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Abstract miRNA has emerged as a crucial regulator in various of pathological and physiological processes, yet its precise mechanism of action the detailed mechanism of their action in Head and neck squamous cell carcinoma (HNSCC) remains incompletely understood. This study sheds light on the role of mi-151-5p, revealing its significantly elevated expression in tumor cells, which notably enhances the invasion and migration of HNSCC cells. This effect is achieved through directly targeting LY6/PLAUR Domain Containing 3 (LYPD3) by miR-151-5p, involving complementary binding to the 3’-untranslated regions (3’-UTR) in the mRNA of LYPD3. Consequently, this interaction accelerates the metastasis of HNSCC. Notably, clinical observations indicate a correlation between high expression of miR-151-5p and low levels of LYPD3 in clinical settings are correlated with poor prognosis of HNSCC patients. Furthermore, our investigation demonstrates that glycosylation of LYPD3 modulates its subcellular localization and reinforces its role in suppressing HNSCC metastasis. Additionally, we uncover a potential regulatory mechanism involving the facilitation of miR-151-5p maturation and accumulation through N6-methyladenosine (m6A) modification. This process is orchestrated by methyltransferase-like 3 (METTL3) and mediated by a newly identified reader, heterogeneous nuclear ribonucleoprotein U (hnRNP U). These findings collectively underscore the significance of the METTL3/miR-151-5p/LYPD3 axis serves as a prominent driver in the malignant progression of HNSCC.

Abstract The lungs were long thought to be sterile until technical advances uncovered the presence of the lung microbial community. The microbiome of healthy lungs is mainly derived from the upper respiratory tract (URT) microbiome but also has its own characteristic flora. The selection mechanisms in the lung, including clearance by coughing, pulmonary macrophages, the oscillation of respiratory cilia, and bacterial inhibition by alveolar surfactant, keep the microbiome transient and mobile, which is different from the microbiome in other organs. The pulmonary bacteriome has been intensively studied recently, but relatively little research has focused on the mycobiome and virome. This up-to-date review retrospectively summarizes the lung microbiome’s history, composition, and function. We focus on the interaction of the lung microbiome with the oropharynx and gut microbiome and emphasize the role it plays in the innate and adaptive immune responses. More importantly, we focus on multiple respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), fibrosis, bronchiectasis, and pneumonia. The impact of the lung microbiome on coronavirus disease 2019 (COVID-19) and lung cancer has also been comprehensively studied. Furthermore, by summarizing the therapeutic potential of the lung microbiome in lung diseases and examining the shortcomings of the field, we propose an outlook of the direction of lung microbiome research.

Abstract The precise regulation of cellular behaviors within a confined, crowded intracellular environment is highly amenable in diagnostics and therapeutics. While synthetic circuitry system through a concatenated chemical reaction network has rarely been reported to mimic dynamic self‐assembly system. Herein, a catalytic self‐defined circuit (CSC) for the hierarchically concatenated assembly of DNA domino nanostructures is engineered. By incorporating pre‐sealed symmetrical fragments into the preying hairpin reactants, the CSC system allows the hierarchical DNA self‐assembly via a microRNA (miRNA)‐powered self‐sorting catalytic hybridization reaction. With minimal strand complexity, this self‐sustainable CSC system streamlined the circuit component and achieved localization‐intensified cascaded signal amplification. Profiting from the self‐adaptively concatenated hybridization reaction, a reliable and robust method has been achieved for discriminating carcinoma tissues from the corresponding para‐carcinoma tissues. The CSC‐sustained self‐assembly strategy provides a comprehensive and smart toolbox for organizing various hierarchical DNA nanostructures, which may facilitate more insights for clinical diagnosis and therapeutic assessment.

Abstract Extrachromosomal circular DNA (eccDNA) is defined as a type of circular DNA that exists widely in nature and is independent of chromosomes. EccDNA has attracted the attention of researchers due to its broad, random distribution, complex biogenesis and tumor-relevant functions. EccDNA can carry complete gene information, especially the oncogenic driver genes that are often carried in tumors, with increased copy number and high transcriptional activity. The high overexpression of oncogenes by eccDNA leads to malignant growth of tumors. Regardless, the exact generation and functional mechanisms of eccDNA in disease progression are not yet clear. There is, however, an emerging body of evidence characterizing that eccDNA can be generated from multiple pathways, including DNA damage repair pathways, breakage-fusion-bridge (BFB) mechanisms, chromothripsis and cell apoptosis, and participates in the regulation of tumor progression with multiplex functions. This up-to-date review summarizes and discusses the origins, biogenesis and functions of eccDNA, including its contribution to the formation of oncogene instability and mutations, the heterogeneity and cellular senescence of tumor cells, and the proinflammatory response of tumors. We highlight the possible cancer-related applications of eccDNA, such as its potential use in the diagnosis, targeted therapy and prognostic assessment of cancer.

Abstract Background Intracellular accumulation of the microtubule-associated protein tau and its hyperphosphorylated forms is a key neuropathological feature of Alzheimer’s disease (AD). Melatonin has been shown to prevent tau hyperphosphorylation in cellular and animal models. However, the molecular mechanisms by which melatonin attenuates tau hyperphosphorylation and tau-related pathologies are not fully understood. Methods Immunofluorescence, immunoblotting analysis and thioflavin-S staining were employed to examine the effects of early and late treatment of melatonin on tau-related pathology in hTau mice, in which nonmutated human tau is overexpressed on a mouse tau knockout background. High-throughput microRNA (miRNA) sequencing, quantitative RT-PCR, luciferase reporter assay and immunoblotting analysis were performed to determine the molecular mechanism. Results We found that both early and late treatment of melatonin efficiently decreased the phosphorylation of soluble and insoluble tau at sites related to AD. Moreover, melatonin significantly reduced the number of neurofibrillary tangles (NFTs) and attenuated neuronal loss in the cortex and hippocampus. Furthermore, using miRNA microarray analysis, we found that miR-504-3p expression was upregulated by melatonin in the hTau mice. The administration of miR-504-3p mimics dramatically decreased tau phosphorylation by targeting p39, an activator of the well-known tau kinase cyclin-dependent kinase 5 (CDK5). Compared with miR-504-3p mimics alone, co-treatment with miR-504-3p mimics and p39 failed to reduce tau hyperphosphorylation. Conclusions Our results suggest for the first time that melatonin alleviates tau-related pathologies through upregulation of miR-504-3p expression by targeting the p39/CDK5 axis and provide novel insights into AD treatment strategies.

The therapeutic application of small interfering RNA (siRNA) is challenging due to its non-specific targeting and delivery issues. Here, the authors report an endogenous micro-RNA guided and hybridisation chain reaction-promoted siRNA delivery system encapsulated in tumour-derived extracellular vesicles, with cancer-specific activation, and achieve silencing of hypoxia-related genes.

Based on the zero-curvature equation and Lenard recursion equations, we propose a vector super long-wave-short-wave hierarchy associated with an (n+2)×(n+2)matrix spectral problem. A typical member in the hierarchy is the vector super Newell long-wave-short-wave equation. An infinite set of conservation laws for the vector super Newell long-wave-short-wave equation is constructed by using Liouville’s formula and the resulting super Riccati equation.

Death-associated protein kinase 1 (DAPK1), a Ca2+/calmodulin-dependent serine/threonine kinase, mediates various neuronal functions, including cell death. Abnormal upregulation of DAPK1 is observed in human patients with neurological diseases, such as Alzheimer’s disease (AD) and epilepsy. Ablation of DAPK1 expression and suppression of DAPK1 activity attenuates neuropathology and behavior impairments. However, whether DAPK1 regulates gene expression in the brain, and whether its gene profile is implicated in neuronal disorders, remains elusive. To reveal the function and pathogenic role of DAPK1 in neurological diseases in the brain, differential transcriptional profiling was performed in the brains of DAPK1 knockout (DAPK1-KO) mice compared with those of wild-type (WT) mice by RNA sequencing. We showed significantly altered genes in the cerebral cortex, hippocampus, brain stem, and cerebellum of both male and female DAPK1-KO mice compared to those in WT mice, respectively. The genes are implicated in multiple neural-related pathways, including: AD, Parkinson’s disease (PD), Huntington’s disease (HD), neurodegeneration, glutamatergic synapse, and GABAergic synapse pathways. Moreover, our findings imply that the potassium voltage-gated channel subfamily A member 1 (Kcna1) may be involved in the modulation of DAPK1 in epilepsy. Our study provides insight into the pathological role of DAPK1 in the regulatory networks in the brain and new therapeutic strategies for the treatment of neurological diseases.

In this paper, we study the long-time asymptotic behavior of the solution of the Cauchy problem for the generalized Sasa-Satsuma equation. Starting with the 3 × 3 Lax pair related to the generalized Sasa-Satsuma equation, we construct a Rieman-Hilbert problem, by which the solution of the generalized Sasa-Satsuma equation is converted into the solution of the corresponding RiemanHilbert problem. Using the nonlinear steepest decent method for the Riemann-Hilbert problem, we obtain the leading-order asymptotics of the solution of the Cauchy problem for the generalized SasaSatsuma equation through several transformations of the Riemann-Hilbert problem and with the aid of the parabolic cylinder function.

Abstract Purpose The diagnostic value of nomogram in pancreatic cancer (PC) with liver metastasis (PCLM) is still largely unknown. We sought to develop and validate a novel nomogram for the prediction of liver metastasis in patients with PC. Method About 604 pathologically confirmed PC patients from the Sun Yat‐sen University Cancer Center (SYSUCC) between July, 2001 and December, 2013 were retrospectively studied. The SYSUCC cohort was randomly assigned to as the training set and internal validation set. Using these two sets, we derived and validated a prognostic model by using concordance index and calibration curves. Another two independent cohorts between August, 2002 and December, 2013 from the Sun Yat‐sen Memorial Hospital (SYSMH, n = 335) and Guangdong General Hospital (GDGH, n = 503) was used for external validation. Result Computed tomography (CT) reported liver metastasis status, carcinoembryonic antigen (CEA) level and differentiation type were identified as risk factors for PCLM in the training set. The final diagnostic model demonstrated good calibration and discrimination with a concordance index of 0.97 and had a robust internal validation. The score ability to diagnose PCLM was further externally validated in SYSMH and GDGH with a concordance index of 0.93. The model showed better calibration and discrimination than CT, CEA and differentiation in each cohort. Conclusion Based on a large multi‐institution database and on the routinely observed CT‐reported status, CEA level and tumor differentiation in clinical practice, we developed and validated a novel nomogram to predict PLCM.

In the present paper, we introduce a 4 × 4 matrix spectral problem and derive a four-component Fokas–Lenells equation. N-fold Darboux transformations for the four-component Fokas–Lenells equation are constructed by using the gauge transformation between spectral problems and an iterative procedure. Resorting to the limit technique and Taylor series, we obtain the N-fold generalized Darboux transformation. As an illustrative example, by utilizing the resulting Darboux transformations and Mathematica software, some exact solutions for the four-component Fokas–Lenells equation are obtained, including soliton, breather solution and rogue wave solution. Moreover, the dynamical behaviour of these solutions is analysed in detail.

The neuropathology of Alzheimer’s disease (AD) is characterized by intracellular aggregation of hyperphosphorylated tau and extracellular accumulation of beta-amyloid (Aβ). Death-associated protein kinase 1 (DAPK1), as a novel therapeutic target, shows promise for the treatment of human AD, but the regulatory mechanisms of DAPK1 expression in AD remain unclear. In this study, we identified miR-143-3p as a promising candidate for targeting DAPK1. miR-143-3p directly bound to the 3′ untranslated region of human DAPK1 mRNA and inhibited its translation. miR-143-3p decreased tau phosphorylation and promoted neurite outgrowth and microtubule assembly. Moreover, miR-143-3p attenuated amyloid precursor protein (APP) phosphorylation and reduced the generation of Aβ40 and Aβ42. Furthermore, restoring DAPK1 expression with miR-143-3p antagonized the effects of miR-143-3p in attenuating tau hyperphosphorylation and Aβ production. In addition, the miR-143-3p levels were downregulated and correlated inversely with the expression of DAPK1 in the hippocampus of AD patients. Our results suggest that miR-143-3p might play critical roles in regulating both aberrant tau phosphorylation and amyloidogenic processing of APP by targeting DAPK1 and thus offer a potential novel therapeutic strategy for AD.

Glutamate excitotoxicity induces neuronal cell death during epileptic seizures. Death-associated protein kinase 1 (DAPK1) expression is highly increased in the brains of epilepsy patients; however, the underlying mechanisms by which DAPK1 influences neuronal injury and its therapeutic effect on glutamate excitotoxicity have not been determined. We assessed multiple electroencephalograms and seizure grades and performed biochemical and cell death analyses with cellular and animal models. We applied small molecules and peptides and knocked out and mutated genes to evaluate the therapeutic efficacy of kainic acid (KA), an analog of glutamate-induced neuronal damage. KA administration increased DAPK1 activity by promoting its phosphorylation by activated extracellular signal-regulated kinase (ERK). DAPK1 activation increased seizure severity and neuronal cell death in mice. Selective ERK antagonist treatment, DAPK1 gene ablation, and uncoupling of DAPK1 and ERK peptides led to potent anti-seizure and anti-apoptotic effects in vitro and in vivo. Moreover, a DAPK1 phosphorylation-deficient mutant alleviated glutamate-induced neuronal apoptosis. These results provide novel insight into the pathogenesis of epilepsy and indicate that targeting DAPK1 may be a potential therapeutic strategy for treating epilepsy.

Facing the challenges of spectrum shortage and complex depolarization effects in wireless communication, a multilevel continuous polarization modulation (MCPoM) scheme is investigated to achieve high spectral efficiency and improve the symbol error rate performance in the practical depolarization channels. The principle of the MCPoM modulation is stated in details on the basis of the MCPoM system model. Then a noncoherent and a coherent MCPoM demodulation methods are proposed as the differential demodulation and the suboptimum sequence detection based demodulation, respectively. Furthermore, considering the depolarization effect of polarization-dependent loss in the practical wireless channels, MCPoM is evaluated with two influences of power attenuation and polarization difference distortion. After that, we propose a polarization pre-compensation algorithm for MCPoM to mitigate the influences of polarization-dependent loss. The performances of the proposed scheme are evaluated with symbol error rate and spectral efficiency. Simulations results demonstrate that higher spectral efficiency and enhanced symbol error rate of the proposed MCPoM scheme are guaranteed in the depolarization channels.

In this paper, a 3 × 3 spectral problem is proposed and a five-component equation that consists of two different mKdV equations is derived. A Darboux transformation of the five-component equation is presented relating to the gauge transformations between the Lax pairs. As applications of the Darboux transformations, interesting exact solutions, including soliton-like solutions and a solution that consists of rational functions of e x and t, for the five-component equation are obtained.

A vector modified Yajima−Oikawa long-wave−short-wave equation is proposed using the zero-curvature presentation. On the basis of the Riccati equations associated with the Lax pair, a method is developed to construct multi-fold classical and generalized Darboux transformations for the vector modified Yajima−Oikawa long-wave−short-wave equation. As applications of the multi-fold classical Darboux transformations and generalized Darboux transformations, various exact solutions for the vector modified long-wave−short-wave equation are obtained, including soliton, breather, and rogue wave solutions.