Hypoxia induced exosomal Circ-ZNF609 promotes pre-metastatic niche formation and cancer progression via miR-150-5p/VEGFA and HuR/ZO-1 axes in esophageal squamous cell carcinoma.

Exosomes derived from cancer are regarded as significant mediators of cancer-host crosstalk. Hypoxia, on the other hand, is one of the essential characteristics of solid tumors. This research set out to discover how circulating exosomes from hypoxic esophageal squamous cell carcinoma (ESCC) contribute to the formation of metastatic niches and distant metastasis. First, we noticed that human umbilical vein endothelial cells (HUVECs) had their tight connections disrupted and the expression of proteins involved in angiogenesis boosted by ESCC hypoxic exosomes. Hypoxia significantly induced Circ-ZNF609 expression in exosomes from ESCC, which was then internalized by HUVECs, as determined by circular RNA screening. High Circ-ZNF609 expression in HUVECs facilitated angiogenesis and vascular permeability, thereby promoting pre-metastatic niche formation, and enhancing distant metastasis in vitro and in vivo. Exosomal Circ-ZNF609 activated vascular endothelial growth factor A (VEGFA) mechanistically by sponging miR-150-5p. Exosomal Circ-ZNF609 also interacted with HuR and inhibited HuR binding to ZO-1, Claudin-1, and Occludin mRNAs, thereby reducing their translation. Collectively, our findings identified an essential function for exosomal Circ-ZNF609 from ESCC cells, suggesting the potential therapeutic value of exosomes for ESCC patients.

ViromeFlowX: a Comprehensive Nextflow-based Automated Workflow for Mining Viral Genomes from Metagenomic Sequencing Data.

Understanding the link between the human gut virome and diseases has garnered significant interest in the research community. Extracting virus-related information from metagenomic sequencing data is crucial for unravelling virus composition, host interactions, and disease associations. However, current metagenomic analysis workflows for viral genomes vary in effectiveness, posing challenges for researchers seeking the most up-to-date tools. To address this, we present ViromeFlowX, a user-friendly Nextflow workflow that automates viral genome assembly, identification, classification, and annotation. This streamlined workflow integrates cutting-edge tools for processing raw sequencing data for taxonomic annotation and functional analysis. Application to a dataset of 200 metagenomic samples yielded high-quality viral genomes. ViromeFlowX enables efficient mining of viral genomic data, offering a valuable resource to investigate the gut virome's role in virus-host interactions and virus-related diseases.

Mechanistic insight into glioma through spatially multidimensional proteomics.

Characterizing the tumor microenvironment at the molecular level is essential for understanding the mechanisms of tumorigenesis and evolution. However, the specificity of the blood proteome in localized region of the tumor and its linkages with other systems is difficult to investigate. Here, we propose a spatially multidimensional comparative proteomics strategy using glioma as an example. The blood proteome signature of tumor microenvironment was specifically identified by in situ collection of arterial and venous blood from the glioma region of the brain for comparison with peripheral blood. Also, by integrating with different dimensions of tissue and peripheral blood proteomics, the information on the genesis, migration, and exchange of glioma-associated proteins was revealed, which provided a powerful method for tumor mechanism research and biomarker discovery. The study recruited multidimensional clinical cohorts, allowing the proteomic results to corroborate each other, reliably revealing biological processes specific to gliomas, and identifying highly accurate biomarkers.

Self-sensing intelligent microrobots for noninvasive and wireless monitoring systems.

Microrobots have garnered tremendous attention due to their small size, flexible movement, and potential for various in situ treatments. However, functional modification of microrobots has become crucial for their interaction with the environment, except for precise motion control. Here, a novel artificial intelligence (AI) microrobot is designed that can respond to changes in the external environment without an onboard energy supply and transmit signals wirelessly in real time. The AI microrobot can cooperate with external electromagnetic imaging equipment and enhance the local radiofrequency (RF) magnetic field to achieve a large penetration sensing depth and a high spatial resolution. The working ranges are determined by the structure of the sensor circuit, and the corresponding enhancement effect can be modulated by the conductivity and permittivity of the surrounding environment, reaching ~560 times at most. Under the control of an external magnetic field, the magnetic tail can actuate the microrobotic agent to move accurately, with great potential to realize in situ monitoring in different places in the human body, almost noninvasively, especially around potential diseases, which is of great significance for early disease discovery and accurate diagnosis. In addition, the compatible fabrication process can produce swarms of functional microrobots. The findings highlight the feasibility of the self-sensing AI microrobots for the development of in situ diagnosis or even treatment according to sensing signals.

In Situ Device-Level TEM Characterization Based on Ultra-Flexible Multilayer MoS2 Micro-Cantilever.

Current state-of-the-art in situ transmission electron microscopy (TEM) characterization technology has been capable of statically or dynamically nanorobotic manipulating specimens, affording abundant atom-level material attributes. However, an insurmountable barrier between material attributes investigations and device-level application explorations exists due to immature in situ TEM manufacturing technology and sufficient external coupled stimulus. These limitations seriously prevent the development of in situ device-level TEM characterization. Herein, a representative in situ opto-electromechanical TEM characterization platform is put forward by integrating an ultra-flexible micro-cantilever chip with optical, mechanical, and electrical coupling fields for the first time. On this platform, static and dynamic in situ device-level TEM characterizations are implemented by utilizing molybdenum disulfide (MoS2 ) nanoflake as channel material. E-beam modulation behavior in MoS2  transistors is demonstrated at ultra-high e-beam acceleration voltage (300 kV), stemming from inelastic scattering electron doping into MoS2  nanoflakes. Moreover, in situ dynamic bending MoS2  nanodevices without/with laser irradiation reveals asymmetric piezoresistive properties based on electromechanical effects and secondary enhanced photocurrent based on opto-electromechanical coupling effects, accompanied by real-time monitoring atom-level characterization. This approach provides a step toward advanced in situ device-level TEM characterization technology with excellent perception ability and inspires in situ TEM characterization with ultra-sensitive force feedback and light sensing.

3D Chiral Micro-Pinwheels Based on Rolling-Up Kirigami Technology.

Expanding micro-/nanostructures into 3D ones results not only in boosting structural integration level with compact geometry but also enhancing a device's complexity and functionality. Herein, a synergetic 3D micro-/nanoshape transformation is proposed by combining kirigami and rolling-up techniques, or rolling-up kirigami, for the first time. As an example, micro-pinwheels with multiple flabella are patterned on pre-stressed bilayer membranes and rolled up into 3D structures. The flabella are designed when they are patterned on a 2D thin film, facilitating the integration of micro-/nanoelement and other functionalization processes during 2D patterning, which is typically much easier than post-shaping an as-fabricated 3D structure by removing redundant materials or 3D printing. The dynamic rolling-up process is simulated using elastic mechanics with a movable releasing boundary. Mutual competition and cooperation among flabella are observed during the whole release process. More importantly, the mutual conversion between translation and rotation offers a reliable platform for developing parallel microrobots and adaptive 3D micro-antennas. Additionally, 3D chiral micro-pinwheel arrays integrated into a microfluidic chip are successfully applied to detect organic molecules in solution using a terahertz apparatus. With an extra actuation, active micro-pinwheels can potentially serve as a base to functionalize 3D kirigami as tunable devices.

Gate-Tunable van der Waals Photodiodes with an Ultrahigh Peak-to-Valley Current Ratio.

Photodetectors and imagers based on 2D layered materials are currently subject to a rapidly expanding application space, with an increasing demand for cost-effective and lightweight devices. However, the underlying carrier transport across the 2D homo- or heterojunction channel driven by the external electric field, like a gate or drain bias, is still unclear. Here, a visible-near infrared photodetector based on van der Waals stacked molybdenum telluride (MoTe2 ) and black phosphorus (BP) is reported. The type-I and type-II band alignment can be tuned by the gate and drain voltage combined showing a dynamic modulation of the conduction polarity and negative differential transconductance. The heterojunction devices show a good photoresponse to light illumination ranging from 520-2000 nm. The built-in potential at the MoTe2 /BP interface can efficiently separate photoexcited electron-hole pairs with a high responsivity of 290 mA W-1 , an external quantum efficiency of 70%, and a fast photoresponse of 78 µs under zero bias.

Melatonin protects against developmental PBDE-47 neurotoxicity by targeting the AMPK/mitophagy axis.

The neurotoxicity of 2,2',4,4'-tetrabromodiphenyl ether (PBDE-47) is closely linked to mitochondrial abnormalities while mitophagy is vital for mitochondrial homeostasis. However, whether PBDE-47 disrupts mitophagy contributing to impaired neurodevelopment remain elusive. Here, this study showed that neonatal PBDE-47 exposure caused learning and memory deficits in adult rats, accompanied with striatal mitochondrial abnormalities, neuronal apoptosis and the resultant neuronal loss. Mechanistically, PBDE-47 suppressed PINK1/Parkin-mediated mitophagy induction and degradation, inducing mitophagosome accumulation and mitochondrial dysfunction in vivo and in vitro. Additionally, stimulation of mitophagy by adenovirus-mediated Parkin or Autophagy-related protein 7 (Atg7) overexpression aggravated PBDE-47-induced mitophagosome accumulation, mitochondrial dysfunction, neuronal apoptosis and death. Conversely, suppression of mitophagy by the siRNA knockdown of Atg7 rescued PBDE-47-induced detrimental consequences. Importantly, melatonin, a hormone secreted rhythmically by the pineal, improved PBDE-47-caused neurotoxicity via preventing neuronal apoptosis and loss by restoring mitophagic activity and mitochondrial function. These neuroprotective effects of melatonin depended on activation of the AMP-activated protein kinase (AMPK)/Unc-51-like kinase 1 (ULK1) signaling. Collectively, these data indicate that PBDE-47 impairs mitophagy to perturb mitochondrial homeostasis, thus triggering apoptosis, leading to neuronal loss and consequent neurobehavioral deficits. Manipulation of the AMPK-mitophagy axis via melatonin could be a novel therapeutic strategy against developmental PBDE-47 neurotoxicity.

High-Performance C60 Coupled Ferroelectric Enhanced MoS2 Nonvolatile Memory.

Nonvolatile memory (NVM) devices based on two-dimensional (2D) materials have recently attracted widespread attention due to their high-density integration potential and the ability to be applied in computing-in-memory systems in the post-Moore era. Considering the high current on/off ratio, programmable threshold voltage, nonvolatile multilevel memory state, and extended logic functions, plenty of breakthroughs related to ferroelectric field-effect transistors (FeFETs), one of the most important NVM devices, have been made in the past decade. Among them, FETs coupled with organic ferroelectric films such as P(VDF-TrFE) displayed properties of remarkable robustness, easy preparation, and low cost. However, the dipoles of the P(VDF-TrFE) film cannot be flipped smoothly at low voltage, impeding the further application of organic FeFET. In this paper, we proposed a high-performance FeFET based on monolayer MoS2 coupled with C60 doped ferroelectric copolymer P(VDF-TrFE). The inserted C60 molecules enhanced the alignment of the dipoles effectively at low voltage, allowing the modified device to demonstrate a large memory window (∼16 V), high current on/off ratio (>106), long retention time (>10 000 s), and remarkable endurance under the reduced operating voltage. In addition, the in situ logic application can be realized by constructing facile device interconnection without building complex complementary semiconductor circuits. Our results are expected to pave the way for future low-consumption computing-in-memory applications based on high-quality 2D FeFETs.

Recent progress in three-terminal artificial synapses based on 2D materials: from mechanisms to applications.

Synapses are essential for the transmission of neural signals. Synaptic plasticity allows for changes in synaptic strength, enabling the brain to learn from experience. With the rapid development of neuromorphic electronics, tremendous efforts have been devoted to designing and fabricating electronic devices that can mimic synapse operating modes. This growing interest in the field will provide unprecedented opportunities for new hardware architectures for artificial intelligence. In this review, we focus on research of three-terminal artificial synapses based on two-dimensional (2D) materials regulated by electrical, optical and mechanical stimulation. In addition, we systematically summarize artificial synapse applications in various sensory systems, including bioplastic bionics, logical transformation, associative learning, image recognition, and multimodal pattern recognition. Finally, the current challenges and future perspectives involving integration, power consumption and functionality are outlined.

A Core-Shell MWCNT-Pt Nanowire Electron Source with Anomalously Long-Term Stable Field Emission.

A hybrid core-shell structured nanowire is proposed for a long-term stable electron source based on an isolated platinum/multi-walled carbon nanotube (Pt/MWCNT). This hybrid nanowire is prepared by growing a Pt shell on a metallic MWCNT through a field-emission-induced deposition (FEID) method. An in situ field emission (FE) platform was constructed inside a scanning electron microscope (SEM) equipped with two nanorobotic manipulators (NRMs) for the preparation and testing of the hybrid nanowire. An in situ fatigue test was conducted with high current intensity (500 nA) to show the influence of the Pt shell. Compared with the pristine bare MWCNT, our hybrid-nanowire-based electron source has a lifetime of hundreds of times longer and can work continuously for up to 48 h under relatively high pressure (3.6×10-3 Pa) without having an apparent change in its structure or emission currents, demonstrating good stability and tolerance to poor working conditions. The anomalous long-term stability is attributed mainly to the shielding of oxygen by Pt from the carbon shells and less heating due to the work function lowering by Pt.

Association between dental fluorosis prevalence and inflammation levels in school-aged children with low-to-moderate fluoride exposure.

Inflammation mediates the neurological deficits caused by fluoride. Thus, whether inflammation is the underlying mechanism of dental fluorosis (DF) in school-aged children is worth exploring. A cross-sectional study was conducted to investigate the association between inflammation and the prevalence and severity of DF with low-to-moderate fluoride exposure. Fasting morning urine and venous blood samples were collected from 593 children aged 7-14 years. The fluoride content in the water and urine samples was measured using a fluoride ion-selective electrode assay. The levels of interleukin-1ß (IL-1ß) and C-reactive protein (CRP) were detected using an enzyme-linked immunosorbent assay. The Dean's index was used when performing dental examinations. Regression, stratified, and mediation analyses were performed to analyze the association between fluoride exposure, inflammation, and DF prevalence. In the adjusted regression models, the prevalence of mild DF was 1.723-fold (95% confidence interval [CI]:1.612, 1.841) and 1.594-fold (1.479, 1.717) greater than that of normal DF for each 1 mg/L increase in water and urinary fluoride content, respectively. The prevalence of mild DF increased by 3.3% for each 1 pg/mL increase in the IL-1ß level and by 26.0% for each 1 mg/L increase in the CRP level. Stratified analysis indicated a weaker association between fluoride concentration and DF prevalence in boys than in girls, and susceptibility in the boys was reflected by the association of IL-1ß with very mild and moderate DF prevalence. For every 1 mg/L increase in water and urinary fluoride levels, the proportion of IL-1ß-mediated effects on the prevalence of mild DF was 10.0% (6.1%, 15.8%) and 8.7% (4.8%, 15.2%), respectively, and the proportion of CRP-mediated effects was 9.2% (5.5%, 14.9%) and 6.1% (3.3%, 11.0%), respectively. This study indicates that the DF prevalence may be sex-specific. Inflammatory factors may partially mediate the increased prevalence of mild DF in school-aged children with low-to-moderate fluoride exposure.

Lipin1 plays complementary roles in myofibre stability and regeneration in dystrophic muscles.

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder caused by dystrophin mutations, leading to the loss of sarcolemmal integrity, and resulting in progressive myofibre necrosis and impaired muscle function. Our previous studies suggest that lipin1 is important for skeletal muscle regeneration and myofibre integrity. Additionally, we discovered that mRNA expression levels of lipin1 were significantly reduced in skeletal muscle of DMD patients and the mdx mouse model. To understand the role of lipin1 in dystrophic muscle, we generated dystrophin/lipin1 double knockout (DKO) mice, and compared the limb muscle pathology and function of wild-type B10, muscle-specific lipin1 deficient (lipin1Myf5cKO ), mdx and DKO mice. We found that further knockout of lipin1 in dystrophic muscle exhibited a more severe phenotype characterized by increased necroptosis, fibrosis and exacerbated membrane damage in DKO compared to mdx mice. In barium chloride-induced muscle injury, both lipin1Myf5cKO and DKO showed prolonged regeneration at day 14 post-injection, suggesting that lipin1 is critical for muscle regeneration. In situ contractile function assays showed that lipin1 deficiency in dystrophic muscle led to reduced specific force production. Using a cell culture system, we found that lipin1 deficiency led to elevated expression levels of necroptotic markers and medium creatine kinase, which could be a result of sarcolemmal damage. Most importantly, restoration of lipin1 inhibited the elevation of necroptotic markers in differentiated primary lipin1-deficient myoblasts. Overall, our data suggests that lipin1 plays complementary roles in myofibre stability and muscle function in dystrophic muscles, and overexpression of lipin1 may serve as a potential therapeutic strategy for dystrophic muscles. KEY POINTS: We identified that lipin1 mRNA expression levels are significantly reduced in skeletal muscles of Duchenne muscular dystrophy patients and mdx mice. We found that further depletion of lipin1 in skeletal muscles of mdx mice induces more severe dystrophic phenotypes, including enhanced myofibre sarcolemma damage, muscle necroptosis, inflammation, fibrosis and reduced specific force production. Lipin1 deficiency leads to elevated expression levels of necroptotic markers, whereas restoration of lipin1 inhibits their expression. Our results suggest that lipin1 is functionally complementary to dystrophin in muscle membrane integrity and muscle regeneration.

LncRNA Taurine Up-Regulated 1 plays a proapoptotic role by regulating nuclear-cytoplasmic shuttle of HuR under the condition of neuronal ischemia.

The study aimed to identify TUG1 as an essential regulator of apoptosis in HT22 (mouse hippocampal neuronal cells) by direct interaction with the RNA-binding protein HuR. In order to study the role of TUG1 in the context of ischemia, we used mouse hippocampal neuronal cells treated with oxyglucose deprivation to establish an in-vitro ischemia model. A bioinformatic analysis and formaldehyde RNA immunoprecipitation (fRIP) were used to investigate the biological functions. A Western blot assay and reverse transcription polymerase chain reaction were used to explore the expression of the molecules involved. A cell proliferation and cytotoxicity assay was performed to detect neuronal apoptosis. TUG1 exhibits a localization-specific expression pattern in HT22 cells under OGD treatment. The bioinformatics analysis showed a strong correlation between the TUG1 and HuR as predicted, and this interaction was subsequently confirmed by fRIP-qPCR. We found that HuR was translocated from the nucleus to the cytoplasm after ischemia treatment and subsequently targeted and stabilized COX-2 mRNA, which led to elevated COX-2 mRNA levels and apoptosis of the HT22 cells. Furthermore, nuclear-specific disruption of TUG1 prevented the translocation of HuR to the cytoplasm and decreased COX-2 mRNA expression, resulting in increased cell viability and partially reversed apoptosis. In conclusion, it was demonstrated that TUG1 accelerates the process of apoptosis by promoting the transfer of HuR to the cytoplasm and stabilizing COX-2 mRNA. These results provide useful information concerning a therapeutic target for ischemic stroke.

Unraveling Atomic-Scale Origins of Selective Ionic Transport Pathways and Sodium-Ion Storage Mechanism in Bi2 S3 Anodes.

It is a major challenge to achieve a high-performance anode for sodium-ion batteries (SIBs) with high specific capacity, high rate capability, and cycling stability. Bismuth sulfide, which features a high theoretical specific capacity, tailorable morphology, and low cost, has been considered as a promising anode for SIBs. Nevertheless, due to a lack of direct atomistic observation, the detailed understanding of fundamental intercalation behavior and Bi2 S3 's (de)sodiation mechanisms remains unclear. Here, by employing in situ high-resolution transmission electron microscopy, consecutive electron diffraction coupled with theoretical calculations, it is not only for the first time identified that Bi2 S3 exhibits specific ionic transport pathways preferred to diffuse along the (110) direction instead of the (200) plane, but also tracks their real-time phase transformations (de)sodiation involving multi-step crystallographic tuning. The finite-element analysis further disclosed multi-reaction induced deformation and the relevant stress evolution originating from the combined effect of the mechanical and electrochemical interaction. These discoveries not only deepen the understanding of fundamental science about the microscopic reaction mechanism of metal chalcogenide anodes but also provide important implications for performance optimization.

Transcriptomic Profiling of Intracranial Arteries in Adult Patients With Moyamoya Disease Reveals Novel Insights Into Its Pathogenesis.

Moyamoya disease (MMD) is a rare, progressively steno-occlusive cerebrovascular disorder of unknown etiology. Here, we revealed the gene expression profile of the intracranial arteries in MMD via the RNA-sequencing (RNA-seq). We identified 556 differentially expressed genes (DEGs) for MMD, including 449 and 107 significantly upregulated or downregulated genes. Compared with atherosclerosis-associated intracranial artery stenosis/occlusion (AS-ICASO) controls, upregulated genes were mainly involved in extracellular matrix (ECM) organization, whereas downregulated genes were primarily associated with mitochondrial function and oxidative phosphorylation in MMD. Moreover, we found that a separate sex analysis uncovers more DEGs (n = 1.022) compared to an combined sex analysis in MMD. We identified 133 and 439 sex-specific DEGs for men and women in MMD, respectively. About 95.6% of sex-specific DEGs were protein-coding genes and 3% of the genes belonged to long non-coding RNAs (lncRNA). Sex-specific DEGs were observed on all chromosomes, of which 95.49 and 96.59% were autosomal genes in men and women, respectively. These sex-specific DEGs, such as aquaporin-4 (AQP4), superoxide dismutase 3 (SOD3), and nuclear receptor subfamily 4 group A member 1 (NR4A1), may contribute to sex differences in MMD. This transcriptomic study highlighted that ECM and mitochondrial function are the central molecular mechanisms underlying MMD, and revealed sex differences in the gene expression in the intracranial arteries, thereby providing new insights into the pathogenesis of MMD.

Simultaneous and trace level quantification of two potential genotoxic impurities in valsartan drug substance using UPLC-MS/MS.

A sensitive and selective Ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method was developed for the identification and quantification of two potential genotoxic impurities (PGIs) - viz. methyl N-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-N-nitroso-L-valinate (PGI-1) and N-nitroso Valsartan (PGI-2) - in the angiotensin II receptor blocker valsartan. Among these impurities, PGI-1 is a distinctive compound which has never been reported. For this, chromatographic separation was performed using a Waters XBridge BEH C18 column (150 mm × 4.6 mm, 2.5 µm), with ammonium acetate aqueous solution (0.01 mol/L) as mobile phase A and acetonitrile as mobile phase B, in a gradient elution mode at a 0.5 mL/min flow rate. Mass spectrometric conditions were optimized using electrospray ionization (ESI) in positive mode. Following the International Conference of Harmonization (ICH) guidelines, this methodology is capable of quantifying 2 PGIs at 0.016 ppm in samples at 50 mg/mL concentration. This validated approach presented good linearity over the concentration range of 0.016-0.06 ppm for 2 PGIs. The correlation coefficient of each impurity was observed greater than 0.999. The accuracy of this method was in the range of 83-113% for the aforementioned PGIs. In addition, expert knowledge rules (Derek-based) and statistical (Q) SAR evaluation system (Sarah-based) were used to evaluate and classify the genotoxicity of both valsartan-related PGIs as well as to define their standard limits. The predicted results were positive and classified into the third category, and the total nitrosamine limit was set to 0.03 ppm. As such, this approach represents a good quality control system for the simultaneous and precise quantitation of PGIs in valsartan.

Rs7853346 Polymorphism in lncRNA-PTENP1 and rs1799864 Polymorphism in CCR2 are Associated with Radiotherapy-Induced Cognitive Impairment in Subjects with Glioma Via Regulating PTENP1/miR-19b/CCR2 Signaling Pathway.

LncRNA-PTENP1 was reported to promote multiple myeloma cancer stem cell proliferation, and the G allele of rs7853346 polymorphism in lncRNA-PTENP1 was demonstrated to enhance the effect of lncRNA-PTENP1. In this study, we aimed to study the potential effect of lncRNA-PTENP1 and CCR2 mRNA polymorphisms on cognitive impairment in glioma patients. In this study, 279 glioma patients were recruited and grouped according to their genotypes of rs7853346 in PTENP1 and rs1799864 in CCR1. Pathogenic parameters were collected from patients before radiotherapy (month 0) or at month 1 and month 3 after radiotherapy to study the effect of rs7853346 and rs1799864 on cognitive impairment. Sequence analysis, luciferase assay, real-time PCR, and Western blot were performed to study the regulatory relationships between lncRNA-PTENP1, miR-18b, and CCR2. The glioma patient groups exhibited no significant differences concerning basic characteristics. However, the CG&GG/GG genotype alleviated radiotherapy-induced cognitive impairment by exhibiting the highest MMSE among the four groups. On the contrary, parameters including the severity of depression, bladder control, global health status, itchy skin, and weakness of legs all showed no difference among different patient groups at month 0, month 1, and month 3. Also, a long-term positive effect of CG&GG/GG genotype on role functioning and social functioning was also observed after radiotherapy. Compared with patients carrying the CC genotype of rs7853346, the expression of lncRNA-PTENP1 was reduced while the miR-19b level was elevated in patients carrying the CG&GG genotypes of rs7853346. Moreover, the expression of CCR2 mRNA was the highest in the CC/GA&AA group and the lowest in the CG&GG/GG group. Subsequent sequence analysis and luciferase assay indicated that miR-19b could bind to lncRNA-PTENP1 and 3'UTR of CCR2 mRNA, and the knockdown of lncRNA-PTENP1 led to evident up-regulation of miR-19b and down-regulation of CCR2 mRNA/protein in a cellular model, thus verifying the presence of the lncRNA-PTENP1/miR-19b/CCR2 mRNA signaling pathway. In conclusion, by studying the changes in the key parameters of glioma patients who were subjected to radiotherapy, we concluded that the rs7853346 polymorphism in lncRNA-PTENP1 and the rs1799864 polymorphism in CCR2 could independently affect cognitive impairment, while a more significant combined effect on cognitive impairment was exerted in glioma patients via the signaling pathway of PTENP1/miR-19b/CCR2.

The G to A transformation of rs4702 polymorphism in 3'UTR of FURIN reduced the risk of radiotherapy-induced cognitive impairment in glioma patients.

The G allele of rs4702 polymorphism has been reported to reduce the production of mature BDNF and FURIN, both of which were closely associated with cognitive functions. Real-time PCR, ELISA and luciferase assay were performed to explore the interactions between miR-338-3p, FURIN and BDNF. T-RFLP was used to assess the intestinal flora in the stool samples of glioma patients after radiotherapy. We grouped the 106 glioma patients recruited according to the rs4702 polymorphism. The results showed no obvious correlation between rs4702 polymorphism and the expression of miR-338-3p. However, rs4702-A was associated with increased expression of FURIN and BDNF in the serum and PBMC of glioma patients after radiotherapy. Besides, the study found that rs4702-A was remarkably associated with increased enterotype I and decreased enterotype III in the stool of glioma patients after radiotherapy. Rs4702-A was also proved to be closely associated with increased MMSE, role functioning and social functioning at three months after radiotherapy. Furthermore, miR-338-3p repressed the expression of FURIN-G. Compared with G allele, the presence of A allele of rs4702 polymorphism in FURIN could obstruct the suppressive effect of miR-338-3p upon the expression of FURIN and BDNF in intestinal flora. Therefore, the carriers of A allele will be challenged with less risk of radiotherapy-induced cognitive impairment.

The cholinergic system, intelligence, and dental fluorosis in school-aged children with low-to-moderate fluoride exposure.

Disruption of cholinergic neurotransmission can affect cognition, but little is known about whether low-to-moderate fluoride exposure affects cholinergic system and its effect on the prevalence of dental fluorosis (DF) and intelligence quotient (IQ). A cross-sectional study was conducted to explore the associations of moderate fluoride exposure and cholinergic system in relation to children's DF and IQ. We recruited 709 resident children in Tianjin, China. Ion selective electrode method was used to detect fluoride concentrations in water and urine. Cholinergic system was assessed by the detection of choline acetyltransferase (ChAT), acetylcholinesterase (AChE) and acetylcholine (ACh) levels in serum. Compared with children in the first quartile, those in fourth quartile the risk of either developing DF or IQ < 120 increased by 19% and 20% for water and urinary fluoride. The risk of having both increased by 58% and 62% in third and fourth quartile for water fluoride, 52% and 65% for urinary fluoride. Water fluoride concentrations were positively associated with AChE and negatively associated with ChAT and ACh, trends were same for urinary fluoride except for ACh. The risk of either developing DF or having non-high intelligence rose by 22% (95%CI: 1.07%, 1.38%) for the fourth quartile than those in the first quartile of AChE, for having the both, the risk was 1.27 (95%CI: 1.07, 1.50), 1.37 (95%CI: 1.17, 1.62) and 1.44 (95%CI: 1.23, 1.68) in second, third and fourth quartiles. The mediation proportion by AChE between water fluoride and either developing DF or IQ < 120 was 15.7%. For both to exist, the proportion was 6.7% and 7.2% for water and urinary fluoride. Our findings suggest low-to-moderate fluoride exposure was associated with dysfunction of cholinergic system for children. AChE may partly mediate the prevalence of DF and lower probability of having superior and above intelligence.