Spin squeezing of 1011 atoms by prediction and retrodiction measurements.

The measurement sensitivity of quantum probes using N uncorrelated particles is restricted by the standard quantum limit1, which is proportional to [Formula: see text]. This limit, however, can be overcome by exploiting quantum entangled states, such as spin-squeezed states2. Here we report the measurement-based generation of a quantum state that exceeds the standard quantum limit for probing the collective spin of 1011 rubidium atoms contained in a macroscopic vapour cell. The state is prepared and verified by sequences of stroboscopic quantum non-demolition (QND) measurements. We then apply the theory of past quantum states3,4 to obtain spin state information from the outcomes of both earlier and later QND measurements. Rather than establishing a physically squeezed state in the laboratory, the past quantum state represents the combined system information from these prediction and retrodiction measurements. This information is equivalent to a noise reduction of 5.6 decibels and a metrologically relevant squeezing of 4.5 decibels relative to the coherent spin state. The past quantum state yields tighter constraints on the spin component than those obtained by conventional QND measurements. Our measurement uses 1,000 times more atoms than previous squeezing experiments5-10, with a corresponding angular variance of the squeezed collective spin of 4.6 × 10-13 radians squared. Although this work is rooted in the foundational theory of quantum measurements, it may find practical use in quantum metrology and quantum parameter estimation, as we demonstrate by applying our protocol to quantum enhanced atomic magnetometry.

Active N6-Methyladenine Demethylation by DMAD Regulates Gene Expression by Coordinating with Polycomb Protein in Neurons.

A ten-eleven translocation (TET) ortholog exists as a DNA N6-methyladenine (6mA) demethylase (DMAD) in Drosophila. However, the molecular roles of 6mA and DMAD remain unexplored. Through genome-wide 6mA and transcriptome profiling in Drosophila brains and neuronal cells, we found that 6mA may epigenetically regulate a group of genes involved in neurodevelopment and neuronal functions. Mechanistically, DMAD interacts with the Trithorax-related complex protein Wds to maintain active transcription by dynamically demethylating intragenic 6mA. Accumulation of 6mA by depleting DMAD coordinates with Polycomb proteins and contributes to transcriptional repression of these genes. Our findings suggest that active 6mA demethylation by DMAD plays essential roles in fly CNS by orchestrating through added epigenetic mechanisms.

Formate-tetrahydrofolate ligase: supplying the cytosolic one-carbon network in roots with one-carbon units originating from glycolate.

The metabolism of tetrahydrofolate (H4PteGlun)-bound one-carbon (C1) units (C1 metabolism) is multifaceted and required for plant growth, but it is unclear what of many possible synthesis pathways provide C1 units in specific organelles and tissues. One possible source of C1 units is via formate-tetrahydrofolate ligase, which catalyzes the reversible ATP-driven production of 10-formyltetrahydrofolate (10-formyl-H4PteGlun) from formate and tetrahydrofolate (H4PteGlun). Here, we report biochemical and functional characterization of the enzyme from Arabidopsis thaliana (AtFTHFL). We show that the recombinant AtFTHFL has lower Km and kcat values with pentaglutamyl tetrahydrofolate (H4PteGlu5) as compared to monoglutamyl tetrahydrofolate (H4PteGlu1), resulting in virtually identical catalytic efficiencies for the two substrates. Stable transformation of Arabidopsis plants with the EGFP-tagged AtFTHFL, followed with fluorescence microscopy, demonstrated cytosolic signal. Two independent T-DNA insertion lines with impaired AtFTHFL function had shorter roots compared to the wild type plants, demonstrating the importance of this enzyme for root growth. Overexpressing AtFTHFL led to the accumulation of H4PteGlun + 5,10-methylene-H4PteGlun and serine, accompanied with the depletion of formate and glycolate, in roots of the transgenic Arabidopsis plants. This metabolic adjustment supports the hypothesis that AtFTHFL feeds the cytosolic C1 network in roots with C1 units originating from glycolate, and that these units are then used mainly for biosynthesis of serine, and not as much for the biosynthesis of 5-methyl-H4PteGlun, methionine, and S-adenosylmethionine. This finding has implications for any future attempts to engineer one-carbon unit-requiring products through manipulation of the one-carbon metabolic network in non-photosynthetic organs.

Platelet-derived microvesicles regulate vascular smooth muscle cell energy metabolism via PRKAA after intimal injury.

Vascular intimal injury initiates various cardiovascular disease processes. Exposure to subendothelial collagen can cause platelet activation, leading to collagen-activated platelet-derived microvesicles (aPMVs) secretion. In addition, vascular smooth muscle cells (VSMCs) exposed to large amounts of aPMVs undergo abnormal energy metabolism; they proliferate excessively and migrate after the loss of endothelium, eventually contributing to neointimal hyperplasia. However, the roles of aPMVs in VSMC energy metabolism are still unknown. Our carotid artery intimal injury model indicated that platelets adhered to injured blood vessels. In vitro, phosphorylated Pka (cAMP-dependent protein kinase) content was increased in aPMVs. We also found that aPMVs significantly reduced VSMC glycolysis and increased oxidative phosphorylation, and promoted VSMC migration and proliferation by upregulating phosphorylated PRKAA (α catalytic subunit of AMP-activated protein kinase) and phosphorylated FoxO1. Compound C, an inhibitor of PRKAA, effectively reversed the enhancement of cellular function and energy metabolism triggered by aPMVs in vitro and neointimal formation in vivo. We show that aPMVs can affect VSMC energy metabolism through the Pka-PRKAA-FoxO1 signaling pathway and this ultimately affects VSMC function, indicating that the shift in VSMC metabolic phenotype by aPMVs can be considered a potential target for the inhibition of hyperplasia. This provides a new perspective for regulating the abnormal activity of VSMCs after injury.

OsGEX3 affects anther development and improves osmotic stress tolerance in rice.

MAIN CONCLUSION: Overexpression and loss of function of OsGEX3 reduce seed setting rates and affect pollen fertility in rice. OsGEX3 positively regulates osmotic stress response by regulating ROS scavenging. GEX3 proteins are conserved in plants. AtGEX3 encodes a plasma membrane protein that plays a crucial role in pollen tube guidance. However, the function of its homolog in rice, OsGEX3, has not been determined. Our results demonstrate that OsGEX3 is localized in the plasma membrane and the nucleus as shown by a transiently transformed assay using Nicotiana benthamiana leaves. The up-regulation of OsGEX3 was detected in response to treatments with polyethylene glycol (PEG) 4000, hydrogen peroxide, and abscisic acid (ABA) via RT-qPCR analysis. Interestingly, we observed a significant decline in the seed setting rates of OsGEX3-OE lines and mutants, compared to the wild type. Further investigations reveal that overexpression and loss of function of OsGEX3 affect pollen maturation. TEM observation revealed a significant decrease in the fertile pollen rates of OsGEX3-OE transgenic lines and Osgex3 mutants due to a delay in pollen development at the late vacuolated stage. Overexpression of OsGEX3 improved osmotic stress and oxidative stress tolerance by enhancing reactive oxygen species (ROS) scavenging in rice seedlings, whereas Osgex3 mutants exhibited an opposite phenotype in osmotic stress. These findings highlight the multifunctional roles of OsGEX3 in pollen development and the response to abiotic stress. The functional characterization of OsGEX3 provides a fundamental basis for rice molecular breeding and can facilitate efforts to cultivate drought resistance and yield-related varieties.

Realizing Exceptional Points by Floquet Dissipative Couplings in Thermal Atoms.

Exceptional degeneracies and generically complex spectra of non-Hermitian systems are at the heart of numerous phenomena absent in the Hermitian realm. Recently, it was suggested that Floquet dissipative coupling in the space-time domain may provide a novel mechanism to drive intriguing spectral topology with no static analogs, though its experimental investigation in quantum systems remains elusive. We demonstrate such Floquet dissipative coupling in an ensemble of thermal atoms interacting with two spatially separated optical beams, and observe an anomalous anti-parity-time symmetry phase transition at an exception point far from the phase-transition threshold of the static counterpart. Our protocol sets the stage for Floquet engineering of non-Hermitian topological spectra, and for engineering new quantum phases that cannot exist in static systems.

Longitudinal evaluation of retinal neuroaxonal loss in epilepsy using optical coherence tomography.

OBJECTIVE: People with epilepsy (PwE) suffer from progressive brain atrophy, which is reflected as neuroaxonal loss on the retinal level. This study aims to provide initial insight into the longitudinal dynamics of the retinal neuroaxonal loss and possible driving factors. METHODS: PwE and healthy controls (HC; 18-55 years of age) underwent spectral domain optical coherence tomography at baseline and 7.0 ± 1.5 and 6.7 ± 1.0 months later, respectively. The change in retinal thickness/volume and annualized percentage change (APC) were calculated for the peripapillary retinal nerve fiber layer (pRNFL), the macular RNFL (mRNFL), the ganglion cell inner plexiform layer (GCIP), the inner nuclear layer, and the total macular volume (TMV). Group comparisons and multiple linear models with stepwise backward selection were performed to evaluate associations with demographic and clinical parameters. RESULTS: PwE (n = 44, 21 females, mean age = 35.6 ± 10.9 years) revealed a significant decrease in the pRNFL, mRNFL, GCIP, and TMV thickness or volume in the study interval. When compared to HC (n = 56, 37 females, mean age = 32.7 ± 8.3 years), the APC of the pRNFL (-.98 ± 3.13%/year) and the GCIP (-1.24 ± 2.56%/year) were significantly more pronounced in PwE (p = .01 and p = .046, respectively). Of note, atrophy of the mRNFL was significantly influenced by the number of antiseizure medications (ASMs; p = .047) and increasing age of PwE (p = .03). Contradictory results, however, were revealed for the impact of seizures. SIGNIFICANCE: In epilepsy, progression of retinal neuroaxonal loss was already detectable at short-term follow-up. PwE who receive a high number of ASMs seem to be at risk for accelerated neuroaxonal loss, stressing the importance of well-considered and effective antiseizure therapy.

Multimodal Theranostic Nanoparticles for Necrosis Targeting, Fluorescence/SPECT Imaging, and Radiotherapy of Residual Tumors after Hepatocellular Carcinoma Ablation.

Thermal ablation has been commonly used as an effective treatment for hepatocellular carcinoma; however, peri-necrotic tumor residues after ablation play a significant role in tumor recurrence and poor prognosis. Therefore, developing agents that can effectively target and eliminate residual tumors is critically needed. Necrosis targeting strategies have potential implications for evaluating tumor necrosis areas and treating the surrounding residual tumors. To address this issue, we have developed a biodegradable nanoparticle with necrosis avidity that is compatible with fluorescence imaging, single photon emission computed tomography (SPECT) imaging, and necrosis targeted radiotherapy. The nanoparticles were synthesized using iodine-131-labeled hypericin (131I-Hyp) as the core and amphiphilic copolymer poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-PCL) as the shell. The developed nanoparticle, PNP@(131I-Hyp), has a uniform spherical morphology with a size of 33.07 ± 3.94 and 45.93 ± 0.58 nm determined by cryogenic transmission electron microscopy (cryo-TEM) and dynamic light-scattering analysis (polydispersity index = 0.19 ± 0.01), respectively, and having a good stability and blood compatibility in vitro. In mouse subcutaneous ablated-residual tumor models, fluorescence and SPECT imaging demonstrated that PNP@(131I-Hyp) prominently accumulated in the tumor and was retained for as long as 168 h following intravenous injection. Moreover, ex vivo analyses showed that PNP@(131I-Hyp) mainly gathered in the necrotic zones of subcutaneous tumors and inhibited residual tumors by radiotherapy. In addition, histological examination of harvested organs and hematological analysis demonstrated that intravenous injection of 5 mCi/kg nanoparticles caused no gross abnormalities. This multifunctional nanoparticle, therefore, has necrosis imaging and targeted therapeutic effects on residual tumors after thermal ablation of hepatocellular carcinoma, showing potential for clinical application.

Long Noncoding RNAs MALAT1 and HOTTIP Act as Serum Biomarkers for Hepatocellular Carcinoma.

BACKGROUND: Circulating tumor markers with satisfactory sensitivity and specificity play crucial roles in cancer diagnosis and therapy. This prospective study aimed to evaluate the potential of circulating lncRNAs as biomarkers for hepatocellular carcinoma (HCC). METHODS: A total of 74 patients with HCC and 94 healthy controls were enrolled. The expression levels of candidate genes in serum were detected by qRT-PCR. Receiver operating characteristic (ROC) curve analysis and logistic regression were employed to investigate the diagnostic capacity of lncRNAs. The analysis of 3-year overall survival (OS) was conducted using the Kaplan-Meier method and log-rank test. RESULTS: Of the 9 candidate genes, 6 lncRNAs could be stably detected in serum. The expression levels of circulating MALAT1 and HOTTIP in HCC patients were significantly higher than those in controls (P < 0.001). ROC analysis showed that MALAT1 and HOTTIP were more effective than alpha-fetoprotein (AFP) (P < 0.010) in the diagnosis of HCC, with AUCs of 0.896 and 0.899, respectively. Additionally, a panel consisting of MALAT1, HOTTIP, and AFP was constructed to obtain an AUC of 0.968 with a sensitivity of 87.8% and specificity of 94.7% in HCC diagnosis. Moreover, the upregulation of MALAT1 was not only related to multiple tumor lesions, HCV infection, AST level, and AFP level, but also suggested shorter OS. A high expression level of HOTTIP was associated with metastasis. CONCLUSION: Serum MALAT1 and HOTTIP play indicative roles as non-invasive biomarkers for HCC.

Ultrafast and Highly Selective Sequestration of Radioactive Barium Ions by a Layered Thiostannate.

As a simulant of hazardous 226Ra2+, the simultaneously selective and rapid elimination of radioactive 133Ba2+ ions from geothermal water is necessary but still challenging. In this paper, we demonstrated the usability of a layered thiostannate with facile synthesis and inexpensive cost, namely, K2xSn4-xS8-x (KTS-3, x = 0.65-1), for the remediation of radioactive 133Ba2+ in multiple conditions, including sorption isotherm, kinetics, and the influences of competitive inorganic/organic ions, pH values, and dosages. KTS-3 has a strong barium uptake ability (171.3 mg/g) and an ultrafast adsorption kinetics (about 2 min). Impressively, it can achieve a high preference for barium regardless of the excessive interference ions (Na+, K+, Mg2+, Ca2+, and humic acid) and acidic/alkaline environments, with the largest distribution coefficient Kd value reaching 6.89 × 105 mL/g. Also, the Ba2+-laden products can be easily eluted by a concentrated KCl solution, and its adsorption performances for barium resist well even after five consecutive cycles. In addition, owing to the regular appearance and excellent mechanical strength, the prepared KTS-3/PAN (PAN = polyacrylonitrile) granule displays a good removal efficiency in the flowing ion-exchange column. These advantages mentioned above render it very promising for the effective and efficient cleanup of radioactive 133Ba2+-contaminated wastewater.

Orthodontic maxillary molar movement-induced zygomatic pillar remodeling and its consequences on occlusal characteristics and stress distribution.

OBJECTIVE: We aimed to evaluate changes in the zygomatic pillar during orthodontic treatment involving premolar extraction, analyze the effects of maxillary first molar movement on zygomatic pillar remodeling, and examine occlusal characteristics and stress distribution after remodeling. METHODS: Twenty-five patients who underwent premolar extraction were included in the study. The zygomatic pillar measurement range was defined, and cross-sectional areas, surface landmark coordinates, alveolar and cortical bone thicknesses, and density changes were assessed using Mimics software based on the cone-beam computed tomography scans taken before (T0) and after the treatment (T1). Multiple linear regression analysis was performed to determine the correlation between changes in the zygomatic pillar and maxillary first molar three-dimensional (3D) movement and rotation. Additionally, the correlation between pillar remodeling and occlusal characteristics was analyzed by Teetester. Pre- and post-reconstruction 3D finite element models were constructed and loaded with an average occlusal force of two periods. RESULTS: The morphological and structural remodeling of the zygomatic pillar after orthodontic treatment involving premolar extraction showed a decreased cross-sectional area of the lower segment of the zygomatic pillar. The zygomatic process point moved inward and backward, whereas the zygomatico-maxillary suture point moved backward. The thicknesses of the zygomatic pillar alveolar and cortical bones were thinner, and reduced alveolar bone density was observed. Simultaneously, the movement and angle change of the maxillary first molar could predict zygomatic pillar reconstruction to a certain extent. With decreasing the total occlusal force and the occlusal force of the first molar, occlusal force distribution was more uniform. With zygomatic pillar remodeling, occlusal stress distribution in the zygomatic alveolar ridge decreased, and occlusal stress was concentrated at the junction of the vertical and horizontal parts of the zygomatic bone and the posterior part of the zygomatic arch. CONCLUSIONS: Orthodontic treatment involving premolar extraction led to zygomatic pillar remodeling, making it more fragile than before and reducing the occlusal force of the maxillary first molar and the entire dentition with stress concentrated in weak areas. CLINICAL RELEVANCE: No other study has focused on the effects of orthodontics on pillar structures. The present study indicates that the mesial movement of the maxillary first molar weakened the zygomatic pillar and reduced occlusal function, thereby providing insights for inserting anchorage screws and facial esthetics.

Untargeted metabolomics revealed the effect of soybean metabolites on poly(γ-glutamic acid) production in fermented natto and its metabolic pathway.

BACKGROUND: Natto mucus is mainly composed of poly(γ-glutamic acid) (γ-PGA), which affects the sensory quality of natto and has some effective functional activities. The soybean metabolites that cause different γ-PGA contents in different fermented natto are unclear. RESULTS: In this study, we use untargeted metabolomics to analyze the metabolites of high-production γ-PGA natto and low-production γ-PGA natto and their fermented substrate soybean. A total of 257 main significantly different metabolites with the same trend among the three comparison groups were screened, of which 114 were downregulated and 143 were upregulated. Through the enrichment of metabolic pathways, the metabolic pathways with significant differences were purine metabolism, nucleotide metabolism, fructose and mannose metabolism, anthocyanin biosynthesis, isoflavonoid biosynthesis and the pentose phosphate pathway. CONCLUSION: For 114 downregulated main significantly different metabolites with the same trend among the three comparison groups, Bacillus subtilis (natto) may directly decompose them to synthesize γ-PGA. Adding downregulated substances before fermentation or cultivating soybean varieties with the goal of high production of such substances has a great effect on the production of γ-PGA by natto fermentation. The enrichment analysis results showed the main pathways affecting the production of γ-PGA by Bacillus subtilis (natto) using soybean metabolites, which provides a theoretical basis for the production of γ-PGA by soybean and promotes the diversification of natto products. © 2023 Society of Chemical Industry.

Effect of hot-air drying on drying characteristics and quality of tiger nut.

BACKGROUND: The delayed drying of newly harvested tiger nuts can lead to mold and rancidity. Timely drying is therefore important. However, few studies have analyzed the impact of hot-air drying on the quality of tiger-nut oil and starch, making it essential to establish optimal drying conditions. RESULTS: The results showed that the drying temperature was the most important factor affecting the drying speed, followed by drying airflow rate and loading capacity. A logarithmic model can describe the hot-air drying process of tiger nuts. The oil yield of tiger nut was highest after drying at 60 °C, reaching 22.40%. Meanwhile, the starch extracted from after drying at 60 °C had the highest solubility and expansion rate, 4.77% and 9.74%, respectively. Starch has the highest viscosity after drying at 70 °C, and it forms gel easily after aging. CONCLUSION: High-quality tiger nuts should be produced under optimal conditions: a hot-air drying temperature of 60 °C, an airflow rate of 1.0 m s-1, and a loading capacity of 100 g. The results of this study have practical implications for the effective drying of tiger nuts. © 2024 Society of Chemical Industry.

Expression of visfatin in gingival crevicular fluid and gingival tissues in different periodontal conditions: a cross-sectional study.

BACKGROUND: Studies have shown that visfatin is an inflammatory factor closely related to periodontitis. We examined the levels of visfatin in gingival crevicular fluid (GCF) and gingival tissues under different periodontal conditions, in order to provide more theoretical basis for exploring the role of visfatin in the pathogenesis of periodontitis. METHODS: We enrolled 87 subjects, with 43 in the chronic periodontitis (CP) group, 21 in the chronic gingivitis (CG) group, and 23 in the periodontal health (PH) group. Periodontal indexes (PD, AL, PLI, and BI) were recorded. GCF samples were collected for visfatin quantification, and gingival tissues were assessed via immunohistochemical staining. RESULTS: Visfatin levels in GCF decreased sequentially from CP to CG and PH groups, with statistically significant differences (P < 0.05). The CP group exhibited the highest visfatin levels, while the PH group had the lowest. Gingival tissues showed a similar trend, with significant differences between groups (P < 0.001). Periodontal indexes were positively correlated with visfatin levels in both GCF and gingival tissues (P < 0.001). A strong positive correlation was observed between visfatin levels in GCF and gingival tissues (rs = 0.772, P < 0.001). CONCLUSION: Greater periodontal destruction corresponded to higher visfatin levels in GCF and gingival tissues, indicating their potential collaboration in damaging periodontal tissues. Visfatin emerges as a promising biomarker for periodontitis and may play a role in its pathogenesis.

Investigating oral microbiome profiles in patients with cleft lip and palate compared with the healthy control.

BACKGROUND: Patients with cleft lip and palate (CLP) have an oronasal communication differed from the closed state in healthy individuals, leading to a unique oral microbiome. This study aimed to determine if variances in the oral microbiota persist among CLP patients who have received treatments for the closure of these fistulas compared to the microbiota of healthy individuals. METHODS: Saliva samples were collected from a cohort comprising 28 CLP patients (CLP group) and 30 healthy controls (HC group). Utilizing 16S rRNA sequencing on the Illumina NovaSeq platform, we conducted a comprehensive analysis of the diversity and composition of the oral microbiota. RESULTS: The analysis of the microbiota in the saliva samples revealed a total of 23 microbial phyla, 38 classes, 111 orders, 184 families, 327 genera and 612 species. The alpha diversity with microbial abundance and evenness indicated the significant difference between the CLP and HC groups. Principal coordinate analysis (PCoA) and the ADONIS test further supported the presence of distinct microorganisms between the two groups. The CLP group displayed elevated abundances of Neisseria, Haemophilus, Porphyromonas, and Granulicatella, as indicated by LefSe analysis. Conversely, Rothia, Veillonella, and Pauljensenia exhibited significant reductions in abundance in the CLP group. The results of the PICRUSt analysis indicated significant differences in the relative abundance of 25 KEGG pathways within the CLP group. Through Spearman correlation analysis, strong associations between Rothia, Veillonella, and Pauljensenia and 25 functional pathways linked to CLP were identified. CONCLUSION: Findings of this study offer a thorough comprehension of the microbiome profiles of CLP patients after the restoration of oronasal structure and are anticipated to present innovative concepts for the treatment of CLP.

Prediction of plant secondary metabolic pathways using deep transfer learning.

BACKGROUND: Plant secondary metabolites are highly valued for their applications in pharmaceuticals, nutrition, flavors, and aesthetics. It is of great importance to elucidate plant secondary metabolic pathways due to their crucial roles in biological processes during plant growth and development. However, understanding plant biosynthesis and degradation pathways remains a challenge due to the lack of sufficient information in current databases. To address this issue, we proposed a transfer learning approach using a pre-trained hybrid deep learning architecture that combines Graph Transformer and convolutional neural network (GTC) to predict plant metabolic pathways. RESULTS: GTC provides comprehensive molecular representation by extracting both structural features from the molecular graph and textual information from the SMILES string. GTC is pre-trained on the KEGG datasets to acquire general features, followed by fine-tuning on plant-derived datasets. Four metrics were chosen for model performance evaluation. The results show that GTC outperforms six other models, including three previously reported machine learning models, on the KEGG dataset. GTC yields an accuracy of 96.75%, precision of 85.14%, recall of 83.03%, and F1_score of 84.06%. Furthermore, an ablation study confirms the indispensability of all the components of the hybrid GTC model. Transfer learning is then employed to leverage the shared knowledge acquired from the KEGG metabolic pathways. As a result, the transferred GTC exhibits outstanding accuracy in predicting plant secondary metabolic pathways with an average accuracy of 98.30% in fivefold cross-validation and 97.82% on the final test. In addition, GTC is employed to classify natural products. It achieves a perfect accuracy score of 100.00% for alkaloids, while the lowest accuracy score of 98.42% for shikimates and phenylpropanoids. CONCLUSIONS: The proposed GTC effectively captures molecular features, and achieves high performance in classifying KEGG metabolic pathways and predicting plant secondary metabolic pathways via transfer learning. Furthermore, GTC demonstrates its generalization ability by accurately classifying natural products. A user-friendly executable program has been developed, which only requires the input of the SMILES string of the query compound in a graphical interface.

MicroRNA-16 inhibits the TLR4/NF-κB pathway and maintains tight junction integrity in irritable bowel syndrome with diarrhea.

Irritable bowel syndrome with diarrhea (IBS-D) is a chronic and relapsing inflammatory disorder in which pathogenesis has been shown to be in part the result of miRNA-mediated signaling. Here, we investigated the alleviatory role of miR-16 in IBS-D. First, we established an IBS-D mouse model using colonic instillation of acetic acid and developed an IBS-D cell model using lipopolysaccharide exposure. The experimental data demonstrated that miR-16 was underexpressed in the serum of IBS-D patients, as well as in the colorectal tissues of IBS-D mouse models and lipopolysaccharide-exposed intestinal epithelial cells. Next, miR-16 and TLR4 were overexpressed or inhibited to characterize their roles in the viability and apoptosis of intestinal epithelial cells, inflammation, and epithelial tight junction. We found that miR-16 overexpression increased the viability of intestinal epithelial cells, maintained tight junction integrity, and inhibited cell apoptosis and inflammation. We showed that miR-16 targeted TLR4 and inhibited the TLR4/NF-κB signaling pathway. Additionally, inhibition of NF-κB suppressed the long noncoding RNA XIST, thereby promoting enterocyte viability, inhibiting apoptosis and cytokine production, and maintaining tight junction integrity. In vivo experiments further verified the alleviatory effect of miR-16 on IBS-D symptoms in mice. Taken together, we conclude that miR-16 downregulates XIST through the TLR4/NF-κB pathway, thereby relieving IBS-D. This study suggests that miR-16 may represent a potential target for therapeutic intervention against IBS-D.

Downregulation of TOP2 modulates neurodegeneration caused by GGGGCC expanded repeats.

GGGGCC repeats in a non-coding region of the C9orf72 gene have been identified as a major genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We previously showed that the GGGGCC expanded repeats alone were sufficient to cause neurodegeneration in Drosophila. Recent evidence indicates that GGGGCC expanded repeats can modify various gene transcriptomes. To determine the role of these genes in GGGGCC-mediated neurotoxicity, we screened an established Drosophila model expressing GGGGCC expanded repeats in this study. Our results showed that knockdown of the DNA topoisomerase II (Top2) gene can specifically modulate GGGGCC-associated neurodegeneration of the eye. Furthermore, chemical inhibition of Top2 or siRNA-induced Top2 downregulation could alleviate the GGGGCC-mediated neurotoxicity in Drosophila assessed by eye neurodegeneration and locomotion impairment. By contrast, upregulated Top2 levels were detected in Drosophila strains, and moreover, TOP2A level was also upregulated in Neuro-2a cells expressing GGGGCC expanded repeats, as well as in the brains of Sod1G93A model mice. This indicated that elevated levels of TOP2A may be involved in a pathway common to the pathophysiology of distinct ALS forms. Moreover, through RNA-sequencing, a total of 67 genes, involved in the pathways of intracellular signaling cascades, peripheral nervous system development, and others, were identified as potential targets of TOP2A to modulate GGGGCC-mediated neurodegeneration.

Activation of endogenous retrovirus triggers microglial immuno-inflammation and contributes to negative emotional behaviors in mice with chronic stress.

BACKGROUND: The "missing" link of complex and multifaceted interplay among endogenous retroviruses (ERVs) transcription, chronic immuno-inflammation, and the development of psychiatric disorders is still far from being completely clarified. The present study was aimed to investigate the mechanism of protective role of inhibiting ERVs on reversing microglial immuno-inflammation in basolateral amygdala (BLA) in chronic stress-induced negative emotional behaviors in mice. METHODS: Male C57BL/6 mice were exposed to chronic unpredictable mild stress (CUMS) for 6 w. Negative emotional behaviors were comprehensively investigated to identify the susceptible mice. Microglial morphology, ERVs transcription, intrinsic nucleic acids sensing response, and immuno-inflammation in BLA were assessed. RESULTS: Mice with chronic stress were presented as obviously depressive- and anxiety-like behaviors, and accompanied with significant microglial morphological activation, murine ERVs genes MuERV-L, MusD, and IAP transcription, cGAS-IFI16-STING pathway activation, NF-κB signaling pathway priming, as well as NLRP3 inflammasome activation in BLA. Antiretroviral therapy, pharmacological inhibition of reverse transcriptases, as well as knocking-down the ERVs transcriptional regulation gene p53 significantly inhibited microglial ERVs transcription and immuno-inflammation in BLA, as well as improved the chronic stress-induced negative emotional behaviors. CONCLUSIONS: Our results provided an innovative therapeutic approach that targeting ERVs-associated microglial immuno-inflammation may be beneficial to the patients with psychotic disorders.

Kynurenine 3-Monooxygenase Gene SsCI51640 Is Required for Sporisorium scitamineum Mating/Filamentation by Regulating cAMP Pathway and Improving Sporidia Environmental Adaptability.

Sugarcane smut is a serious disease caused by Sporisorium scitamineum, which causes significant losses to the sugar industry. It is critical to reveal the molecular pathogenic mechanism of S. scitamineum to explore a new control strategy for sugarcane smut. On the basis of transcriptome sequencing data of two S. scitamineum strains with different pathogenicity, we identified the gene, SsCI51640, which was predicted to encode kynurenine 3-monooxygenase. In this study, we obtained knockout mutants and complementary mutants of this gene and identified gene function. The results showed that the sporidial growth rate and acid production ability of knockout mutants were significantly higher and stronger than those of the wild-type and complementary mutants. The growth of knockout mutants under abiotic stress (osmotic stress and cell wall stress) was significantly inhibited. In addition, the sexual mating ability and pathogenicity of knockout mutants were significantly reduced, while this phenomenon could be restored by adding exogenous cyclic adenosine monophosphate (cAMP). It is thus speculated that the SsCI51640 gene may regulate sexual mating and pathogenicity of S. scitamineum by the cAMP signaling pathway. Moreover, the SsCI51640 gene enhanced the sporidial environmental adaptability, which promoted sexual mating and development of pathogenicity. This study provides a theoretical basis for the molecular pathogenesis of S. scitamineum.