEG1, and BETLs. Gene expression of the canonical starch biosynthesis pathway was marginally disturbed in bt1774. Combined with the residual 60 % of starch in this nearly null mutant of Bt2, this data strongly suggests that an AGPase-independent pathway compensates for starch synthesis in the endosperm. Consistent with the BETL defects, zein accumulation was impaired in bt1774. Co-expression network analysis revealed that Bt2 probably has a role in intracellular signal transduction, besides starch synthesis. Altogether, we propose that Bt2 is likely involved in carbohydrate flux and balance, thus regulating both the BETL development and the starchy endosperm filling.

Synergistic effects of combined treatment of 1,2-dichloroethane and high-dose ethanol on liver damage in mice and the related mechanisms.

Our previous studies have shown that the metabolism of 1,2-dichloroethane (1,2-DCE) mediated by CYP2E1 could result in oxidative damage in the liver of mice. In the current study, we further investigated the effects of combined treatment with 1,2-DCE and high dose ethanol on liver and the mechanisms since both of them can be metabolized by CYP2E1 in the liver. There are several novel findings in the current study. First, combined treatment of mice with 1,2-DCE and high-dose ethanol could synergistically upregulate both protein and mRNA levels of CYP2E1, which might aggravate liver damage through CYP2E1-mediated oxidative stress. Second, the combined treatment could also synergistically trigger NLRP3 inflammasome activation and inflammatory responses in the liver. Third, the combined treatment synergistically upregulated the antioxidant defence systems in response to oxidative stress, however the compensatory mechanisms of antioxidant defence systems appeared to be insufficient to protect liver damage in the mice. Finally, the upregulated CYP2E1 expression was confirmed by using its specific inhibitor to play the crucial roles in liver damage in the mice during the combined treatment.

Novel mRNA Signature for Anti-TNF-α Therapy Primary Response in Patients With Ulcerative Colitis.

BACKGROUND: Ulcerative colitis (UC), an idiopathic, chronic inflammatory disorder of the colonic mucosa, is commonly treated with antitumor necrosis factor α (anti-TNF-α) agents. However, only approximately two-thirds have an initial response to these therapies. METHODS: We integrated gene expression profiling from 3 independent data sets of 79 UC patients before they began anti-TNF-α therapy and calculated the differentially expressed genes between patient response and nonresponse to anti-TNF-α therapy and developed a de novo response-associated transcription signature score (logOR_Score) to demonstrate the predictive capability of anti-TNF-α therapy for therapeutic efficacy. Furthermore, we performed association analysis of the logOR_Score and clinical features, such as disease activity and immune microenvironment. RESULTS: A total of 2522 responsive and 1824 nonresponsive genes were identified from the integrated data set. Responsive genes were significantly enriched in metabolism-related pathways, whereas nonresponsive ones were associated with immune response-related pathways. The logOR_Score enabled the accurate prediction of the therapeutic efficacy of anti-TNF-α in 4 independent patient cohorts and outperformed the predictions made based on 6 transcriptome-based signatures. In terms of clinical features, the logOR_Score correlated highly with the activity of UC. From an immune microenvironment perspective, logOR_Scores of CD8+IL-17+ T cells, follicular B cells, and innate lymphoid cells significantly decreased in inflamed UC tissue. CONCLUSIONS: The de novo response-associated transcription signature may provide novel insights into the personalized treatment of patients with UC. Comprehensive analyses of the response-related subtypes and the association between logOR_Score and clinical features and immune microenvironment may provide insights into the underlying UC pathogenesis.

We developed a de novo response-associated transcription signature score (logOR_Score) to predict the response of patients with UC to anti-TNF-α agents prior to treatment and explored the different response mechanisms of UC.

Circularly Polarized Light-Enabled Chiral Nanomaterials: From Fabrication to Application.

For decades, chiral nanomaterials have been extensively studied because of their extraordinary properties. Chiral nanostructures have attracted a lot of interest because of their potential applications including biosensing, asymmetric catalysis, optical devices, and negative index materials. Circularly polarized light (CPL) is the most attractive source for chirality owing to its high availability, and now it has been used as a chiral source for the preparation of chiral matter. In this review, the recent progress in the field of CPL-enabled chiral nanomaterials is summarized. Firstly, the recent advancements in the fabrication of chiral materials using circularly polarized light are described, focusing on the unique strategies. Secondly, an overview of the potential applications of chiral nanomaterials driven by CPL is provided, with a particular emphasis on biosensing, catalysis, and phototherapy. Finally, a perspective on the challenges in the field of CPL-enabled chiral nanomaterials is given.

Peptide-directed synthesis of chiral nano-bipyramids for controllable antibacterial application.

The emergence of antibiotic resistance makes the therapeutic effect of traditional antibiotics far from satisfactory. Here, chiral gold nano-bipyramids (GBPs) with sea cucumber-like morphology are reported, and used in the fight against bacterial infection. Specifically, the dipeptide of d-/l-Cys-Phe (CF) caused the nano-bipyramids to form a spike shape with an optical anisotropy factor of 0.102 at 573 nm. The antibacterial effects showed that d-GBPs and l-GBPs could efficiently destroy bacteria with a death ratio of 98% and 70% in vitro. Also, both in vivo skin infection and sepsis models showed that the chiral GBPs could effectively promote wound healing and prevent sepsis in mice. Mechanistic studies showed that the binding affinity of d-GBPs (1.071 ± 0.023 × 108 M-1) was 12.39-fold higher than l-GBPs (8.664 ± 0.251 × 106 M-1) to protein A of Staphylococcus aureus, which caused further adsorption of d-GBPs onto the bacterial surface. Moreover, the physical destruction of the bacterial cell wall caused by the spike chiral GBPs, resulted in a stronger antibacterial effect for d-GBPs than l-GBPs. Furthermore, the excellent PTT of d-/l-GBPs further exacerbated the death of bacteria without any side-effect. Overall, chiral nano-bipyramids have opened a new avenue for improved antibacterial efficacy in the treatment of bacterial infections.

Six-Pointed Star Chiral Cobalt Superstructures with Strong Antibacterial Activity.

Chiral inorganic nanomaterials have shown promise as a potential means of combating bacteria due to their high levels of biocompatibility, easy surface modification, and excellent optical properties. In this study, a diverse range of chiral hierarchical nanomaterials are prepared from Co2+ and L/D-Tartaric acid (Tar) ligands. By combining the ligands in different ratios, chiral Co superstructures (Co SS) are obtained with different morphologies, including chiral nanoflowers, chiral nanohanamaki, a chiral six-pointed star, a chiral fan shape, and a chiral fusiform shape. It is found that the chiral six-pointed star structures exhibit chiroptical activity across a broad range of wavelengths from 300 to 1300 nm and that the g-factor is as high as 0.033 with superparamagnetic properties. Under the action of electromagnetic fields, the chiral six-pointed star Co SS shows excellent killing ability against Gram-positive Staphylococcus aureus (ATCC 25923). Compared to L-Co SS, D-Co SS shows stronger levels of antibacterial ability. It is found that the levels of reactive oxygen species generated by D-Co SS are 1.59-fold higher than L-Co SS which is attributed to chiral-induced spin selectivity effects. These findings are of significance for the further development of chiral materials with antibacterial properties.

Characterization of Immune-Related Alternative Polyadenylation Events in Cancer Immunotherapy.

Alternative polyadenylation (APA) is an important posttranscriptional modification commonly involved in tumor development. However, the functional roles of APA in tumor immunity remain largely unknown. Here, we performed an in-depth analysis of the 3'UTR usage of protein-coding genes and tumor immune response in 10,303 tumor samples across 31 cancer types to develop the immune-related APA event (ImmAPA) score pipeline, an integrated algorithm to characterize the regulatory landscape of APA events in cancer immunity-related pathways. Tumor-specific ImmAPAs that strongly correlate with immune cell infiltration and immune checkpoint blockade (ICB) treatment-related biomarkers were identified. Among these ImmAPAs, the top-ranking COL1A1 3'UTR usage was strongly associated with worse prognosis and tumor immune evasion. Furthermore, a machine learning approach to construct an ICB-related ImmAPA score model predicted immunotherapy efficacy. Overall, the characterization of immune-related APA that corresponds to tumor progression and tumor immunity highlights the clinical utility of APA events as potential biomarkers in cancer immunotherapy. SIGNIFICANCE: Elucidation of the landscape of immune-related alternative polyadenylation in cancer identifies alternative polyadenylation events that may play a role in immune modulation and immunotherapy efficacy.

Disturbance of glutamate metabolism and inhibition of CaM-CaMKII-CREB signaling pathway in the hippocampus of mice induced by 1,2-dichloroethane exposure.

1,2-Dichloroethane (1,2-DCE) is a highly toxic neurotoxicity, and the brain tissue is the main target organ. At present, long-term exposure to 1,2-DCE has been shown to cause cognitive dysfunction in some studies, but the mechanism is not clear. The results of this study showed that long-term 1,2-DCE exposure decreased learning and memory abilities in mice and impaired the structure and morphology of neurons in the hippocampal region. Moreover, except for the mRNA level of PAG, the enzymatic activities and protein levels of GS and PAG, as well as the mRNA level of GS were inhibited. With increasing dose of exposure, the protein and mRNA expression of GLAST and GLT-1 also decreased. Contrarily, there were protein and mRNA expression upregulation of GluN1, GluN2A and GluN2B in the hippocampus, as well as increased levels of extracellular Glu and intracellular Ca2+. In addition, 1,2-DCE exposure also downregulated the protein expression levels of CaM, CaMKII and CREB. Taken together, our results suggest that long-term 1,2-DCE exposure impairs the learning and memory capacity in mice, which may be attributed to the disruption of Glu metabolism and the inhibition of CaM- CaMKII-CREB signaling pathway in the hippocampus.

Development of an enhanced immunoassay based on protein nanoparticles displaying an IgG-binding domain and luciferase.

Detection of small amounts of target molecules with high sensitivity is important for the diagnosis of many diseases, including cancers, and is particularly important to detect early stages of disease. Here, we report the development of a temperature-responsive fusion protein (ELP-DCN) comprised of an elastin-like polypeptide (ELP), poly-aspartic acid (D), antibody-binding domain C (C), and NanoLuc luciferase (N). ELP-DCN proteins form nanoparticles above a certain threshold temperature that display an antibody-binding domain and NanoLuc luciferase on their surface. ELP-DCN nanoparticles can be applied for enhancement of immunoassay systems because they provide more antibody-binding sites and an increased number of luciferase molecules, resulting in an increase in assay signal. Here, we report the detection of human serum albumin (HSA) as a model protein using anti-HSA and ELP-DCN proteins. Upon formation of ELP-DCN nanoparticles, the detection limit improved tenfold compared to the monomeric form of ELP-DCN.

Self-Assembled Porphyrin Nanoleaves with Unique Crossed Transportation of Photogenerated Carriers to Enhance Photocatalytic Hydrogen Production.

The preparation of self-assembled porphyrins with orderly stacked nanostructures for emulating natural photosynthesis has stimulated extensive efforts to optimize the energy conversion efficiency. However, the elucidation of how orderly stacked structures promote photocatalysis at the molecular level remains a great challenge. Here, unique porphyrin nanoleaves with designed and ordered structure are synthesized and show a hydrogen evolution rate higher than that of commercial powder. Photodeposition of cocatalysts and Kelvin probe force microscopy measurement suggest selective aggregation of photogenerated electrons and holes at different active sites. Combined with theoretical calculations, we find that the orderly packing changes molecular symmetry and induces a molecular dipole, which increases linearly along the π-π stacking direction and forms a strong built-in electric field. The built-in electric field drives photogenerated electrons and holes for the unique crossed transportation along different directions. These findings reveal how orderly stacked structures promote photocatalysis and provide a novel approach for highly efficient water splitting.

Roles of Crosstalk between Astrocytes and Microglia in Triggering Neuroinflammation and Brain Edema Formation in 1,2-Dichloroethane-Intoxicated Mice.

We have previously reported that the activation of astrocytes and microglia may lead to the overproduction of proinflammatory mediators, which could induce neuroinflammation and cause brain edema in 1,2-dichloroethane (1,2-DCE)-intoxicated mice. In this research, we further hypothesized that astrocyte-microglia crosstalk might trigger neuroinflammation and contribute to brain edema in 1,2-DCE-intoxicated mice. The present research revealed, for the first time, that subacute intoxication with 1,2-DCE might provoke the proinflammatory polarization of microglia, and pretreatment with minocycline, a specific inhibitor of microglial activation, may attenuate the enhanced protein levels of ionized calcium-binding adapter molecule1 (Iba-1), cluster of differentiation 11b (CD11b), glial fibrillary acidic protein (GFAP), soluble calcium-binding protein 100B (S100B), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), inducible nitric oxide synthase (iNOS), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), matrix metalloproteinase-9 (MMP-9), Toll-like receptor 4 (TLR4), MyD88, and p-p65, and ameliorate the suppressed protein expression levels of occludin and claudin 5; we also observed changes in water content and made pathological observations on edema in the brains of 1,2-DCE-intoxicated mice. Moreover, pretreatment with fluorocitrate, an inhibitor of reactive astrocytes, could also reverse the alteration in protein expression levels of GFAP, S100B, Iba-1, CD11b, TNF-α, IL-6, iNOS, VCAM-1, ICAM-1, MMP-9, occludin, and claudin 5 in the brain of 1,2-DCE intoxicated mice. Furthermore, pretreatment with melatonin, a well-known anti-inflammatory drug, could also attenuate the above-mentioned changes in the brains of 1,2-DCE-intoxicated mice. Altogether, the findings from this research indicated that microglial activation might play an important role in triggering neuroinflammation, and hence may contribute to brain edema formation; additionally, the findings suggested that molecular crosstalk between reactive astrocytes and activated microglia may amplify the neuroinflammatory reaction, which could induce secondary brain injury in 1,2-DCE-intoxicated mice.

Reactive astrocytes induced by 2-chloroethanol modulate microglia polarization through IL-1ß, TNF-α, and iNOS upregulation.

The synthetic organic chemical, 1,2-dichloroethane (1,2-DCE), can cause brain edemas under subacute poisoning. Our previous studies indicated that neuroinflammation could be induced due to astrocytes and microglia activation during brain edemas in 1,2-DCE-intoxicated mice. However, the crosstalk between these two glial cells in 1,2-DCE-induced neuroinflammation remained unclear. In this study, primary cultured rat astrocytes and microglia, as well as an immortalized microglia cell line were employed to study the effects of 2-chloroethanol (2-CE, a 1,2-DCE intermediate metabolite in vivo) treated astrocytes on microglia polarization. Our current results revealed that 2-CE treated rat astrocytes were activated through p38 mitogen-activated protein kinase (p38 MAPK)/nuclear factor-κB (NF-κB), and activator protein-1 (AP-1) signaling pathways. Theses pathways were triggered by reactive oxygen species (ROS) produced during 2-CE metabolism. Also, astrocytes were more sensitive to 2-CE effects than microglia. Interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS) expressions were upregulated in 2-CE-induced reactive astrocytes, enhancing IL-1ß, TNF-α, and nitric oxide (NO) excretions, which stimulated microglia polarization. Therefore, the neuroinflammation induced by 1,2-DCE in mice's brains is probably triggered by reactive astrocytes.

Chiral Plasmonic Triangular Nanorings with SERS Activity for Ultrasensitive Detection of Amyloid Proteins in Alzheimer's Disease.

Chiral plasmonic nanomaterials have attracted unprecedented attention due to their broad applications in biomedicine, negative refractive index, and chiral sensing. Here, using a wet-chemistry process, chiral triangular Au nanorings are fabricated with a platinum (Pt) framework (l/d-Pt@Au triangular nanorings, named l/d-Pt@Au TNRs). The l/d-Pt@Au TNRs exhibit strong optical activity with a g-factor of 0.023 and can be used effectively for the discrimination of enantiomers due to selective resonance coupling between the induced electric and magnetic dipoles associated with enantiomers and the chiral plasmonic TNRs, also known as the surface-enhanced Raman scattering-chiral anisotropy (SERS-ChA) effect. The chiral d-Pt@Au TNRs represent a label-free SERS platform that can be applied to detect Aß monomers and fibrils, the hallmarks of Alzheimer's disease (AD), achieving a limit of detection (LOD) down to 0.045 × 10-12 m and 4 × 10-15 m for 42-residue-long amyloid-ß (Aß42 ) monomer and fibrils, respectively. Furthermore, chiral d-Pt@Au TNRs can also be successfully carried out to detect Aß42 proteins in AD patients with ultrahigh levels of sensitivity, thus allowing picogram quantities of Aß42 proteins to be identified. This research opens up an avenue for the use of chiral plasmonic nanomaterials as ultrasensitive SERS substrates to early diagnosis of protein-misfolding diseases.

Cross-talk of four types of RNA modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancer.

BACKGROUND: The four major RNA adenosine modifications, i.e., m6A, m1A, alternative polyadenylation, and adenosine-to-inosine RNA editing, are mediated mostly by the "writer" enzymes and constitute critical mechanisms of epigenetic regulation in immune response and tumorigenesis. However, the cross-talk and potential roles of these "writers" in the tumor microenvironment (TME), drug sensitivity, and immunotherapy remain unknown. METHODS: We systematically characterized mRNA expression and genetic alterations of 26 RNA modification "writers" in colorectal cancer (CRC), and evaluated their expression pattern in 1697 CRC samples from 8 datasets. We used an unsupervised clustering method to assign the samples into two patterns of expression of RNA modification "writers". Subsequently, we constructed the RNA modification "writer" Score (WM_Score) model based on differentially expressed genes (DEGs) responsible for the RNA modification patterns to quantify the RNA modification-related subtypes of individual tumors. Furthermore, we performed association analysis for WM_Score and characteristics of TME, consensus molecular subtypes (CMSs), clinical features, transcriptional and post-transcriptional regulation, drug response, and the efficacy of immunotherapy. RESULTS: We demonstrated that multi-layer alterations of RNA modification "writer" are associated with patient survival and TME cell-infiltrating characteristics. We identified two distinct RNA modification patterns, characterized by a high and a low WM_Score. The WM_Score-high group was associated with worse patient overall survival and with the infiltration of inhibitory immune cells, such as M2 macrophages, EMT activation, and metastasis, while the WM_Score-low group was associated with a survival advantage, apoptosis, and cell cycle signaling pathways. WM_Score correlated highly with the regulation of transcription and post-transcriptional events contributing to the development of CRC. In response to anti-cancer drugs, WM_Score highly negatively correlated (drug sensitive) with drugs which targeted oncogenic related pathways, such as MAPK, EGFR, and mTOR signaling pathways, positively correlated (drug resistance) with drugs which targeted in apoptosis and cell cycle. Importantly, the WM_Score was associated with the therapeutic efficacy of PD-L1 blockade, suggesting that the development of potential drugs targeting these "writers" to aid the clinical benefits of immunotherapy. CONCLUSIONS: Our study is the first to provide a comprehensive analysis of four RNA modifications in CRC. We revealed the potential function of these writers in TME, transcriptional and post-transcriptional events, and identified their therapeutic liability in targeted therapy and immunotherapy. This work highlights the cross-talk and potential clinical utility of RNA modification "writers" in cancer therapy.