Water-Regulated Evolution of Inversion, Reinversion, and Amplification of Circularly Polarized Luminescence of Supramolecular Organogels Based on Glutamide-Cyanostilbene Amphiphile.

Water incorporated with supramolecular building blocks in organic solvents can play a key role in the circularly polarized luminescence (CPL) inversion and amplification of supramolecular assemblies. Herein, we demonstrate that fine-tuning the water content regulated the assembly structure evolution and made the circular dichroism and CPL sign of the system undergo intriguing inversion, reinversion, and amplification processes based on a unique and interesting glutamide-cyanostilbene system, as supported by morphology, spectroscopic observations, and time-dependent density functional theory calculation.

Do PACS1 variants impeding adaptor protein binding predispose to syndromic intellectual disability?

To date, PACS1-neurodevelopmental disorder (PACS1-NDD) has been associated with recurrent variation of Arg203 and is considered diagnostic of PACS1-NDD, an autosomal dominant syndromic intellectual disability disorder. Although incompletely defined, the proposed disease mechanism for this variant is altered PACS1 affinity for its client proteins. Given this proposed mechanism, we hypothesized that PACS1 variants that interfere with binding of adaptor proteins might also give rise to syndromic intellectual disability. Herein, we report a proposita and her mother with phenotypic features overlapping PACS1-NDD and a novel PACS1 variant (NM_018026.3:c.[755C > T];[=], p.(Ser252Phe)) that impedes binding of the adaptor protein GGA3 (Golgi-associated, gamma-adaptin ear-containing, ARF-binding protein 3). We hypothesize that attenuating PACS1 binding of GGA3 also gives rise to a disorder with features overlapping those of PACS1-NDD. This observation better delineates the mechanism by which PACS1 variation predisposes to syndromic intellectual disability.

Fabrication of molecularly-imprinted gold nanoparticle-embedded Fe-MOFs for highly selective SERS detection of 17ß-estradiol in milk.

17ß-Estradiol (17ß-E2) could accumulate in humans through milk, thus causing diseases by interfering with the function of the endocrine system. However, its detection at a trace level in milk is still a challenge because of matrix interferences. In this work, a core-shell structured polydopamine molecular-imprinted gold nanoparticles (AuNP@MIP-PDA) were embedded into Fe metal-organic framework materials to form a well-defined hexagonal microspindle structure of AuNP@MIP-PDA@MIL-101(Fe). AuNP@MIP-PDA were successfully encapsulated within the MIL-101 crystals through the hydrophobic interaction between organic ligands and the aromatic groups of PDA, the chelating power of catechol groups, as well as the introduction of acetic acid. Combined with the SERS activity of AuNPs, the specific recognition sites from MIPs, and the adsorption and enrichment capability of MIL-101, the fabricated nanohybrids could be designed as highly selective SERS sensors for the detection. By effectively preventing the macromolecule adsorption and the preconcentration of 17ß-E2 near the SERS-active surface, the SERS sensor could be directly applied in the selective detection of 17ß-E2 in milk without tedious pretreatment. The method demonstrated an outstanding detection limit of 1.95 × 10-16 mol L-1, without the interference mainly originating from the two analogues, estrone and estriol. These promising results foresee the potential application of this novel MIP-based SERS sensor in food and environmental sensing.

Induction of Protective Response Associated with Expressional Alterations in Neuronal G Protein-Coupled Receptors in Polystyrene Nanoparticle Exposed Caenorhabditis elegans.

In this study, the association of expressional alterations in neuronal G protein-coupled receptors (GPCRs) with induction of protective response to polystyrene nanoparticles (PS-NPs) was investigated in Caenorhabditis elegans. On the basis of both phenotypic analysis and expression levels, the alterations in expressions of NPR-1, NPR-4, NPR-8, NPR-9, NPR-12, DCAR-1, GTR-1, DOP-2, SER-4, and DAF-37 in neuronal cells mediated the protective response to PS-NPs exposure. In neuronal cells, NPR-9, NPR-12, DCAR-1, and GTR-1 controlled the PS-NPs toxicity by activating or inhibiting JNK-1/JNK MAPK signaling. Neuronal NPR-8, NPR-9, DCAR-1, DOP-2, and DAF-37 controlled the PS-NPs toxicity by activating or inhibiting MPK-1/ERK MAPK signaling. Neuronal NPR-4, NPR-8, NPR-9, NPR-12, GTR-1, DOP-2, and DAF-37 controlled the PS-NPs toxicity by activating or inhibiting DBL-1/TGF-ß signaling. Neuronal NPR-1, NPR-4, NPR-12, and GTR-1 controlled the PS-NPs toxicity by activating or inhibiting DAF-7/TGF-ß signaling. Our data provides an important neuronal basis for induction of protective response to PS-NPs in C. elegans.

Neuronal Gα subunits required for the control of response to polystyrene nanoparticles in the range of µg/L in C. elegans.

The aim of this study was to identify Gα proteins mediating function of neuronal G protein-coupled receptors (GPCRs) in controlling the response to polystyrene nanoparticles (PS-NPs). Caenorhabditis elegans was used as an animal model, and both gene expression and functional analysis were performed to identify the Gα proteins in controlling PS-NPs toxicity. In nematodes, exposure to PS-NPs (1-100 µg/L) significantly altered transcriptional expressions of some neuronal Gα genes, including gpa-5, gpa-10, gpa-11, gpa-15 gsa-1, egl-30, and goa-1. Among these 7 Gα genes, only neuronal RNAi knockdown of gsa-1, gpa-10, and goa-1 affected toxicity of PS-NPs in inducing ROS production and in decreasing locomotion behavior. Some neuronal GPCRs (such as GTR-1, DCAR-1, DOP-2, NPR-8, NPR-12, NPR-9, and DAF-37) functioned upstream of GOA-1, some neuronal GPCRs (such as DCAR-1, DOP-2, NPR-9, NPR-8, and DAF-37) functioned upstream of GSA-1, and some neuronal GPCRs (such as DOP-2, NPR-8, DAF-37, and DCAR-1) functioned upstream of GPA-10 to regulate the toxicity of PS-NPs. Moreover, GOA-1 acted upstream of MPK-1/ERK MAPK, JNK-1/JNK MAPK, DBL-1/TGF-ß, and DAF-7/ TGF-ß, GSA-1 functioned upstream of MPK-1/ERK MAPK, JNK-1/JNK MAPK, and DBL-1/TGF-ß, and GPA-10 functioned upstream of GLB-1/Globin and DBL-1/TGF-ß to control the PS-NPs toxicity. Therefore, neuronal Gα proteins of GOA-1, GSA-1, and GPA-10 functioned to transduce signals of multiple GPCRs to different downstream signaling pathways during the control of PS-NPs toxicity in nematodes. Our results provide clues for understanding the important function of GPCRs-Gα signaling cascade in the neurons in controlling response to nanoplastics in organisms.

Epigenetic response to nanopolystyrene in germline of nematode Caenorhabditis elegans.

microRNAs (miRNAs) provide an epigenetic regulation mechanism for the response to environmental toxicants. mir-38, a germline miRNA, was increased by exposure to nanopolystyrene (100 nm). In this study, we further found that germline overexpression of mir-38 decreased expressions of nhl-2 encoding a miRISC cofactor, ndk-1 encoding a homolog of NM23-H1, and wrt-3 encoding a homolog of PPIL-2. Meanwhile, germline-specific RNAi knockdown of nhl-2, ndk-1, or wrt-3 caused the resistance to nanopolystyrene toxicity. Additionally, mir-38 overexpression suppressed the resistance of nematodes overexpressing germline nhl-2, ndk-1, or wrt-3 containing 3'UTR, suggesting the role of NHL-2, NDK-1, and WRT-3 as the targets of germline mir-38 in regulating the response to nanopolystyrene. Moreover, during the control of response to nanopolystyrene, EKL-1, a Tudor domain protein, was identified as the downstream target of germline NHL-2, kinase suppressors of Ras (KSR-1 and KSR-2) were identified as the downstream targets of germline NDK-1, and ASP-2, a homolog of BACE1, was identified as the downstream target of germline WRT-3. Our results raised a mir-38-mediated molecular network in the germline in response to nanopolystyrene in nematodes. Our data provided an important basis for our understanding the response of germline of organisms to nanoplastic exposure.

Impact of TGEV infection on the pig small intestine.

BACKGROUND: Pig diarrhea causes high mortality and large economic losses in the swine industry. Transmissible gastroenteritis virus (TGEV) causes pig diarrhea, with 100% mortality in piglets less than 2 weeks old. No investigation has yet been made of the small intestine of piglets that survived infection by TGEV. METHODS: In this study, we evaluated the impact of TGEV infection on the small intestine of recovered pigs. RESULTS: Histological analyses showed that TGEV infection led to villi atrophy, and reduced villous height and crypt depth. The number of SIgA positive cells, CD3+T cells, and dendritic cells (DCs) in jejunum decreased after TGEV infection in vivo. In contrast, microfold cell (M cell) numbers and cell proliferation increased in infected pigs. TGEV infection also significantly enhanced the mRNA expression levels of cytokine IL-1ß, IL-6, TNF-α, IL-10, and TGF-ß. Additionally, lower gene copy numbers of Lactobacillus, and higher numbers of Enterobacteriaceae, were detected in mucosal scraping samples from TGEV-infected pigs. CONCLUSIONS: TGEV infection damages the small intestine, impairs immune functions, and increases pathogenic bacterial loading, all of which may facilitate secondary infections by other pathogens. These findings help quantify the impact of TGEV infection and clarify the pathogenic mechanisms underlying its effects in pigs.

Metal-ion-triggered symmetry breaking of completely achiral azobenzene amphiphiles in water.

Achieving control over symmetry breaking of completely achiral components in the aqueous phase is a significant challenge in supramolecular chemistry. Herein, we demonstrate that it is possible to construct chiral nanoassemblies by introducing metal ions (Zn2+, Fe3+, Al3+, Cu2+, and Ca2+) into completely achiral azobenzene amphiphiles with key structural factors in the pure aqueous phase. It is found that the coordination interactions, π-π stacking, hydrophilic and hydrophobic interactions, hydrogen bonding, and electrostatic interactions are crucial to the metal-ion-induced symmetry breaking of completely achiral building blocks. This study may provide an intriguing model system for constructing chiral assemblies based on completely achiral molecules.

High-altitude hypoxia promotes BRD4-mediated activation of the Wnt/ß-catenin pathway and disruption of intestinal barrier.

Hypobaric hypoxia, commonly experienced at elevated altitudes, presents significant physiological challenges. Our investigation is centered on the impact of the bromodomain protein 4 (BRD4) under these conditions, especially its interaction with the Wnt/ß-Catenin pathway and resultant effects on glycolytic inflammation and intestinal barrier stability. By combining transcriptome sequencing with bioinformatics, we identified BRD4's key role in hypoxia-related intestinal anomalies. Clinical parameters of altitude sickness patients, including serum BRD4 levels, inflammatory markers, and barrier integrity metrics, were scrutinized. In vitro studies using CCD 841 CoN cells depicted expression changes in BRD4, Interleukin (IL)-1ß, IL-6, and ß-Catenin. Transepithelial electrical resistance (TEER) and FD4 analyses assessed barrier resilience. Hypoxia-induced mouse models, analyzed via H&E staining and Western blot, provided insights into barrier and protein alterations. Under hypoxic conditions, marked BRD4 expression variations emerged. Elevated serum BRD4 in patients coincided with intensified Wnt signaling, inflammation, and barrier deterioration. In vitro, findings showed hypoxia-induced upregulation of BRD4 and inflammatory markers but a decline in Occludin and ZO1, affecting barrier strength-effects mitigated by BRD4 inhibition. Mouse models echoed these patterns, linking BRD4 upregulation in hypoxia to barrier perturbations. Hypobaric hypoxia-induced BRD4 upregulation disrupts the Wnt/ß-Catenin signaling, sparking glycolysis-fueled inflammation and weakening intestinal tight junctions and barrier degradation.

Comparative study on Al-SBA-15 prepared by spray drying and traditional methods for bulky hydrocarbon cracking: Properties, performance and influencing factors.

Mesoporous aluminosilicates Al-SBA-15 with large pore sizes and suitable acid properties are promising substitutes to zeolites for catalytic cracking of bulky hydrocarbons without molecular diffusion limitation. The conventional processes to synthesize Al-SBA-15 are time-consuming and often suffer from low "framework" Al contents. Herein, Al-SBA-15 microspheres are synthesized using the rapid and scalable microfluidic jet spray drying technique. They possess uniform particle sizes (45-60 µm), variable surface morphologies, high surface areas (264-340 m2/g), uniform mesopores (3.8-4.9 nm) and rich acid sites (126-812 µmol/g) and high acid strength. Their physicochemical properties are compared with the counterparts synthesized using traditional hydrothermal and evaporation-induced self-assembly methods. The spray drying technique results in a higher incorporation of aluminum (Al) atoms into the silica "framework" compared to the other two methods. The catalytic cracking efficiencies of 1,3,5-triisopropylbenzene (TIPB) on the Al-SBA-15 materials synthesized using the three different methods and nanosized ZSM-5 are compared. The optimal spray-dried Al-SBA-15 exhibits the best performance with 100 % TIPB conversion, excellent selectivity (about 75 %) towards the formation of deeply cracked products (benzene and propylene) and high stability. The catalytic performances of the spray-dried Al-SBA-15 with varying Si/Al ratios are also compared. The reasons for the different performances of the different materials are discussed, where the mesopores, high acid density and strength are observed to play the most critical role. This work might provide a basis for the synthesis of mesoporous rich metal-substituted silica materials for different catalytic applications.

SUMOylation regulation of ribosome biogenesis: Emerging roles for USP36.

Ribosome biogenesis is essential for cell growth, proliferation, and animal development. Its deregulation leads to various human disorders such as ribosomopathies and cancer. Thus, tight regulation of ribosome biogenesis is crucial for normal cell homeostasis. Emerging evidence suggests that posttranslational modifications such as ubiquitination and SUMOylation play a crucial role in regulating ribosome biogenesis. Our recent studies reveal that USP36, a nucleolar deubiquitinating enzyme (DUB), acts also as a SUMO ligase to regulate nucleolar protein group SUMOylation, thereby being essential for ribosome biogenesis. Here, we provide an overview of the current understanding of the SUMOylation regulation of ribosome biogenesis and discuss the role of USP36 in nucleolar SUMOylation.

HIF-1α Pathway Orchestration by LCN2: A Key Player in Hypoxia-Mediated Colitis Exacerbation.

In this study, we investigated the role of hypoxia in the development of chronic inflammatory bowel disease (IBD), focusing on its impact on the HIF-1α signaling pathway through the upregulation of lipocalin 2 (LCN2). Using a murine model of colitis induced by sodium dextran sulfate (DSS) under hypoxic conditions, transcriptome sequencing revealed LCN2 as a key gene involved in hypoxia-mediated exacerbation of colitis. Bioinformatics analysis highlighted the involvement of crucial pathways, including HIF-1α and glycolysis, in the inflammatory process. Immune infiltration analysis demonstrated the polarization of M1 macrophages in response to hypoxic stimulation. In vitro studies using RAW264.7 cells further elucidated the exacerbation of inflammation and its impact on M1 macrophage polarization under hypoxic conditions. LCN2 knockout cells reversed hypoxia-induced inflammatory responses, and the HIF-1α pathway activator dimethyloxaloylglycine (DMOG) confirmed LCN2's role in mediating inflammation via the HIF-1α-induced glycolysis pathway. In a DSS-induced colitis mouse model, oral administration of LCN2-silencing lentivirus and DMOG under hypoxic conditions validated the exacerbation of colitis. Evaluation of colonic tissues revealed altered macrophage polarization, increased levels of inflammatory factors, and activation of the HIF-1α and glycolysis pathways. In conclusion, our findings suggest that hypoxia exacerbates colitis by modulating the HIF-1α pathway through LCN2, influencing M1 macrophage polarization in glycolysis. This study contributes to a better understanding of the mechanisms underlying IBD, providing potential therapeutic targets for intervention.

Pathogen-Mimicking Nanoparticles Based on Rigid Nanomaterials as an Efficient Subunit Vaccine Delivery System for Intranasal Immunization.

Despite the safety profile of subunit vaccines, the inferior immunogenicity hinders their application in the nasal cavity. This study introduces a novel antigen delivery and adjuvant system utilizing mucoadhesive chitosan-catechol (Chic) on silica spiky nanoparticles (Ssp) to enhance immunity through multiple mechanisms. The Chic functionalizes the Ssp surface and incorporates with SARS-CoV-2 spike protein receptor-binding domain (RBD) and toll-like receptor (TLR)9 agonist unmethylated cytosine-guanine (CpG) motif, forming uniform virus-like nanoparticles (Ssp-Chic-RBD-CpG) via electrostatic and covalent interactions. Ssp-Chic-RBD-CpG, mimicking the morphology and function of inactive virions, effectively prolongs the retention time of RBD in the nasal mucosa by 3.92-fold compared to RBD alone, enhances the maturation of dendritic cells (DCs), and facilitates the antigen trafficking to the draining lymph nodes, which subsequently induces a stronger mucosal immunity. Mechanistically, the enhanced chemokine chemokine (C-C motif) ligand 20 (CCL20)-driven DCs recruitment and maturation by Ssp-Chic-RBD-CpG are evidenced by a cell co-culture model. In addition, the overexpression of TLR4/9 and activation of MYD88/NF-κB signaling pathway in activation of DCs are observed. Proof of principle is obtained for RBD, but similar delivery mechanisms can be applied in other protein-based subunit vaccines as well when intranasal administration is needed.

Designing and preparing supramolecular encapsulation systems based on fraxetin and cyclodextrins for highly selective detection of nicotine.

Herein, a series of water-soluble supramolecular inclusion complexes (ICs) probes were prepared using cyclodextrins (CDs) and fraxetin (FRA) to detect nicotine (NT) with high selectivity in vitro and in vivo. The FRA/CD ICs prepared through the saturated solution method exhibited excellent water solubility, stability, and biocompatibility. A clear host-guest inclusion model was provided by the theoretical calculations. The investigation revealed that NT was able to enter into the cavities of FRA/ß-CD IC and FRA/γ-CD IC, and further formed charge transfer complexes with FRA in the CD cavities, resulting in a rapid and highly selective fluorescence-enhanced response with the lowest detection limits of 1.9 × 10-6 M and 9.7 × 10-7 M, and the linear response ranged from 0.02 to 0.3 mM and 0.01-0.05 mM, respectively. The IC probes showed good anti-interference performance to common interferents or different pH environments, with satisfactory reproducibility and repeatability of response to NT. Furthermore, the potentiality of the probes was confirmed through fluorescence imaging experiments using human lung cancer cells and the lung tissue of mice. This study offers a fresh perspective for detecting NT in environmental and biomedical analysis.

Inhibitory protein-protein interactions of the SIRT1 deacetylase are choreographed by post-translational modification.

Regulation of SIRT1 activity is vital to energy homeostasis and plays important roles in many diseases. We previously showed that insulin triggers the epigenetic regulator DBC1 to prime SIRT1 for repression by the multifunctional trafficking protein PACS-2. Here, we show that liver DBC1/PACS-2 regulates the diurnal inhibition of SIRT1, which is critically important for insulin-dependent switch in fuel metabolism from fat to glucose oxidation. We present the x-ray structure of the DBC1 S1-like domain that binds SIRT1 and an NMR characterization of how the SIRT1 N-terminal region engages DBC1. This interaction is inhibited by acetylation of K112 of DBC1 and stimulated by the insulin-dependent phosphorylation of human SIRT1 at S162 and S172, catalyzed sequentially by CK2 and GSK3, resulting in the PACS-2-dependent inhibition of nuclear SIRT1 enzymatic activity and translocation of the deacetylase in the cytoplasm. Finally, we discuss how defects in the DBC1/PACS-2-controlled SIRT1 inhibitory pathway are associated with disease, including obesity and non-alcoholic fatty liver disease.

N6 -methyladenosine-modified circRNA RERE modulates osteoarthritis by regulating ß-catenin ubiquitination and degradation.

OBJECTIVES: N6 -methyladenosine (m6A) is one of the most abundant internal RNA modifications. We investigated the role of m6A-modified circRERE in osteoarthritis (OA) and its mechanism. MATERIALS AND METHODS: CircRERE and IRF2BPL were screened by microarrays. The role of m6A-modification in circRERE was examined by methylated RNA precipitation and morpholino oligo (MOs) treatment. The axis of circRERE/miR-195-5p/IRF2BPL/ß-catenin was determined using flow cytometry, western blotting and immunofluorescence in human chondrocytes (HCs) and corroborated using a mouse model of destabilization of medial meniscus (DMM) with intra-articular (IA) injection of adeno-associated viruses (AAV). RESULTS: CircRERE was decreased in OA cartilage and chondrocytes compared with control. CircRERE downregulation was likely attributed to its increased m6A modification prone to endoribonucleolytic cleavage by YTHDF2-HRSP12-RNase P/MRP in OA chondrocytes. MOs transfection targeting HRSP12 binding motifs in circRERE partially reversed decreased circRERE expression and increased apoptosis in HCs treated with IL-1ß for 6 h. CircRERE exerted chondroprotective effects by targeting miR-195-5p/IRF2BPL, thus regulating the ubiquitination and degradation of ß-catenin. CircRere (mouse homologue) overexpression by IA-injection of AAV-circRere into mice attenuated the severity of DMM-induced OA, whereas AAV-miR-195a-5p or AAV-sh-Irf2bpl reduced the protective effects. The detrimental effects of AAV-sh-Irf2bpl on DMM-induced OA were substantially counteracted by ICG-001, an inhibitor of ß-catenin. CONCLUSIONS: Our study is a proof-of-concept demonstration for targeting m6A-modified circRERE and its target miR-195-5p/IRF2BPL/ß-catenin as potential therapeutic strategies for OA treatment.

Diethylenetriamine-ß-CD-modified carbon quantum dots for selective fluorescence sensing of Hg2+ and Fe3+ and cellular imaging.

Diethylenetriamine-ß-cyclodextrin-modified carbon quantum dots (3 N-CQDs) were synthesized via a one-step hydrothermal method using citric acid as the carbon source and diethylenetriamine-ß-cyclodextrin (3 N-ß-CD) as the nitrogen source. The successful preparation of 3 N-CQDs were revealed by infrared absorption spectroscopy, ultraviolet (UV)-visible absorption spectroscopy, fluorescence spectroscopy, XRD, XPS, TEM, and TG. Further spectroscopic studies showed that the synthesized carbon quantum dots offered good anti-interference capability. The relative fluorescence quantum yield was 67.2 %. The limits of detection for Hg2+ and Fe3+ were 0.25 µM and 0.57 µM, respectively. Cytotoxicity and imaging studies showed that the prepared carbon quantum dots had low cytotoxicity, good biocompatibility, and good cellular imaging capability for HeLa cells. They offered fluorescent sensing of Hg2+ and Fe3+ in live cells. Therefore, 3 N-CQDs were ideal fluorescent probes for the detection of Hg2+ and Fe3+ in water.

Immune function, gastrointestinal hormone levels, and their clinical significance in patients with gastric ulcers complicated with depression.

BACKGROUND: Gastric ulcer (GU) is a common digestive tract disease, and medical records of GU combined with depression are increasingly common. Currently, the risk factors and pathogenesis of GU complicated with depression remain unclear. Low immune function and gastrointestinal hormone levels may also be significant risk factors. Therefore, this study explored the immune function and gastrointestinal hormone levels in patients with GU combined with depression. AIM: To explore the immune function, gastrointestinal hormone level, and clinical significance of patients with GU combined with depression. METHODS: A retrospective analysis was conducted on 300 patients with GU combined with depression admitted to Guizhou Provincial People's Hospital from January 2021 to June 2022 as the study subjects. According to the Hamilton Depression Scale (HAMD) score, patients were divided into mild-to-moderate (n = 210) and heavy (n = 90) groups. Basic data, immune function indices [immunoglobulin A (IgA), IgM, IgG, serum CD4+ and CD8+ percentage, and CD4+/CD8+ ratio], and gastrointestinal hormone indices [serum gastrin (GAS), cholecystokinin (CCK), and motilin (MTL) levels] were collected. The basic data of the two groups were compared, and the immune function and gastrointestinal hormone indices were analyzed. Multivariate logistic regression was used to analyze the factors influencing the severity of GU complicated with depression. The receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) were used to analyze the value of the immune function index, gastrointestinal hormone index, and combined index in predicting the severity of GU complicated with depression. RESULTS: There were no marked differences in sex, age, body mass index, abdominal distension, abdominal pain, belching, nausea, vomiting, or sleep disorders between the heavy and mild-to-moderate groups (P > 0.05). There was a marked difference in the family history of depression between the heavy and mild-to-moderate groups (P < 0.05). There were significant differences in serum IgA and IgM levels and serum CD4+, CD8+, and CD4+/CD8+ ratios between the heavy and mild-to-moderate groups (P < 0.05). Multivariate analysis showed that IgA, IgM, GAS, and CCK serum levels influenced the severity of GU with depression (P < 0.05). The AUC of the ROC curve for serum IgA level predicting GU with depression severity was 0.808 [95% confidence interval (CI): 0.760-0.857], the AUC of the serum IgM level was 0.757 (95%CI: 0.700-0.814), the AUC of the serum GAS level was 0.853 (95%CI: 0.810-0.897), the AUC of the serum CCK level was 0.762 (95%CI: 0.709-0.822), the AUC of immune function (IgA, IgM) and gastrointestinal hormone levels (GAS, CCK) for the prediction of GU with depression severity was 0.958 (95%CI: 0.933-0.976). CONCLUSION: Important factors influencing GU complicated with depression are serum IgA, IgM, GAS, and CCK indicators. They can be used as indicators to predict the severity of GU complicated with depression.

RNA-targeted therapy corrects neuronal deficits in PACS1 syndrome mice.

Neurodevelopmental disorders (NDDs) are frequently associated with dendritic abnormalities in pyramidal neurons that affect arbor complexity, spine density, and synaptic communication 1,2. The underlying genetic causes are often complex, obscuring the molecular pathways that drive these disorders 3. Next-generation sequencing has identified recurrent de novo missense mutations in a handful of genes associated with NDDs, offering a unique opportunity to decipher the molecular pathways 4. One such gene is PACS1, which encodes the multi-functional trafficking protein PACS1 (or PACS-1); a single recurrent de novo missense mutation, c607C>T (PACS1R203W), causes developmental delay and intellectual disability (ID) 5,6. The processes by which PACS1R203W causes PACS1 syndrome are unknown, and there is no curative treatment. We show that PACS1R203W increases the interaction between PACS1 and the α-tubulin deacetylase HDAC6, elevating enzyme activity and appropriating control of its posttranscriptional regulation. Consequently, PACS1R203W reduces acetylation of α-tubulin and cortactin, causing the Golgi to fragment and enter developing neurites, leading to increased dendrite arborization. The dendrites, however, are beset with diminished spine density and fewer functional synapses, characteristic of ID pathology. Treatment of PACS1 syndrome mice with PACS1- or HDAC6-targeting antisense oligonucleotides restores neuronal structure and synaptic transmission, suggesting PACS1R203W/HDAC6 may be targeted for treating PACS1 syndrome neuropathology.

Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.

PACS1 syndrome is a neurodevelopmental disorder (NDD) caused by a recurrent de novo missense mutation in PACS1 (p.Arg203Trp (PACS1R203W)). The mechanism by which PACS1R203W causes PACS1 syndrome is unknown, and no curative treatment is available. Here, we use patient cells and PACS1 syndrome mice to show that PACS1 (or PACS-1) is an HDAC6 effector and that the R203W substitution increases the PACS1/HDAC6 interaction, aberrantly potentiating deacetylase activity. Consequently, PACS1R203W reduces acetylation of α-tubulin and cortactin, causing the Golgi ribbon in hippocampal neurons and patient-derived neural progenitor cells (NPCs) to fragment and overpopulate dendrites, increasing their arborization. The dendrites, however, are beset with varicosities, diminished spine density, and fewer functional synapses, characteristic of NDDs. Treatment of PACS1 syndrome mice or patient NPCs with PACS1- or HDAC6-targeting antisense oligonucleotides, or HDAC6 inhibitors, restores neuronal structure and synaptic transmission in prefrontal cortex, suggesting that targeting PACS1R203W/HDAC6 may be an effective therapy for PACS1 syndrome.