Mitochondrial dysfunction gene expression, DNA methylation, and inflammatory cytokines interaction activate Alzheimer's disease: a multi-omics Mendelian randomization study.

BACKGROUND: Mitochondrial dysfunction (MD) is increasingly recognized as a key pathophysiological contributor in Alzheimer disease (AD). As differential MD genes expression may serve as either a causative factor or a consequence in AD, and expression of these genes could be influenced by epigenetic modifications or interact with inflammatory cytokines, hence, the precise role of MD in AD remains uncertain. METHODS: Meta-analysis of brain transcriptome datasets was conducted to pinpoint differentially expressed genes (DEGs) associated with MD in AD. We utilized three-step SMR to analyze the AD genome-wide association study summaries with expression quantitative trait loci (eQTLs) and DNA methylation QTLs from the blood and brain tissues, respectively. Through SMR and colocalization analysis, we further explored the interactions between brain eQTLs and inflammatory cytokines. RESULTS: Five datasets were meta-analyzed to prioritize 825 DEGs in AD from 1339 MD-related genes. Among these, seven genes from blood samples such as NDUFS8 and SPG7 and thirty-two genes from brain tissue including CLU and MAPT were identified as candidate AD-causal MD genes and regulated by methylation level. Furthermore, we revealed 13 MD gene expression-inflammatory pathway pairs involving LDLR, ACE and PTPMT1 along with interleukin-17C, interleukin-18 and hepatocyte growth factor. CONCLUSIONS: This study highlighted that the AD-causal MD genes could be regulated by epigenetic changes and interact with inflammatory cytokines, providing evidence for AD prevention and intervention.

Embedding Quantum Many-Body Scars into Decoherence-Free Subspaces.

Quantum many-body scars are nonthermal excited eigenstates of nonintegrable Hamiltonians, which could support coherent revival dynamics from special initial states when scars form an equally spaced tower in the energy spectrum. For open quantum systems, engineering many-body scarred dynamics by a controlled coupling to the environment remains largely unexplored. Here, we provide a general framework to exactly embed quantum many-body scars into the decoherence-free subspaces of Lindblad master equations. The dissipative scarred dynamics manifest persistent periodic oscillations for generic initial states, and can be practically utilized to prepare scar states with potential quantum metrology applications. We construct the Liouvillian dissipators with the local projectors that annihilate the whole scar towers, and utilize the Hamiltonian part to rotate the undesired states out of the null space of dissipators. We demonstrate our protocol through several typical models hosting many-body scar towers and propose an experimental scheme to observe the dissipative scarred dynamics based on digital quantum simulations and resetting ancilla qubits.

Family history and breast cancer risk for Asian women: a systematic review and meta-analysis.

BACKGROUND: Studies of women of European ancestry have shown that the average familial relative risk for first-degree relatives of women with breast cancer is approximately twofold, but little is known for Asian women. We aimed to provide evidence for the association between family history and breast cancer risk for Asian women by systematically reviewing published literature. METHODS: Studies reporting the familial relative risk of breast cancer for Asian women were searched in three online databases and complemented by a manual search. Odds ratios (ORs) for the association between family history and breast cancer risk were pooled across all included studies and by subgroups in terms of the type of family history, age, menopausal status and geographical region. RESULTS: The pooled OR for women who have a first-degree relative with breast cancer was 2.46 (95% confidence interval [CI]: 2.03, 2.97). There was no evidence that the familial risk differed by the type of affected relative (mother versus sisters), the woman's age (< 50 years versus ≥ 50 years), menopausal status (pre versus post) and geographical region (East and Southeast Asia versus other regions) (all P > 0.3). The pooled ORs for women of Asian ancestry with a family history in any relative were similar for those living in non-Asian countries (2.26, 95% CI: 1.42, 3.59) compared with those living in Asian countries (2.18, 95% CI: 1.85, 2.58). CONCLUSIONS: Family history of breast cancer is associated with an approximately twofold relative risk of breast cancer for Asian women, which is of similar magnitude to that observed for women of European ancestry. This implies that similar familial factors are implicated in breast cancer risk between women of European and Asian ancestries. Genetic factors are likely to play a substantial role in explaining the breast cancer familial risk for Asian women, as similar risks were observed across different living environments and cultures.

Solving the Liouvillian Gap with Artificial Neural Networks.

We propose a machine-learning inspired variational method to obtain the Liouvillian gap, which plays a crucial role in characterizing the relaxation time and dissipative phase transitions of open quantum systems. By using "spin bi-base mapping," we map the density matrix to a pure restricted-Boltzmann-machine (RBM) state and transform the Liouvillian superoperator to a rank-two non-Hermitian operator. The Liouvillian gap can be obtained by a variational real-time evolution algorithm under this non-Hermitian operator. We apply our method to the dissipative Heisenberg model in both one and two dimensions. For the isotropic case, we find that the Liouvillian gap can be analytically obtained and in one dimension even the whole Liouvillian spectrum can be exactly solved using the Bethe ansatz method. By comparing our numerical results with their analytical counterparts, we show that the Liouvillian gap could be accessed by the RBM approach efficiently to a desirable accuracy, regardless of the dimensionality and entanglement properties.

Zinc-finger protein YY1 suppresses tumor growth of human nasopharyngeal carcinoma by inactivating c-Myc-mediated microRNA-141 transcription.

Yin Yang 1 (YY1) is a zinc-finger protein that plays critical roles in various biological processes by interacting with DNA and numerous protein partners. YY1 has been reported to play dual biological functions as either an oncogene or tumor suppressor in the development and progression of multiple cancers, but its role in human nasopharyngeal carcinoma (NPC) has not yet been revealed. In this study, we found that YY1 overexpression significantly inhibits cell proliferation and cell-cycle progression from G1 to S and promotes apoptosis in NPC cells. Moreover, we identified YY1 as a component of the c-Myc complex and observed that ectopic expression of YY1 inhibits c-Myc transcriptional activity, as well as the promoter activity and expression of the c-Myc target gene microRNA-141 (miR-141). Furthermore, restoring miR-141 expression could at least partially reverse the inhibitory effect of YY1 on cell proliferation and tumor growth and on the expression of some critical c-Myc targets, such as PTEN/AKT pathway components both in vitro and in vivo We also found that YY1 expression is reduced in NPC tissues, negatively correlates with miR-141 expression and clinical stages in NPC patients, and positively correlates with survival prognosis. Our results reveal a previously unappreciated mechanism in which the YY1/c-Myc/miR-141 axis plays a critical role in NPC progression and may provide some potential and valuable targets for the diagnosis and treatment of NPC.

p53/Lactate dehydrogenase A axis negatively regulates aerobic glycolysis and tumor progression in breast cancer expressing wild-type p53.

Tumor suppressor p53 is a master regulator of apoptosis and plays key roles in cell cycle checkpoints. p53 responds to metabolic changes and alters metabolism through several mechanisms in cancer. Lactate dehydrogenase A (LDHA), a key enzyme in glycolysis, is highly expressed in a variety of tumors and catalyzes pyruvate to lactate. In the present study, we first analyzed the association and clinical significance of p53 and LDHA in breast cancer expressing wild-type p53 (wt-p53) and found that LDHA mRNA levels are negatively correlated with wt-p53 but not with mutation p53 mRNA levels, and low p53 and high LDHA expression are significantly associated with poor overall survival rates. Furthermore, p53 negatively regulates LDHA expression by directly binding its promoter region. Moreover, a series of LDHA gain-of-function and rescore experiments were carried out in breast cancer MCF7 cells expressing endogenous wt-p53, showing that ectopic expression of p53 decreases aerobic glycolysis, cell proliferation, migration, invasion and tumor formation of breast cancer cells and that restoration of the expression of LDHA in p53-overexpressing cells could abolish the suppressive effect of p53 on aerobic glycolysis and other malignant phenotypes. In conclusion, our findings showed that repression of LDHA induced by wt-p53 blocks tumor growth and invasion through downregulation of aerobic glycolysis in breast cancer, providing new insights into the mechanism by which p53 contributes to the development and progression of breast cancer.

Induction of Pro-Inflammatory Response via Activated Macrophage-Mediated NF-κB and STAT3 Pathways in Gastric Cancer Cells.

BACKGROUND/AIMS: Chronic inflammation plays an important role in the initiation and progression of gastric cancer (GC). However, the role and relationship of activated macrophages with gastric mucous epithelium cells in initiating and maintaining the inflammatory process during gastric carcinogenesis remains unclear. METHODS: The tumour associated macrophages (TAMs) density of gastric cancer was characterized by immunohistochemistry, and the relationship between macrophages and gastric epithelium cells was analysed using an in vitro culture system that imitates the inflammatory microenvironment. The production of pro-inflammatory cytokines was detected by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR (qRT-PCR). MTT assays, Western blotting, qRT-PCR, and luciferase reporter assays were used to detect the effects of cell proliferation, as well as the NF-κB and STAT3 signalling pathways. RESULTS: TAMs infiltrated with a high intensity in GC and were significantly correlated with histology grade (P = 0.012), metastasis (P = 0.001), TNM stage (P = 0.002), and poor prognosis in patients (PFS, P = 0.005; OS, P = 0.028). In addition, IL-6 and IL-8 were elevated in the serum of GC patients and significantly promoted the growth of GC. The exposure of BGC823 gastric cancer cells to a conditioned medium from LPS-treated D-THP-1 cells significantly induced the production of TNF-α, IL-6, IL-1ß and IL-8 (P< 0.01). LPS and LPS-treated D-THP-1-conditioned media promoted gastric cancer cell proliferation and triggered the significant activation of NF-κB and STAT3 with a concomitant degradation of IκBα and an increase in JAK2 phosphorylation (P < 0.05). Moreover, gastric cancer cells markedly expressed cell membrane LPS receptors, such as TLR1, TLR4, TLR6, CD14 and MD2. CONCLUSIONS: TAMs are closely associated with the growth of GC and prognosis in GC patients. GC cells may directly sustain and amplify the local pro-inflammatory response upon encountering activated macrophages and LPS via NF-κB and STAT3 signalling pathways, thereby promoting tumour progression.

LncRNAs in DNA damage response and repair in cancer cells.

In order to maintain integrity of the genome, eukaryotic cells develop a complex DNA damage/repair response network, which can induce cell cycle arrest, apoptosis, or DNA repair. Chemo- and radiation therapies, which act primarily through the induction of DNA damage, are the most commonly used therapies for cancer. Impairment in the DNA damage response and repair system that protect cells from persistent DNA damage can affect the therapeutic efficacy of cancer. To date, accumulating evidence has suggested that long non-coding RNAs (lncRNAs) are involved in the regulation of the DNA damage/repair network. LncRNAs have been demonstrated to be master regulators of the genome at the transcriptional and post-transcriptional levels and play a key role in many physiological and pathological processes of cells. In this review, we will discuss the function of lncRNAs in regulating the cellular response to DNA damage.

Integrating ChIP-sequencing and digital gene expression profiling to identify BRD7 downstream genes and construct their regulating network.

BRD7 is a single bromodomain-containing protein that functions as a subunit of the SWI/SNF chromatin-remodeling complex to regulate transcription. It also interacts with the well-known tumor suppressor protein p53 to trans-activate genes involved in cell cycle arrest. In this paper, we report an integrative analysis of genome-wide chromatin occupancy of BRD7 by chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) and digital gene expression (DGE) profiling by RNA-sequencing upon the overexpression of BRD7 in human cells. We localized 156 BRD7-binding peaks representing 184 genes by ChIP-sequencing, and most of these peaks were co-localized with histone modification sites. Four novel motifs were significantly represented in these BRD7-enriched regions. Ingenuity pathway analysis revealed that 22 of these BRD7 target genes were involved in a network regulating cell death and survival. DGE profiling identified 560 up-regulated genes and 1088 down-regulated genes regulated by BRD7. Using Gene Ontology and pathway analysis, we found significant enrichment of the cell cycle and apoptosis pathway genes. For the integrative analysis of the ChIP-seq and DEG data, we constructed a regulating network of BRD7 downstream genes, and this network suggests multiple feedback regulations of the pathways. Furthermore, we validated BIRC2, BIRC3, TXN2, and NOTCH1 genes as direct, functional BRD7 targets, which were involved in the cell cycle and apoptosis pathways. These results provide a genome-wide view of chromatin occupancy and the gene regulation network of the BRD7 signaling pathway.

NGX6a is degraded through a proteasome-dependent pathway without ubiquitination mediated by ezrin, a cytoskeleton-membrane linker.

Our previous study demonstrated that the NGX6b gene acts as a suppressor in the invasion and migration of nasopharyngeal carcinoma (NPC). Recently, we identified the novel isoform NGX6a, which is longer than NGX6b. In this study, we first found that NGX6a was degraded in NPC cells and that this degradation was mediated by ezrin, a linker between membrane proteins and the cytoskeleton. Specific siRNAs against ezrin increase the protein level of NGX6a in these cells. During degradation, NGX6a is not ubiquitinated but is degraded through a proteasome-dependent pathway. The distribution pattern of ezrin was negatively associated with NGX6a in an immunochemistry analysis of a nasopharyngeal carcinoma tissue microarray and fetus multiple organ tissues and Western blot analysis in nasopharyngeal and NPC cell lines, suggesting that ezrin and NGX6a are associated and are involved in the progression and invasion of NPC. By mapping the interacting binding sites, the seven-transmembrane domain of NGX6a was found to be the critical region for the degradation of NGX6a, and the amino terminus of ezrin is required for the induction of NGX6a degradation. The knockdown of ezrin or transfection of the NGX6a mutant CO, which has an EGF-like domain and a transmembrane 1 domain, resulted in no degradation, significantly reducing the ability of invasion and migration of NPC cells. This study provides a novel molecular mechanism for the low expression of NGX6a in NPC cells and an important molecular event in the process of invasion and metastasis of nasopharyngeal carcinoma cells.

Knockdown of c-Myc inhibits cell proliferation by negatively regulating the Cdk/Rb/E2F pathway in nasopharyngeal carcinoma cells.

The proto-oncogene c-Myc encodes a transcription factor that is involved in the regulation of cellular proliferation, differentiation, and apoptosis. Several studies indicate that the over-expression of c-Myc is a frequent genetic abnormality in nasopharyngeal carcinoma (NPC). Therefore, specifically reducing its level by genetic means in established NPC cell lines helps to better understand its role in the pathogenesis of NPC. In this study, for the first time, we successfully established and characterized NPC 5-8F cell line with stably suppressed c-Myc expression by employing a DNA-based RNA interference approach. The suppression of c-Myc resulted in reduced cell growth, colony formation, and cell cycle progression in 5-8F cells. In vivo tumor formation assays revealed that the knockdown of c-Myc reduced the tumorigenic potential of 5-8F cells in nude mice. At the molecular level, we found that the knockdown of c-Myc could decrease the expression of several critical molecules involved in the Cdk/Rb/E2F pathway, including CDK4, cyclin D1, CDK2, pRb, E2F3, and DP2, and significantly reduced the promoter activity of cyclin D1. Taken together, these findings provide valuable mechanistic insights into the role of c-Myc in nasopharyngeal carcinogenesis and suggest that the knockdown of c-Myc may be a potential therapeutic approach for the treatment of NPC.

Quantitative Biofabrication Platform for Collagen-Based Peripheral Nerve Grafts with Structural and Chemical Guidance.

Owing to its crucial role in the human body, collagen has immense potential as a material for the biofabrication of tissues and organs. However, highly refined fabrication using collagen remains difficult, primarily because of its notably soft properties. A quantitative biofabrication platform to construct collagen-based peripheral nerve grafts, incorporating bionic structural and chemical guidance cues, is introduced. A viscoelastic model for collagen, which facilitates simulating material relaxation and fabricating collagen-based neural grafts, achieving a maximum channel density similar to that of the native nerve structure of longitudinal microchannel arrays, is established. For axonal regeneration over considerable distances, a gradient printing control model and quantitative method are developed to realize the high-precision gradient distribution of nerve growth factor required to obtain nerve grafts through one-step bioprinting. Experiments verify that the bioprinted graft effectively guides linear axonal growth in vitro and in vivo. This study should advance biofabrication methods for a variety of human tissue-engineering applications requiring tailored cues.

High-precision 3D printing of multi-branch vascular scaffold with plasticized PLCL thermoplastic elastomer.

Three-dimensional (3D) printing has emerged as a transformative technology for tissue engineering, enabling the production of structures that closely emulate the intricate architecture and mechanical properties of native biological tissues. However, the fabrication of complex microstructures with high accuracy using biocompatible, degradable thermoplastic elastomers poses significant technical obstacles. This is primarily due to the inherent soft-matter nature of such materials, which complicates real-time control of micro-squeezing, resulting in low fidelity or even failure. In this study, we employ Poly (L-lactide-co-ϵ-caprolactone) (PLCL) as a model material and introduce a novel framework for high-precision 3D printing based on the material plasticization process. This approach significantly enhances the dynamic responsiveness of the start-stop transition during printing, thereby reducing harmful errors by up to 93%. Leveraging this enhanced material, we have efficiently fabricated arrays of multi-branched vascular scaffolds that exhibit exceptional morphological fidelity and possess elastic moduli that faithfully approximate the physiological modulus spectrum of native blood vessels, ranging from 2.5 to 45 MPa. The methodology we propose for the compatibilization and modification of elastomeric materials addresses the challenge of real-time precision control, representing a significant advancement in the domain of melt polymer 3D printing. This innovation holds considerable promise for the creation of detailed multi-branch vascular scaffolds and other sophisticated organotypic structures critical to advancing tissue engineering and regenerative medicine.

HIF-2α/TFR1 mediated iron homeostasis disruption aggravates cartilage endplate degeneration through ferroptotic damage and mtDNA release: A new mechanism of intervertebral disc degeneration.

Backgroud: Iron overload is a prevalent condition in the elderly, often associated with various degenerative diseases, including intervertebral disc degeneration (IDD). Nevertheless, the mechanisms responsible for iron ion accumulation in tissues and the mechanism that regulate iron homeostasis remain unclear. Transferrin receptor-1 (TFR1) serves as the primary cellular iron gate, playing a pivotal role in controlling intracellular iron levels, however its involvement in IDD pathogenesis and the underlying mechanism remains obscure. Methods: Firstly, IDD mice model was established to determine the iron metabolism associated proteins changes during IDD progression. Then CEP chondrocytes were isolated and treated with TBHP or pro-inflammatory cytokines to mimic pathological environment, western blotting, immunofluorescence assay and tissue staining were employed to explore the underlying mechanisms. Lastly, TfR1 siRNA and Feristatin II were employed and the degeneration of IDD was examined using micro-CT and immunohistochemical analysis. Results: We found that the IDD pathological environment, characterized by oxidative stress and pro-inflammatory cytokines, could enhance iron influx by upregulating TFR1 expression in a HIF-2α dependent manner. Excessive iron accumulation not only induces chondrocytes ferroptosis and exacerbates oxidative stress, but also triggers the innate immune response mediated by c-GAS/STING, by promoting mitochondrial damage and the release of mtDNA. The inhibition of STING through siRNA or the reduction of mtDNA replication using ethidium bromide alleviated the degeneration of CEP chondrocytes induced by iron overload. Conclusion: Our study systemically explored the role of TFR1 mediated iron homeostasis in IDD and its underlying mechanisms, implying that targeting TFR1 to maintain balanced iron homeostasis could offer a promising therapeutic approach for IDD management. The translational potential of this article: Our study demonstrated the close link between iron metabolism dysfunction and IDD, indicated that targeting TfR1 may be a novel therapeutic strategy for IDD.

Drug Repurposing and Screening for Multiple Sclerosis Targeting Microglia and Macrophages.

Microglia/macrophages (MG/Mφ) play a central role in the pathogenesis of multiple sclerosis (MS). However, the intricacies of the immunomodulatory microenvironment in MS, particularly the heterogeneity and regulatory mechanisms of MG/Mφ subpopulations, remain elusive. The commonly used treatment options for MS have several drawbacks, such as significant side effects and uncertain efficacy. The exploration of developing new drugs targeting MG/Mφ for the treatment of MS remains to be investigated. We identified three distinct subpopulations of MG/Mφ, among which MG/Mφ_3 significantly increased as the experimental autoimmune encephalomyelitis (EAE) progressed. Ifenprodil and RO-25-6981 demonstrated notable inhibition of inflammatory factor expression, accompanied by reduced cytotoxicity. The interaction modes of these compounds with the common binding pocket in the GluN1b-GluN2B amino terminal domain heterodimer were elucidated. Virtual docking, based on the N-methyl-D-aspartate (NMDA) receptor, showed that homo-skeleton compounds of ifenprodil potentially exhibit low binding free energy with the receptor, including eliprodil and volinanserin. In vitro cell models corroborated the effective inhibition of inflammatory factor expression and minimal cytotoxicity of eliprodil and volinanserin. CoMFA (standard error of estimate = 0.378, R2 = 0.928, F values = 241.255, Prob. of R2 = 0) and topomer CoMFA (q2 = 0.553, q2 stderr = 0.77, intercept = - 1.48, r2 = 0.908, r2 stderr = 0.35) were established based on the inhibitors of NMDA receptor. The contour maps of CoMFA and topomer CoMFA models give structural information to improve the inhibitory function. This study underscores the involvement of MG/Mφ in inflammatory pathways during MS progression and offers promising compound candidates for MS therapy targeting MG/Mφ.

Association of Vitamin D Levels with Risk of Cognitive Impairment and Dementia: A Systematic Review and Meta-Analysis of Prospective Studies.

Background: Emerging evidence suggests the potential relationship between vitamin D deficiency and risk of cognitive impairment or dementia. To what extent the excess risk of dementia conferred by vitamin D deficiency is less clear. Objective: We summarized the current evidence from several aspects and further quantified these associations. Methods: We collected relevant prospective cohort studies by searching PubMed, Embase and Cochrane up to July 2023. The pooled relative risks (RR) were evaluated by random-effects models. Dose-response analyses were conducted by the method of two-stage generalized least squares regression. Results: Of 9,267 identified literatures, 23 were eligible for inclusion in the meta-analyses, among which 9 and 4 literatures were included in the dose-response analyses for the risk of dementia and Alzheimer's disease (AD). Vitamin D deficiency exhibited a 1.42 times risk for dementia (95% confidence interval (CI) = 1.21-1.65) and a 1.57-fold excess risk for AD (95% CI = 1.15-2.14). And vitamin D deficiency was associated with 34% elevated risk with cognitive impairment (95% CI = 1.19-1.52). Additionally, vitamin D was non-linearly related to the risk of dementia (pnonlinearity = 0.0000) and AD (pnonlinearity = 0.0042). The approximate 77.5-100 nmol/L 25-hydroxyvitamin D [25(OH)D] was optimal for reducing dementia risk. And the AD risk seemed to be decreased when the 25(OH)D level >40.1 nmol/L. Conclusions: Vitamin D deficiency was a risk factor for dementia, AD, and cognitive impairment. The nonlinear relationships may further provide the optimum dose of 25(OH)D for dementia prevention.

Multiple targeted drugs carrying biodegradable membrane barrier: anti-adhesion, hemostasis, and anti-infection.

A multiple targeted drug carrying bilayer membrane for preventing an abdominal adhesion is prepared by electrospinning. Two bioactive drugs were successfully incorporated into this bilayer membrane and can be independently released from nanofibrous scaffolds without losing structural integrity and functionality of the anti-adhesion membrane. Besides, the drug release profile could be easily adjusted by optimizing the swelling behavior of the fibrous scaffold. The inner layer of the bilayered fibrous membranes loaded with carbazochrome sodium sulfonate (CA) showed an excellent vascular hemostatic efficacy and formed little clot during in vivo experiment. The outer layer loaded with tinidazole (TI) had outstanding antibacterial effect against the anaerobe. We believe this approach could serve as a model technique to guide the design of implants with drug delivery functions.

[MiRNA regulatory mechanism in tumor initiation and progression].

MiRNAs can function as oncogenes or tumor suppressor genes. The abnormal expression of miRNAs leads to tumor malignant phenotypes, such as cell proliferation, apoptosis, invasion and metastasis, through which it is involved in the process of tumor initiation, progression and transcriptional regulation network. Therefore, it is important to clarify the mechanism of miRNA involved in the process of tumor initiation and progression. MiRNA regulation mechanism in tumor initiation and progression includes one-to-many and many-to-one regulation between TFto- miRNA and miRNA-to-target gene, which increases the complexity of miRNA regulation, thus affecting the biological behavior of the tumor, The expression and activity of Drosha and Dicer in the process of miRNA affect the synthesis of mature miRNA and involve in the process of tumor initiation and progression; ceRNA may bind with miRNA by competing with miRNA targeting genes and affect biological function of miRNA as miRNA inhibitor. Therefore the abnormal expression and structure of ceRNA is an important molecular mechanism of tumor initiation and progression. This complicated regulation network comprised by multi-dimensional regulation model and specific regulation of tumor initiation and progression provides impetus to exploring the functional restoration of miRNA as a novel target for cancer diagnosis and therapy.

Design and evaluation of a stick-slip piezoelectric actuator with flexure hinge mechanism inspired by the earthworm.

In this work, a new bionic piezoelectric actuator inspired by the earthworm is proposed, fabricated, and tested. The operating principle of the actuator imitates the crawling motion of the earthworm. The piezoelectric stack is embedded in the stator with a flexure hinge mechanism. One side of the stator is inspired by the earthworm body. Then the elongation of the piezoelectric stack is transmitted to the driving tip to produce oblique displacement under such a stator. The vertical and horizontal components are used to press and drive the slider, respectively. The principle of the proposed actuator is described in detail. The static deformation is investigated by the FEM method. A dynamic model of the actuator is developed to further reveal the motion characteristics of the slider via theoretical analysis. Finally, the output characteristics of the proposed BPA are tested. The experimental results show that the actuator achieves a maximum output speed of 12.72 mm/s at a voltage of 100 V and a frequency of 710 Hz. The maximum output force is 3 N under a locking force of 2 N. Besides, the displacement resolution is tested at 87 nm at a frequency of 710 Hz, which indicates that the developed actuator can be applied in the field of precision actuation.

Design and evaluation of a magnetically coupled piezoelectric energy harvester with parallel connection.

This work proposed a magnetically coupled piezoelectric energy harvester with parallel connections. The rectangular piezoelectric patch in the upper part of the device generates regular vibrations due to the nonlinear forces caused by magnetic coupling. The lower rectangular piezoelectric patch is deformed by contact collision excitation. The parallel connection effectively connects the two sets of piezoelectric patches together and fully exploits the performance of the piezoelectric energy harvester. The intrinsic frequency of the rectangular piezoelectric patch was simulated and verified experimentally. The rectangular piezoelectric patch generates a large vibration amplitude in high-speed operation due to its elasticity property. From the experimental results, it can be seen that the piezoelectric energy harvester can work well in different frequency bands. The parallel piezoelectric energy harvester with a three-contact rotor has a peak-to-peak voltage of 252 V at a speed of 120 r/min and 200 V at a speed of 240 r/min. The maximum voltage achieved by the piezoelectric energy harvester in parallel is 266 V at a speed of 180 r/min with a resistance of 1000 kΩ. The maximum voltage reached by a series-connected piezoelectric energy harvester is 256 V at a speed of 180 r/min and a resistance of 100 kΩ. The peak-to-peak power of the piezoelectric energy harvester connected in parallel is 0.313 W under a resistance of 100 kΩ and a speed of 180 r/min. Besides, the developed piezoelectric energy harvester can light up to 60 light-emitting diodes. Accordingly, the energy can be effectively harvested by the piezoelectric energy harvester and then supplied to the microelectronic device.