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Abstract Background The epigenetic-age acceleration (EAA) represents the difference between chronological age and epigenetic age, reflecting accelerated biological aging. Observational studies suggested that oral disorders may impact DNA methylation patterns and aging, but their causal relationship remains largely unexplored. This study aimed to investigate potential causal associations between dental traits and EAA, as well as to identify possible mediators. Methods Using summary statistics of genome-wide association studies of predominantly European ancestry, we conducted univariable and multivariable Mendelian randomization (MR) to estimate the overall and independent effects of ten dental traits (dentures, bleeding gums, painful gums, loose teeth, toothache, ulcers, periodontitis, number of teeth, and two measures of caries) on four EAA subtypes (GrimAge acceleration [GrimAA], PhenoAge acceleration [PhenoAA], HannumAge acceleration [HannumAA] and intrinsic EAA [IEAA]), and used two-step Mendelian randomization to evaluate twelve potential mediators of the associations. Comprehensive sensitivity analyses were used to verity the robustness, heterogeneity, and pleiotropy. Results Univariable inverse variance weighted MR analyses revealed a causal effect of dentures on greater GrimAA (β: 2.47, 95% CI: 0.93–4.01, p = 0.002), PhenoAA (β: 3.00, 95% CI: 1.15–4.85, p = 0.001), and HannumAA (β: 1.96, 95% CI: 0.58–3.33, p = 0.005). In multivariable MR, the associations remained significant after adjusting for periodontitis, caries, number of teeth and bleeding gums. Three out of 12 aging risk factors were identified as mediators of the association between dentures and EAA, including body mass index, body fat percentage, and waist circumference. No evidence for reverse causality and pleiotropy were detected (p > 0.05). Conclusions Our findings supported the causal effects of genetic liability for denture wearing on epigenetic aging, with partial mediation by obesity. More attention should be paid to the obesity-monitoring and management for slowing EAA among denture wearers.

BackgroundThe role of autoimmune diseases (ADs) in temporomandibular disorders (TMDs) has been emphasized in observational studies. However, whether the causation exists is unclear, and controversy remains about which specific disorder is destructive in TMDs. This Mendelian randomization (MR) study aims to estimate the causal effect of common ADs on TMDs.MethodsGenetic data from published genome-wide association studies for fourteen common ADs, specifically multiple sclerosis (MS, N = 15,283), ankylosing spondylitis (AS, N = 22,647), asthma (N = 408,422), celiac disease (N = 15,283), Graves’ disease (N = 458,620), Hashimoto thyroiditis (N = 395,640), primary biliary cirrhosis (PBC, N = 11,375), primary sclerosing cholangitis (PSC, N = 14,890), psoriasis vulgaris (N = 483,174), rheumatoid arthritis (RA, N = 417,256), systemic lupus erythematosus (SLE, N = 23,210), Type 1 diabetes (T1D, N = 520,580), inflammatory bowel disease (IBD, N = 34,652), and Sjogren’s syndrome (SS, N = 407,746) were collected. Additionally, the latest summary-level data for TMDs (N = 228,812) were extracted from the FinnGen database. The overall effects of each immune traits were assessed via inverse-variance weighted (IVW), weighted median, and MR-Egger methods, and performed extensive sensitivity analyses. Finally, 731 immune cell phenotypes (N = 3,757) were analyzed for their mediating role in the significant causality.ResultsUnivariable MR analyses revealed that genetically predicted RA (IVW OR: 1.12, 95% CI: 1.05-1.19, p < 0.001) and MS (IVW OR: 1.06, 95% CI: 1.03-1.10, p = 0.001) were associated with increased risk of TMDs. Two out of 731 immune cell phenotypes were identified as causal mediators in the associations of RA with TMDs, including “CD25++ CD8+ T cell % CD8+ T cell” (mediation proportion: 6.2%) and “CD3 on activated CD4 regulatory T cell” (5.4%). Additionally, “CD127 on granulocyte” mediated 10.6% of the total effect of MS on TMDs. No reverse directions, heterogeneity, and pleiotropy were detected in the analyses (p > 0.05).ConclusionThis MR study provides new evidence regarding the causal impact of genetic predisposition to RA or MS on the increased risk of TMDs, potentially mediated by the modulation of immune cells. These findings highlight the importance for clinicians to pay more attention to patients with RA or MS when consulting for temporomandibular discomfort. The mediating role of specific immune cells is proposed but needs further investigation.

Abstract Background The role of thyroid health in temporomandibular disorders (TMDs) has been emphasized in observational studies. However, whether the causation exists is unclear, and controversy remains about which specific disorder, such as hypothyroidism or hyperthyroidism, is destructive in TMDs. This study aims to investigate the overall and specific causal effects of various thyroid conditions on TMDs. Methods Mendelian randomization (MR) studies were performed using genetic instruments for thyrotropin (TSH, N = 119,715), free thyroxine (fT4, N = 49,269), hypothyroidism (N = 410,141), hyperthyroidism (N = 460,499), and TMDs (N = 211,023). We assessed the overall effect of each thyroid factor via inverse-variance weighted (IVW), weighted median, and MR-Egger methods, and performed extensive sensitivity analyses. Additionally, multivariable MR was conducted to evaluate the direct or indirect effects of hypothyroidism on TMDs whilst accounting for TSH, fT4 and hyperthyroidism, and vice versa. Results Univariable MR analyses revealed a causal effect of hypothyroidism on an increased risk of TMDs (IVW OR: 1.12, 95% CI: 1.05–1.20, p = 0.001). No significant association between genetically predicted hyperthyroidism, TSH, or fT4 and TMDs. In the multivariable MR analyses, the effects of hypothyroidism on TMDs occurrence remained significant even after adjSusting for TSH, fT4 and hyperthyroidism (multivariable IVW OR: 1.10, 95% CI: 1.03–1.17, p = 0.006). No pleiotropy and heterogeneity were detected in the analyses (p > 0.05). Conclusions Hypothyroidism might causally increase the risk of TMDs through a direct pathway, highlighting the critical role of managing thyroid health in the prevention of TMDs. Clinicians should give heightened attention to patients with hypothyroidism when seeking medical advice for temporomandibular discomfort. However, caution is warranted due to the potential confounders, pleiotropy, and selection bias in the MR study.

Abstract Motor proteins, encoded by Kinesin superfamily (KIF) genes, are critical for brain development and plasticity. Increasing studies reported KIF’s roles in neurodevelopmental disorders. Here, a 6 years and 3 months‐old Chinese boy with markedly symptomatic epilepsy, intellectual disability, brain atrophy, and psychomotor retardation was investigated. His parents and younger sister were phenotypically normal and had no disease‐related family history. Whole exome sequencing identified a novel heterozygous in‐frame deletion (c.265_267delTCA) in exon 3 of the KIF5C in the proband, resulting in the removal of evolutionarily highly conserved p.Ser90, located in its ATP‐binding domain. Sanger sequencing excluded the proband's parents and family members from harboring this variant. The activity of ATP hydrolysis in vitro was significantly reduced as predicted. Immunofluorescence studies showed wild‐type KIF5C was widely distributed throughout the cytoplasm, while mutant KIF5C was colocalized with microtubules. The live‐cell imaging of the cargo‐trafficking assay revealed that mutant KIF5C lost the peroxisome‐transporting ability. Drosophila models also confirmed p.Ser90del's essential role in nervous system development. This study emphasized the importance of the KIF5C gene in intracellular cargo‐transport as well as germline variants that lead to neurodevelopmental disorders and might enable clinicians for timely and accurate diagnosis and disease management in the future.

Abstract Background Observational studies have shown that body mass index (BMI) is highly correlated with the occurrence of temporomandibular disorders (TMDs). However, these studies failed to present a causal relationship. Thus, we aimed to performed a Mendelian randomization (MR) study to investigate causality between BMI and TMDs. Methods We performed a two-sample bidirectional MR analysis using large-scale genome-wide association studies (GWAS). Data were obtained from a large-scale BMI dataset (N = 322,154), TMDs dataset (N = 134,280). The causal effects were estimated with inverse-variance weighted (IVW) method, MR Egger, weighted median. Sensitivity analyses were implemented with Cochran’s Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis and the funnel plot. Results In the forward MR analysis, a genetic prediction of low BMI was causally associated with a higher risk of TMDs (IVW OR: 0.575, 95% CI: 0.415–0.798, p: 0.001). Similar results were obtained using other complementary methods (MR Egger OR: 0.270, 95% CI: 0.104–0.698, p: 0.009; weighted median OR: 0.496, 95% CI: 0.298–0.826, p: 0.007). In the reverse MR results, TMDs was shown to have no significant effect on BMI (all p > 0.05). No pleiotropy and heterogeneity were detected in the bidirectional analysis (p > 0.05). Conclusion A lower BMI might be causally associated with increased risk of TMDs, supporting the importance of weight control for the prevention of TMDs. Clinicians should pay more attention to the low-BMI patients among those seeking medical advice due to temporomandibular joint discomfort.

A straightforward and efficient methodology has been developed for the synthesis of 3-cyano-2-pyridones via the C–C and C–N bond formation processes. A total of 51 diverse 3-cyano-2-pyridone derivatives were obtained in moderate to excellent yields. This reaction featured advantages such as a metal-free process, wide functional group tolerance, simple operation, and mild conditions. A plausible mechanism for the reaction was proposed. 3-cyano-2-pyridones as ricinine analogues for insecticidal properties were evaluated, and the compound 3ci (LC50 = 2.206 mg/mL) showed the best insecticidal property.

Epilepsy is one of the most common neurological disorders. Neuroinflammation involving the activation of microglia and astrocytes constitutes an important and common mechanism in epileptogenesis. Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, non-selective cation channel that plays pathological roles in various inflammation-related diseases. Our previous study demonstrated that Trpm2 knockout exhibits therapeutic effects on pilocarpine-induced glial activation and neuroinflammation. However, whether TRPM2 in microglia and astrocytes plays a common pathogenic role in this process and the underlying molecular mechanisms remained undetermined. Here, we demonstrate a previously unknown role for microglial TRPM2 in epileptogenesis. Trpm2 knockout in microglia attenuated kainic acid (KA)-induced glial activation, inflammatory cytokines production and hippocampal paroxysmal discharges, whereas Trpm2 knockout in astrocytes exhibited no significant effects. Furthermore, we discovered that these therapeutic effects were mediated by upregulated autophagy via the adenosine monophosphate activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in microglia. Thus, our findings highlight an important deleterious role of microglial TRPM2 in temporal lobe epilepsy.

The accumulation of myeloid derived suppressor cells (MDSC) has been associated with prostate cancer progression and castration resistance. Here the authors show that loss of ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, results in polymorphonuclear-MDSC infiltration and cooperates with Pten loss to accelerate prostate tumorigenesis.

An efficient, straightforward, and metal-free methodology to rapidly access functionalised pyrazolo-[1,5-c]quinazolinones via a [3 + 2] dipolar cycloaddition and regioselective ring expansion process was developed. The synthesised compounds were characterised by methods such as NMR, HRMS, and HPLC. The in vitro antiproliferative activity against A549 cells (non-small cell lung cancer) was significant for compounds 4i, 4m, and 4n with IC50 values of 17.0, 14.2, and 18.1 μM, respectively. In particular, compounds 4t and 4n showed inhibitory activity against CDK9/2. Predicted biological target and molecular modelling studies suggest that the compound 4t may target CDKs for antitumour effects. The synthesised derivatives were considered to have moderate drug-likeness and sufficient safety in silico. In summary, a series of pyrazolo-[1,5-c]quinazolinone derivatives with antitumour activity is reported for the first time. We provide not only a simple and efficient synthetic method but also helpful lead compounds for the further development of novel cyclin-dependent kinase (CDK) inhibitors.

Glioblastoma (GBM) is a deadly brain tumor characterized by signaling dysregulation and aberrant cell cycle control. The CDK4/6-Rb axis is dysregulated in approximately 80% of all GBM cases. In this study, the anti-GBM effect of a novel pyrimidin-2-amine, LH20 was evaluated in vitro using the primary GBM cell lines U87MG and U251. GBM cells were administered LH20 at concentrations of 0.1, 1, 4, 8, 10, 20, 100, and 200 µM for 24 and 48 h, and the proliferation rate was evaluated using a CCK8 assay. Migration, apoptosis, and cell cycle were also assessed using a wound healing assay, Annexin V-FITC/PI apoptosis assay, and cell cycle staining, respectively. The targets of LH20 were predicted using SwissTargetPrediction and molecular docking. Western blotting analysis was performed to confirm the anti-GBM mechanism of LH20. We found that at concentrations of 4, 8, and 10 µM, LH20 significantly inhibited the proliferation and migration of U87MG and U251 cells, induced late phase apoptosis, promoted tumor cell necrosis, and arrested the G2/M phase of the cell cycle. LH20 also inhibited CDK4 and CDK6 activities by decreasing the phosphorylation of Rb. Our results suggest LH20 as a potential treatment strategy against GBM.

Dynamic microtubules play a critical role in cell structure and function. In nervous system, microtubules are the major route for cargo protein trafficking and they specially extend into and out of synapses to regulate synaptic development and plasticity. However, the detailed depolymerization mechanism that regulates dynamic microtubules in synapses and dendrites is still unclear. In this study, we find that KIF2C, a dynamic microtubule depolymerization protein without known function in the nervous system, plays a pivotal role in the structural and functional plasticity of synapses and regulates cognitive function in mice. Through its microtubule depolymerization capability, KIF2C regulates microtubule dynamics in dendrites, and regulates microtubule invasion of spines in neurons in a neuronal activity-dependent manner. Using RNAi knockdown and conditional knockout approaches, we showed that KIF2C regulates spine morphology and synaptic membrane expression of AMPA receptors. Moreover, KIF2C deficiency leads to impaired excitatory transmission, long-term potentiation, and altered cognitive behaviors in mice. Collectively, our study explores a novel function of KIF2C in the nervous system and provides an important regulatory mechanism on how activity-dependent microtubule dynamic regulates synaptic plasticity and cognition behaviors.

The purpose of the present study was to investigate the impact of genetic polymorphism on fluvastatin pharmacokinetics. In addition, we compared the fluvastatin pharmacokinetics differences between extended-release (ER) 80 mg tablet and immediate-release (IR) 40 mg capsule in terms of drug metabolism enzyme and transporter genetic polymorphisms. In this open-label, randomized, two-period, two-treatment, crossover study (n = 24), effects of ABCG2, SLCO1B1, ABCB1, CYP2C9 and CYP3A5 polymorphisms on the pharmacokinetics of fluvastatin were analyzed. The administration dosage for IR 40 mg and ER 80 mg were twice and once daily, respectively, for total 7 d. Blood samples for pharmacokinetic evaluation were taken on the 1st and 7th d. The lower exposure following ER was observed. For ER tablets, SLCO1B1 T521C genotype correlated with AUC0-24 of repeat doses (P = 0.010). SLCO1B1 T521C genotype had no statistically significant effect on AUC0-24 of IR capsule of fluvastatin after single or repeated doses. In vitro study demonstrated that when the concentration of fluvastatin was low (< 1 µmol/l), the uptake of fluvastatin in the HEK293-OATP1B1 with SLCO1B1 521TT (Km=0.18 µmol/l) was faster than that with SLCO1B1 521CC (Km=0.49 µmol/l), On the other hand, when concentration reached to higher level (> 1 µmol/l), transport velocity of fluvastatin by HEK293-OATP1B1 with SLCO1B1 521TT (Km = 11.4 µmol/l) and with SLCO1B1 521TCC (Km=15.1 µmol/l) tend to be the same. It suggests that the increased effect of SLCO1B1 T521C genotype on ER formulation of fluvastatin was mainly caused by lower blood concentrations. We recommend that formulation should be incorporated into future pharmacogenomics studies. Keywords: Genetic polymorphisms, SLCO1B1, Fluvastatin, Immediate-release, Extended-release

When the radio communication of an armed squad fighting in a jungle is interfered with by enemy's radio jamming equipment and their command and intelligence cannot be transmitted and exchanged, are there any other communication methods that can be used to solve such an emergency and covert communication problem? Focusing on this problem, a camouflage covert communication method (CCCM) in air is proposed by imitating cricket's sound. As well-known, there exist all kinds of animals' sounds in the jungle; however, hearing these animals' sounds, people generally considers them as background noise and ignores them. Based on this fact, the proposed CCCM uses the cricket's sound as the carrier wave, imitates the features of the cricket's call sequence to construct the camouflage communication sequence, and utilizes the time interval (TI) between two adjacent pulses to encode information. Meanwhile, other animals' sound is superimposed to the camouflage communication sequence to improve the camouflage ability of the generated communication sequence. Experimental results are provided to demonstrate the performance of the proposed CCCM.

3D shape retrieval is an important researching field due to its wide applications in computer vision and multimedia fields. With the development of deep learning technology, great progress has been made in recent years and lots of methods have achieved promising 3D shape retrieval results. Due to the effective description of point cloud data on structural information for 3D shapes, lots of methods based on point cloud data format are proposed for better shape representation. However, most of them focus on extracting a global descrisptor from the whole 3D shape while the local features and detailed structural information are ignored, which negatively affect the effectiveness of shape descriptors. In addition, these methods also ignore the correlations among different parts of point clouds, which may introduce redundant information to the final shape descriptors. In order to address these issues, we propose a Multi-part attention network (MPAN) for 3D model retrieval based on point cloud. Firstly, we segment a 3D shape into multiple parts by employing a pre-trained PointNet++ segmentation model. After extracting the local features from them, we introduce a novel self-attention mechanism to explore the correlations between different parts. Meanwhile, by considering the structural relevance of them, the redundancy for representing 3D shapes is removed while the effective information is utilized. Finally, informative and discriminative shape descriptors, considering both local features and spatial correlations, are generated for 3D shape retrieval task. To validate the effectiveness of our method, we conduct several experiments on the public 3D shape benchmark, ShapeNetPart dataset. Experimental results and comparisons with state-of-the-art methods demonstrate the superiority of our proposed method.

Summary: Drugs targeting N-methyl-D-aspartate receptors (NMDARs) have been approved to treat major depressive disorder (MDD); however, the presence of undesirable psychotomimetic and cognitive side effects may limit their utility. In this study, we show that the phosphorylation levels of the GluN2B subunit at tyrosine (Y) 1070 increase in mice after both acute and chronic restraint stress (CRS) exposure. Preventing GluN2B-Y1070 phosphorylation via Y1070F mutation knockin produces effects similar to those of antidepressants but does not affect cognitive or anxiety-related behaviors in subject mice. Mechanistically, the Y1070F mutation selectively reduces non-synaptic NMDAR currents and increases the number of excitatory synapses in the layer 5 pyramidal neurons of medial prefrontal cortex (mPFC) but not in the hippocampus. Altogether, our study identifies phosphorylation levels of GluN2B-Y1070 in the mPFC as a dynamic, master switch guarding depressive behaviors, suggesting that disrupting the Y1070 phosphorylation of GluN2B subunit has the potential for developing new antidepressants.

Lung squamous cell carcinoma (LUSC) is one of the leading causes of tumor-driven deaths in the world. To date, studies on the tumor heterogeneity of LUSC at genomic level have only revealed limited therapeutic benefits. Therefore, system-wide research of LUSC at proteomic level may further improve precision medicine strategies on individual demands. To this end, we performed proteomic and phosphoproteomic study for LUSC samples of 25 Chinese patients. From our results, two subgroups (Cluster I and II) based on proteomic data were identified, which were associated with distinct molecular characteristics and clinicopathologic features. Combined with phosphoproteomic data, our result showed that spliceosome pathway was enriched in Cluster I, while focal adhesion pathway, immune-related pathways and Ras signaling pathway were enriched in Cluster II. In addition, we found that lymph node metastasis (LNM) was associated with our proteomic subgroups and cell cycle pathway was enriched in patients with LNM. Further analysis showed that MCM2, a DNA replication licensing factor involved in cell cycle pathway, was highly expressed in patients with poor prognosis, which was further proved by immunohistochemistry (IHC) analysis. In summary, our study provided a resource of the proteomic and phosphoproteomic features of LUSC in Chinese patients.

Autism spectrum disorder (ASD) and dyslexia are both neurodevelopmental disorders with high prevalence in children. Both disorders have strong genetic basis, and share similar social communication deficits co-occurring with impairments of reading or language. However, whether these two disorders share common genetic risks remain elusive. DOCK4 (dedicator for cytokinesis 4), a guanine nucleotide exchange factor (GEF) for the small GTPase Rac1, is one of few genes that are associated with both ASD and dyslexia. Dock4 is important for neuronal development and social behaviors. Two DOCK4 variations, Exon27-52 deletion (protein product: Dock4-945VS) and a missense mutation at rs2074130 (protein product: Dock4-R853H), are associated with dyslexia and/or ASD with reading difficulties. The present study explores the molecular and cellular functions of these two DOCK4 variants on neuronal development, by comparing them with the wild-type Dock4 protein. Notably, it is revealed that both mutants of Dock4 showed decreased ability to activate not only Rac1, but also another small GTPase Rap1. Consistently, both mutants were dysfunctional for regulation of cell morphology and cytoskeleton. Using Neuro-2a cells and hippocampus neurons as models, we found that both mutants had compromised function in promoting neurite outgrowth and dendritic spine formation. Electrophysiological recordings further showed that R853H partially lost the ability to promote excitatory synaptic transmission, whereas 945VS totally lost the ability. Together, we identified R853 as a previously uncharacterized site for the regulation of the integrity of Dock4 function, and provides insights in understanding the common molecular pathophysiology of ASD and dyslexia.

Neuroligins (NLs) are a group of postsynaptic cell adhesion molecules that function in synaptogenesis and synaptic transmission. Genetic defects in neuroligin 3 (NL3), a member of the NL protein family, are associated with autism. Studies in rodents have revealed that mutations of NL3 gene lead to increased growth and complexity in dendrites in the central nervous system. However, the detailed mechanism is still unclear. In our study, we found that deficiency of NL3 led to morphological changes of the pyramidal neurons in layer II/III somatosensory cortex in mice, including enlarged somata, elongated dendritic length, and increased dendritic complexity. Knockdown of NL3 in cultured rat neurons upregulated Akt/mTOR signaling, resulting in both increased protein synthesis and dendritic growth. Treating neurons with either rapamycin to inhibit the mTOR or LY294002 to inhibit the PI3K/Akt activity rescued the morphological abnormalities resulting from either NL3 knockdown or knockout (KO). In addition, we found that the hyperactivated Akt/mTOR signaling associated with NL3 defects was mediated by a reduction in phosphatase and tensin (PTEN) expression, and that MAGI-2, a scaffold protein, interacted with both NL3 and PTEN and could be a linker between NL3 and Akt/mTOR signaling pathway. In conclusion, our results suggest that NL3 regulates neuronal morphology, especially dendritic outgrowth, by modulating the PTEN/Akt/mTOR signaling pathway, probably via MAGI-2. Thereby, this study provides a new link between NL3 and neuronal morphology.

Abstract Background Our study aimed to investigate the roles of autophagy against high glucose induced response in retinal pigment epithelium (ARPE-19 cells). Methods The morphological changes and reactive oxygen species (ROS) generation in ARPE-19 cells under high glucose treatment were respectively detected using the transmission electron microscopy and flow cytometry. The expression levels of Parkin, PINK1, BNIP3L, LC3-I and LC3-II in ARPE-19 cells received high glucose treatment were measured by western blot after pretreatment of carbonyl cyanide m-chlorophenylhydrazone (CCCP), 3-methyladenine (3-MA), N-acetyl cysteine (NAC) or cyclosporin A (CsA) followed by high glucose treatment. Results ARPE-19 cells subjected to high glucose stress showed an obvious reduction in the LC3-I expression and significant increase in the number of autophagosomes, in the intracellular ROS level, and in the expression levels of Parkin, PINK1, BNIP3L and LC3-II (p

The growing amount of plastic solid waste (PSW) is a global concern. Despite increasing efforts to reduce the residual amounts of PSW to be disposed off through segregated collection and recycling, a considerable amount of PSW is still landfilled and the extent of PSW ocean pollution has become a worldwide issue. Particularly, polyethylene (PE) and polystyrene (PS) are considered as notably recalcitrant to biodegradation due to the carbon-carbon backbone that is highly resistant to enzymatic degradation via oxidative reactions. The present research investigated the catalytic mechanism of P450 monooxygenases by quantum mechanics to determine the bio-catalytic degradation of PE or PS. The findings indicated that the oxygenase-induced free radical transition caused the carbon-carbon backbone cleavage of aliphatic compounds. This work provides a fundamental knowledge of the biodegradation process of PE or PS at the atomic level and facilitates predicting the pathway of plastics’ biodegradation by microbial enzymes.

Huntington-interacting protein 1-related protein (HIP1R) was identified on the basis of its structural homology with HIP1. Based on its domain structure, HIP1R is a putative endocytosis-related protein. Our previous study had shown that knockdown of HIP1R induces a dramatic decrease of dendritic growth and branching in cultured rat hippocampal neurons. However, the underlying mechanism remains elucidative. In this study, we found that knockdown of HIP1R impaired the endocytosis of activated epidermal growth factor receptor (EGFR) and the consequent activation of the downstream ERK and Akt proteins. Meanwhile, it blocked the EGF-induced dendritic outgrowth. We also showed that the HIP1R fragment, amino acids 633–822 (HIP1R633–822), interacted with EGFR and revealed a dominant negative effect in disrupting the HIP1R-EGFR interaction-mediated neuronal development. Collectively, these results reveal a novel mechanism that HIP1R plays a critical role in neurite initiation and dendritic branching in cultured hippocampal neurons via mediating the endocytosis of EGFR and downstream signaling.

An all-optical non-inverted parity generator and checker based on semiconductor optical amplifiers (SOAs) are proposed with four-wave mixing (FWM) and cross-gain modulation (XGM) non-linear effects. A 2-bit parity generator and checker using by exclusive NOR (XNOR) and exclusive OR (XOR) gates are implemented by first SOA and second SOA with 10 Gb/s return-to-zero (RZ) code, respectively. The parity and check bits are provided by adjusting the center wavelength of the tunable optical bandpass filter (TOBPF). A saturable absorber (SA) is used to reduce the negative effect of small signal clock (Clk) probe light to improve extinction ratio (ER) and optical signal-to-noise ratio (OSNR). For Pe and Ce (even parity bit and even check bit) without Clk probe light, ER and OSNR still maintain good performance because of the amplified effect of SOA. For Po (odd parity bit), ER and OSNR are improved to 1 dB difference for the original value. For Co (odd check bit), ER is deteriorated by 4 dB without SA, while OSNR is deteriorated by 12 dB. ER and OSNR are improved by about 2 dB for the original value with the SA. This design has the advantages of simple structure and great integration capability and low cost.

Developing therapeutic approaches that target neuronal differentiation will be greatly beneficial for the regeneration of neurons and synaptic networks in neurological diseases. Protein synthesis (mRNA translation) has recently been shown to regulate neurogenesis of neural stem/progenitor cells (NSPCs). However, it has remained unknown whether engineering translational machinery is a valid approach for manipulating neuronal differentiation. The present study identifies that a bivalent securinine compound SN3-L6, previously designed and synthesized by our group, induces potent neuronal differentiation through a novel translation-dependent mechanism. An isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomic analysis in Neuro-2a progenitor cells revealed that SN3-L6 upregulated a group of neurogenic transcription regulators, and also upregulated proteins involved in RNA processing, translation, and protein metabolism. Notably, puromycylation and metabolic labeling of newly synthesized proteins demonstrated that SN3-L6 induced rapid and robust activation of general mRNA translation. Importantly, mRNAs of the proneural transcription factors Foxp1, Foxp4, Hsf1, and Erf were among the targets that were translationally upregulated by SN3-L6. Either inhibition of translation or knockdown of these transcription factors blocked SN3-L6 activity. We finally confirmed that protein synthesis of a same set of transcription factors was upregulated in primary cortical NPCs. These findings together identify a new compound for translational activation and neuronal differentiation, and provide compelling evidence that reprogramming transcriptional regulation network at translational levels is a promising strategy for engineering NSPCs.

Huntingtin-interacting protein 1-related (HIP1R) protein is considered to be an endocytic adaptor protein like the other two members of the Sla2 family, Sla2p and HIP1. They all contain homology domains responsible for the binding of clathrin, inositol lipids and F-actin. Previous studies have revealed that HIP1R is highly expressed in different regions of the mouse brain and localizes at synaptic structures. However, the function of HIP1R in the nervous system remains unknown. In this study, we investigated HIP1R function in cultured rat hippocampal neurons using an shRNA knockdown approach. We found that, after HIP1R knockdown, the dynamics and density of dendritic filopodia, and dendritic branching and complexity were significantly reduced in developing neurons, as well as the densities of dendritic spines and PSD95 clusters in mature neurons. Moreover, HIP1R deficiency led to significantly reduced expression of the ionotropic glutamate receptor GluA1, GluN2A and GluN2B subunits, but not the GABAA receptor α1 subunit. Similarly, HIP1R knockdown reduced the amplitude and frequency of the miniature excitatory postsynaptic current, but not of the miniature inhibitory postsynaptic current. In addition, the C-terminal proline-rich region of HIP1R responsible for cortactin binding was found to confer a dominant-negative effect on dendritic branching in cultured developing neurons, implying a critical role of cortactin binding in HIP1R function. Taken together, the results of our study suggest that HIP1R plays important roles in dendritic development and excitatory synapse formation and function.

Alzheimer's disease (AD) is the most common cause of dementia. One of the pathological hallmarks of AD is amyloid β (Aβ) deposition. MicroRNAs (miRNAs) are small non-coding RNAs whose expression levels change significantly during neuronal pathogenesis and may be used as diagnostic markers. Some miRNAs are important in AD development by targeting genes responsible for Aβ metabolism. However, a systematic assessment of the miRNA expression profile induced by Aβ-mediated neuronal pathogenesis is still lacking. In the present study, we examined miRNA expression profile by using the APPswe/PS1ΔE9 mouse model of AD. Two sibling pairs of mice were examined, showing 30 and 24 miRNAs with significantly altered expression levels from each paired control, respectively. Nine known miRNAs were common in both groups. Prediction of putative target genes and functional annotation implied that these altered miRNAs affect many target genes mainly involved in PI3K/Akt signaling pathway. This study provides a general profile of miRNAs regulated by Aβ-associated signal pathways, which is helpful to understand the mechanism of Aβ-induced neuronal dysfunction in AD development.

BRAF or RAS mutation-induced aberrant activation of the mitogen-activated protein kinase (MAPK) pathway is frequently observed in human cancers. As the key downstream node of MAPK pathway, ERK1/2 is as an important therapeutic target. GDC-0994 (ravoxertinib), an orally bioavailable, highly selective small-molecule inhibitor of ERK1/2, showed acceptable safety and pharmacodynamic profile in a recent phase I clinical trial. In this study, we investigated dependence of the anti-tumor effect of ERK inhibitor GDC-0994 on genetic alterations in the MAPK pathway. The results showed that GDC-0994 sharply inhibited cell proliferation and colony formation and induced remarkable G1 phase cell-cycle arrest in cancer cells harboring BRAF mutation but had little effect on cell behaviors in most RAS mutant or wild-type cell lines. The expression of a large number of genes, particularly the genes in the cell cycle pathway, were significantly changed after GDC-0994 treatment in BRAF mutant cells, while no remarkable expression change of such genes was observed in wild-type cells. Moreover, GDC-0994 selectively inhibited tumor growth in a BRAF mutant xenograft mice model. Our findings demonstrate a BRAF mutation-dependent anti-tumor effect of GDC-0994 and provide a rational strategy for patient selection for ERK1/2 inhibitor treatment.

Idiopathic pulmonary fibrosis (IPF) is caused by persistent micro-injuries and aberrant repair processes. Myofibroblast differentiation in lung is a key event for abnormal repair. Dihydroartemisinin(DHA), a well-known anti-malarial drug, have been shown to alleviate pulmonary fibrosis, but its mechanism is not clear. Ferroptosis is involved in the pathgenesis of many diseases, including IPF. Ferritinophagy is a form of cellular autophagy which regulates intracellular iron homeostasis. The function of DHA on myofibroblasts differentiation of pulmonary and whether related with ferroptosis and ferritinophagy are unknown now. Using human fetal lung fibroblast 1(HFL1) cell line and the qRT-PCR, immunofluorescent and Western blotting techniques, we found that after TGF-β1 treatment, the levels of ɑ-SMA expression and ROS increased; the mRNA and protein levels of FTH1 and NCOA4, the content of Fe2+ and 4-HNE increased significantly at 6h, then gradually reduced with time. After DHA treatment, FHL1 cells appeared ferroptosis; the levels of α-SMA mRNA and protein reduced and the levels of ROS and 4-HNE increased; the Fe2+ levels decreased sharply at 6h, then increased with time, and were higher than normal since 24h; the mRNA and protein levels of FTH1 and NCOA4 decreased, exhibited a downward trend. These results show that Fe2+, ROS and lipid peroxidation are involved in and ferritinophagy is inhibited during fibroblast-to-myofibroblast differentiation; The depletion of Fe2+ at early stage induced by DHA treatment triggers the ferritinophagy in HFL1 cells, leading to degradation of FTH1 and NCOA4 and following increase of Fe2+ levels. DHA may inhibit the fibroblast-to-myofibroblast differentiation through inducing ferroptosis mediated by ferritinophagy.

The telomerase reverse transcriptase (TERT) is overexpressed and associated with poor prognosis in papillary thyroid cancer (PTC), the most common subtype of thyroid cancer. The overexpression of TERT in PTC was partially attributed to transcriptional activation by two hotspot mutations in the core promoter region of this gene. As one of the major epigenetic mechanisms of gene expression regulation, DNA methylation has been proved to regulate several tumor-related genes in PTC. However, the association of TERT promoter DNA methylation with TERT expression and PTC progression is still unclear. By treating PTC cell lines with demethylating agent decitabine, we found that the TERT promoter methylation and the genes’ expression were remarkably decreased. Consistently, PTC patients with TERT hypermethylation had significantly higher TERT expression than patients with TERT hypomethylation. Moreover, TERT hypermethylated patients showed significant higher rates of poor clinical outcomes than patients with TERT hypomethylation. Results from the cox regression analysis showed that the hazard ratios (HRs) of TERT hypermethylation for overall survival, disease-specific survival, disease-free interval (DFI) and progression-free interval (PFI) were 4.81 (95% CI, 1.61-14.41), 8.28 (95% CI, 2.14-32.13), 3.56 (95% CI, 1.24-10.17) and 3.32 (95% CI, 1.64-6.71), respectively. The HRs for DFI and PFI remained significant after adjustment for clinical risk factors. These data suggest that promoter DNA methylation upregulates TERT expression and associates with poor clinical outcomes of PTC, thus holds the potential to be a valuable prognostic marker for PTC risk stratification.

Abstract Background Thyroid cancer is the most frequent malignancy of the endocrine system, of which papillary thyroid cancer (PTC) is the predominant form with a rapid increasing incidence worldwide. Rearranged during transfection (RET) fusions are common genetic drivers of PTC and the potent RET inhibitor selpercatinib has been recently approved for treating advanced or metastatic RET fusion-positive thyroid cancer. In this study we aimed to develop a droplet digital PCR (ddPCR) system to accurately detect RET fusion in PTC samples. Methods The frequency and distribution of RET fusions in PTC were analyzed using genomic data of 402 PTC patients in The Cancer Genome Atlas (TCGA) database. To establish the ddPCR system for detecting CCDC6::RET fusion, a plasmid containing CCDC6::RET infusion fragment was constructed as standard template, the annealing temperature and concentrations of primers and probe were optimized. The analytical performance of ddPCR and quantitative reverse transcription PCR (qRT-PCR) were assessed in standard templates and tissue samples from 112 PTC patients. Sanger sequencing was performed in all the RET fusion-positive samples identified by ddPCR. Results RET fusions were observed in 25 (6.2%) of the 402 TCGA samples, and 15 (60%) of the RET fusion-positive patients had the CCDC6::RET fusion. Compared with qRT-PCR, the ddPCR method showed a lower limit of detection (128.0 and 430.7 copies/reaction for ddPCR and qRT-PCR, respectively). When applying the two methods to 112 tissue samples of PTC, eleven (9.8%) CCDC6::RET fusion-positive samples were detected by qRT-PCR, while ddPCR identified 4 additional positive samples (15/112, 13.4%). All the CCDC6::RET fusion-positive cases identified by ddPCR were confirmed by Sanger sequencing except for one case with 0.14 copies/uL of the fusion. Conclusion The accurate and sensitive ddPCR method reported here is powerful to detection CCDC6::RET fusion in PTC samples, application of this method would benefit more RET fusion-positive patients in the clinic.

Utilization and exploitation of marine resources by humans have contributed to the growth of marine research. As technology progresses, artificial intelligence (AI) approaches are progressively being applied to maritime research, complementing traditional marine forecasting models and observation techniques to some degree. This article takes the artificial intelligence algorithmic model as its starting point, references several application trials, and methodically elaborates on the emerging research trend of mixing machine learning and physical modeling concepts. This article discusses the evolution of methodologies for the building of ocean observations, the application of artificial intelligence to remote sensing satellites, smart sensors, and intelligent underwater robots, and the construction of ocean big data. We also cover the method of identifying internal waves (IW), heatwaves, El Niño-Southern Oscillation (ENSO), and sea ice using artificial intelligence algorithms. In addition, we analyze the applications of artificial intelligence models in the prediction of ocean components, including physics-driven numerical models, model-driven statistical models, traditional machine learning models, data-driven deep learning models, and physical models combined with artificial intelligence models. This review shows the growth routes of the application of artificial intelligence in ocean observation, ocean phenomena identification, and ocean elements forecasting, with examples and forecasts of their future development trends from several angles and points of view, by categorizing the various uses of artificial intelligence in the ocean sector.

Hotspot mutations in the core promoter region of the telomerase reverse transcriptase (TERT) gene have been well established to associate with aggressive clinical characteristics, radioiodine refractory, tumor recurrence, and mortality in thyroid cancer. Several E-twenty-six (ETS) transcription factors were reported to selectively bound to the mutant TERT promoter and activated TERT expression. In this study we aimed to investigate whether TERT promoter mutations confer sensitivity to ETS inhibitor YK-4-279 in thyroid cancer cells and whether this inhibitor could be served as a potential therapeutic agent for thyroid cancer. In vitro assays showed that YK-4-279 treatment sharply suppressed cell viability, colony formation, migration, and invasion, as well as induced cell cycle arrest and apoptosis in a panel of thyroid cancer cells. The cell viability after YK-4-279 treatment was similar between cell lines harboring mutant and wild-type TERT promoters. Furthermore, YK-4-279 treatment reduced both luciferase activity and mRNA expression of TERT independent of TERT promoter mutation status. Data from RNA-seq further revealed that YK-4-279 significantly affected biological processes including DNA replication and cell cycle. Reduced DNA helicase activity and decreased expression of several helicase genes were observed after YK-4-279 treatment. Moreover, YK-4-279 significantly inhibited tumor growth and induced apoptosis in a xenograft mice model. Thus, ETS inhibitor YK-4-279 suppressed TERT expression and conferred anti-tumor activity in a TERT promoter mutation-independent manner, and it could be a potential agent for the treatment of advanced thyroid cancers.

Thyroid cancer is the most common endocrine malignancy, and its incidence has increased in the past decades. Selenium has been shown to have therapeutic effects against several tumors. However, its role in thyroid cancer and its underlying molecular mechanism remains to be explored. In the present study, we demonstrated that sodium selenite significantly decreased cell viability and induced G0/G1 cell cycle arrest and apoptosis in thyroid cancer cells in a dose-dependent manner. Transcriptomics revealed that sodium selenite induced intracellular reactive oxygen species (ROS) by promoting oxidative phosphorylation. Increased intracellular ROS levels inhibited the AKT/mTOR signaling pathway and upregulated EIF4EBP3. Intracellular ROS inhibition by N-acetylcysteine (NAC) ameliorated the cellular effects of sodium selenite. The in vitro findings were reproduced in xenograft thyroid tumor models. Our data demonstrated that sodium selenite exhibits strong anticancer effects against thyroid cancer cells, which involved ROS-mediated inhibition of the AKT/mTOR pathway. This suggests that sodium selenite may serve as a therapeutic option for advanced thyroid cancer.

The explosive increasing of the social media data on the Web has created and promoted the development of the social media big data mining area welcomed by researchers from both academia and industry. The sentiment computing of news event is a significant component of the social media big data. It has also attracted a lot of researches, which could support many real-world applications, such as public opinion monitoring for governments and news recommendation for Websites. However, existing sentiment computing methods are mainly based on the standard emotion thesaurus or supervised methods, which are not scalable to the social media big data. Therefore, we propose an innovative method to do the sentiment computing for news events. More specially, based on the social media data (i.e., words and emoticons) of a news event, a word emotion association network (WEAN) is built to jointly express its semantic and emotion, which lays the foundation for the news event sentiment computation. Based on WEAN, a word emotion computation algorithm is proposed to obtain the initial words emotion, which are further refined through the standard emotion thesaurus. With the words emotion in hand, we can compute every sentence's sentiment. Experimental results on real-world data sets demonstrate the excellent performance of the proposed method on the emotion computing for news events.

Reinforcement learning (RL) aims to resolve the sequential decision-making under uncertainty problem where an agent needs to interact with an unknown environment with the expectation of optimising the cumulative long-term reward. Many real-world problems could benefit from RL, e.g., industrial robotics, medical treatment, and trade execution. As a representative model-free RL algorithm, deep Q-network (DQN) has recently achieved great success on RL problems and even exceed the human performance through introducing deep neural networks. However, such classical deep neural network-based models cannot well handle the uncertainty in sequential decision-making and then limit their learning performance. In this paper, we propose a new model-free RL algorithm based on a Bayesian deep model. To be specific, deep kernel learning (i.e., a Gaussian process with deep kernel) is adopted to learn the hidden complex action-value function instead of classical deep learning models, which could encode more uncertainty and fully take advantage of the replay memory. The comparative experiments on standard RL testing platform, i.e., OpenAI-Gym, show that the proposed algorithm outweighs the DQN. Further investigations will be directed to applying RL for supporting dynamic decision-making in complex environments.